Mixed Topics

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

The field of GI is rapidly evolving, fueled by new scientific discoveries leading to improved understanding of disease mechanisms and more effective treatment approaches for patients with digestive and liver diseases. But there are many challenges confronting the pipeline of early-career investigators essential to future discovery, most notably a constrained funding environment leading to decreased protected time for research during these critical early years.

Foundation awards, such as those funded by the AGA Research Foundation, play a pivotal role in supporting the career development of promising young investigators in basic, translational, clinical, and health services research and ensure that we have a strong pipeline of independent investigators to stimulate ongoing discovery and innovation in our field. This year, the AGA Research Foundation distributed $2.6 million in funding to 76 investigators, including six coveted Research Scholar Awards awarded to early-career investigators. These promising young researchers represent the best and the brightest in our field — I hope you enjoy learning more about them in the pages of this issue and will join me in continuing to support the Foundation and its work under the leadership of Dr. Michael Camilleri.

University of Michigan

Also in our August issue, we bring you continued coverage from DDW and June’s EASL Congress, and report on innovative science published in AGA’s flagship journals, including a study investigating the impact of H pylori eradication on esophageal cancer risk. We also highlight several important studies relating to eosinophilic esophagitis, including a recent RCT published in The New England Journal of Medicine demonstrating the effectiveness of dupilumab in treatment of PPI-refractory pediatric EoE. Our August Member Spotlight features Dr. Neelendu Dey of Fred Hutchinson Cancer Center, who shares his perspectives on pursuing a career as a physician-scientist and chronicles his research focused on harnessing the microbiome for cancer prevention.

Finally, our quarterly In Focus column from The New Gastroenterologist provides practical advice regarding how best to evaluate patients with chronic bloating symptoms, a frequent presentation in our GI clinics. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.
 

Megan A. Adams, MD, JD, MSc

Editor in Chief

The field of GI is rapidly evolving, fueled by new scientific discoveries leading to improved understanding of disease mechanisms and more effective treatment approaches for patients with digestive and liver diseases. But there are many challenges confronting the pipeline of early-career investigators essential to future discovery, most notably a constrained funding environment leading to decreased protected time for research during these critical early years.

Foundation awards, such as those funded by the AGA Research Foundation, play a pivotal role in supporting the career development of promising young investigators in basic, translational, clinical, and health services research and ensure that we have a strong pipeline of independent investigators to stimulate ongoing discovery and innovation in our field. This year, the AGA Research Foundation distributed $2.6 million in funding to 76 investigators, including six coveted Research Scholar Awards awarded to early-career investigators. These promising young researchers represent the best and the brightest in our field — I hope you enjoy learning more about them in the pages of this issue and will join me in continuing to support the Foundation and its work under the leadership of Dr. Michael Camilleri.

University of Michigan

Also in our August issue, we bring you continued coverage from DDW and June’s EASL Congress, and report on innovative science published in AGA’s flagship journals, including a study investigating the impact of H pylori eradication on esophageal cancer risk. We also highlight several important studies relating to eosinophilic esophagitis, including a recent RCT published in The New England Journal of Medicine demonstrating the effectiveness of dupilumab in treatment of PPI-refractory pediatric EoE. Our August Member Spotlight features Dr. Neelendu Dey of Fred Hutchinson Cancer Center, who shares his perspectives on pursuing a career as a physician-scientist and chronicles his research focused on harnessing the microbiome for cancer prevention.

Finally, our quarterly In Focus column from The New Gastroenterologist provides practical advice regarding how best to evaluate patients with chronic bloating symptoms, a frequent presentation in our GI clinics. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.
 

Megan A. Adams, MD, JD, MSc

Editor in Chief

The field of GI is rapidly evolving, fueled by new scientific discoveries leading to improved understanding of disease mechanisms and more effective treatment approaches for patients with digestive and liver diseases. But there are many challenges confronting the pipeline of early-career investigators essential to future discovery, most notably a constrained funding environment leading to decreased protected time for research during these critical early years.

Foundation awards, such as those funded by the AGA Research Foundation, play a pivotal role in supporting the career development of promising young investigators in basic, translational, clinical, and health services research and ensure that we have a strong pipeline of independent investigators to stimulate ongoing discovery and innovation in our field. This year, the AGA Research Foundation distributed $2.6 million in funding to 76 investigators, including six coveted Research Scholar Awards awarded to early-career investigators. These promising young researchers represent the best and the brightest in our field — I hope you enjoy learning more about them in the pages of this issue and will join me in continuing to support the Foundation and its work under the leadership of Dr. Michael Camilleri.

University of Michigan

Also in our August issue, we bring you continued coverage from DDW and June’s EASL Congress, and report on innovative science published in AGA’s flagship journals, including a study investigating the impact of H pylori eradication on esophageal cancer risk. We also highlight several important studies relating to eosinophilic esophagitis, including a recent RCT published in The New England Journal of Medicine demonstrating the effectiveness of dupilumab in treatment of PPI-refractory pediatric EoE. Our August Member Spotlight features Dr. Neelendu Dey of Fred Hutchinson Cancer Center, who shares his perspectives on pursuing a career as a physician-scientist and chronicles his research focused on harnessing the microbiome for cancer prevention.

Finally, our quarterly In Focus column from The New Gastroenterologist provides practical advice regarding how best to evaluate patients with chronic bloating symptoms, a frequent presentation in our GI clinics. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.
 

Megan A. Adams, MD, JD, MSc

Editor in Chief

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Peter Grinspoon, MD, has some advice for clinicians when patients ask questions about microdosing of psychedelics: Keep the lines of communication open — and don’t be judgmental.

“If you’re dismissive or critical or sound like you’re judging them, then the patients just clam up,” said Dr. Grinspoon, a professor of medicine at Harvard Medical School and a primary care physician at Massachusetts General Hospital, both in Boston.

Psychedelic drugs are still illegal in the majority of states despite the growth of public interest in and use of these substances. That growth is evidenced by a flurry of workshops, reports, law enforcement seizures, and pressure by Congressional members for the Food and Drug Administration to approve new psychedelic drugs, just in the past year.

A recent study in JAMA Health Forum showed a nearly 14-fold increase in Google searches — from 7.9 to 105.6 per 10 million nationwide — for the term “microdosing” and related wording, between 2015 and 2023.

Two states — Oregon and Colorado — have decriminalized certain psychedelic drugs and are in various stages of establishing regulations and centers for prospective clients. Almost two dozen localities, like Ann Arbor, Michigan, have decriminalized psychedelic drugs. A handful of states have active legislation to decriminalize use, while others have bills that never made it out of committee.

But no definitive studies have reported that microdosing produces positive mental effects at a higher rate than placebo, according to Dr. Grinspoon. So responding to patient inquiries about microdosing can be complicated, and clinicians must provide counsel on issues of legality and therapeutic appropriateness.

“We’re in this renaissance where everybody is idealizing these medications, as opposed to 20 years ago when we were in the war on drugs and everybody was dismissing them,” Dr. Grinspoon said. “The truth is somewhere in between.”
 

The Science

Microdosing is defined as taking doses of 1/5 to 1/20 of the conventional recreational amount, which might include a dried psilocybin mushroom, lysergic acid diethylamide, or 3,4-methylenedioxymethamphetamine. But even that much may be neither effective nor safe.

Dr. Grinspoon said clinicians should tell patients that psychedelics may cause harm, although the drugs are relatively nontoxic and are not addictive. An illegally obtained psilocybin could cause negative reactions, especially if the drug has been adulterated with other substances and if the actual dose is higher than what was indicated by the seller.

He noted that people have different reactions to psychedelics, just as they have to prescription medications. He cited one example of a woman who microdosed and could not sleep for 2 weeks afterward. Only recently have randomized, double-blinded studies begun on benefits and harms.

Researchers have also begun investigating whether long-term microdosing of psilocybin could lead to valvular heart disease (VHD), said Kevin Yang, MD, a psychiatry resident at the University of California San Diego School of Medicine. A recent review of evidence concluded that microdosing various psychedelics over a period of months can lead to drug-induced VHD.

“It’s extremely important to emphasize with patients that not only do we not know if it works or not, we also don’t really know how safe it is,” Dr. Yang said.

Dr. Yang also said clinicians should consider referring patients to a mental health professional, and especially those that may have expertise in psychedelic therapies.

One of those experts is Rachel Yehuda, PhD, director of the Center for Psychedelic Psychotherapy and Trauma Research at Icahn School of Medicine at Mount Sinai in New York City. She said therapists should be able to assess the patient’s perceived need for microdosing and “invite reflections about why current approaches are falling short.”

“I would also not actively discourage it either but remain curious until both of you have a better understanding of the reasons for seeking this out and potential alternative strategies for obtaining more therapeutic benefits,” she said. “I think it is really important to study the effects of both micro- and macrodosing of psychedelics but not move in advance of the data.”
 

Navigating Legality

Recent ballot measures in Oregon and Colorado directed the states to develop regulated and licensed psilocybin-assisted therapy centers for legal “trips.” Oregon’s first center was opened in 2023, and Colorado is now developing its own licensing model.

According to the Oregon Health Authority, the centers are not medical facilities, and prescription or referral from a medical professional is not required.

The Oregon Academy of Family Physicians (OAFP) has yet to release guidance to clinicians on how to talk to their patients about these drugs or potential interest in visiting a licensed therapy center.

However, Betsy Boyd-Flynn, executive director of OAFP, said the organization is working on continuing medical education for what the average family physician needs to know if a patient asks about use.

“We suspect that many of our members have interest and want to learn more,” she said.

Dr. Grinspoon said clinicians should talk with patients about legality during these conversations.

“The big question I get is: ‘I really want to try microdosing, but how do I obtain the mushrooms?’ ” he said. “You can’t really as a physician tell them to do anything illegal. So you tell them to be safe, be careful, and to use their judgment.”

Patients who want to pursue microdosing who do not live in Oregon have two legal and safe options, Dr. Grinspoon said: Enroll in a clinical study or find a facility in a state or country — such as Oregon or Jamaica — that offers microdosing with psilocybin.

Clinicians also should warn their patients that the consequences of obtaining illicit psilocybin could exacerbate the mental health stresses they are seeking to alleviate.

“It’s going to get worse if they get tangled up with law enforcement or take something that’s contaminated and they get real sick,” he said.

Lisa Gillespie contributed reporting to this story. A version of this article appeared on Medscape.com.

Peter Grinspoon, MD, has some advice for clinicians when patients ask questions about microdosing of psychedelics: Keep the lines of communication open — and don’t be judgmental.

“If you’re dismissive or critical or sound like you’re judging them, then the patients just clam up,” said Dr. Grinspoon, a professor of medicine at Harvard Medical School and a primary care physician at Massachusetts General Hospital, both in Boston.

Psychedelic drugs are still illegal in the majority of states despite the growth of public interest in and use of these substances. That growth is evidenced by a flurry of workshops, reports, law enforcement seizures, and pressure by Congressional members for the Food and Drug Administration to approve new psychedelic drugs, just in the past year.

A recent study in JAMA Health Forum showed a nearly 14-fold increase in Google searches — from 7.9 to 105.6 per 10 million nationwide — for the term “microdosing” and related wording, between 2015 and 2023.

Two states — Oregon and Colorado — have decriminalized certain psychedelic drugs and are in various stages of establishing regulations and centers for prospective clients. Almost two dozen localities, like Ann Arbor, Michigan, have decriminalized psychedelic drugs. A handful of states have active legislation to decriminalize use, while others have bills that never made it out of committee.

But no definitive studies have reported that microdosing produces positive mental effects at a higher rate than placebo, according to Dr. Grinspoon. So responding to patient inquiries about microdosing can be complicated, and clinicians must provide counsel on issues of legality and therapeutic appropriateness.

“We’re in this renaissance where everybody is idealizing these medications, as opposed to 20 years ago when we were in the war on drugs and everybody was dismissing them,” Dr. Grinspoon said. “The truth is somewhere in between.”
 

The Science

Microdosing is defined as taking doses of 1/5 to 1/20 of the conventional recreational amount, which might include a dried psilocybin mushroom, lysergic acid diethylamide, or 3,4-methylenedioxymethamphetamine. But even that much may be neither effective nor safe.

Dr. Grinspoon said clinicians should tell patients that psychedelics may cause harm, although the drugs are relatively nontoxic and are not addictive. An illegally obtained psilocybin could cause negative reactions, especially if the drug has been adulterated with other substances and if the actual dose is higher than what was indicated by the seller.

He noted that people have different reactions to psychedelics, just as they have to prescription medications. He cited one example of a woman who microdosed and could not sleep for 2 weeks afterward. Only recently have randomized, double-blinded studies begun on benefits and harms.

Researchers have also begun investigating whether long-term microdosing of psilocybin could lead to valvular heart disease (VHD), said Kevin Yang, MD, a psychiatry resident at the University of California San Diego School of Medicine. A recent review of evidence concluded that microdosing various psychedelics over a period of months can lead to drug-induced VHD.

“It’s extremely important to emphasize with patients that not only do we not know if it works or not, we also don’t really know how safe it is,” Dr. Yang said.

Dr. Yang also said clinicians should consider referring patients to a mental health professional, and especially those that may have expertise in psychedelic therapies.

One of those experts is Rachel Yehuda, PhD, director of the Center for Psychedelic Psychotherapy and Trauma Research at Icahn School of Medicine at Mount Sinai in New York City. She said therapists should be able to assess the patient’s perceived need for microdosing and “invite reflections about why current approaches are falling short.”

“I would also not actively discourage it either but remain curious until both of you have a better understanding of the reasons for seeking this out and potential alternative strategies for obtaining more therapeutic benefits,” she said. “I think it is really important to study the effects of both micro- and macrodosing of psychedelics but not move in advance of the data.”
 

Navigating Legality

Recent ballot measures in Oregon and Colorado directed the states to develop regulated and licensed psilocybin-assisted therapy centers for legal “trips.” Oregon’s first center was opened in 2023, and Colorado is now developing its own licensing model.

According to the Oregon Health Authority, the centers are not medical facilities, and prescription or referral from a medical professional is not required.

The Oregon Academy of Family Physicians (OAFP) has yet to release guidance to clinicians on how to talk to their patients about these drugs or potential interest in visiting a licensed therapy center.

However, Betsy Boyd-Flynn, executive director of OAFP, said the organization is working on continuing medical education for what the average family physician needs to know if a patient asks about use.

“We suspect that many of our members have interest and want to learn more,” she said.

Dr. Grinspoon said clinicians should talk with patients about legality during these conversations.

“The big question I get is: ‘I really want to try microdosing, but how do I obtain the mushrooms?’ ” he said. “You can’t really as a physician tell them to do anything illegal. So you tell them to be safe, be careful, and to use their judgment.”

Patients who want to pursue microdosing who do not live in Oregon have two legal and safe options, Dr. Grinspoon said: Enroll in a clinical study or find a facility in a state or country — such as Oregon or Jamaica — that offers microdosing with psilocybin.

Clinicians also should warn their patients that the consequences of obtaining illicit psilocybin could exacerbate the mental health stresses they are seeking to alleviate.

“It’s going to get worse if they get tangled up with law enforcement or take something that’s contaminated and they get real sick,” he said.

Lisa Gillespie contributed reporting to this story. A version of this article appeared on Medscape.com.

Peter Grinspoon, MD, has some advice for clinicians when patients ask questions about microdosing of psychedelics: Keep the lines of communication open — and don’t be judgmental.

“If you’re dismissive or critical or sound like you’re judging them, then the patients just clam up,” said Dr. Grinspoon, a professor of medicine at Harvard Medical School and a primary care physician at Massachusetts General Hospital, both in Boston.

Psychedelic drugs are still illegal in the majority of states despite the growth of public interest in and use of these substances. That growth is evidenced by a flurry of workshops, reports, law enforcement seizures, and pressure by Congressional members for the Food and Drug Administration to approve new psychedelic drugs, just in the past year.

A recent study in JAMA Health Forum showed a nearly 14-fold increase in Google searches — from 7.9 to 105.6 per 10 million nationwide — for the term “microdosing” and related wording, between 2015 and 2023.

Two states — Oregon and Colorado — have decriminalized certain psychedelic drugs and are in various stages of establishing regulations and centers for prospective clients. Almost two dozen localities, like Ann Arbor, Michigan, have decriminalized psychedelic drugs. A handful of states have active legislation to decriminalize use, while others have bills that never made it out of committee.

But no definitive studies have reported that microdosing produces positive mental effects at a higher rate than placebo, according to Dr. Grinspoon. So responding to patient inquiries about microdosing can be complicated, and clinicians must provide counsel on issues of legality and therapeutic appropriateness.

“We’re in this renaissance where everybody is idealizing these medications, as opposed to 20 years ago when we were in the war on drugs and everybody was dismissing them,” Dr. Grinspoon said. “The truth is somewhere in between.”
 

The Science

Microdosing is defined as taking doses of 1/5 to 1/20 of the conventional recreational amount, which might include a dried psilocybin mushroom, lysergic acid diethylamide, or 3,4-methylenedioxymethamphetamine. But even that much may be neither effective nor safe.

Dr. Grinspoon said clinicians should tell patients that psychedelics may cause harm, although the drugs are relatively nontoxic and are not addictive. An illegally obtained psilocybin could cause negative reactions, especially if the drug has been adulterated with other substances and if the actual dose is higher than what was indicated by the seller.

He noted that people have different reactions to psychedelics, just as they have to prescription medications. He cited one example of a woman who microdosed and could not sleep for 2 weeks afterward. Only recently have randomized, double-blinded studies begun on benefits and harms.

Researchers have also begun investigating whether long-term microdosing of psilocybin could lead to valvular heart disease (VHD), said Kevin Yang, MD, a psychiatry resident at the University of California San Diego School of Medicine. A recent review of evidence concluded that microdosing various psychedelics over a period of months can lead to drug-induced VHD.

“It’s extremely important to emphasize with patients that not only do we not know if it works or not, we also don’t really know how safe it is,” Dr. Yang said.

Dr. Yang also said clinicians should consider referring patients to a mental health professional, and especially those that may have expertise in psychedelic therapies.

One of those experts is Rachel Yehuda, PhD, director of the Center for Psychedelic Psychotherapy and Trauma Research at Icahn School of Medicine at Mount Sinai in New York City. She said therapists should be able to assess the patient’s perceived need for microdosing and “invite reflections about why current approaches are falling short.”

“I would also not actively discourage it either but remain curious until both of you have a better understanding of the reasons for seeking this out and potential alternative strategies for obtaining more therapeutic benefits,” she said. “I think it is really important to study the effects of both micro- and macrodosing of psychedelics but not move in advance of the data.”
 

Navigating Legality

Recent ballot measures in Oregon and Colorado directed the states to develop regulated and licensed psilocybin-assisted therapy centers for legal “trips.” Oregon’s first center was opened in 2023, and Colorado is now developing its own licensing model.

According to the Oregon Health Authority, the centers are not medical facilities, and prescription or referral from a medical professional is not required.

The Oregon Academy of Family Physicians (OAFP) has yet to release guidance to clinicians on how to talk to their patients about these drugs or potential interest in visiting a licensed therapy center.

However, Betsy Boyd-Flynn, executive director of OAFP, said the organization is working on continuing medical education for what the average family physician needs to know if a patient asks about use.

“We suspect that many of our members have interest and want to learn more,” she said.

Dr. Grinspoon said clinicians should talk with patients about legality during these conversations.

“The big question I get is: ‘I really want to try microdosing, but how do I obtain the mushrooms?’ ” he said. “You can’t really as a physician tell them to do anything illegal. So you tell them to be safe, be careful, and to use their judgment.”

Patients who want to pursue microdosing who do not live in Oregon have two legal and safe options, Dr. Grinspoon said: Enroll in a clinical study or find a facility in a state or country — such as Oregon or Jamaica — that offers microdosing with psilocybin.

Clinicians also should warn their patients that the consequences of obtaining illicit psilocybin could exacerbate the mental health stresses they are seeking to alleviate.

“It’s going to get worse if they get tangled up with law enforcement or take something that’s contaminated and they get real sick,” he said.

Lisa Gillespie contributed reporting to this story. A version of this article appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

An easy-to-use web-based prognostic tool, MetroPancreas, may help predict the likelihood of futile pancreatectomy in patients with resectable pancreatic ductal adenocarcinoma and improve patient selection for upfront surgery.

METHODOLOGY:

• Immediate resection is associated with a high incidence of postoperative complications and disease recurrence within a year of surgery in patients with pancreatic ductal adenocarcinoma. Predicting which patients likely won’t benefit from upfront pancreatectomy is important.
• To identify preoperative risk factors for futile pancreatectomy, researchers evaluated 1426 patients (median age, 69 years; 53.2% men) with anatomically resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection between January 2010 and December 2021.
• The patients were divided into derivation (n = 885) and validation (n = 541) cohorts.
• The primary outcome was the rate of futile upfront pancreatectomy, defined as death or disease recurrence within 6 months of surgery. Patients were divided into three risk categories — low, intermediate, and high risk — each with escalating likelihoods of futile resection, worse pathological features, and worse outcomes.
• The secondary endpoint was to develop criteria for surgical candidacy, setting a futility likelihood threshold of < 20%. This threshold corresponds to the lower bound of the 95% confidence interval (CI) for postneoadjuvant resection rates (resection rate, 0.90; 95% CI, 0.80-1.01) from recent meta-analyses.

TAKEAWAY:

• The futility rate for pancreatectomy was 18.9% — 19.2% in the development cohort and 18.6% in the validation cohort. Three independent risk factors for futile resection included American Society of Anesthesiologists (ASA) class (95% CI for coefficients, 0.68-0.87), preoperative cancer antigen 19.9 serum levels (95% CI for coefficients, 0.05-0.75), and radiologic tumor size (95% CI for coefficients, 0.28-0.46).
• Using these independent risk factors, the predictive model demonstrated adequate calibration and discrimination in both the derivation and validation cohorts.
• The researchers then identified three risk groups. In the derivation cohort, the rate of futile pancreatectomy was 9.2% in the low-risk group, 18.0% in the intermediate-risk group, and 28.7% in the high-risk group (P < .001 for trend). In the validation cohort, the futility rate was 10.9% in the low-risk group, 20.2% in the intermediate-risk group, and 29.2% in the high-risk group (P < .001 for trend).
• Researchers identified four conditions associated with a futility likelihood below 20%, where larger tumor size is paired with lower cancer antigen 19.9 levels (defined as cancer antigen 19.9–adjusted-to-size). Patients who met these criteria experienced significantly longer disease-free survival (median 18.4 months vs 11.2 months) and overall survival (38.5 months vs 22.1 months).

IN PRACTICE:

“Although the study provides an easy-to-use calculator for clinical decision-making, there are some methodological limitations,” according to the authors of accompanying commentary. These limitations include failing to accurately describe how ASA class, cancer antigen 19.9 level, and tumor size were chosen for the model. “While we do not think the model is yet ready for standard clinical use, it may prove to be a viable tool if tested in future randomized trials comparing the neoadjuvant approach to upfront surgery in resectable pancreatic cancer,” the editorialists added.

SOURCE:

This study, led by Stefano Crippa, MD, PhD, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and the accompanying commentary were published online in JAMA Surgery.

LIMITATIONS:

In addition to the limitations noted by the editorialists, others include the study’s retrospective design, which could introduce bias. Because preoperative imaging was not revised, the assigned resectability classes could show variability. Institutional differences existed in the selection process for upfront pancreatectomy. The model cannot be applied to cancer antigen 19.9 nonsecretors and was not externally validated.

DISCLOSURES:

The Italian Association for Cancer Research Special Program in Metastatic Disease and Italian Ministry of Health/Italian Foundation for the Research of Pancreatic Diseases supported the study in the form of a grant. Two authors reported receiving personal fees outside the submitted work. No other disclosures were reported.

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

TOPLINE:

An easy-to-use web-based prognostic tool, MetroPancreas, may help predict the likelihood of futile pancreatectomy in patients with resectable pancreatic ductal adenocarcinoma and improve patient selection for upfront surgery.

METHODOLOGY:

• Immediate resection is associated with a high incidence of postoperative complications and disease recurrence within a year of surgery in patients with pancreatic ductal adenocarcinoma. Predicting which patients likely won’t benefit from upfront pancreatectomy is important.
• To identify preoperative risk factors for futile pancreatectomy, researchers evaluated 1426 patients (median age, 69 years; 53.2% men) with anatomically resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection between January 2010 and December 2021.
• The patients were divided into derivation (n = 885) and validation (n = 541) cohorts.
• The primary outcome was the rate of futile upfront pancreatectomy, defined as death or disease recurrence within 6 months of surgery. Patients were divided into three risk categories — low, intermediate, and high risk — each with escalating likelihoods of futile resection, worse pathological features, and worse outcomes.
• The secondary endpoint was to develop criteria for surgical candidacy, setting a futility likelihood threshold of < 20%. This threshold corresponds to the lower bound of the 95% confidence interval (CI) for postneoadjuvant resection rates (resection rate, 0.90; 95% CI, 0.80-1.01) from recent meta-analyses.

TAKEAWAY:

• The futility rate for pancreatectomy was 18.9% — 19.2% in the development cohort and 18.6% in the validation cohort. Three independent risk factors for futile resection included American Society of Anesthesiologists (ASA) class (95% CI for coefficients, 0.68-0.87), preoperative cancer antigen 19.9 serum levels (95% CI for coefficients, 0.05-0.75), and radiologic tumor size (95% CI for coefficients, 0.28-0.46).
• Using these independent risk factors, the predictive model demonstrated adequate calibration and discrimination in both the derivation and validation cohorts.
• The researchers then identified three risk groups. In the derivation cohort, the rate of futile pancreatectomy was 9.2% in the low-risk group, 18.0% in the intermediate-risk group, and 28.7% in the high-risk group (P < .001 for trend). In the validation cohort, the futility rate was 10.9% in the low-risk group, 20.2% in the intermediate-risk group, and 29.2% in the high-risk group (P < .001 for trend).
• Researchers identified four conditions associated with a futility likelihood below 20%, where larger tumor size is paired with lower cancer antigen 19.9 levels (defined as cancer antigen 19.9–adjusted-to-size). Patients who met these criteria experienced significantly longer disease-free survival (median 18.4 months vs 11.2 months) and overall survival (38.5 months vs 22.1 months).

IN PRACTICE:

“Although the study provides an easy-to-use calculator for clinical decision-making, there are some methodological limitations,” according to the authors of accompanying commentary. These limitations include failing to accurately describe how ASA class, cancer antigen 19.9 level, and tumor size were chosen for the model. “While we do not think the model is yet ready for standard clinical use, it may prove to be a viable tool if tested in future randomized trials comparing the neoadjuvant approach to upfront surgery in resectable pancreatic cancer,” the editorialists added.

SOURCE:

This study, led by Stefano Crippa, MD, PhD, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and the accompanying commentary were published online in JAMA Surgery.

LIMITATIONS:

In addition to the limitations noted by the editorialists, others include the study’s retrospective design, which could introduce bias. Because preoperative imaging was not revised, the assigned resectability classes could show variability. Institutional differences existed in the selection process for upfront pancreatectomy. The model cannot be applied to cancer antigen 19.9 nonsecretors and was not externally validated.

DISCLOSURES:

The Italian Association for Cancer Research Special Program in Metastatic Disease and Italian Ministry of Health/Italian Foundation for the Research of Pancreatic Diseases supported the study in the form of a grant. Two authors reported receiving personal fees outside the submitted work. No other disclosures were reported.

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

TOPLINE:

An easy-to-use web-based prognostic tool, MetroPancreas, may help predict the likelihood of futile pancreatectomy in patients with resectable pancreatic ductal adenocarcinoma and improve patient selection for upfront surgery.

METHODOLOGY:

• Immediate resection is associated with a high incidence of postoperative complications and disease recurrence within a year of surgery in patients with pancreatic ductal adenocarcinoma. Predicting which patients likely won’t benefit from upfront pancreatectomy is important.
• To identify preoperative risk factors for futile pancreatectomy, researchers evaluated 1426 patients (median age, 69 years; 53.2% men) with anatomically resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection between January 2010 and December 2021.
• The patients were divided into derivation (n = 885) and validation (n = 541) cohorts.
• The primary outcome was the rate of futile upfront pancreatectomy, defined as death or disease recurrence within 6 months of surgery. Patients were divided into three risk categories — low, intermediate, and high risk — each with escalating likelihoods of futile resection, worse pathological features, and worse outcomes.
• The secondary endpoint was to develop criteria for surgical candidacy, setting a futility likelihood threshold of < 20%. This threshold corresponds to the lower bound of the 95% confidence interval (CI) for postneoadjuvant resection rates (resection rate, 0.90; 95% CI, 0.80-1.01) from recent meta-analyses.

TAKEAWAY:

• The futility rate for pancreatectomy was 18.9% — 19.2% in the development cohort and 18.6% in the validation cohort. Three independent risk factors for futile resection included American Society of Anesthesiologists (ASA) class (95% CI for coefficients, 0.68-0.87), preoperative cancer antigen 19.9 serum levels (95% CI for coefficients, 0.05-0.75), and radiologic tumor size (95% CI for coefficients, 0.28-0.46).
• Using these independent risk factors, the predictive model demonstrated adequate calibration and discrimination in both the derivation and validation cohorts.
• The researchers then identified three risk groups. In the derivation cohort, the rate of futile pancreatectomy was 9.2% in the low-risk group, 18.0% in the intermediate-risk group, and 28.7% in the high-risk group (P < .001 for trend). In the validation cohort, the futility rate was 10.9% in the low-risk group, 20.2% in the intermediate-risk group, and 29.2% in the high-risk group (P < .001 for trend).
• Researchers identified four conditions associated with a futility likelihood below 20%, where larger tumor size is paired with lower cancer antigen 19.9 levels (defined as cancer antigen 19.9–adjusted-to-size). Patients who met these criteria experienced significantly longer disease-free survival (median 18.4 months vs 11.2 months) and overall survival (38.5 months vs 22.1 months).

IN PRACTICE:

“Although the study provides an easy-to-use calculator for clinical decision-making, there are some methodological limitations,” according to the authors of accompanying commentary. These limitations include failing to accurately describe how ASA class, cancer antigen 19.9 level, and tumor size were chosen for the model. “While we do not think the model is yet ready for standard clinical use, it may prove to be a viable tool if tested in future randomized trials comparing the neoadjuvant approach to upfront surgery in resectable pancreatic cancer,” the editorialists added.

SOURCE:

This study, led by Stefano Crippa, MD, PhD, Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy, and the accompanying commentary were published online in JAMA Surgery.

LIMITATIONS:

In addition to the limitations noted by the editorialists, others include the study’s retrospective design, which could introduce bias. Because preoperative imaging was not revised, the assigned resectability classes could show variability. Institutional differences existed in the selection process for upfront pancreatectomy. The model cannot be applied to cancer antigen 19.9 nonsecretors and was not externally validated.

DISCLOSURES:

The Italian Association for Cancer Research Special Program in Metastatic Disease and Italian Ministry of Health/Italian Foundation for the Research of Pancreatic Diseases supported the study in the form of a grant. Two authors reported receiving personal fees outside the submitted work. No other disclosures were reported.

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

TOPLINE:

Upadacitinib, an oral Janus kinase (JAK) 1 inhibitor, showed an 80% complete response rate in patients with granulomatous cheilitis, with no serious adverse events, in a small retrospective case series.

METHODOLOGY:

• Granulomatous cheilitis is a rare, nonnecrotizing granulomatous inflammatory disorder characterized by intermittent or persistent swelling of the lips.
• In a retrospective case series of five patients (median age, 30 years; four women) with granulomatous cheilitis resistant to systemic treatments at a Belgian hospital between June 2023 and March 2024, all five were treated with a high dose of upadacitinib (30 mg daily).
• The primary endpoint was objective clinical improvement in lip swelling and infiltration over a median follow-up of 7.2 months.
• Three patients had concomitant dormant Crohn’s disease (CD); a secondary outcome was disease activity in these patients.

TAKEAWAY:

• Upadacitinib treatment resulted in a complete response in four patients (80%) within a median of 3.8 months and a partial response in one patient.
• CD remained dormant in the three patients with CD.
• The safety profile of upadacitinib was favorable, and no serious adverse events were reported. Two patients experienced headaches, acne, mild changes in lipids, and/or transaminitis.

IN PRACTICE:

“Upadacitinib was effective in treating patients with recalcitrant and long-lasting granulomatous cheilitis, even in cases of concomitant CD, which could substantially improve the quality of life of affected patients,” the authors wrote. More studies are needed to confirm these results in larger groups of patients over longer periods of time, “and with other JAK inhibitors.”

SOURCE:

The study was led by Axel De Greef, MD, Department of Dermatology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium. It was published online in JAMA Dermatology.

LIMITATIONS:

The small sample size and short follow-up may limit the generalizability of the findings to a larger population of patients with granulomatous cheilitis.

DISCLOSURES:

The study did not report any funding sources. Some authors reported receiving nonfinancial support and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Upadacitinib, an oral Janus kinase (JAK) 1 inhibitor, showed an 80% complete response rate in patients with granulomatous cheilitis, with no serious adverse events, in a small retrospective case series.

METHODOLOGY:

• Granulomatous cheilitis is a rare, nonnecrotizing granulomatous inflammatory disorder characterized by intermittent or persistent swelling of the lips.
• In a retrospective case series of five patients (median age, 30 years; four women) with granulomatous cheilitis resistant to systemic treatments at a Belgian hospital between June 2023 and March 2024, all five were treated with a high dose of upadacitinib (30 mg daily).
• The primary endpoint was objective clinical improvement in lip swelling and infiltration over a median follow-up of 7.2 months.
• Three patients had concomitant dormant Crohn’s disease (CD); a secondary outcome was disease activity in these patients.

TAKEAWAY:

• Upadacitinib treatment resulted in a complete response in four patients (80%) within a median of 3.8 months and a partial response in one patient.
• CD remained dormant in the three patients with CD.
• The safety profile of upadacitinib was favorable, and no serious adverse events were reported. Two patients experienced headaches, acne, mild changes in lipids, and/or transaminitis.

IN PRACTICE:

“Upadacitinib was effective in treating patients with recalcitrant and long-lasting granulomatous cheilitis, even in cases of concomitant CD, which could substantially improve the quality of life of affected patients,” the authors wrote. More studies are needed to confirm these results in larger groups of patients over longer periods of time, “and with other JAK inhibitors.”

SOURCE:

The study was led by Axel De Greef, MD, Department of Dermatology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium. It was published online in JAMA Dermatology.

LIMITATIONS:

The small sample size and short follow-up may limit the generalizability of the findings to a larger population of patients with granulomatous cheilitis.

DISCLOSURES:

The study did not report any funding sources. Some authors reported receiving nonfinancial support and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Upadacitinib, an oral Janus kinase (JAK) 1 inhibitor, showed an 80% complete response rate in patients with granulomatous cheilitis, with no serious adverse events, in a small retrospective case series.

METHODOLOGY:

• Granulomatous cheilitis is a rare, nonnecrotizing granulomatous inflammatory disorder characterized by intermittent or persistent swelling of the lips.
• In a retrospective case series of five patients (median age, 30 years; four women) with granulomatous cheilitis resistant to systemic treatments at a Belgian hospital between June 2023 and March 2024, all five were treated with a high dose of upadacitinib (30 mg daily).
• The primary endpoint was objective clinical improvement in lip swelling and infiltration over a median follow-up of 7.2 months.
• Three patients had concomitant dormant Crohn’s disease (CD); a secondary outcome was disease activity in these patients.

TAKEAWAY:

• Upadacitinib treatment resulted in a complete response in four patients (80%) within a median of 3.8 months and a partial response in one patient.
• CD remained dormant in the three patients with CD.
• The safety profile of upadacitinib was favorable, and no serious adverse events were reported. Two patients experienced headaches, acne, mild changes in lipids, and/or transaminitis.

IN PRACTICE:

“Upadacitinib was effective in treating patients with recalcitrant and long-lasting granulomatous cheilitis, even in cases of concomitant CD, which could substantially improve the quality of life of affected patients,” the authors wrote. More studies are needed to confirm these results in larger groups of patients over longer periods of time, “and with other JAK inhibitors.”

SOURCE:

The study was led by Axel De Greef, MD, Department of Dermatology, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium. It was published online in JAMA Dermatology.

LIMITATIONS:

The small sample size and short follow-up may limit the generalizability of the findings to a larger population of patients with granulomatous cheilitis.

DISCLOSURES:

The study did not report any funding sources. Some authors reported receiving nonfinancial support and personal fees from various pharmaceutical companies outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.