To the Editor:

Morphea, atrophoderma, guttate lichen sclerosus et atrophicus (LS&A), anetoderma, and their subtypes are inflammatory processes ultimately leading to dermal remodeling. We report a case of a scaly, hypopigmented, macular rash that clinically appeared as an entity along the morphea-atrophoderma spectrum and demonstrated unique histopathologic changes in both collagen and elastin confined to the upper reticular and papillary dermis. This case is a potentially rare variant representing a combination of clinical and microscopic findings.

A 29-year-old woman presented for an increasing number of white spots distributed on the trunk, arms, and legs. She denied local and systemic symptoms. The patient reported that she was stung by 100 wasps 23 years prior. Following the assault, her grandmother placed chewed tobacco leaves atop the painful erythematous wheals and flares. Upon resolution, hypopigmented macules and patches remained in their place. The patient denied associated symptoms or new lesions; she did not seek care at that time.

In her early 20s, the patient noted new, similarly distributed hypopigmented macules and patches without associated arthropod assault. She was treated by an outside dermatologist without result for presumed tinea versicolor. A follow-up superficial shave biopsy cited subtle psoriasiform dermatitis. Topical steroids did not improve the lesions. Her medical history also was remarkable for a reportedly unprovoked complete rotator cuff tear.

Physical examination revealed 0.5- to 2.0-cm, ill-defined, perifollicular and nonfollicular, slightly scaly macules and patches on the trunk, arms, and legs. There was no follicular plugging (Figure 1A). The hands, feet, face, and mucosal surfaces were spared. She had no family history of similar lesions. Although atrophic in appearance, a single lesion on the left thigh was palpably depressed (Figure 1B). Serology demonstrated a normal complete blood cell count and comprehensive metabolic panel, and negative Lyme titers. Light therapy and topical steroids failed to improve the lesions; calcipotriene cream 0.005% made the lesions erythematous and pruritic.

A biopsy from a flank lesion demonstrated a normal epithelium without thinning, a normal basal melanocyte population, and minimally effaced rete ridges. Thin collagen bundles were noted in the upper reticular and papillary dermis with associated fibroplasia (Figure 2). Verhoeff-van Gieson stain revealed decreased and fragmented elastin filaments in the same dermal distribution as the changed collagen (Figure 3). There was no evidence of primary inflammatory disease. The dermis was thinned. Periodic acid–Schiff stain confirmed the absence of hyphae and spores.

The relevant findings in our patient including the following: (1) onset of hypopigmented macules and patches following resolution of a toxic insult; (2) initially stable number of lesions that progressed in number but not size; (3) thinned collagen associated with fibroplasia in the upper reticular and papillary dermis; (4) decreased number and fragmentation of elastin filaments confined to the same region; (5) no congenital lesions or similar lesions in family members; and (6) a complete rotator cuff tear with no findings of a systemic connective-tissue disorder such as Ehlers-Danlos syndrome.

We performed a literature search of PubMed articles indexed for MEDLINE using combinations of the terms atrophic, hypopigmented, white, spot disease, confetti-like, guttate, macules, atrophoderma, morphea, anetoderma, elastin, and collagen to identify potentially similar reports of guttate hypopigmented macules demonstrating changes of the collagen and elastin in the papillary and upper reticular dermis. Some variants, namely atrophoderma of Pasini and Pierini (APP), guttate morphea, and superficial morphea, demonstrate similar clinical and histopathologic findings.

Findings similar to our case were documented in case reports of 2 women (aged 34 and 42 years)¹ presenting with asymptomatic, atrophic, well-demarcated, shiny, hypopigmented macules over the trunk and upper extremities, which demonstrated a thinned epidermis with coarse hyalinized collagen bundles in the mid and lower dermis. There was upper and diffuse dermal elastolysis (patient 1 and patient 2, respectively).¹ Our patient’s lesions were hypopigmented and atrophic in appearance but were slightly scaly and also involved the extremities. Distinct from these patient reports, histopathology from our case demonstrated thin packed collagen bundles and decreased fragmented elastin filaments confined to the upper reticular and papillary dermis.

Plaque morphea is the most common type of localized scleroderma.² The subtype APP demonstrates round to ovoid, gray-brown depressions with cliff-drop borders. They may appear flesh colored or hypopigmented.^3,4 These sclerodermoid lesions lack the violaceous border classic to morphea. Sclerosis and induration also are typically absent.⁵ Clinically, our patient’s macules resembled this entity. Histopathologically, APP shows normal epithelium with an increased basal layer pigmentation; preserved adnexal structures; and mid to lower dermal collagen edema, clumping, and homogenization.^3,4 Elastic fibers classically are unchanged, with exceptions.^6-11 Changes in the collagen and elastin of our patient were unlike those reported in APP, which occur in the mid to lower dermis.

Guttate morphea demonstrates small, pale, minimally indurated, coin-shaped lesions on the trunk. Histopathology reveals less sclerosis and more edema, resembling LS&A.¹² The earliest descriptions of this entity describe 3 stages: ivory/chalk white, scaly, and atrophic. Follicular plugging (absent in this patient) and fine scale can exist at any stage.^13,14 Flattened rete ridges mark an otherwise preserved epidermis; hyalinized collagen typically is superficial and demonstrates less sclerosis yet increased edema.^12-14 Fewer elastic fibers typically are present compared to normal skin. Changes seen in this entity are more superficial, as with our patient, than classic scleroderma. However, classic edema was not found in our patient’s biopsy specimen.

Superficial morphea, occurring predominantly in females, presents with hyperpigmented or hypopigmented patches having minimal to no induration. The lesions typically are asymptomatic. Histopathologically, collagen deposition and inflammation are confined to the superficial dermis without homogenization associated with LS&A, findings that were consistent with this patient’s biopsy.^15,16 However, similar to other morpheaform variants, elastic fibers are unchanged.¹⁵ Verhoeff-van Gieson stain of the biopsy (Figure 3) showed the decreased and fragmented elastin network in the upper reticular and papillary dermis, making this entity less compatible.

Guttate LS&A may present with interfollicular, bluish white macules or papules coalescing into patches or plaques. Lesions evolve to reveal atrophic thin skin with follicular plugging. Histology demonstrates a thinned epidermis with orthohypokeratosis marked by flattened rete ridges. The dermis reveals short hyalinized collagen fibrils with a loss of elastic fibers in the papillary and upper reticular dermis, giving a homogenized appearance. Early disease is marked by an inflammatory infiltrate.¹⁷ Most of these findings are consistent with our patient’s pathology, which was confined to the upper dermis. Lacking, however, were characteristic findings of LS&A, including upper dermal homogenization, near-total effacement of rete ridges, orthokeratosis, and vacuolar degeneration at the dermoepidermal junction. As such, this entity is less compatible.

Atrophoderma elastolyticum discretum has clinical features of atrophoderma with elastolytic histopathologic findings.¹ Anetoderma presents with outpouchings of atrophic skin with a surrounding ring of normal tissue. Histopathologically, this entity shows normal collagen with elastolysis; there also is a decrease in desmosine, an elastin cross-linker.^1,3 Neither the clinical nor histopathologic findings in this patient matched these 2 entities.

The reported chronologic association of these lesions with an arthropod assault raised suspicion to their association with toxic insult or postinflammatory changes. One study reported mechanical trauma, including insect bites, as a possible inciting factor of morphea.¹¹ These data, gathered from patient surveys, reported trauma associated to lesion development.^1,17 A review of the literature regarding atrophoderma, morphea, and LS&A failed to identify pathogenic changes seen in this patient following initial trauma. Moreover, although it is difficult to prove causality in the formation of the original hypopigmented spots, the development of identical spots in a similar distribution without further trauma suggests against these etiologies to fully explain her lesions. Nonetheless, circumstance makes it difficult to prove whether the original arthropod insult spurred a smoldering reactive process that caused the newer lesions.

Hereditary connective-tissue disorders also were considered in the differential diagnosis. Because of the patient’s history of an unprovoked complete rotator cuff tear, Ehlers-Danlos syndrome was considered; however, the remainder of her examination was normal, making a syndromic systemic disorder a less likely etiology.Because of the distinct clinical and histopathologic findings, this case may represent a rare and previously unreported variant of morphea. Clinically, these hypopigmented macules and patches exist somewhere along the morphea-atrophoderma spectrum. Histopathologic findings do not conform to prior reports. The name atrophodermalike guttate morphea may be an appropriate appellation. It is possible this presentation represents a variant of what dermatologists have referred to as white spot disease.¹⁸ We hope that this case may bring others to discussion, allowing for the identification of a more precise entity and etiology so that patients may receive more directed therapy.

To the Editor:

Morphea, atrophoderma, guttate lichen sclerosus et atrophicus (LS&A), anetoderma, and their subtypes are inflammatory processes ultimately leading to dermal remodeling. We report a case of a scaly, hypopigmented, macular rash that clinically appeared as an entity along the morphea-atrophoderma spectrum and demonstrated unique histopathologic changes in both collagen and elastin confined to the upper reticular and papillary dermis. This case is a potentially rare variant representing a combination of clinical and microscopic findings.

A 29-year-old woman presented for an increasing number of white spots distributed on the trunk, arms, and legs. She denied local and systemic symptoms. The patient reported that she was stung by 100 wasps 23 years prior. Following the assault, her grandmother placed chewed tobacco leaves atop the painful erythematous wheals and flares. Upon resolution, hypopigmented macules and patches remained in their place. The patient denied associated symptoms or new lesions; she did not seek care at that time.

In her early 20s, the patient noted new, similarly distributed hypopigmented macules and patches without associated arthropod assault. She was treated by an outside dermatologist without result for presumed tinea versicolor. A follow-up superficial shave biopsy cited subtle psoriasiform dermatitis. Topical steroids did not improve the lesions. Her medical history also was remarkable for a reportedly unprovoked complete rotator cuff tear.

Physical examination revealed 0.5- to 2.0-cm, ill-defined, perifollicular and nonfollicular, slightly scaly macules and patches on the trunk, arms, and legs. There was no follicular plugging (Figure 1A). The hands, feet, face, and mucosal surfaces were spared. She had no family history of similar lesions. Although atrophic in appearance, a single lesion on the left thigh was palpably depressed (Figure 1B). Serology demonstrated a normal complete blood cell count and comprehensive metabolic panel, and negative Lyme titers. Light therapy and topical steroids failed to improve the lesions; calcipotriene cream 0.005% made the lesions erythematous and pruritic.

A biopsy from a flank lesion demonstrated a normal epithelium without thinning, a normal basal melanocyte population, and minimally effaced rete ridges. Thin collagen bundles were noted in the upper reticular and papillary dermis with associated fibroplasia (Figure 2). Verhoeff-van Gieson stain revealed decreased and fragmented elastin filaments in the same dermal distribution as the changed collagen (Figure 3). There was no evidence of primary inflammatory disease. The dermis was thinned. Periodic acid–Schiff stain confirmed the absence of hyphae and spores.

The relevant findings in our patient including the following: (1) onset of hypopigmented macules and patches following resolution of a toxic insult; (2) initially stable number of lesions that progressed in number but not size; (3) thinned collagen associated with fibroplasia in the upper reticular and papillary dermis; (4) decreased number and fragmentation of elastin filaments confined to the same region; (5) no congenital lesions or similar lesions in family members; and (6) a complete rotator cuff tear with no findings of a systemic connective-tissue disorder such as Ehlers-Danlos syndrome.

We performed a literature search of PubMed articles indexed for MEDLINE using combinations of the terms atrophic, hypopigmented, white, spot disease, confetti-like, guttate, macules, atrophoderma, morphea, anetoderma, elastin, and collagen to identify potentially similar reports of guttate hypopigmented macules demonstrating changes of the collagen and elastin in the papillary and upper reticular dermis. Some variants, namely atrophoderma of Pasini and Pierini (APP), guttate morphea, and superficial morphea, demonstrate similar clinical and histopathologic findings.

Findings similar to our case were documented in case reports of 2 women (aged 34 and 42 years)¹ presenting with asymptomatic, atrophic, well-demarcated, shiny, hypopigmented macules over the trunk and upper extremities, which demonstrated a thinned epidermis with coarse hyalinized collagen bundles in the mid and lower dermis. There was upper and diffuse dermal elastolysis (patient 1 and patient 2, respectively).¹ Our patient’s lesions were hypopigmented and atrophic in appearance but were slightly scaly and also involved the extremities. Distinct from these patient reports, histopathology from our case demonstrated thin packed collagen bundles and decreased fragmented elastin filaments confined to the upper reticular and papillary dermis.

Plaque morphea is the most common type of localized scleroderma.² The subtype APP demonstrates round to ovoid, gray-brown depressions with cliff-drop borders. They may appear flesh colored or hypopigmented.^3,4 These sclerodermoid lesions lack the violaceous border classic to morphea. Sclerosis and induration also are typically absent.⁵ Clinically, our patient’s macules resembled this entity. Histopathologically, APP shows normal epithelium with an increased basal layer pigmentation; preserved adnexal structures; and mid to lower dermal collagen edema, clumping, and homogenization.^3,4 Elastic fibers classically are unchanged, with exceptions.^6-11 Changes in the collagen and elastin of our patient were unlike those reported in APP, which occur in the mid to lower dermis.

Guttate morphea demonstrates small, pale, minimally indurated, coin-shaped lesions on the trunk. Histopathology reveals less sclerosis and more edema, resembling LS&A.¹² The earliest descriptions of this entity describe 3 stages: ivory/chalk white, scaly, and atrophic. Follicular plugging (absent in this patient) and fine scale can exist at any stage.^13,14 Flattened rete ridges mark an otherwise preserved epidermis; hyalinized collagen typically is superficial and demonstrates less sclerosis yet increased edema.^12-14 Fewer elastic fibers typically are present compared to normal skin. Changes seen in this entity are more superficial, as with our patient, than classic scleroderma. However, classic edema was not found in our patient’s biopsy specimen.

Superficial morphea, occurring predominantly in females, presents with hyperpigmented or hypopigmented patches having minimal to no induration. The lesions typically are asymptomatic. Histopathologically, collagen deposition and inflammation are confined to the superficial dermis without homogenization associated with LS&A, findings that were consistent with this patient’s biopsy.^15,16 However, similar to other morpheaform variants, elastic fibers are unchanged.¹⁵ Verhoeff-van Gieson stain of the biopsy (Figure 3) showed the decreased and fragmented elastin network in the upper reticular and papillary dermis, making this entity less compatible.

Guttate LS&A may present with interfollicular, bluish white macules or papules coalescing into patches or plaques. Lesions evolve to reveal atrophic thin skin with follicular plugging. Histology demonstrates a thinned epidermis with orthohypokeratosis marked by flattened rete ridges. The dermis reveals short hyalinized collagen fibrils with a loss of elastic fibers in the papillary and upper reticular dermis, giving a homogenized appearance. Early disease is marked by an inflammatory infiltrate.¹⁷ Most of these findings are consistent with our patient’s pathology, which was confined to the upper dermis. Lacking, however, were characteristic findings of LS&A, including upper dermal homogenization, near-total effacement of rete ridges, orthokeratosis, and vacuolar degeneration at the dermoepidermal junction. As such, this entity is less compatible.

Atrophoderma elastolyticum discretum has clinical features of atrophoderma with elastolytic histopathologic findings.¹ Anetoderma presents with outpouchings of atrophic skin with a surrounding ring of normal tissue. Histopathologically, this entity shows normal collagen with elastolysis; there also is a decrease in desmosine, an elastin cross-linker.^1,3 Neither the clinical nor histopathologic findings in this patient matched these 2 entities.

The reported chronologic association of these lesions with an arthropod assault raised suspicion to their association with toxic insult or postinflammatory changes. One study reported mechanical trauma, including insect bites, as a possible inciting factor of morphea.¹¹ These data, gathered from patient surveys, reported trauma associated to lesion development.^1,17 A review of the literature regarding atrophoderma, morphea, and LS&A failed to identify pathogenic changes seen in this patient following initial trauma. Moreover, although it is difficult to prove causality in the formation of the original hypopigmented spots, the development of identical spots in a similar distribution without further trauma suggests against these etiologies to fully explain her lesions. Nonetheless, circumstance makes it difficult to prove whether the original arthropod insult spurred a smoldering reactive process that caused the newer lesions.

Hereditary connective-tissue disorders also were considered in the differential diagnosis. Because of the patient’s history of an unprovoked complete rotator cuff tear, Ehlers-Danlos syndrome was considered; however, the remainder of her examination was normal, making a syndromic systemic disorder a less likely etiology.Because of the distinct clinical and histopathologic findings, this case may represent a rare and previously unreported variant of morphea. Clinically, these hypopigmented macules and patches exist somewhere along the morphea-atrophoderma spectrum. Histopathologic findings do not conform to prior reports. The name atrophodermalike guttate morphea may be an appropriate appellation. It is possible this presentation represents a variant of what dermatologists have referred to as white spot disease.¹⁸ We hope that this case may bring others to discussion, allowing for the identification of a more precise entity and etiology so that patients may receive more directed therapy.

To the Editor:

Morphea, atrophoderma, guttate lichen sclerosus et atrophicus (LS&A), anetoderma, and their subtypes are inflammatory processes ultimately leading to dermal remodeling. We report a case of a scaly, hypopigmented, macular rash that clinically appeared as an entity along the morphea-atrophoderma spectrum and demonstrated unique histopathologic changes in both collagen and elastin confined to the upper reticular and papillary dermis. This case is a potentially rare variant representing a combination of clinical and microscopic findings.

A 29-year-old woman presented for an increasing number of white spots distributed on the trunk, arms, and legs. She denied local and systemic symptoms. The patient reported that she was stung by 100 wasps 23 years prior. Following the assault, her grandmother placed chewed tobacco leaves atop the painful erythematous wheals and flares. Upon resolution, hypopigmented macules and patches remained in their place. The patient denied associated symptoms or new lesions; she did not seek care at that time.

In her early 20s, the patient noted new, similarly distributed hypopigmented macules and patches without associated arthropod assault. She was treated by an outside dermatologist without result for presumed tinea versicolor. A follow-up superficial shave biopsy cited subtle psoriasiform dermatitis. Topical steroids did not improve the lesions. Her medical history also was remarkable for a reportedly unprovoked complete rotator cuff tear.

Physical examination revealed 0.5- to 2.0-cm, ill-defined, perifollicular and nonfollicular, slightly scaly macules and patches on the trunk, arms, and legs. There was no follicular plugging (Figure 1A). The hands, feet, face, and mucosal surfaces were spared. She had no family history of similar lesions. Although atrophic in appearance, a single lesion on the left thigh was palpably depressed (Figure 1B). Serology demonstrated a normal complete blood cell count and comprehensive metabolic panel, and negative Lyme titers. Light therapy and topical steroids failed to improve the lesions; calcipotriene cream 0.005% made the lesions erythematous and pruritic.

A biopsy from a flank lesion demonstrated a normal epithelium without thinning, a normal basal melanocyte population, and minimally effaced rete ridges. Thin collagen bundles were noted in the upper reticular and papillary dermis with associated fibroplasia (Figure 2). Verhoeff-van Gieson stain revealed decreased and fragmented elastin filaments in the same dermal distribution as the changed collagen (Figure 3). There was no evidence of primary inflammatory disease. The dermis was thinned. Periodic acid–Schiff stain confirmed the absence of hyphae and spores.

The relevant findings in our patient including the following: (1) onset of hypopigmented macules and patches following resolution of a toxic insult; (2) initially stable number of lesions that progressed in number but not size; (3) thinned collagen associated with fibroplasia in the upper reticular and papillary dermis; (4) decreased number and fragmentation of elastin filaments confined to the same region; (5) no congenital lesions or similar lesions in family members; and (6) a complete rotator cuff tear with no findings of a systemic connective-tissue disorder such as Ehlers-Danlos syndrome.

We performed a literature search of PubMed articles indexed for MEDLINE using combinations of the terms atrophic, hypopigmented, white, spot disease, confetti-like, guttate, macules, atrophoderma, morphea, anetoderma, elastin, and collagen to identify potentially similar reports of guttate hypopigmented macules demonstrating changes of the collagen and elastin in the papillary and upper reticular dermis. Some variants, namely atrophoderma of Pasini and Pierini (APP), guttate morphea, and superficial morphea, demonstrate similar clinical and histopathologic findings.

Findings similar to our case were documented in case reports of 2 women (aged 34 and 42 years)¹ presenting with asymptomatic, atrophic, well-demarcated, shiny, hypopigmented macules over the trunk and upper extremities, which demonstrated a thinned epidermis with coarse hyalinized collagen bundles in the mid and lower dermis. There was upper and diffuse dermal elastolysis (patient 1 and patient 2, respectively).¹ Our patient’s lesions were hypopigmented and atrophic in appearance but were slightly scaly and also involved the extremities. Distinct from these patient reports, histopathology from our case demonstrated thin packed collagen bundles and decreased fragmented elastin filaments confined to the upper reticular and papillary dermis.

Plaque morphea is the most common type of localized scleroderma.² The subtype APP demonstrates round to ovoid, gray-brown depressions with cliff-drop borders. They may appear flesh colored or hypopigmented.^3,4 These sclerodermoid lesions lack the violaceous border classic to morphea. Sclerosis and induration also are typically absent.⁵ Clinically, our patient’s macules resembled this entity. Histopathologically, APP shows normal epithelium with an increased basal layer pigmentation; preserved adnexal structures; and mid to lower dermal collagen edema, clumping, and homogenization.^3,4 Elastic fibers classically are unchanged, with exceptions.^6-11 Changes in the collagen and elastin of our patient were unlike those reported in APP, which occur in the mid to lower dermis.

Guttate morphea demonstrates small, pale, minimally indurated, coin-shaped lesions on the trunk. Histopathology reveals less sclerosis and more edema, resembling LS&A.¹² The earliest descriptions of this entity describe 3 stages: ivory/chalk white, scaly, and atrophic. Follicular plugging (absent in this patient) and fine scale can exist at any stage.^13,14 Flattened rete ridges mark an otherwise preserved epidermis; hyalinized collagen typically is superficial and demonstrates less sclerosis yet increased edema.^12-14 Fewer elastic fibers typically are present compared to normal skin. Changes seen in this entity are more superficial, as with our patient, than classic scleroderma. However, classic edema was not found in our patient’s biopsy specimen.

Superficial morphea, occurring predominantly in females, presents with hyperpigmented or hypopigmented patches having minimal to no induration. The lesions typically are asymptomatic. Histopathologically, collagen deposition and inflammation are confined to the superficial dermis without homogenization associated with LS&A, findings that were consistent with this patient’s biopsy.^15,16 However, similar to other morpheaform variants, elastic fibers are unchanged.¹⁵ Verhoeff-van Gieson stain of the biopsy (Figure 3) showed the decreased and fragmented elastin network in the upper reticular and papillary dermis, making this entity less compatible.

Guttate LS&A may present with interfollicular, bluish white macules or papules coalescing into patches or plaques. Lesions evolve to reveal atrophic thin skin with follicular plugging. Histology demonstrates a thinned epidermis with orthohypokeratosis marked by flattened rete ridges. The dermis reveals short hyalinized collagen fibrils with a loss of elastic fibers in the papillary and upper reticular dermis, giving a homogenized appearance. Early disease is marked by an inflammatory infiltrate.¹⁷ Most of these findings are consistent with our patient’s pathology, which was confined to the upper dermis. Lacking, however, were characteristic findings of LS&A, including upper dermal homogenization, near-total effacement of rete ridges, orthokeratosis, and vacuolar degeneration at the dermoepidermal junction. As such, this entity is less compatible.

Atrophoderma elastolyticum discretum has clinical features of atrophoderma with elastolytic histopathologic findings.¹ Anetoderma presents with outpouchings of atrophic skin with a surrounding ring of normal tissue. Histopathologically, this entity shows normal collagen with elastolysis; there also is a decrease in desmosine, an elastin cross-linker.^1,3 Neither the clinical nor histopathologic findings in this patient matched these 2 entities.

The reported chronologic association of these lesions with an arthropod assault raised suspicion to their association with toxic insult or postinflammatory changes. One study reported mechanical trauma, including insect bites, as a possible inciting factor of morphea.¹¹ These data, gathered from patient surveys, reported trauma associated to lesion development.^1,17 A review of the literature regarding atrophoderma, morphea, and LS&A failed to identify pathogenic changes seen in this patient following initial trauma. Moreover, although it is difficult to prove causality in the formation of the original hypopigmented spots, the development of identical spots in a similar distribution without further trauma suggests against these etiologies to fully explain her lesions. Nonetheless, circumstance makes it difficult to prove whether the original arthropod insult spurred a smoldering reactive process that caused the newer lesions.

Hereditary connective-tissue disorders also were considered in the differential diagnosis. Because of the patient’s history of an unprovoked complete rotator cuff tear, Ehlers-Danlos syndrome was considered; however, the remainder of her examination was normal, making a syndromic systemic disorder a less likely etiology.Because of the distinct clinical and histopathologic findings, this case may represent a rare and previously unreported variant of morphea. Clinically, these hypopigmented macules and patches exist somewhere along the morphea-atrophoderma spectrum. Histopathologic findings do not conform to prior reports. The name atrophodermalike guttate morphea may be an appropriate appellation. It is possible this presentation represents a variant of what dermatologists have referred to as white spot disease.¹⁸ We hope that this case may bring others to discussion, allowing for the identification of a more precise entity and etiology so that patients may receive more directed therapy.

Medicare pays hundreds of millions of dollars each year for compounded topical prescriptions, mainly as pain treatments. But a new report finds that officials are concerned about possible fraud and patient safety risks from products made at nearly a quarter of the pharmacies that fill the bulk of those prescriptions.

“Although some of this billing may be legitimate, all of these pharmacies warrant further scrutiny,” concludes the report from the Office of Inspector General for the Department of Health and Human Services.

In total, 547 pharmacies – nearly 23% of those that submit most of the bills to Medicare for making these creams – hit one or more of five red-flag markers set by investigators. Those included what the researchers called “extremely high” prices; large percentages of Medicare members getting identical drugs – 16 of the pharmacies billed for identical drugs for 200 or more customers; “greatly increased” year-over-year billing – 20 pharmacies increased their billing by more than 10,000%; or having a single medical provider writing more than 131 prescriptions. More than half of those pharmacies hit two or more measures – and 10 hit all five.

One Oregon pharmacy, for example, submitted claims for 91% of its customers. A pharmacy in New York submitted 5,342 prescriptions ordered by one podiatrist, while a Florida pharmacy saw its Medicare billing for such treatments go from $7,468 in 2015 to $1.8 million the following year.

Many of the pharmacies are clustered in four cities: Detroit, Houston, Los Angeles, and New York.

The report comes amid ongoing concern by Medicare officials about compounded drugs. In addition to questions like those raised in the report about overuse and pricing, safety has been a key issue in recent years. A meningitis outbreak in 2012 was linked to a Massachusetts pharmacy that did not maintain sterile conditions and sold tainted made-to-order injections that killed 64 Americans.

When done safely, pharmacy-made compounded drugs provide a legitimate option for patients whose medical needs can’t be met by commercially available products mass-produced by pharmaceutical companies. For example, a patient who can’t swallow a commercially available prescription pill might get a liquid version of a drug.

State boards of pharmacy generally oversee compounding pharmacies, and the drugs they produce are not considered approved by the Food and Drug Administration.

The new report focuses on concerns with compounded topical medications.

Medicare spending for such treatments has skyrocketed, rising more than 2,350%, from $13.2 million in 2010 to $323.5 million in 2016. Price hikes and an increase in the number of prescriptions written drove the increase, the report said.

It is not the first time the inspector general has looked at compounded drugs. A 2016 report found that overall spending on all types of compounded drugs – not just topical medications – rose sharply. The U.S. Postal Service inspector general and the Department of Defense also have raised concerns about rising spending and possible fraud for compounded drugs.

In response to those previous reports, the International Academy of Compounding Pharmacists, the industry’s trade group, has said that legitimately compounded drugs “can dramatically improve a patient’s quality of life,” noting that proper billing controls need to be in place. The inspector general’s report in 2016, it added, found that “such controls are not in place.”

This report, which the compounding trade group has not yet reviewed, focuses on topical drugs and a subset of the 15,290 pharmacies that provide at least one such prescription each year. It looked at billing records from the 2,388 pharmacies that do at least 10 such prescriptions a year – providing 93% of all compounded topical drugs paid for by Medicare.

Most of the prescriptions were for pain treatment, made from ingredients such as lidocaine or diclofenac sodium.

On average, those compounds were more expensive than noncompounded drugs with the same ingredients.

For example, Medicare paid an average of $751 per tube of compounded lidocaine, and $1,506 for the diclofenac, according to the inspector general’s report. Noncompounded tubes of those drugs averaged $445 and $128, respectively.

FDA Commissioner Scott Gottlieb, MD, recently outlined new efforts his agency is taking to oversee compounded drugs in the wake of legislation passed by Congress following the meningitis outbreak.

“The FDA is inspecting compounding facilities to assess whether drugs that are essentially copies of FDA-approved drugs are being compounded for patients” who could otherwise take a product sold commercially, he said in a statement issued on June 28.

Dr. Gottlieb also said the FDA plans to make more information available to patients and their doctors about compounded topical pain creams, including information about their effectiveness and any potential safety risks.

Not being effective is a safety risk, noted Miriam Anderson, a researcher with the inspector general’s office who helped write the report.

The report urged the Centers for Medicare & Medicaid Services to clarify some of its policies to emphasize that insurers can limit the use of compounded drugs by requiring prior authorization or other steps. The agency concurred with the recommendations, according to the report, including the need to “follow up on pharmacies with questionable Part D billing and the prescribers associated with these pharmacies.”

Ms. Anderson said the inspector general’s office is continuing to probe the issue.

“We will investigate a number of leads on specific pharmacies and prescribers who were identified as having these questionable patterns,” she said. “Whenever we see that kind of increase in spending, it raises concern about fraud, waste, and abuse.”
 

KHN’s coverage of prescription drug development, costs, and pricing is supported in part by the Laura and John Arnold Foundation.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Medicare pays hundreds of millions of dollars each year for compounded topical prescriptions, mainly as pain treatments. But a new report finds that officials are concerned about possible fraud and patient safety risks from products made at nearly a quarter of the pharmacies that fill the bulk of those prescriptions.

“Although some of this billing may be legitimate, all of these pharmacies warrant further scrutiny,” concludes the report from the Office of Inspector General for the Department of Health and Human Services.

In total, 547 pharmacies – nearly 23% of those that submit most of the bills to Medicare for making these creams – hit one or more of five red-flag markers set by investigators. Those included what the researchers called “extremely high” prices; large percentages of Medicare members getting identical drugs – 16 of the pharmacies billed for identical drugs for 200 or more customers; “greatly increased” year-over-year billing – 20 pharmacies increased their billing by more than 10,000%; or having a single medical provider writing more than 131 prescriptions. More than half of those pharmacies hit two or more measures – and 10 hit all five.

One Oregon pharmacy, for example, submitted claims for 91% of its customers. A pharmacy in New York submitted 5,342 prescriptions ordered by one podiatrist, while a Florida pharmacy saw its Medicare billing for such treatments go from $7,468 in 2015 to $1.8 million the following year.

Many of the pharmacies are clustered in four cities: Detroit, Houston, Los Angeles, and New York.

The report comes amid ongoing concern by Medicare officials about compounded drugs. In addition to questions like those raised in the report about overuse and pricing, safety has been a key issue in recent years. A meningitis outbreak in 2012 was linked to a Massachusetts pharmacy that did not maintain sterile conditions and sold tainted made-to-order injections that killed 64 Americans.

When done safely, pharmacy-made compounded drugs provide a legitimate option for patients whose medical needs can’t be met by commercially available products mass-produced by pharmaceutical companies. For example, a patient who can’t swallow a commercially available prescription pill might get a liquid version of a drug.

State boards of pharmacy generally oversee compounding pharmacies, and the drugs they produce are not considered approved by the Food and Drug Administration.

The new report focuses on concerns with compounded topical medications.

Medicare spending for such treatments has skyrocketed, rising more than 2,350%, from $13.2 million in 2010 to $323.5 million in 2016. Price hikes and an increase in the number of prescriptions written drove the increase, the report said.

It is not the first time the inspector general has looked at compounded drugs. A 2016 report found that overall spending on all types of compounded drugs – not just topical medications – rose sharply. The U.S. Postal Service inspector general and the Department of Defense also have raised concerns about rising spending and possible fraud for compounded drugs.

In response to those previous reports, the International Academy of Compounding Pharmacists, the industry’s trade group, has said that legitimately compounded drugs “can dramatically improve a patient’s quality of life,” noting that proper billing controls need to be in place. The inspector general’s report in 2016, it added, found that “such controls are not in place.”

This report, which the compounding trade group has not yet reviewed, focuses on topical drugs and a subset of the 15,290 pharmacies that provide at least one such prescription each year. It looked at billing records from the 2,388 pharmacies that do at least 10 such prescriptions a year – providing 93% of all compounded topical drugs paid for by Medicare.

Most of the prescriptions were for pain treatment, made from ingredients such as lidocaine or diclofenac sodium.

On average, those compounds were more expensive than noncompounded drugs with the same ingredients.

For example, Medicare paid an average of $751 per tube of compounded lidocaine, and $1,506 for the diclofenac, according to the inspector general’s report. Noncompounded tubes of those drugs averaged $445 and $128, respectively.

FDA Commissioner Scott Gottlieb, MD, recently outlined new efforts his agency is taking to oversee compounded drugs in the wake of legislation passed by Congress following the meningitis outbreak.

“The FDA is inspecting compounding facilities to assess whether drugs that are essentially copies of FDA-approved drugs are being compounded for patients” who could otherwise take a product sold commercially, he said in a statement issued on June 28.

Dr. Gottlieb also said the FDA plans to make more information available to patients and their doctors about compounded topical pain creams, including information about their effectiveness and any potential safety risks.

Not being effective is a safety risk, noted Miriam Anderson, a researcher with the inspector general’s office who helped write the report.

The report urged the Centers for Medicare & Medicaid Services to clarify some of its policies to emphasize that insurers can limit the use of compounded drugs by requiring prior authorization or other steps. The agency concurred with the recommendations, according to the report, including the need to “follow up on pharmacies with questionable Part D billing and the prescribers associated with these pharmacies.”

Ms. Anderson said the inspector general’s office is continuing to probe the issue.

“We will investigate a number of leads on specific pharmacies and prescribers who were identified as having these questionable patterns,” she said. “Whenever we see that kind of increase in spending, it raises concern about fraud, waste, and abuse.”
 

KHN’s coverage of prescription drug development, costs, and pricing is supported in part by the Laura and John Arnold Foundation.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Medicare pays hundreds of millions of dollars each year for compounded topical prescriptions, mainly as pain treatments. But a new report finds that officials are concerned about possible fraud and patient safety risks from products made at nearly a quarter of the pharmacies that fill the bulk of those prescriptions.

“Although some of this billing may be legitimate, all of these pharmacies warrant further scrutiny,” concludes the report from the Office of Inspector General for the Department of Health and Human Services.

In total, 547 pharmacies – nearly 23% of those that submit most of the bills to Medicare for making these creams – hit one or more of five red-flag markers set by investigators. Those included what the researchers called “extremely high” prices; large percentages of Medicare members getting identical drugs – 16 of the pharmacies billed for identical drugs for 200 or more customers; “greatly increased” year-over-year billing – 20 pharmacies increased their billing by more than 10,000%; or having a single medical provider writing more than 131 prescriptions. More than half of those pharmacies hit two or more measures – and 10 hit all five.

One Oregon pharmacy, for example, submitted claims for 91% of its customers. A pharmacy in New York submitted 5,342 prescriptions ordered by one podiatrist, while a Florida pharmacy saw its Medicare billing for such treatments go from $7,468 in 2015 to $1.8 million the following year.

Many of the pharmacies are clustered in four cities: Detroit, Houston, Los Angeles, and New York.

The report comes amid ongoing concern by Medicare officials about compounded drugs. In addition to questions like those raised in the report about overuse and pricing, safety has been a key issue in recent years. A meningitis outbreak in 2012 was linked to a Massachusetts pharmacy that did not maintain sterile conditions and sold tainted made-to-order injections that killed 64 Americans.

When done safely, pharmacy-made compounded drugs provide a legitimate option for patients whose medical needs can’t be met by commercially available products mass-produced by pharmaceutical companies. For example, a patient who can’t swallow a commercially available prescription pill might get a liquid version of a drug.

State boards of pharmacy generally oversee compounding pharmacies, and the drugs they produce are not considered approved by the Food and Drug Administration.

The new report focuses on concerns with compounded topical medications.

Medicare spending for such treatments has skyrocketed, rising more than 2,350%, from $13.2 million in 2010 to $323.5 million in 2016. Price hikes and an increase in the number of prescriptions written drove the increase, the report said.

It is not the first time the inspector general has looked at compounded drugs. A 2016 report found that overall spending on all types of compounded drugs – not just topical medications – rose sharply. The U.S. Postal Service inspector general and the Department of Defense also have raised concerns about rising spending and possible fraud for compounded drugs.

In response to those previous reports, the International Academy of Compounding Pharmacists, the industry’s trade group, has said that legitimately compounded drugs “can dramatically improve a patient’s quality of life,” noting that proper billing controls need to be in place. The inspector general’s report in 2016, it added, found that “such controls are not in place.”

This report, which the compounding trade group has not yet reviewed, focuses on topical drugs and a subset of the 15,290 pharmacies that provide at least one such prescription each year. It looked at billing records from the 2,388 pharmacies that do at least 10 such prescriptions a year – providing 93% of all compounded topical drugs paid for by Medicare.

Most of the prescriptions were for pain treatment, made from ingredients such as lidocaine or diclofenac sodium.

On average, those compounds were more expensive than noncompounded drugs with the same ingredients.

For example, Medicare paid an average of $751 per tube of compounded lidocaine, and $1,506 for the diclofenac, according to the inspector general’s report. Noncompounded tubes of those drugs averaged $445 and $128, respectively.

FDA Commissioner Scott Gottlieb, MD, recently outlined new efforts his agency is taking to oversee compounded drugs in the wake of legislation passed by Congress following the meningitis outbreak.

“The FDA is inspecting compounding facilities to assess whether drugs that are essentially copies of FDA-approved drugs are being compounded for patients” who could otherwise take a product sold commercially, he said in a statement issued on June 28.

Dr. Gottlieb also said the FDA plans to make more information available to patients and their doctors about compounded topical pain creams, including information about their effectiveness and any potential safety risks.

Not being effective is a safety risk, noted Miriam Anderson, a researcher with the inspector general’s office who helped write the report.

The report urged the Centers for Medicare & Medicaid Services to clarify some of its policies to emphasize that insurers can limit the use of compounded drugs by requiring prior authorization or other steps. The agency concurred with the recommendations, according to the report, including the need to “follow up on pharmacies with questionable Part D billing and the prescribers associated with these pharmacies.”

Ms. Anderson said the inspector general’s office is continuing to probe the issue.

“We will investigate a number of leads on specific pharmacies and prescribers who were identified as having these questionable patterns,” she said. “Whenever we see that kind of increase in spending, it raises concern about fraud, waste, and abuse.”
 

KHN’s coverage of prescription drug development, costs, and pricing is supported in part by the Laura and John Arnold Foundation.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

PD-1 blockade should still be considered as a second-line approach in patients with EGFR-mutant non–small-cell lung cancer (NSCLC), as some may still respond to this therapy, investigators reported.

The researchers described a patient who was diagnosed with epidermal growth factor receptor (EGFR)-mutant NSCLC but who also showed high expression of PD-L1.

The 62-year-old woman first presented with a lung nodule and metastasis in the right hip, which were EGFR-mutant and had a PD-L1 tumor proportion score of 90%. She was treated with erlotinib – an EGFR tyrosine kinase inhibitor – and radiotherapy, according to the report, published in Annals of Oncology.

Two months later, she developed multiple new metastases in the chest wall. These also showed high PD-L1 expression, but no EGFR mutations, so she was treated with pembrolizumab as second-line therapy.

After the first course of treatment with pembrolizumab, the hip pain improved dramatically, and after three cycles the primary and metastatic lesions disappeared completely.

“Immunofluorescent analysis of both right ilium and chest wall lesions with an anti-EGFR antibody specific to Ex.19 del and an anti-PD-L1 antibody revealed the presence of distinct heterogeneity of EGFR-mutant clones and PD-L1 highly-expressing clones,” wrote Kei Kunimasa, MD, of Osaka International Cancer Institute, and coauthors.

Current clinical trials suggested that patients with EGFR mutations are likely to have a poor response to PD-1 blockade therapies for NSCLC, and the authors agreed that patients with EGFR mutations should be treated with EGFR tyrosine kinase inhibitors as first-line therapy.

“However, the present case suggested that shorter PFS in EGFR-TKI treatment for EGFR-mutant NSCLC patients with high PD-L1 TPS and without acquired T790M mutation could encourage us to try PD-1 blockade therapy as second line therapy,” they wrote.

The investigators suggested that certain clinical factors could identify patients with EGFR-mutant NSCLC who might respond well to PD-1 blockade, such as progression-free survival on EGFR tyrosine kinase inhibitor treatment, other targetable resistant mutations, tumor mutation burden, and PD-L1 expression.

Two authors reported grants and personal fees from pharmaceutical companies outside the submitted work. No other conflicts of interest were declared.

SOURCE: Kunimasa K et al. Ann Oncol, 2018 Aug 7. doi: 10.1093/annonc/mdy312.

PD-1 blockade should still be considered as a second-line approach in patients with EGFR-mutant non–small-cell lung cancer (NSCLC), as some may still respond to this therapy, investigators reported.

The researchers described a patient who was diagnosed with epidermal growth factor receptor (EGFR)-mutant NSCLC but who also showed high expression of PD-L1.

The 62-year-old woman first presented with a lung nodule and metastasis in the right hip, which were EGFR-mutant and had a PD-L1 tumor proportion score of 90%. She was treated with erlotinib – an EGFR tyrosine kinase inhibitor – and radiotherapy, according to the report, published in Annals of Oncology.

Two months later, she developed multiple new metastases in the chest wall. These also showed high PD-L1 expression, but no EGFR mutations, so she was treated with pembrolizumab as second-line therapy.

After the first course of treatment with pembrolizumab, the hip pain improved dramatically, and after three cycles the primary and metastatic lesions disappeared completely.

“Immunofluorescent analysis of both right ilium and chest wall lesions with an anti-EGFR antibody specific to Ex.19 del and an anti-PD-L1 antibody revealed the presence of distinct heterogeneity of EGFR-mutant clones and PD-L1 highly-expressing clones,” wrote Kei Kunimasa, MD, of Osaka International Cancer Institute, and coauthors.

Current clinical trials suggested that patients with EGFR mutations are likely to have a poor response to PD-1 blockade therapies for NSCLC, and the authors agreed that patients with EGFR mutations should be treated with EGFR tyrosine kinase inhibitors as first-line therapy.

“However, the present case suggested that shorter PFS in EGFR-TKI treatment for EGFR-mutant NSCLC patients with high PD-L1 TPS and without acquired T790M mutation could encourage us to try PD-1 blockade therapy as second line therapy,” they wrote.

The investigators suggested that certain clinical factors could identify patients with EGFR-mutant NSCLC who might respond well to PD-1 blockade, such as progression-free survival on EGFR tyrosine kinase inhibitor treatment, other targetable resistant mutations, tumor mutation burden, and PD-L1 expression.

Two authors reported grants and personal fees from pharmaceutical companies outside the submitted work. No other conflicts of interest were declared.

SOURCE: Kunimasa K et al. Ann Oncol, 2018 Aug 7. doi: 10.1093/annonc/mdy312.

PD-1 blockade should still be considered as a second-line approach in patients with EGFR-mutant non–small-cell lung cancer (NSCLC), as some may still respond to this therapy, investigators reported.

The researchers described a patient who was diagnosed with epidermal growth factor receptor (EGFR)-mutant NSCLC but who also showed high expression of PD-L1.

The 62-year-old woman first presented with a lung nodule and metastasis in the right hip, which were EGFR-mutant and had a PD-L1 tumor proportion score of 90%. She was treated with erlotinib – an EGFR tyrosine kinase inhibitor – and radiotherapy, according to the report, published in Annals of Oncology.

Two months later, she developed multiple new metastases in the chest wall. These also showed high PD-L1 expression, but no EGFR mutations, so she was treated with pembrolizumab as second-line therapy.

After the first course of treatment with pembrolizumab, the hip pain improved dramatically, and after three cycles the primary and metastatic lesions disappeared completely.

“Immunofluorescent analysis of both right ilium and chest wall lesions with an anti-EGFR antibody specific to Ex.19 del and an anti-PD-L1 antibody revealed the presence of distinct heterogeneity of EGFR-mutant clones and PD-L1 highly-expressing clones,” wrote Kei Kunimasa, MD, of Osaka International Cancer Institute, and coauthors.

Current clinical trials suggested that patients with EGFR mutations are likely to have a poor response to PD-1 blockade therapies for NSCLC, and the authors agreed that patients with EGFR mutations should be treated with EGFR tyrosine kinase inhibitors as first-line therapy.

“However, the present case suggested that shorter PFS in EGFR-TKI treatment for EGFR-mutant NSCLC patients with high PD-L1 TPS and without acquired T790M mutation could encourage us to try PD-1 blockade therapy as second line therapy,” they wrote.

The investigators suggested that certain clinical factors could identify patients with EGFR-mutant NSCLC who might respond well to PD-1 blockade, such as progression-free survival on EGFR tyrosine kinase inhibitor treatment, other targetable resistant mutations, tumor mutation burden, and PD-L1 expression.

Two authors reported grants and personal fees from pharmaceutical companies outside the submitted work. No other conflicts of interest were declared.

SOURCE: Kunimasa K et al. Ann Oncol, 2018 Aug 7. doi: 10.1093/annonc/mdy312.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

Click here to view the articles published in August 2018.

Click here to view the articles published in August 2018.

Click here to view the articles published in August 2018.

MIAMI—For patients with Parkinson’s disease, a regime of transcranial magnetic stimulation (TMS) and aerobic exercise results in motor improvements that are sustained for one month, according to a study presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Another study by the same researchers indicates that stimulation of two regions in the premotor associative cortex, compared with stimulation of one region, improves axial symptoms in Parkinson’s disease. Both studies suggest that TMS prolongs the cortical silent period.

TMS Prolonged Cortical Silent Period

Aerobic exercise improves the motor symptoms of Parkinson’s disease. A proposed mechanism for this improvement is the enhancement of brain-derived neurotrophic factor (BDNF) signaling or activity. TMS also improves motor symptoms of Parkinson’s disease, and rat studies indicate that it enhances BDNF-tropomyosin receptor kinase B (TrkB) signaling, which is a biomarker of plasticity.

Milton C. Biagioni, MD, Assistant Professor of Neurology at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone Health in New York, and colleagues studied differences in BDNF-TrkB signaling between 16 patients with Parkinson’s disease and five healthy controls. Levels of all TrkB signaling biomarkers were significantly higher in healthy controls than in patients with Parkinson’s disease.

Dr. Biagioni and colleagues also investigated the biologic effects, motor outcomes, and physiologic outcomes of repetitive TMS and aerobic exercise in patients with Parkinson’s disease in a randomized, double-blind trial. In this trial, 16 patients with Parkinson’s disease participated in daily 40-minute sessions of aerobic exercise. Participants were randomized 1:1 to receive high-frequency repetitive TMS or sham stimulation over the motor cortex. Patients exercised on a recumbent linear cross trainer.

Motor outcomes included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Timed Up and Go (TUG) test. Neurophysiologic outcomes included the cortical silent period, motor threshold, and paired-associative stimulation (PAS-25). The researchers obtained peripheral blood lymphocytes from participants in the morning to measure BDNF activity. Outcomes were measured at baseline, two weeks after the intervention, and one month after the intervention.

Among patients with Parkinson’s disease, mean age was about 65. Mean disease duration was eight years, and mean UPDRS III score was 46.4. The researchers found no significant differences at baseline between patients randomized to TMS and those randomized to sham.

BDNF-TrkB signaling increased by 29.3% in the sham group and by 36.6% in the TMS group. Both increases were statistically significant, but the difference between groups was not significant. At one month, the cortical silent period was significantly prolonged after TMS, compared with sham. All patients had significant improvement in UPDRS III. Improvements in UPDRS III and TUG were sustained for one month in the TMS group.

Multifocal Stimulation Improved Axial Score

A previous study indicated that low-frequency repetitive TMS over the supplementary motor area (SMA) effectively improves motor symptoms in Parkinson’s disease. Like the SMA, the dorsal premotor cortex (PMd) is involved in motor planning and motor control. Researchers had not previously studied multifocal TMS over both targets, and Dr. Biagioni and colleagues decided to examine this technique.

They conducted a parallel, active-controlled, double-blind, randomized study of four weekly sessions of low-frequency repetitive TMS in 22 patients with Parkinson’s disease. The control group received TMS over the SMA and sham stimulation over the PMd. The experimental group received TMS over both areas. The study outcomes included all components of the UPDRS, as well as UPDRS III axial, tremor, rigidity, and bradykinesia scores. Dr. Biagioni and colleagues assessed patients in the on state at baseline and at four weeks after treatment.

Participants’ mean age was 65, and eight patients were female. Mean disease duration was approximately nine years, mean UPDRS total score was 53.1, and mean UPDRS III score was 35.9. The only significant difference between the control and experimental groups at baseline was Montreal Cognitive Assessment score, which was 24.2 in the control group and 26.4 in the experimental group.

Both interventions were well tolerated. After one month, UPDRS III decreased by 5.5 points in the control group and by 6.5 points in the experimental group. Both changes were statistically significant, but the difference between groups was not significant. The researchers found no difference between groups in total UPDRS and UPDRS III after one month. Axial score significantly decreased in the experimental group, compared with the control group, but the researchers found no significant differences between groups in rigidity, tremor, or bradykinesia scores. In addition, the cortical silent period was significantly prolonged in the experimental group, compared with the control group.

—Erik Greb

Suggested Reading

Chou YH, Hickey PT, Sundman M, et al. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol. 2015;72(4):432-440.

Shirota Y, Ohtsu H, Hamada M, et al. Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology. 2013;80(15):1400-1405.

MIAMI—For patients with Parkinson’s disease, a regime of transcranial magnetic stimulation (TMS) and aerobic exercise results in motor improvements that are sustained for one month, according to a study presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Another study by the same researchers indicates that stimulation of two regions in the premotor associative cortex, compared with stimulation of one region, improves axial symptoms in Parkinson’s disease. Both studies suggest that TMS prolongs the cortical silent period.

TMS Prolonged Cortical Silent Period

Aerobic exercise improves the motor symptoms of Parkinson’s disease. A proposed mechanism for this improvement is the enhancement of brain-derived neurotrophic factor (BDNF) signaling or activity. TMS also improves motor symptoms of Parkinson’s disease, and rat studies indicate that it enhances BDNF-tropomyosin receptor kinase B (TrkB) signaling, which is a biomarker of plasticity.

Milton C. Biagioni, MD, Assistant Professor of Neurology at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone Health in New York, and colleagues studied differences in BDNF-TrkB signaling between 16 patients with Parkinson’s disease and five healthy controls. Levels of all TrkB signaling biomarkers were significantly higher in healthy controls than in patients with Parkinson’s disease.

Dr. Biagioni and colleagues also investigated the biologic effects, motor outcomes, and physiologic outcomes of repetitive TMS and aerobic exercise in patients with Parkinson’s disease in a randomized, double-blind trial. In this trial, 16 patients with Parkinson’s disease participated in daily 40-minute sessions of aerobic exercise. Participants were randomized 1:1 to receive high-frequency repetitive TMS or sham stimulation over the motor cortex. Patients exercised on a recumbent linear cross trainer.

Motor outcomes included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Timed Up and Go (TUG) test. Neurophysiologic outcomes included the cortical silent period, motor threshold, and paired-associative stimulation (PAS-25). The researchers obtained peripheral blood lymphocytes from participants in the morning to measure BDNF activity. Outcomes were measured at baseline, two weeks after the intervention, and one month after the intervention.

Among patients with Parkinson’s disease, mean age was about 65. Mean disease duration was eight years, and mean UPDRS III score was 46.4. The researchers found no significant differences at baseline between patients randomized to TMS and those randomized to sham.

BDNF-TrkB signaling increased by 29.3% in the sham group and by 36.6% in the TMS group. Both increases were statistically significant, but the difference between groups was not significant. At one month, the cortical silent period was significantly prolonged after TMS, compared with sham. All patients had significant improvement in UPDRS III. Improvements in UPDRS III and TUG were sustained for one month in the TMS group.

Multifocal Stimulation Improved Axial Score

A previous study indicated that low-frequency repetitive TMS over the supplementary motor area (SMA) effectively improves motor symptoms in Parkinson’s disease. Like the SMA, the dorsal premotor cortex (PMd) is involved in motor planning and motor control. Researchers had not previously studied multifocal TMS over both targets, and Dr. Biagioni and colleagues decided to examine this technique.

They conducted a parallel, active-controlled, double-blind, randomized study of four weekly sessions of low-frequency repetitive TMS in 22 patients with Parkinson’s disease. The control group received TMS over the SMA and sham stimulation over the PMd. The experimental group received TMS over both areas. The study outcomes included all components of the UPDRS, as well as UPDRS III axial, tremor, rigidity, and bradykinesia scores. Dr. Biagioni and colleagues assessed patients in the on state at baseline and at four weeks after treatment.

Participants’ mean age was 65, and eight patients were female. Mean disease duration was approximately nine years, mean UPDRS total score was 53.1, and mean UPDRS III score was 35.9. The only significant difference between the control and experimental groups at baseline was Montreal Cognitive Assessment score, which was 24.2 in the control group and 26.4 in the experimental group.

Both interventions were well tolerated. After one month, UPDRS III decreased by 5.5 points in the control group and by 6.5 points in the experimental group. Both changes were statistically significant, but the difference between groups was not significant. The researchers found no difference between groups in total UPDRS and UPDRS III after one month. Axial score significantly decreased in the experimental group, compared with the control group, but the researchers found no significant differences between groups in rigidity, tremor, or bradykinesia scores. In addition, the cortical silent period was significantly prolonged in the experimental group, compared with the control group.

—Erik Greb

Suggested Reading

Chou YH, Hickey PT, Sundman M, et al. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol. 2015;72(4):432-440.

Shirota Y, Ohtsu H, Hamada M, et al. Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology. 2013;80(15):1400-1405.

MIAMI—For patients with Parkinson’s disease, a regime of transcranial magnetic stimulation (TMS) and aerobic exercise results in motor improvements that are sustained for one month, according to a study presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Another study by the same researchers indicates that stimulation of two regions in the premotor associative cortex, compared with stimulation of one region, improves axial symptoms in Parkinson’s disease. Both studies suggest that TMS prolongs the cortical silent period.

TMS Prolonged Cortical Silent Period

Aerobic exercise improves the motor symptoms of Parkinson’s disease. A proposed mechanism for this improvement is the enhancement of brain-derived neurotrophic factor (BDNF) signaling or activity. TMS also improves motor symptoms of Parkinson’s disease, and rat studies indicate that it enhances BDNF-tropomyosin receptor kinase B (TrkB) signaling, which is a biomarker of plasticity.

Milton C. Biagioni, MD, Assistant Professor of Neurology at the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone Health in New York, and colleagues studied differences in BDNF-TrkB signaling between 16 patients with Parkinson’s disease and five healthy controls. Levels of all TrkB signaling biomarkers were significantly higher in healthy controls than in patients with Parkinson’s disease.

Dr. Biagioni and colleagues also investigated the biologic effects, motor outcomes, and physiologic outcomes of repetitive TMS and aerobic exercise in patients with Parkinson’s disease in a randomized, double-blind trial. In this trial, 16 patients with Parkinson’s disease participated in daily 40-minute sessions of aerobic exercise. Participants were randomized 1:1 to receive high-frequency repetitive TMS or sham stimulation over the motor cortex. Patients exercised on a recumbent linear cross trainer.

Motor outcomes included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Timed Up and Go (TUG) test. Neurophysiologic outcomes included the cortical silent period, motor threshold, and paired-associative stimulation (PAS-25). The researchers obtained peripheral blood lymphocytes from participants in the morning to measure BDNF activity. Outcomes were measured at baseline, two weeks after the intervention, and one month after the intervention.

Among patients with Parkinson’s disease, mean age was about 65. Mean disease duration was eight years, and mean UPDRS III score was 46.4. The researchers found no significant differences at baseline between patients randomized to TMS and those randomized to sham.

BDNF-TrkB signaling increased by 29.3% in the sham group and by 36.6% in the TMS group. Both increases were statistically significant, but the difference between groups was not significant. At one month, the cortical silent period was significantly prolonged after TMS, compared with sham. All patients had significant improvement in UPDRS III. Improvements in UPDRS III and TUG were sustained for one month in the TMS group.

Multifocal Stimulation Improved Axial Score

A previous study indicated that low-frequency repetitive TMS over the supplementary motor area (SMA) effectively improves motor symptoms in Parkinson’s disease. Like the SMA, the dorsal premotor cortex (PMd) is involved in motor planning and motor control. Researchers had not previously studied multifocal TMS over both targets, and Dr. Biagioni and colleagues decided to examine this technique.

They conducted a parallel, active-controlled, double-blind, randomized study of four weekly sessions of low-frequency repetitive TMS in 22 patients with Parkinson’s disease. The control group received TMS over the SMA and sham stimulation over the PMd. The experimental group received TMS over both areas. The study outcomes included all components of the UPDRS, as well as UPDRS III axial, tremor, rigidity, and bradykinesia scores. Dr. Biagioni and colleagues assessed patients in the on state at baseline and at four weeks after treatment.

Participants’ mean age was 65, and eight patients were female. Mean disease duration was approximately nine years, mean UPDRS total score was 53.1, and mean UPDRS III score was 35.9. The only significant difference between the control and experimental groups at baseline was Montreal Cognitive Assessment score, which was 24.2 in the control group and 26.4 in the experimental group.

Both interventions were well tolerated. After one month, UPDRS III decreased by 5.5 points in the control group and by 6.5 points in the experimental group. Both changes were statistically significant, but the difference between groups was not significant. The researchers found no difference between groups in total UPDRS and UPDRS III after one month. Axial score significantly decreased in the experimental group, compared with the control group, but the researchers found no significant differences between groups in rigidity, tremor, or bradykinesia scores. In addition, the cortical silent period was significantly prolonged in the experimental group, compared with the control group.

—Erik Greb

Suggested Reading

Chou YH, Hickey PT, Sundman M, et al. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol. 2015;72(4):432-440.

Shirota Y, Ohtsu H, Hamada M, et al. Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology. 2013;80(15):1400-1405.

“Follow your passion” has long been a self-help mantra when it comes to a career. The idea has been that doing what you love will provide the fuel for success. The thinking goes back decades to Richard Bolles’s self-published 1972 classic “What Color is Your Parachute”. The thinking has inspired countless career aspirants, including business titans.

“You’ve got to find what you love. … The only way to do great work is to love what you do. If you haven’t found it yet, keep looking, and don’t settle,” related the late Apple founder Steve Jobs in a commencement address delivered in 2005 at Stanford (Calif.) University. For Mr. Jobs and others over the past 4 decades, the bedrock foundation of a career is passion for the work and dreaming the big dream.

Cal Newport, the author of “So Good They Can’t Ignore You” (New York: Business Plus, 2012), takes the polar opposite view. The job-passion trail has little to do with why most people love the work they do, and can spawn anxiety and a pattern of moving from one job to another, according to Mr. Newport. Rather, passion for the job comes after the hours of hard work that are needed to become really good at something. How the work is done is more important than what the work is.

In “Designing Your Life” (New York: Alfred A. Knopf, 2016), Bill Burnett and Dave Evans go even further, arguing that a career based on passion is usually useless and sometimes dangerous, since many people don’t know what they are passionate about or are passionate about something that is a clunker from a career perspective. Following your passion can lead to chasing pipe dreams.

A better tact might be to insert “interest” instead of “passion” when pondering career choices, according to Crystal Holly, PhD, a clinical psychologist in Ottawa. “Our careers are just one part of our lives, and not always the most important one,” she said in an interview for the article published on the website of the Canadian Broadcasting Corporation (CBC).

Looking at interests more abstractly, rather than setting up a score sheet of definitive career goals, can be helpful, according to career coach Jen Polk, PhD, since that approach can lead to work areas not previously considered, which prove to be satisfying and fulfilling.

The path of job passion worked for Steve Jobs. But it might not be the way for many people.

Click here to read the CBC article.

“Follow your passion” has long been a self-help mantra when it comes to a career. The idea has been that doing what you love will provide the fuel for success. The thinking goes back decades to Richard Bolles’s self-published 1972 classic “What Color is Your Parachute”. The thinking has inspired countless career aspirants, including business titans.

“You’ve got to find what you love. … The only way to do great work is to love what you do. If you haven’t found it yet, keep looking, and don’t settle,” related the late Apple founder Steve Jobs in a commencement address delivered in 2005 at Stanford (Calif.) University. For Mr. Jobs and others over the past 4 decades, the bedrock foundation of a career is passion for the work and dreaming the big dream.

Cal Newport, the author of “So Good They Can’t Ignore You” (New York: Business Plus, 2012), takes the polar opposite view. The job-passion trail has little to do with why most people love the work they do, and can spawn anxiety and a pattern of moving from one job to another, according to Mr. Newport. Rather, passion for the job comes after the hours of hard work that are needed to become really good at something. How the work is done is more important than what the work is.

In “Designing Your Life” (New York: Alfred A. Knopf, 2016), Bill Burnett and Dave Evans go even further, arguing that a career based on passion is usually useless and sometimes dangerous, since many people don’t know what they are passionate about or are passionate about something that is a clunker from a career perspective. Following your passion can lead to chasing pipe dreams.

A better tact might be to insert “interest” instead of “passion” when pondering career choices, according to Crystal Holly, PhD, a clinical psychologist in Ottawa. “Our careers are just one part of our lives, and not always the most important one,” she said in an interview for the article published on the website of the Canadian Broadcasting Corporation (CBC).

Looking at interests more abstractly, rather than setting up a score sheet of definitive career goals, can be helpful, according to career coach Jen Polk, PhD, since that approach can lead to work areas not previously considered, which prove to be satisfying and fulfilling.

The path of job passion worked for Steve Jobs. But it might not be the way for many people.

Click here to read the CBC article.

“Follow your passion” has long been a self-help mantra when it comes to a career. The idea has been that doing what you love will provide the fuel for success. The thinking goes back decades to Richard Bolles’s self-published 1972 classic “What Color is Your Parachute”. The thinking has inspired countless career aspirants, including business titans.

“You’ve got to find what you love. … The only way to do great work is to love what you do. If you haven’t found it yet, keep looking, and don’t settle,” related the late Apple founder Steve Jobs in a commencement address delivered in 2005 at Stanford (Calif.) University. For Mr. Jobs and others over the past 4 decades, the bedrock foundation of a career is passion for the work and dreaming the big dream.

Cal Newport, the author of “So Good They Can’t Ignore You” (New York: Business Plus, 2012), takes the polar opposite view. The job-passion trail has little to do with why most people love the work they do, and can spawn anxiety and a pattern of moving from one job to another, according to Mr. Newport. Rather, passion for the job comes after the hours of hard work that are needed to become really good at something. How the work is done is more important than what the work is.

In “Designing Your Life” (New York: Alfred A. Knopf, 2016), Bill Burnett and Dave Evans go even further, arguing that a career based on passion is usually useless and sometimes dangerous, since many people don’t know what they are passionate about or are passionate about something that is a clunker from a career perspective. Following your passion can lead to chasing pipe dreams.

A better tact might be to insert “interest” instead of “passion” when pondering career choices, according to Crystal Holly, PhD, a clinical psychologist in Ottawa. “Our careers are just one part of our lives, and not always the most important one,” she said in an interview for the article published on the website of the Canadian Broadcasting Corporation (CBC).

Looking at interests more abstractly, rather than setting up a score sheet of definitive career goals, can be helpful, according to career coach Jen Polk, PhD, since that approach can lead to work areas not previously considered, which prove to be satisfying and fulfilling.

The path of job passion worked for Steve Jobs. But it might not be the way for many people.

Click here to read the CBC article.

The Internet can be the antithesis of pondering before doing. “Take a breath,” “count to 10,” and “sleep on it” are all pearls of wisdom meant to keep people from doing or saying something that they will regret later. But the world of Facebook, Twitter, and WhatsApp is rife with rude responses and is a conduit for “virality” – the global dissemination of information.

The information can be silly and harmless. But it also can be false and damaging. A compelling example of the latter is the meddling in the 2016 U.S. presidential election by Russian operatives via Facebook.

The information also can prove lethal. An article in The Economist cites the example of at least two dozen people who were killed in India after stories linking them (falsely) to child abductions went viral on WhatsApp, a messaging service owned by Facebook.

Part of the problem with WhatsApp has been the capability of mass dissemination of a post. Users now are able to forward messages to only 20 others. Since WhatsApp is not fueled by advertiser revenue, a drop in traffic does not affect the financial bottom line. A similar limit on Facebook and Twitter seems harder to envision.

And yet, the move could prove wise, according to the article. “The short-term pain caused by a decline in virality may be in the long-term interest of the social networks. Fake news and concerns about digital addiction, among other things, have already damaged the reputations of tech platforms. Moves to slow sharing could help see off draconian action by regulators and lawmakers,” according to the authors.

More than half the population of the planet uses the Internet. Fostering a climate of honest exchange of information and limiting the spread of malicious information could have a transformative effect.

Click here to read The Economist article.

The Internet can be the antithesis of pondering before doing. “Take a breath,” “count to 10,” and “sleep on it” are all pearls of wisdom meant to keep people from doing or saying something that they will regret later. But the world of Facebook, Twitter, and WhatsApp is rife with rude responses and is a conduit for “virality” – the global dissemination of information.

The information can be silly and harmless. But it also can be false and damaging. A compelling example of the latter is the meddling in the 2016 U.S. presidential election by Russian operatives via Facebook.

The information also can prove lethal. An article in The Economist cites the example of at least two dozen people who were killed in India after stories linking them (falsely) to child abductions went viral on WhatsApp, a messaging service owned by Facebook.

Part of the problem with WhatsApp has been the capability of mass dissemination of a post. Users now are able to forward messages to only 20 others. Since WhatsApp is not fueled by advertiser revenue, a drop in traffic does not affect the financial bottom line. A similar limit on Facebook and Twitter seems harder to envision.

And yet, the move could prove wise, according to the article. “The short-term pain caused by a decline in virality may be in the long-term interest of the social networks. Fake news and concerns about digital addiction, among other things, have already damaged the reputations of tech platforms. Moves to slow sharing could help see off draconian action by regulators and lawmakers,” according to the authors.

More than half the population of the planet uses the Internet. Fostering a climate of honest exchange of information and limiting the spread of malicious information could have a transformative effect.

Click here to read The Economist article.

The Internet can be the antithesis of pondering before doing. “Take a breath,” “count to 10,” and “sleep on it” are all pearls of wisdom meant to keep people from doing or saying something that they will regret later. But the world of Facebook, Twitter, and WhatsApp is rife with rude responses and is a conduit for “virality” – the global dissemination of information.

The information can be silly and harmless. But it also can be false and damaging. A compelling example of the latter is the meddling in the 2016 U.S. presidential election by Russian operatives via Facebook.

The information also can prove lethal. An article in The Economist cites the example of at least two dozen people who were killed in India after stories linking them (falsely) to child abductions went viral on WhatsApp, a messaging service owned by Facebook.

Part of the problem with WhatsApp has been the capability of mass dissemination of a post. Users now are able to forward messages to only 20 others. Since WhatsApp is not fueled by advertiser revenue, a drop in traffic does not affect the financial bottom line. A similar limit on Facebook and Twitter seems harder to envision.

And yet, the move could prove wise, according to the article. “The short-term pain caused by a decline in virality may be in the long-term interest of the social networks. Fake news and concerns about digital addiction, among other things, have already damaged the reputations of tech platforms. Moves to slow sharing could help see off draconian action by regulators and lawmakers,” according to the authors.

More than half the population of the planet uses the Internet. Fostering a climate of honest exchange of information and limiting the spread of malicious information could have a transformative effect.

Click here to read The Economist article.

Nulliparous women who were induced at 39 weeks had the same relative risk of adverse perinatal outcomes but a lower risk of a cesarean delivery, compared with women who received expectant management, results that researchers say contrast traditional recommendations for perinatal care, according to study from the New England Journal of Medicine.

Michele G. Sullivan/Frontline Medical News

“These findings contradict the conclusions of multiple observational studies that have suggested that labor induction is associated with an increased risk of adverse maternal and perinatal outcomes,” William A. Grobman, MD, the Arthur Hale Curtis, MD, Professor of Obstetrics and Gynecology at Northwestern University in Chicago, and his colleagues wrote. “These studies, however, compared women who underwent labor induction with those who had spontaneous labor, which is not a comparison that is useful to guide clinical decision making.”

Dr. Grobman and his colleagues evaluated the deliveries of 3,062 women who underwent labor induction between 39 weeks of gestation and 39 weeks and 4 days of gestation, and compared them with outcomes of 3,044 women who received expectant management until 40 weeks and 5 days of gestation. Women in both groups had a singleton fetus, no indication of early delivery, and did not plan on delivering by C-section. The participants were assessed again at about 38 weeks of gestation and randomly assigned to receive labor induction or expectant management as part of a multicenter randomized, controlled, parallel-group, unmasked trial in 41 maternal-fetal medicine departments in hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development network screened between March 2014, and August 2017.

Primary perinatal outcomes and components were defined as perinatal death, respiratory support, an Apgar score of 3 or less at 5 minutes, hypoxic-ischemic encephalopathy, seizure, infection, meconium aspiration syndrome, birth trauma, intracranial or subgaleal hemorrhage, or hypotension that requires vasopressor support. The principal secondary outcome was cesarean delivery, but other secondary outcomes included neonatal or intensive care, infection, postpartum hospital stay, and hypertension, among others.

Dr. Grobman and his colleagues found 132 (4.3%) of neonates in the induction group and 164 (5.4%) in the expectant-management group experienced a primary composite outcome (relative risk, 0.80; 95% confidence interval, 0.64-1.00; P = .049).

Regarding secondary outcomes, there was a significantly lower risk of cesarean delivery in the induction group, with 18.6% of women undergoing a cesarean delivery, compared with 22.2% of women in the expectant-management group (RR, 0.84; 95% CI, 0.76-0.93; P less than .001). Women in the labor induction group had a significantly lower relative risk of hypertensive disorders of pregnancy (9.1%), compared with the expectant-management (14.1%) group (RR, 0.64; 95% CI, 0.56-0.74; P less than .001). The investigators said women who underwent induced labor had lower 10-point Likert scale scores, were more likely to have “extensions of the uterine incision during cesarean delivery,” perceived they had “more control” during delivery, and had a shorter postpartum stay in the hospital, compared with women who received expectant management. However, women in the induced labor group also had a longer stay in the labor and delivery units, they said.

The researchers noted the limitations in this study, which included its unmasked design, lack of power to detect infrequent outcome differences, and the lack of information surrounding labor induction at 39 weeks in low-risk nulliparous women.

“These results suggest that policies aimed at the avoidance of elective labor induction among low-risk nulliparous women at 39 weeks of gestation are unlikely to reduce the rate of cesarean delivery on a population level; the trial provides information that can be incorporated into discussions that rely on principles of shared decision making,” Dr. Grobman and his colleagues wrote.

This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Silver reports receiving personal fees from Gestavision. The other authors report no relevant financial disclosures.

SOURCE: Grobman WA et al. N Engl J Med. 2018 Aug 9. doi: 10.1056/NEJMoa1800566.

Nulliparous women who were induced at 39 weeks had the same relative risk of adverse perinatal outcomes but a lower risk of a cesarean delivery, compared with women who received expectant management, results that researchers say contrast traditional recommendations for perinatal care, according to study from the New England Journal of Medicine.

Michele G. Sullivan/Frontline Medical News

“These findings contradict the conclusions of multiple observational studies that have suggested that labor induction is associated with an increased risk of adverse maternal and perinatal outcomes,” William A. Grobman, MD, the Arthur Hale Curtis, MD, Professor of Obstetrics and Gynecology at Northwestern University in Chicago, and his colleagues wrote. “These studies, however, compared women who underwent labor induction with those who had spontaneous labor, which is not a comparison that is useful to guide clinical decision making.”

Dr. Grobman and his colleagues evaluated the deliveries of 3,062 women who underwent labor induction between 39 weeks of gestation and 39 weeks and 4 days of gestation, and compared them with outcomes of 3,044 women who received expectant management until 40 weeks and 5 days of gestation. Women in both groups had a singleton fetus, no indication of early delivery, and did not plan on delivering by C-section. The participants were assessed again at about 38 weeks of gestation and randomly assigned to receive labor induction or expectant management as part of a multicenter randomized, controlled, parallel-group, unmasked trial in 41 maternal-fetal medicine departments in hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development network screened between March 2014, and August 2017.

Primary perinatal outcomes and components were defined as perinatal death, respiratory support, an Apgar score of 3 or less at 5 minutes, hypoxic-ischemic encephalopathy, seizure, infection, meconium aspiration syndrome, birth trauma, intracranial or subgaleal hemorrhage, or hypotension that requires vasopressor support. The principal secondary outcome was cesarean delivery, but other secondary outcomes included neonatal or intensive care, infection, postpartum hospital stay, and hypertension, among others.

Dr. Grobman and his colleagues found 132 (4.3%) of neonates in the induction group and 164 (5.4%) in the expectant-management group experienced a primary composite outcome (relative risk, 0.80; 95% confidence interval, 0.64-1.00; P = .049).

Regarding secondary outcomes, there was a significantly lower risk of cesarean delivery in the induction group, with 18.6% of women undergoing a cesarean delivery, compared with 22.2% of women in the expectant-management group (RR, 0.84; 95% CI, 0.76-0.93; P less than .001). Women in the labor induction group had a significantly lower relative risk of hypertensive disorders of pregnancy (9.1%), compared with the expectant-management (14.1%) group (RR, 0.64; 95% CI, 0.56-0.74; P less than .001). The investigators said women who underwent induced labor had lower 10-point Likert scale scores, were more likely to have “extensions of the uterine incision during cesarean delivery,” perceived they had “more control” during delivery, and had a shorter postpartum stay in the hospital, compared with women who received expectant management. However, women in the induced labor group also had a longer stay in the labor and delivery units, they said.

The researchers noted the limitations in this study, which included its unmasked design, lack of power to detect infrequent outcome differences, and the lack of information surrounding labor induction at 39 weeks in low-risk nulliparous women.

“These results suggest that policies aimed at the avoidance of elective labor induction among low-risk nulliparous women at 39 weeks of gestation are unlikely to reduce the rate of cesarean delivery on a population level; the trial provides information that can be incorporated into discussions that rely on principles of shared decision making,” Dr. Grobman and his colleagues wrote.

This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Silver reports receiving personal fees from Gestavision. The other authors report no relevant financial disclosures.

SOURCE: Grobman WA et al. N Engl J Med. 2018 Aug 9. doi: 10.1056/NEJMoa1800566.

Nulliparous women who were induced at 39 weeks had the same relative risk of adverse perinatal outcomes but a lower risk of a cesarean delivery, compared with women who received expectant management, results that researchers say contrast traditional recommendations for perinatal care, according to study from the New England Journal of Medicine.

Michele G. Sullivan/Frontline Medical News

“These findings contradict the conclusions of multiple observational studies that have suggested that labor induction is associated with an increased risk of adverse maternal and perinatal outcomes,” William A. Grobman, MD, the Arthur Hale Curtis, MD, Professor of Obstetrics and Gynecology at Northwestern University in Chicago, and his colleagues wrote. “These studies, however, compared women who underwent labor induction with those who had spontaneous labor, which is not a comparison that is useful to guide clinical decision making.”

Dr. Grobman and his colleagues evaluated the deliveries of 3,062 women who underwent labor induction between 39 weeks of gestation and 39 weeks and 4 days of gestation, and compared them with outcomes of 3,044 women who received expectant management until 40 weeks and 5 days of gestation. Women in both groups had a singleton fetus, no indication of early delivery, and did not plan on delivering by C-section. The participants were assessed again at about 38 weeks of gestation and randomly assigned to receive labor induction or expectant management as part of a multicenter randomized, controlled, parallel-group, unmasked trial in 41 maternal-fetal medicine departments in hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development network screened between March 2014, and August 2017.

Primary perinatal outcomes and components were defined as perinatal death, respiratory support, an Apgar score of 3 or less at 5 minutes, hypoxic-ischemic encephalopathy, seizure, infection, meconium aspiration syndrome, birth trauma, intracranial or subgaleal hemorrhage, or hypotension that requires vasopressor support. The principal secondary outcome was cesarean delivery, but other secondary outcomes included neonatal or intensive care, infection, postpartum hospital stay, and hypertension, among others.

Dr. Grobman and his colleagues found 132 (4.3%) of neonates in the induction group and 164 (5.4%) in the expectant-management group experienced a primary composite outcome (relative risk, 0.80; 95% confidence interval, 0.64-1.00; P = .049).

Regarding secondary outcomes, there was a significantly lower risk of cesarean delivery in the induction group, with 18.6% of women undergoing a cesarean delivery, compared with 22.2% of women in the expectant-management group (RR, 0.84; 95% CI, 0.76-0.93; P less than .001). Women in the labor induction group had a significantly lower relative risk of hypertensive disorders of pregnancy (9.1%), compared with the expectant-management (14.1%) group (RR, 0.64; 95% CI, 0.56-0.74; P less than .001). The investigators said women who underwent induced labor had lower 10-point Likert scale scores, were more likely to have “extensions of the uterine incision during cesarean delivery,” perceived they had “more control” during delivery, and had a shorter postpartum stay in the hospital, compared with women who received expectant management. However, women in the induced labor group also had a longer stay in the labor and delivery units, they said.

The researchers noted the limitations in this study, which included its unmasked design, lack of power to detect infrequent outcome differences, and the lack of information surrounding labor induction at 39 weeks in low-risk nulliparous women.

“These results suggest that policies aimed at the avoidance of elective labor induction among low-risk nulliparous women at 39 weeks of gestation are unlikely to reduce the rate of cesarean delivery on a population level; the trial provides information that can be incorporated into discussions that rely on principles of shared decision making,” Dr. Grobman and his colleagues wrote.

This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Silver reports receiving personal fees from Gestavision. The other authors report no relevant financial disclosures.

SOURCE: Grobman WA et al. N Engl J Med. 2018 Aug 9. doi: 10.1056/NEJMoa1800566.