Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Case Report

A 54-year-old woman presented with a pruritic and slightly painful skin eruption that began perinasally and progressed over 1 week to involve the labial commissures, finger webs, dorsal surfaces of the feet, heels, and bilateral gluteal folds. In addition, the eruption involved the left thigh at the donor site of a prior skin graft. She received no relief after an intramuscular steroid injection and hydrocortisone cream 1% prescribed by a primary care physician who diagnosed the rash as poison ivy contact dermatitis despite no exposure to plants. Review of systems was negative and she denied any new medication use. Her medical history was notable for extensive mesenteric injury secondary to a motor vehicle accident. She subsequently had multiple enterocutaneous fistulas that resulted in a complete small bowel enterectomy 10 months prior to presentation, which caused her to become dependent on total parenteral nutrition (TPN).

Physical examination revealed sharply demarcated, erythematous, scaly plaques perinasally, periorally, and on the bilateral gluteal folds (Figure 1). There were sharply demarcated, erythematous, scaly plaques on the right and left finger webs, dorsal surface of the right foot, and left upper thigh. Hemorrhagic bullae were appreciated on the left finger webs. Large flaccid bullae were present on the bilateral heels and dorsum of the right foot (Figure 2).

Suspecting a diagnosis of acrodermatitis enteropathica (AE), laboratory testing included a serum zinc level, which was 42 µg/dL (reference range, 70–130 µg/dL). The copper and selenium levels also were low with values of 71 µg/dL (reference range, 80–155 µg/dL) and 31 µg/dL (reference range, 79–326 µg/dL), respectively. No additional vitamin or mineral deficiencies were discovered. A complete blood cell count and comprehensive metabolic panel were performed and showed no abnormalities other than a mildly elevated sodium level of 147 mEq/L (reference range, 136–142 mEq/L).

A punch biopsy was performed. Histopathology revealed subcorneal neutrophils and neutrophilic crust, mild spongiosis, and a dense upper dermal mixed neutrophilic and lymphohistiocytic infiltrate. The specimen also exhibited mild intercellular edema and prominent capillaries (Figure 3).

After further investigation, the company providing the patient’s TPN confirmed that zinc had been removed several weeks prior to the onset of symptoms due to a critical national shortage of trace element additives. Zinc was supplemented at 15 mg daily to the TPN solution. Three days later a skin examination revealed dramatic changes with notable improvement of the finger web plaques and complete resolution of the facial lesions. The plaques and bullae on the lower extremities also had resolved (Figure 4).

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.

Long-term use of statins may protect against lethal forms of prostate cancer by altering the inflammatory profile of the tumor microenvironment. Also today, Verma unveils Medicaid scorecard but refuses to judge efforts, the AMA reports that opioid prescriptions are down since 2013, and a prior knee injury creates a ‘distinct group’ in osteoarthritis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Long-term use of statins may protect against lethal forms of prostate cancer by altering the inflammatory profile of the tumor microenvironment. Also today, Verma unveils Medicaid scorecard but refuses to judge efforts, the AMA reports that opioid prescriptions are down since 2013, and a prior knee injury creates a ‘distinct group’ in osteoarthritis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Long-term use of statins may protect against lethal forms of prostate cancer by altering the inflammatory profile of the tumor microenvironment. Also today, Verma unveils Medicaid scorecard but refuses to judge efforts, the AMA reports that opioid prescriptions are down since 2013, and a prior knee injury creates a ‘distinct group’ in osteoarthritis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Case Report

A 25-year-old man who was a dairy farmer in Ahmednagar, Maharashtra, India, presented with a history of slowly growing, occasionally itchy lesions on both cheeks of 20 years’ duration. Most of the right cheek was covered by a well-defined, lobulated, gray-brown verrucous mass with a cerebriform surface (Figure 1). The left cheek was covered with a gray-brown infiltrated plaque surrounded by brown-tinged monomorphic papules.

Routine investigations were normal at presentation. Tests for purified protein derivative (tuberculin) and antibodies to human immunodeficiency virus were negative. Magnetic resonance imaging of the head showed soft tissue thickening with ulcerations involving the skin, subcutaneous tissue, and underlying facial muscles of the right cheek.

On histopathology, a hematoxylin and eosin–stained section showed hyperkeratosis, parakeratosis, pseudoepitheliomatous hyperplasia, and follicular plugs in the epidermis, as well as a mixed cellular infiltrate with Langhans giant cells and sclerotic bodies in the dermis (Figure 2). Periodic acid–Schiff and methenamine silver special stains revealed sclerotic bodies.

Fungal culture on Sabouraud dextrose agar at 25°C and 37°C grew olive green, rugose, velvety, leathery colonies within 48 hours, with pigmentation front and reverse (Figure 3). A panfungal polymerase chain reaction assay was positive. Direct microscopic examination of a 10% potassium hydroxide mount of the colonies showed mycelia with dematiaceous septate hyphae (Figure 4), apical branching, branching conidiophores, elliptical conidia in long chains, and pathognomonic round yeastlike bodies resembling copper pennies known as sclerotic cells (also called muriform cells and medlar bodies).^1,2 The causative organism was identified as Cladosporium carrionii. A final diagnosis of chromoblastomycosis was made.

After 2 months of treatment with oral itraconazole 400 mg daily, there was no notable clinical improvement and fungal elements were still seen on culture. Four treatment cycles of intravenous liposomal amphotericin B 50 mg daily (1 mg/kg daily) for 15 days followed by itraconazole 200 mg daily for another 15 days caused substantial reduction and flattening of the lesion on the right side and resolution of the lesions on the left side. Healing was accompanied by central erythema and depigmentation (Figure 5). With a suspicion of continuing C carrionii activity on the right cheek, intralesional liposomal amphotericin B 0.2 mL (in a dilution of 5 mg in 1 mL) was given weekly in the peripheral hyperpigmented raised margin, which resulted in further flattening and reduction in tissue resistance. Fungal elements were absent on repeat biopsy and culture after 4 weeks.

Six months after negative culture, further cosmetic correction of the scar on the right cheek was performed with a patterned full-thickness graft for the upper half and excision with approximation of the edges for the lower half (Figure 6). Cultures have been negative for the last 20 months; as of this writing, there has been no recurrence of lesions.

Comment

Distribution
Chromoblastomycosis, also known as chromomycosis and verrucous dermatitis,³ is a chronic subcutaneous mycosis found in tropical and subtropical regions.^3,4 It is caused by traumatic inoculation of any of several members of a specific group of dematiaceous fungi through the skin.^2,3 Common causative organisms include Fonsecaea pedrosoi, C carrionii, Fonsecaea compacta, and Phialophora verrucosa, all of which are saprophytes in soil and plants. Fonsecaea pedrosoi is the most common causative agent worldwide (70%–90% of cases).²Cladosporium carrionii tends to be the predominant pathogen isolated in patients who present in drier climates, with F pedrosoi in humid forests.^1-4

In India, chromoblastomycosis has been reported from the sub-Himalayan belt and western and eastern coasts.^1,5 Our patient resided in Ahmednagar, Maharashtra, India, which has a predominantly hot and dry climate. The history might include vegetational trauma, such as a thorn prick. Time between inoculation and development of disease is believed to be years.

Clinical Presentation
Chromoblastomycosis is characterized by a slowly enlarging lesion at the site of inoculation. Five morphological variants are known: nodular, tumoral, verrucous, plaque, and cicatricial; verrucous and nodular types are most common.^3,4

The disease is limited to the skin and subcutaneous tissue, growing in extent rather than in depth and not directly invading muscle or bone.⁴ Lymphatic and hematogenous dissemination can occur.^3,4 Secondary bacterial infection is common. The most common affected site is the lower limb, especially the foot.^1,3 The upper limb and rarely the ear, trunk, face, and breast can be affected.

Diagnosis
Routine laboratory investigations are usually within reference range. Diagnosis is made by histopathological and mycological studies. Preferably, scrapings or biopsy material are taken from lesions that are covered with what is described as “black dots” (an area of transepidermal elimination of the fungus) where there is a better diagnostic yield.^2-4 Routine histopathology shows hyperkeratosis, pseudoepitheliomatous hyperplasia of the epidermis, a mixed granulomatous neutrophil response with multinucleated giant cells and neutrophil abscesses, refractile fungal spores, typical sclerotic cells around abscesses or granulomas, and a dense fibrous response in the dermis and subcutaneous tissue.

Extensive fibrosis, coupled with a chronic inflammatory infiltrate and increased susceptibility to secondary infection, leads to obstruction of lymphatic flow and lymphedema below the affected site.^2-4 Periodic acid–Schiff and Gomori methenamine silver stains confirm the presence of fungus. Direct microscopic examination of a 10% potassium hydroxide mount of scrapings reveals spherical, thick-walled, darkly pigmented, multiseptate sclerotic cells known as medlar bodies, copper pennies, and muriform cells that are pathognomonic for chromoblastomycosis.^1-4Cladosporium carrionii culture on Sabouraud dextrose agar at 37°C shows olive green, dark, rugose, smooth, hairy, leathery or velvety colonies with pigmentation front and reverse. Direct microscopic examination of the colonies shows dematiaceous septate hyphae and sparsely branching conidiophores bearing ellipsoidal, smooth-walled conidia in long acropetal chains.^1,4

Treatment
Treatment options for chromoblastomycosis can be divided into antifungal agents and physical methods.Antifungal agents include itraconazole (200–400 mg daily),³ terbinafine (250–500 mg daily),³ 5-fluorocytosine (100–150 mg/kg daily),³ amphotericin B (intravenous/intralesional), and others (eg, fluconazole, ketoconazole, posaconazole [800 mg daily],^6,7 potassium iodide, voriconazole). Physical methods include CO₂ laser, cryosurgery, local heat therapy, Mohs micrographic surgery, and standard surgery.³ There is no evidence-based treatment protocol. Itraconazole and terbinafine are considered drugs of first choice^1,8; however, combination therapy is the best option.⁹

Case Report

A 25-year-old man who was a dairy farmer in Ahmednagar, Maharashtra, India, presented with a history of slowly growing, occasionally itchy lesions on both cheeks of 20 years’ duration. Most of the right cheek was covered by a well-defined, lobulated, gray-brown verrucous mass with a cerebriform surface (Figure 1). The left cheek was covered with a gray-brown infiltrated plaque surrounded by brown-tinged monomorphic papules.

Routine investigations were normal at presentation. Tests for purified protein derivative (tuberculin) and antibodies to human immunodeficiency virus were negative. Magnetic resonance imaging of the head showed soft tissue thickening with ulcerations involving the skin, subcutaneous tissue, and underlying facial muscles of the right cheek.

On histopathology, a hematoxylin and eosin–stained section showed hyperkeratosis, parakeratosis, pseudoepitheliomatous hyperplasia, and follicular plugs in the epidermis, as well as a mixed cellular infiltrate with Langhans giant cells and sclerotic bodies in the dermis (Figure 2). Periodic acid–Schiff and methenamine silver special stains revealed sclerotic bodies.

Fungal culture on Sabouraud dextrose agar at 25°C and 37°C grew olive green, rugose, velvety, leathery colonies within 48 hours, with pigmentation front and reverse (Figure 3). A panfungal polymerase chain reaction assay was positive. Direct microscopic examination of a 10% potassium hydroxide mount of the colonies showed mycelia with dematiaceous septate hyphae (Figure 4), apical branching, branching conidiophores, elliptical conidia in long chains, and pathognomonic round yeastlike bodies resembling copper pennies known as sclerotic cells (also called muriform cells and medlar bodies).^1,2 The causative organism was identified as Cladosporium carrionii. A final diagnosis of chromoblastomycosis was made.

After 2 months of treatment with oral itraconazole 400 mg daily, there was no notable clinical improvement and fungal elements were still seen on culture. Four treatment cycles of intravenous liposomal amphotericin B 50 mg daily (1 mg/kg daily) for 15 days followed by itraconazole 200 mg daily for another 15 days caused substantial reduction and flattening of the lesion on the right side and resolution of the lesions on the left side. Healing was accompanied by central erythema and depigmentation (Figure 5). With a suspicion of continuing C carrionii activity on the right cheek, intralesional liposomal amphotericin B 0.2 mL (in a dilution of 5 mg in 1 mL) was given weekly in the peripheral hyperpigmented raised margin, which resulted in further flattening and reduction in tissue resistance. Fungal elements were absent on repeat biopsy and culture after 4 weeks.

Six months after negative culture, further cosmetic correction of the scar on the right cheek was performed with a patterned full-thickness graft for the upper half and excision with approximation of the edges for the lower half (Figure 6). Cultures have been negative for the last 20 months; as of this writing, there has been no recurrence of lesions.

Comment

Distribution
Chromoblastomycosis, also known as chromomycosis and verrucous dermatitis,³ is a chronic subcutaneous mycosis found in tropical and subtropical regions.^3,4 It is caused by traumatic inoculation of any of several members of a specific group of dematiaceous fungi through the skin.^2,3 Common causative organisms include Fonsecaea pedrosoi, C carrionii, Fonsecaea compacta, and Phialophora verrucosa, all of which are saprophytes in soil and plants. Fonsecaea pedrosoi is the most common causative agent worldwide (70%–90% of cases).²Cladosporium carrionii tends to be the predominant pathogen isolated in patients who present in drier climates, with F pedrosoi in humid forests.^1-4

In India, chromoblastomycosis has been reported from the sub-Himalayan belt and western and eastern coasts.^1,5 Our patient resided in Ahmednagar, Maharashtra, India, which has a predominantly hot and dry climate. The history might include vegetational trauma, such as a thorn prick. Time between inoculation and development of disease is believed to be years.

Clinical Presentation
Chromoblastomycosis is characterized by a slowly enlarging lesion at the site of inoculation. Five morphological variants are known: nodular, tumoral, verrucous, plaque, and cicatricial; verrucous and nodular types are most common.^3,4

The disease is limited to the skin and subcutaneous tissue, growing in extent rather than in depth and not directly invading muscle or bone.⁴ Lymphatic and hematogenous dissemination can occur.^3,4 Secondary bacterial infection is common. The most common affected site is the lower limb, especially the foot.^1,3 The upper limb and rarely the ear, trunk, face, and breast can be affected.

Diagnosis
Routine laboratory investigations are usually within reference range. Diagnosis is made by histopathological and mycological studies. Preferably, scrapings or biopsy material are taken from lesions that are covered with what is described as “black dots” (an area of transepidermal elimination of the fungus) where there is a better diagnostic yield.^2-4 Routine histopathology shows hyperkeratosis, pseudoepitheliomatous hyperplasia of the epidermis, a mixed granulomatous neutrophil response with multinucleated giant cells and neutrophil abscesses, refractile fungal spores, typical sclerotic cells around abscesses or granulomas, and a dense fibrous response in the dermis and subcutaneous tissue.

Extensive fibrosis, coupled with a chronic inflammatory infiltrate and increased susceptibility to secondary infection, leads to obstruction of lymphatic flow and lymphedema below the affected site.^2-4 Periodic acid–Schiff and Gomori methenamine silver stains confirm the presence of fungus. Direct microscopic examination of a 10% potassium hydroxide mount of scrapings reveals spherical, thick-walled, darkly pigmented, multiseptate sclerotic cells known as medlar bodies, copper pennies, and muriform cells that are pathognomonic for chromoblastomycosis.^1-4Cladosporium carrionii culture on Sabouraud dextrose agar at 37°C shows olive green, dark, rugose, smooth, hairy, leathery or velvety colonies with pigmentation front and reverse. Direct microscopic examination of the colonies shows dematiaceous septate hyphae and sparsely branching conidiophores bearing ellipsoidal, smooth-walled conidia in long acropetal chains.^1,4

Treatment
Treatment options for chromoblastomycosis can be divided into antifungal agents and physical methods.Antifungal agents include itraconazole (200–400 mg daily),³ terbinafine (250–500 mg daily),³ 5-fluorocytosine (100–150 mg/kg daily),³ amphotericin B (intravenous/intralesional), and others (eg, fluconazole, ketoconazole, posaconazole [800 mg daily],^6,7 potassium iodide, voriconazole). Physical methods include CO₂ laser, cryosurgery, local heat therapy, Mohs micrographic surgery, and standard surgery.³ There is no evidence-based treatment protocol. Itraconazole and terbinafine are considered drugs of first choice^1,8; however, combination therapy is the best option.⁹

Case Report

A 25-year-old man who was a dairy farmer in Ahmednagar, Maharashtra, India, presented with a history of slowly growing, occasionally itchy lesions on both cheeks of 20 years’ duration. Most of the right cheek was covered by a well-defined, lobulated, gray-brown verrucous mass with a cerebriform surface (Figure 1). The left cheek was covered with a gray-brown infiltrated plaque surrounded by brown-tinged monomorphic papules.

Routine investigations were normal at presentation. Tests for purified protein derivative (tuberculin) and antibodies to human immunodeficiency virus were negative. Magnetic resonance imaging of the head showed soft tissue thickening with ulcerations involving the skin, subcutaneous tissue, and underlying facial muscles of the right cheek.

On histopathology, a hematoxylin and eosin–stained section showed hyperkeratosis, parakeratosis, pseudoepitheliomatous hyperplasia, and follicular plugs in the epidermis, as well as a mixed cellular infiltrate with Langhans giant cells and sclerotic bodies in the dermis (Figure 2). Periodic acid–Schiff and methenamine silver special stains revealed sclerotic bodies.

Fungal culture on Sabouraud dextrose agar at 25°C and 37°C grew olive green, rugose, velvety, leathery colonies within 48 hours, with pigmentation front and reverse (Figure 3). A panfungal polymerase chain reaction assay was positive. Direct microscopic examination of a 10% potassium hydroxide mount of the colonies showed mycelia with dematiaceous septate hyphae (Figure 4), apical branching, branching conidiophores, elliptical conidia in long chains, and pathognomonic round yeastlike bodies resembling copper pennies known as sclerotic cells (also called muriform cells and medlar bodies).^1,2 The causative organism was identified as Cladosporium carrionii. A final diagnosis of chromoblastomycosis was made.

After 2 months of treatment with oral itraconazole 400 mg daily, there was no notable clinical improvement and fungal elements were still seen on culture. Four treatment cycles of intravenous liposomal amphotericin B 50 mg daily (1 mg/kg daily) for 15 days followed by itraconazole 200 mg daily for another 15 days caused substantial reduction and flattening of the lesion on the right side and resolution of the lesions on the left side. Healing was accompanied by central erythema and depigmentation (Figure 5). With a suspicion of continuing C carrionii activity on the right cheek, intralesional liposomal amphotericin B 0.2 mL (in a dilution of 5 mg in 1 mL) was given weekly in the peripheral hyperpigmented raised margin, which resulted in further flattening and reduction in tissue resistance. Fungal elements were absent on repeat biopsy and culture after 4 weeks.

Six months after negative culture, further cosmetic correction of the scar on the right cheek was performed with a patterned full-thickness graft for the upper half and excision with approximation of the edges for the lower half (Figure 6). Cultures have been negative for the last 20 months; as of this writing, there has been no recurrence of lesions.

Comment

Distribution
Chromoblastomycosis, also known as chromomycosis and verrucous dermatitis,³ is a chronic subcutaneous mycosis found in tropical and subtropical regions.^3,4 It is caused by traumatic inoculation of any of several members of a specific group of dematiaceous fungi through the skin.^2,3 Common causative organisms include Fonsecaea pedrosoi, C carrionii, Fonsecaea compacta, and Phialophora verrucosa, all of which are saprophytes in soil and plants. Fonsecaea pedrosoi is the most common causative agent worldwide (70%–90% of cases).²Cladosporium carrionii tends to be the predominant pathogen isolated in patients who present in drier climates, with F pedrosoi in humid forests.^1-4

In India, chromoblastomycosis has been reported from the sub-Himalayan belt and western and eastern coasts.^1,5 Our patient resided in Ahmednagar, Maharashtra, India, which has a predominantly hot and dry climate. The history might include vegetational trauma, such as a thorn prick. Time between inoculation and development of disease is believed to be years.

Clinical Presentation
Chromoblastomycosis is characterized by a slowly enlarging lesion at the site of inoculation. Five morphological variants are known: nodular, tumoral, verrucous, plaque, and cicatricial; verrucous and nodular types are most common.^3,4

The disease is limited to the skin and subcutaneous tissue, growing in extent rather than in depth and not directly invading muscle or bone.⁴ Lymphatic and hematogenous dissemination can occur.^3,4 Secondary bacterial infection is common. The most common affected site is the lower limb, especially the foot.^1,3 The upper limb and rarely the ear, trunk, face, and breast can be affected.

Diagnosis
Routine laboratory investigations are usually within reference range. Diagnosis is made by histopathological and mycological studies. Preferably, scrapings or biopsy material are taken from lesions that are covered with what is described as “black dots” (an area of transepidermal elimination of the fungus) where there is a better diagnostic yield.^2-4 Routine histopathology shows hyperkeratosis, pseudoepitheliomatous hyperplasia of the epidermis, a mixed granulomatous neutrophil response with multinucleated giant cells and neutrophil abscesses, refractile fungal spores, typical sclerotic cells around abscesses or granulomas, and a dense fibrous response in the dermis and subcutaneous tissue.

Extensive fibrosis, coupled with a chronic inflammatory infiltrate and increased susceptibility to secondary infection, leads to obstruction of lymphatic flow and lymphedema below the affected site.^2-4 Periodic acid–Schiff and Gomori methenamine silver stains confirm the presence of fungus. Direct microscopic examination of a 10% potassium hydroxide mount of scrapings reveals spherical, thick-walled, darkly pigmented, multiseptate sclerotic cells known as medlar bodies, copper pennies, and muriform cells that are pathognomonic for chromoblastomycosis.^1-4Cladosporium carrionii culture on Sabouraud dextrose agar at 37°C shows olive green, dark, rugose, smooth, hairy, leathery or velvety colonies with pigmentation front and reverse. Direct microscopic examination of the colonies shows dematiaceous septate hyphae and sparsely branching conidiophores bearing ellipsoidal, smooth-walled conidia in long acropetal chains.^1,4

Treatment
Treatment options for chromoblastomycosis can be divided into antifungal agents and physical methods.Antifungal agents include itraconazole (200–400 mg daily),³ terbinafine (250–500 mg daily),³ 5-fluorocytosine (100–150 mg/kg daily),³ amphotericin B (intravenous/intralesional), and others (eg, fluconazole, ketoconazole, posaconazole [800 mg daily],^6,7 potassium iodide, voriconazole). Physical methods include CO₂ laser, cryosurgery, local heat therapy, Mohs micrographic surgery, and standard surgery.³ There is no evidence-based treatment protocol. Itraconazole and terbinafine are considered drugs of first choice^1,8; however, combination therapy is the best option.⁹

Parents’ disapproval of marijuana use has dropped since 1979 – at least that’s what their teenage children say, according to results of the 2017 Monitoring the Future survey.

The approximately 13,500 12th graders involved in the 2017 survey believe that their parents are much less likely to disapprove of marijuana use, compared with the students who responded to the survey during 1976-1979. At that time, 15% of the 12th graders said that their parents would not disapprove of using marijuana once or twice, but by 2017 the number had made a statistically significant rise to 23%, Richard A. Miech, PhD, and his associates said in their report on the 2017 survey.

Perceived approval of occasional marijuana use, which had garnered only an 8% share of respondents in 1976-1979, was up to a significantly higher 17% in 2017, and regular use went from 4% to 13%, said Dr. Miech and his associates, of the University of Michigan Institute for Social Research, Ann Arbor.

Parents’ increased acceptance of marijuana, as perceived by the 12th-grade students, was not matched for other substances. Disapproval for smoking one or more packs of cigarettes a day, for example, climbed from 89% in 1976-1979 to 92% in 2017, while disapproval of weekend binge drinking rose just a bit, going from 85% to 86%, they said.

[email protected]

Parents’ disapproval of marijuana use has dropped since 1979 – at least that’s what their teenage children say, according to results of the 2017 Monitoring the Future survey.

The approximately 13,500 12th graders involved in the 2017 survey believe that their parents are much less likely to disapprove of marijuana use, compared with the students who responded to the survey during 1976-1979. At that time, 15% of the 12th graders said that their parents would not disapprove of using marijuana once or twice, but by 2017 the number had made a statistically significant rise to 23%, Richard A. Miech, PhD, and his associates said in their report on the 2017 survey.

Perceived approval of occasional marijuana use, which had garnered only an 8% share of respondents in 1976-1979, was up to a significantly higher 17% in 2017, and regular use went from 4% to 13%, said Dr. Miech and his associates, of the University of Michigan Institute for Social Research, Ann Arbor.

Parents’ increased acceptance of marijuana, as perceived by the 12th-grade students, was not matched for other substances. Disapproval for smoking one or more packs of cigarettes a day, for example, climbed from 89% in 1976-1979 to 92% in 2017, while disapproval of weekend binge drinking rose just a bit, going from 85% to 86%, they said.

[email protected]

Parents’ disapproval of marijuana use has dropped since 1979 – at least that’s what their teenage children say, according to results of the 2017 Monitoring the Future survey.

The approximately 13,500 12th graders involved in the 2017 survey believe that their parents are much less likely to disapprove of marijuana use, compared with the students who responded to the survey during 1976-1979. At that time, 15% of the 12th graders said that their parents would not disapprove of using marijuana once or twice, but by 2017 the number had made a statistically significant rise to 23%, Richard A. Miech, PhD, and his associates said in their report on the 2017 survey.

Perceived approval of occasional marijuana use, which had garnered only an 8% share of respondents in 1976-1979, was up to a significantly higher 17% in 2017, and regular use went from 4% to 13%, said Dr. Miech and his associates, of the University of Michigan Institute for Social Research, Ann Arbor.

Parents’ increased acceptance of marijuana, as perceived by the 12th-grade students, was not matched for other substances. Disapproval for smoking one or more packs of cigarettes a day, for example, climbed from 89% in 1976-1979 to 92% in 2017, while disapproval of weekend binge drinking rose just a bit, going from 85% to 86%, they said.

[email protected]

©ASCO/Rodney White 2018

CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.

“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.

Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.

Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).

Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).

“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.

Mivebresib (NCT02391480)

Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.

Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.

The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.

Bemcentinib (NCT02488408)

Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).

For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.

In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.

Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.

Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.

“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said. 

*Data presented at the meeting differ from the abstracts.

©ASCO/Rodney White 2018

CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.

“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.

Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.

Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).

Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).

“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.

Mivebresib (NCT02391480)

Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.

Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.

The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.

Bemcentinib (NCT02488408)

Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).

For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.

In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.

Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.

Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.

“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said. 

*Data presented at the meeting differ from the abstracts.

©ASCO/Rodney White 2018

CHICAGO—Two agents targeting novel pathways in myeloid malignancies—mivebresib and bencentinib—are showing promise in early studies, according to a speaker at the 2018 ASCO Annual Meeting.

“Both BET and AXL inhibition appear to be new and exciting targets in myeloid malignancies,” said Alice S. Mims, MD, and both have produced responses as single agents.

Dr Mims, of Ohio State University Wexner Medical Center in Columbus, made these observations in a poster discussion presentation that included commentary on the two agents.

Mivebresib (ABBV-075), an inhibitor of bromodomain and extra terminal (BET) proteins, yielded some responses in relapsed/refractory acute myeloid leukemia (AML) patients in a first-in-human study presented at the meeting (abstract 7019*).

Bemcentinib (BGB324), a first-in class selective inhibitor of the AXL tyrosine kinase, also showed activity in preliminary results of a study including patients with relapsed/refractory disease (abstract 7020*).

“It will be important to know individual patient characteristics to determine the potential response predictors,” Dr Mims said.

Mivebresib (NCT02391480)

Mivebresib is the subject of an ongoing phase 1 dose-escalation study in which 23 patients have been treated. That includes 12 who received the BET inhibitor as monotherapy, and 11 who got it in combination with the BCL-2 inhibitor venetoclax, which is indicated in CLL and has breakthrough therapy designation for AML.

Investigators observed responses in 3 of 17 evaluable patients (17.6%), including 1 complete remission with incomplete blood count recovery in a patient on mivebresib monotherapy, plus 1 partial response and 1 patient achieving a morphologic leukemia-free state with the combination.

The most common grade 3/4 treatment-emergent adverse events included anemia in 52%, thrombocytopenia in 44%, and febrile neutropenia in 26% of patients, with no dose-limiting toxicities noted as of this report.

Bemcentinib (NCT02488408)

Bemcentinib is being evaluated in a phase 1/2 trial including patients with relapsed/refractory AML and myelodysplastic syndromes (MDS).

For 32 patients treated so far, 3 patients achieved a complete remission, including 1 AML and 2 MDS patients.

In addition, 3 patients achieved partial response, including 1 MDS and 2 AML patients.

Treatment with bemcentinib was generally well-tolerated, and most adverse events were mild or moderate, investigators reported in their poster.

Pre-treatment levels of soluble AXL were lower in responders compared with non-responders, investigators also noted.

“Soluble AXL levels may be a predictive biomarker for AXL inhibition, but further assessment is necessary,” Dr Mims said. 

*Data presented at the meeting differ from the abstracts.

By Crystal (Crystl) from Bloomington, USA - Flickr

The US Food and Drug Administration (FDA) has granted priority review for emicizumab (Hemlibra®) for adults and children with hemophilia A without factor VIII inhibitors.

Earlier this year, the agency awarded emicizumab breakthrough therapy designation for the same population.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody approved by the FDA for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A with factor VIII inhibitors.

The FDA based its decision to grant emicizumab priority review on the phase 3 HAVEN 3 study, results of which were presented recently at the World Federation of Hemophilia congress.

In HAVEN 3, emicizumab demonstrated a 68% reduction (P<0.0001) in treated bleeds based on an intra-patient comparison in patients who were previously enrolled in a prospective non-interventional study.

According to Genentech, co-developer of the drug, this makes emicizumab the first medicine to show superior efficacy to prior treatment with factor VIII prophylaxis, the current standard of care for people with hemophilia A without factor VIII inhibitors.

About HAVEN 3

The randomized, multicenter, open-label trial evaluated prophylaxis versus no prophylaxis in patients without factor VIII inhibitors.

The study included 152 patients 12 years or older who were previously treated with factor VIII therapy on-demand or as prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to 1 of 3 treatment groups:

• Arm A received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study.
• Arm B received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks.
• Arm C received no prophylaxis

Patients previously treated prophylactically with factor VIII were enrolled in Arm D and received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study.

The protocol permitted episodic treatment of breakthrough bleeds with factor VIII therapy.

Patients in the prophylaxis groups achieved a 96% (P<0.0001) and 97% (P<0.0001) reduction in treated bleeds, respectively, compared to those who received no prophylaxis.

Additionally, 55.6% of patients treated weekly and 60% treated every 2 weeks had no treated bleeds. In contrast, 0% in the prophylaxis group achieved zero treated bleeds.

Investigators observed no unexpected or serious adverse events (AEs), no thrombotic events, and no cases of thrombotic microangiopathy.

The most common AEs occurring in 5% or more of patients were injection site reactions, arthralgia, nasopharyngitis, headache, upper respiratory tract infection, and influenza.

The FDA is expected to make a decision regarding approval by October 4. 

By Crystal (Crystl) from Bloomington, USA - Flickr

The US Food and Drug Administration (FDA) has granted priority review for emicizumab (Hemlibra®) for adults and children with hemophilia A without factor VIII inhibitors.

Earlier this year, the agency awarded emicizumab breakthrough therapy designation for the same population.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody approved by the FDA for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A with factor VIII inhibitors.

The FDA based its decision to grant emicizumab priority review on the phase 3 HAVEN 3 study, results of which were presented recently at the World Federation of Hemophilia congress.

In HAVEN 3, emicizumab demonstrated a 68% reduction (P<0.0001) in treated bleeds based on an intra-patient comparison in patients who were previously enrolled in a prospective non-interventional study.

According to Genentech, co-developer of the drug, this makes emicizumab the first medicine to show superior efficacy to prior treatment with factor VIII prophylaxis, the current standard of care for people with hemophilia A without factor VIII inhibitors.

About HAVEN 3

The randomized, multicenter, open-label trial evaluated prophylaxis versus no prophylaxis in patients without factor VIII inhibitors.

The study included 152 patients 12 years or older who were previously treated with factor VIII therapy on-demand or as prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to 1 of 3 treatment groups:

• Arm A received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study.
• Arm B received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks.
• Arm C received no prophylaxis

Patients previously treated prophylactically with factor VIII were enrolled in Arm D and received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study.

The protocol permitted episodic treatment of breakthrough bleeds with factor VIII therapy.

Patients in the prophylaxis groups achieved a 96% (P<0.0001) and 97% (P<0.0001) reduction in treated bleeds, respectively, compared to those who received no prophylaxis.

Additionally, 55.6% of patients treated weekly and 60% treated every 2 weeks had no treated bleeds. In contrast, 0% in the prophylaxis group achieved zero treated bleeds.

Investigators observed no unexpected or serious adverse events (AEs), no thrombotic events, and no cases of thrombotic microangiopathy.

The most common AEs occurring in 5% or more of patients were injection site reactions, arthralgia, nasopharyngitis, headache, upper respiratory tract infection, and influenza.

The FDA is expected to make a decision regarding approval by October 4. 

By Crystal (Crystl) from Bloomington, USA - Flickr

The US Food and Drug Administration (FDA) has granted priority review for emicizumab (Hemlibra®) for adults and children with hemophilia A without factor VIII inhibitors.

Earlier this year, the agency awarded emicizumab breakthrough therapy designation for the same population.

Emicizumab is a bispecific factor IXa- and factor X-directed antibody approved by the FDA for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children who have hemophilia A with factor VIII inhibitors.

The FDA based its decision to grant emicizumab priority review on the phase 3 HAVEN 3 study, results of which were presented recently at the World Federation of Hemophilia congress.

In HAVEN 3, emicizumab demonstrated a 68% reduction (P<0.0001) in treated bleeds based on an intra-patient comparison in patients who were previously enrolled in a prospective non-interventional study.

According to Genentech, co-developer of the drug, this makes emicizumab the first medicine to show superior efficacy to prior treatment with factor VIII prophylaxis, the current standard of care for people with hemophilia A without factor VIII inhibitors.

About HAVEN 3

The randomized, multicenter, open-label trial evaluated prophylaxis versus no prophylaxis in patients without factor VIII inhibitors.

The study included 152 patients 12 years or older who were previously treated with factor VIII therapy on-demand or as prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to 1 of 3 treatment groups:

• Arm A received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study.
• Arm B received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks.
• Arm C received no prophylaxis

Patients previously treated prophylactically with factor VIII were enrolled in Arm D and received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study.

The protocol permitted episodic treatment of breakthrough bleeds with factor VIII therapy.

Patients in the prophylaxis groups achieved a 96% (P<0.0001) and 97% (P<0.0001) reduction in treated bleeds, respectively, compared to those who received no prophylaxis.

Additionally, 55.6% of patients treated weekly and 60% treated every 2 weeks had no treated bleeds. In contrast, 0% in the prophylaxis group achieved zero treated bleeds.

Investigators observed no unexpected or serious adverse events (AEs), no thrombotic events, and no cases of thrombotic microangiopathy.

The most common AEs occurring in 5% or more of patients were injection site reactions, arthralgia, nasopharyngitis, headache, upper respiratory tract infection, and influenza.

The FDA is expected to make a decision regarding approval by October 4. 

The FP recognized the lesion as a linear epidermal nevus.

Epidermal nevi (EN) are congenital hamartomas of ectodermal origin that are uncommon (occurring in < 1% of newborns and children), sporadic, and usually present at birth, although they can appear in early childhood. EN are associated with disorders of the eye, nervous system, and musculoskeletal system in 10% to 30% of patients.

EN are linear, round or oblong, well circumscribed, elevated, and flat topped. EN are often yellow-tan to dark brown in color, with a surface that is uniformly velvety or warty. They most commonly occur on the head and neck, although they can occur on the trunk and proximal extremities.

The FP determined that the patient had no neurological, musculoskeletal, or vision problems that could be associated with a linear epidermal nevus syndrome and reassured the patient and his mother that the nevus was not dangerous and did not need to be removed.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Epidermal nevus and nevus sebaceous. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine, 2nd ed. New York, NY: McGraw-Hill; 2013:958-962.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized the lesion as a linear epidermal nevus.

Epidermal nevi (EN) are congenital hamartomas of ectodermal origin that are uncommon (occurring in < 1% of newborns and children), sporadic, and usually present at birth, although they can appear in early childhood. EN are associated with disorders of the eye, nervous system, and musculoskeletal system in 10% to 30% of patients.

EN are linear, round or oblong, well circumscribed, elevated, and flat topped. EN are often yellow-tan to dark brown in color, with a surface that is uniformly velvety or warty. They most commonly occur on the head and neck, although they can occur on the trunk and proximal extremities.

The FP determined that the patient had no neurological, musculoskeletal, or vision problems that could be associated with a linear epidermal nevus syndrome and reassured the patient and his mother that the nevus was not dangerous and did not need to be removed.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Epidermal nevus and nevus sebaceous. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine, 2nd ed. New York, NY: McGraw-Hill; 2013:958-962.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized the lesion as a linear epidermal nevus.

Epidermal nevi (EN) are congenital hamartomas of ectodermal origin that are uncommon (occurring in < 1% of newborns and children), sporadic, and usually present at birth, although they can appear in early childhood. EN are associated with disorders of the eye, nervous system, and musculoskeletal system in 10% to 30% of patients.

EN are linear, round or oblong, well circumscribed, elevated, and flat topped. EN are often yellow-tan to dark brown in color, with a surface that is uniformly velvety or warty. They most commonly occur on the head and neck, although they can occur on the trunk and proximal extremities.

The FP determined that the patient had no neurological, musculoskeletal, or vision problems that could be associated with a linear epidermal nevus syndrome and reassured the patient and his mother that the nevus was not dangerous and did not need to be removed.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Epidermal nevus and nevus sebaceous. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine, 2nd ed. New York, NY: McGraw-Hill; 2013:958-962.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

Nearly one-third of patients with primary biliary cholangitis treated with bezafibrate showed clinical improvement after 24 months, according to data from a randomized trial of 100 adults.

Ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), but many patients have an incomplete response to the treatment, and consequently their long-term survival is limited, wrote Christophe Corpechot, MD, of Sorbonne University, Paris, and his colleagues. PBC is also known as primary biliary cirrhosis.

In the BEZURSO trial (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis), published in the New England Journal of Medicine, the researchers randomized 100 primary PBC patients with an inadequate response to ursodeoxycholic acid to receive 400 mg per day of bezafibrate or a placebo for 24 months. Inadequate response was defined as “a serum level of alkaline phosphatase or aspartate aminotransferase more than 1.5 times the upper limit of the normal range or an abnormal total bilirubin level, assessed after at least 6 months of treatment with ursodeoxycholic acid,” the researchers said.

Baseline demographics were not significantly different between the groups. The average age of the patients was 53 years, and 95% were white women.

After 24 months, 31% of the patients in the treatment group met the primary outcome, which was the achievement of normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin, plus a normal prothrombin index. By contrast, none of the patients in the placebo group achieved the primary outcome.

In particular, bezafibrate patients showed a 60% reduction in alkaline phosphatase levels from baseline to 3 months, and a 14% decrease in total bilirubin from baseline during the course of the study.

Clinical outcomes were similar between the groups; 20% of the bezafibrate group and 18% of the placebo group developed portal hypertension, and two patients in each group developed liver complications. No deaths occurred in either group during the study. Approximately half of the patients in each group reported adverse events. Serious adverse events occurred in 14 bezafibrate patients and 12 placebo patients.

The findings were limited by the small study population, which prevented assessment of bezafibrate on liver transplantation and death, and by the limited histologic data to look at the impact on liver fibrosis and hepatic inflammation, the researchers said.

However, the results support the use of bezafibrate as an add-on to ursodeoxycholic acid in PBC patients, and merit larger, longer studies, they noted.

The study was supported by the Programme Hospitalier de Recherche Clinique 2010, Ministry of Health, and Arrow Génériques. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.

SOURCE: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.

Nearly one-third of patients with primary biliary cholangitis treated with bezafibrate showed clinical improvement after 24 months, according to data from a randomized trial of 100 adults.

Ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), but many patients have an incomplete response to the treatment, and consequently their long-term survival is limited, wrote Christophe Corpechot, MD, of Sorbonne University, Paris, and his colleagues. PBC is also known as primary biliary cirrhosis.

In the BEZURSO trial (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis), published in the New England Journal of Medicine, the researchers randomized 100 primary PBC patients with an inadequate response to ursodeoxycholic acid to receive 400 mg per day of bezafibrate or a placebo for 24 months. Inadequate response was defined as “a serum level of alkaline phosphatase or aspartate aminotransferase more than 1.5 times the upper limit of the normal range or an abnormal total bilirubin level, assessed after at least 6 months of treatment with ursodeoxycholic acid,” the researchers said.

Baseline demographics were not significantly different between the groups. The average age of the patients was 53 years, and 95% were white women.

After 24 months, 31% of the patients in the treatment group met the primary outcome, which was the achievement of normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin, plus a normal prothrombin index. By contrast, none of the patients in the placebo group achieved the primary outcome.

In particular, bezafibrate patients showed a 60% reduction in alkaline phosphatase levels from baseline to 3 months, and a 14% decrease in total bilirubin from baseline during the course of the study.

Clinical outcomes were similar between the groups; 20% of the bezafibrate group and 18% of the placebo group developed portal hypertension, and two patients in each group developed liver complications. No deaths occurred in either group during the study. Approximately half of the patients in each group reported adverse events. Serious adverse events occurred in 14 bezafibrate patients and 12 placebo patients.

The findings were limited by the small study population, which prevented assessment of bezafibrate on liver transplantation and death, and by the limited histologic data to look at the impact on liver fibrosis and hepatic inflammation, the researchers said.

However, the results support the use of bezafibrate as an add-on to ursodeoxycholic acid in PBC patients, and merit larger, longer studies, they noted.

The study was supported by the Programme Hospitalier de Recherche Clinique 2010, Ministry of Health, and Arrow Génériques. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.

SOURCE: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.

Nearly one-third of patients with primary biliary cholangitis treated with bezafibrate showed clinical improvement after 24 months, according to data from a randomized trial of 100 adults.

Ursodeoxycholic acid remains the standard first-line therapy for primary biliary cholangitis (PBC), but many patients have an incomplete response to the treatment, and consequently their long-term survival is limited, wrote Christophe Corpechot, MD, of Sorbonne University, Paris, and his colleagues. PBC is also known as primary biliary cirrhosis.

In the BEZURSO trial (Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis), published in the New England Journal of Medicine, the researchers randomized 100 primary PBC patients with an inadequate response to ursodeoxycholic acid to receive 400 mg per day of bezafibrate or a placebo for 24 months. Inadequate response was defined as “a serum level of alkaline phosphatase or aspartate aminotransferase more than 1.5 times the upper limit of the normal range or an abnormal total bilirubin level, assessed after at least 6 months of treatment with ursodeoxycholic acid,” the researchers said.

Baseline demographics were not significantly different between the groups. The average age of the patients was 53 years, and 95% were white women.

After 24 months, 31% of the patients in the treatment group met the primary outcome, which was the achievement of normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin, plus a normal prothrombin index. By contrast, none of the patients in the placebo group achieved the primary outcome.

In particular, bezafibrate patients showed a 60% reduction in alkaline phosphatase levels from baseline to 3 months, and a 14% decrease in total bilirubin from baseline during the course of the study.

Clinical outcomes were similar between the groups; 20% of the bezafibrate group and 18% of the placebo group developed portal hypertension, and two patients in each group developed liver complications. No deaths occurred in either group during the study. Approximately half of the patients in each group reported adverse events. Serious adverse events occurred in 14 bezafibrate patients and 12 placebo patients.

The findings were limited by the small study population, which prevented assessment of bezafibrate on liver transplantation and death, and by the limited histologic data to look at the impact on liver fibrosis and hepatic inflammation, the researchers said.

However, the results support the use of bezafibrate as an add-on to ursodeoxycholic acid in PBC patients, and merit larger, longer studies, they noted.

The study was supported by the Programme Hospitalier de Recherche Clinique 2010, Ministry of Health, and Arrow Génériques. Dr. Corpechot disclosed relationships with companies including Intercept France, Inventiva Pharma, and GlaxoSmithKline.

SOURCE: Corpechot C et al. N Engl J Med. 2018 June 6. doi: 10.1056/NEJMoa1714519.

In a randomized trial of women with early pregnancy loss, pretreatment with mifepristone before misoprostol was superior to misoprostol alone at achieving gestational sac expulsion by the time of the first follow-up visit without additional intervention.

“Women generally prefer active management; the ability to have control over the management of miscarriage may relieve some of the emotional burden that accompanies first trimester pregnancy loss,” Courtney A. Schreiber, MD, of the University of Pennsylvania, Philadelphia, and her coauthors wrote in the New England Journal of Medicine. But misoprostol (Cytotec) alone for women with a closed cervical os can require a second dose or intervention.

The trial enrolled 300 participants. Each had an ultrasound showing a nonviable intrauterine pregnancy of 5-12 weeks’ gestation. Women with an incomplete or inevitable abortion (that is, the absence of a gestational sac, an open cervical os, or both) were excluded, as misoprostol alone is effective for management of that diagnosis.

After randomization, 149 participants received 200 mg of oral mifepristone (Mifeprex), with 800 mcg misoprostol administered approximately 24 hours later. The other 151 participants received the standard 800 mcg dose of misoprostol alone. In both groups, the misoprostol was self-administered vaginally at home by inserting four 200-mcg tablets.

Follow-up came 24 hours to 4 days after misoprostol administration. The primary outcome was a gestational sac expulsion by the time of this follow-up, and no additional surgical or medical intervention within 30 days. If the gestational sac was present at follow-up, participants chose either expectant management, surgical management, or a second misoprostol dose.

The primary outcome was achieved in 124 of 148 women (83.8%; 95% confidence interval, 76.8-89.3) in the mifepristone-pretreatment group and in 100 of 149 women (67.1%; 95% CI, 59.0-74.6) in the misoprostol-alone group for a relative risk of 1.25 (95% CI, 1.09 to 1.43). Two women were lost to follow-up and one who was declared ineligible because of a possible ectopic pregnancy.

At 30 days’ follow-up, the cumulative rate of gestational sac expulsion with up to two doses of misoprostol was 91.2% (95% CI, 85.4-95.2) in the mifepristone-pretreatment group and 75.8% (95% CI, 68.2%-82.5%) in the misoprostol-alone group. Also by 30 days’ follow-up, 13 women in the mifepristone-pretreatment group and 35 women in the misoprostol-alone group had undergone uterine aspiration (relative risk, 0.37; 95% CI, 0.21-0.68).

[email protected]

SOURCE: Schreiber CA et al. N Engl J Med. 2018;378:2161-70.
 

In a randomized trial of women with early pregnancy loss, pretreatment with mifepristone before misoprostol was superior to misoprostol alone at achieving gestational sac expulsion by the time of the first follow-up visit without additional intervention.

“Women generally prefer active management; the ability to have control over the management of miscarriage may relieve some of the emotional burden that accompanies first trimester pregnancy loss,” Courtney A. Schreiber, MD, of the University of Pennsylvania, Philadelphia, and her coauthors wrote in the New England Journal of Medicine. But misoprostol (Cytotec) alone for women with a closed cervical os can require a second dose or intervention.

The trial enrolled 300 participants. Each had an ultrasound showing a nonviable intrauterine pregnancy of 5-12 weeks’ gestation. Women with an incomplete or inevitable abortion (that is, the absence of a gestational sac, an open cervical os, or both) were excluded, as misoprostol alone is effective for management of that diagnosis.

After randomization, 149 participants received 200 mg of oral mifepristone (Mifeprex), with 800 mcg misoprostol administered approximately 24 hours later. The other 151 participants received the standard 800 mcg dose of misoprostol alone. In both groups, the misoprostol was self-administered vaginally at home by inserting four 200-mcg tablets.

Follow-up came 24 hours to 4 days after misoprostol administration. The primary outcome was a gestational sac expulsion by the time of this follow-up, and no additional surgical or medical intervention within 30 days. If the gestational sac was present at follow-up, participants chose either expectant management, surgical management, or a second misoprostol dose.

The primary outcome was achieved in 124 of 148 women (83.8%; 95% confidence interval, 76.8-89.3) in the mifepristone-pretreatment group and in 100 of 149 women (67.1%; 95% CI, 59.0-74.6) in the misoprostol-alone group for a relative risk of 1.25 (95% CI, 1.09 to 1.43). Two women were lost to follow-up and one who was declared ineligible because of a possible ectopic pregnancy.

At 30 days’ follow-up, the cumulative rate of gestational sac expulsion with up to two doses of misoprostol was 91.2% (95% CI, 85.4-95.2) in the mifepristone-pretreatment group and 75.8% (95% CI, 68.2%-82.5%) in the misoprostol-alone group. Also by 30 days’ follow-up, 13 women in the mifepristone-pretreatment group and 35 women in the misoprostol-alone group had undergone uterine aspiration (relative risk, 0.37; 95% CI, 0.21-0.68).

[email protected]

SOURCE: Schreiber CA et al. N Engl J Med. 2018;378:2161-70.
 

In a randomized trial of women with early pregnancy loss, pretreatment with mifepristone before misoprostol was superior to misoprostol alone at achieving gestational sac expulsion by the time of the first follow-up visit without additional intervention.

“Women generally prefer active management; the ability to have control over the management of miscarriage may relieve some of the emotional burden that accompanies first trimester pregnancy loss,” Courtney A. Schreiber, MD, of the University of Pennsylvania, Philadelphia, and her coauthors wrote in the New England Journal of Medicine. But misoprostol (Cytotec) alone for women with a closed cervical os can require a second dose or intervention.

The trial enrolled 300 participants. Each had an ultrasound showing a nonviable intrauterine pregnancy of 5-12 weeks’ gestation. Women with an incomplete or inevitable abortion (that is, the absence of a gestational sac, an open cervical os, or both) were excluded, as misoprostol alone is effective for management of that diagnosis.

After randomization, 149 participants received 200 mg of oral mifepristone (Mifeprex), with 800 mcg misoprostol administered approximately 24 hours later. The other 151 participants received the standard 800 mcg dose of misoprostol alone. In both groups, the misoprostol was self-administered vaginally at home by inserting four 200-mcg tablets.

Follow-up came 24 hours to 4 days after misoprostol administration. The primary outcome was a gestational sac expulsion by the time of this follow-up, and no additional surgical or medical intervention within 30 days. If the gestational sac was present at follow-up, participants chose either expectant management, surgical management, or a second misoprostol dose.

The primary outcome was achieved in 124 of 148 women (83.8%; 95% confidence interval, 76.8-89.3) in the mifepristone-pretreatment group and in 100 of 149 women (67.1%; 95% CI, 59.0-74.6) in the misoprostol-alone group for a relative risk of 1.25 (95% CI, 1.09 to 1.43). Two women were lost to follow-up and one who was declared ineligible because of a possible ectopic pregnancy.

At 30 days’ follow-up, the cumulative rate of gestational sac expulsion with up to two doses of misoprostol was 91.2% (95% CI, 85.4-95.2) in the mifepristone-pretreatment group and 75.8% (95% CI, 68.2%-82.5%) in the misoprostol-alone group. Also by 30 days’ follow-up, 13 women in the mifepristone-pretreatment group and 35 women in the misoprostol-alone group had undergone uterine aspiration (relative risk, 0.37; 95% CI, 0.21-0.68).

[email protected]

SOURCE: Schreiber CA et al. N Engl J Med. 2018;378:2161-70.
 

LOS ANGELES—Plasma levels of neurofilament light indicate repetitive concussive traumatic brain injury (TBI) and axonal injury, according to data presented at the 70th Annual Meeting of the American Academy of Neurology. Differences in this biomarker are detectable for more than a year after the insult. Furthermore, plasma levels of neurofilament light reflect CSF levels of neurofilament light and may identify patients at increased risk of persistent postconcussion syndrome (PCS), according to the researchers.

In a previous study of boxers, Pashtun Shahim, MD, PhD, researcher at the University of Gothenburg in Sweden, and colleagues found that CSF levels of neurofilament light increased more after a bout than did other potential biomarkers such as total tau, phosphorylated tau, and amyloid beta. They also observed that concentrations of serum neurofilament light were higher in boxers with severe head impact, compared with those with mild head impact. In a study of hockey players, Dr. Shahim and colleagues found that neurofilament light measured in the acute setting could distinguish those who would have a prolonged return to play from those who would have a quick return to play.

A Study of Professional Athletes

In their latest study, Dr. Shahim and colleagues sought to determine whether professional athletes with PCS resulting from repetitive concussive TBI have elevated CSF and plasma neurofilament light and tau, compared with controls. They also investigated whether elevated concentrations of these biomarkers are associated with persistent PCS.

Between September 2013 and September 2017, the investigators enrolled 31 athletes (ie, professional players of hockey and soccer) with PCS resulting from repetitive concussive TBI, 48 athletes with concussion but without PCS, and 30 control athletes into their study. Participants underwent CSF and plasma biomarker assessments, responded to the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), and underwent structural brain MRI. The population’s median time since the last concussion was 1.5 years. The three groups were matched on sport.

Biomarker Indicated Duration of PCS

Dr. Shahim and colleagues found “a tight correlation between plasma concentrations of neurofilament [light] and CSF neurofilament [light], while there was no correlation between plasma tau and CSF tau.”

Plasma neurofilament light concentrations were significantly increased in participants with concussion and those with PCS, compared with controls. The concentration of plasma neurofilament light was higher in patients with concussion but without PCS, compared with the PCS group. This finding was “expected, as we are comparing acute cases of concussion versus chronic cases,” said Dr. Shahim.

When they examined only participants with PCS, athletes who had had PCS for more than one year had higher concentrations of neurofilament light, compared with athletes who had had PCS for less than one year. The latter returned to play, while the former resigned, said Dr. Shahim. In addition, plasma neurofilament light concentration correlated with RPQ scores and lifetime number of concussions.

Levels of tau were lower among participants with PCS than among control athletes, and the researchers found no correlation between tau level and duration of PCS. Levels of tau also had no association with RPQ scores.

Dr. Shahim and colleagues next examined whether these biomarkers had prognostic value. They found that CSF neurofilament concentrations could distinguish between participants who had had PCS for less than a year and those who had had PCS for more than a year (area under the curve [AUC], 0.86). Plasma neurofilament light distinguished between these groups with an AUC of 0.85. Neither CSF tau nor plasma tau reliably indicated duration of PCS, however. In addition, the investigators found no correlation between CSF and plasma tau concentrations from the same individual. This finding casts doubt on the hypothesis that tau concentrations reflect axonal injury, said Dr. Shahim.

—Erik Greb

Suggested Reading

Shahim P, Tegner Y, Marklund N, et al. Neurofilament light and tau as blood biomarkers for sports-related concussion. Neurology. 2018;90(20):e1780-e1788.

Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017;88(19):1788-1794.

LOS ANGELES—Plasma levels of neurofilament light indicate repetitive concussive traumatic brain injury (TBI) and axonal injury, according to data presented at the 70th Annual Meeting of the American Academy of Neurology. Differences in this biomarker are detectable for more than a year after the insult. Furthermore, plasma levels of neurofilament light reflect CSF levels of neurofilament light and may identify patients at increased risk of persistent postconcussion syndrome (PCS), according to the researchers.

In a previous study of boxers, Pashtun Shahim, MD, PhD, researcher at the University of Gothenburg in Sweden, and colleagues found that CSF levels of neurofilament light increased more after a bout than did other potential biomarkers such as total tau, phosphorylated tau, and amyloid beta. They also observed that concentrations of serum neurofilament light were higher in boxers with severe head impact, compared with those with mild head impact. In a study of hockey players, Dr. Shahim and colleagues found that neurofilament light measured in the acute setting could distinguish those who would have a prolonged return to play from those who would have a quick return to play.

A Study of Professional Athletes

In their latest study, Dr. Shahim and colleagues sought to determine whether professional athletes with PCS resulting from repetitive concussive TBI have elevated CSF and plasma neurofilament light and tau, compared with controls. They also investigated whether elevated concentrations of these biomarkers are associated with persistent PCS.

Between September 2013 and September 2017, the investigators enrolled 31 athletes (ie, professional players of hockey and soccer) with PCS resulting from repetitive concussive TBI, 48 athletes with concussion but without PCS, and 30 control athletes into their study. Participants underwent CSF and plasma biomarker assessments, responded to the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), and underwent structural brain MRI. The population’s median time since the last concussion was 1.5 years. The three groups were matched on sport.

Biomarker Indicated Duration of PCS

Dr. Shahim and colleagues found “a tight correlation between plasma concentrations of neurofilament [light] and CSF neurofilament [light], while there was no correlation between plasma tau and CSF tau.”

Plasma neurofilament light concentrations were significantly increased in participants with concussion and those with PCS, compared with controls. The concentration of plasma neurofilament light was higher in patients with concussion but without PCS, compared with the PCS group. This finding was “expected, as we are comparing acute cases of concussion versus chronic cases,” said Dr. Shahim.

When they examined only participants with PCS, athletes who had had PCS for more than one year had higher concentrations of neurofilament light, compared with athletes who had had PCS for less than one year. The latter returned to play, while the former resigned, said Dr. Shahim. In addition, plasma neurofilament light concentration correlated with RPQ scores and lifetime number of concussions.

Levels of tau were lower among participants with PCS than among control athletes, and the researchers found no correlation between tau level and duration of PCS. Levels of tau also had no association with RPQ scores.

Dr. Shahim and colleagues next examined whether these biomarkers had prognostic value. They found that CSF neurofilament concentrations could distinguish between participants who had had PCS for less than a year and those who had had PCS for more than a year (area under the curve [AUC], 0.86). Plasma neurofilament light distinguished between these groups with an AUC of 0.85. Neither CSF tau nor plasma tau reliably indicated duration of PCS, however. In addition, the investigators found no correlation between CSF and plasma tau concentrations from the same individual. This finding casts doubt on the hypothesis that tau concentrations reflect axonal injury, said Dr. Shahim.

—Erik Greb

Suggested Reading

Shahim P, Tegner Y, Marklund N, et al. Neurofilament light and tau as blood biomarkers for sports-related concussion. Neurology. 2018;90(20):e1780-e1788.

Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017;88(19):1788-1794.

LOS ANGELES—Plasma levels of neurofilament light indicate repetitive concussive traumatic brain injury (TBI) and axonal injury, according to data presented at the 70th Annual Meeting of the American Academy of Neurology. Differences in this biomarker are detectable for more than a year after the insult. Furthermore, plasma levels of neurofilament light reflect CSF levels of neurofilament light and may identify patients at increased risk of persistent postconcussion syndrome (PCS), according to the researchers.

In a previous study of boxers, Pashtun Shahim, MD, PhD, researcher at the University of Gothenburg in Sweden, and colleagues found that CSF levels of neurofilament light increased more after a bout than did other potential biomarkers such as total tau, phosphorylated tau, and amyloid beta. They also observed that concentrations of serum neurofilament light were higher in boxers with severe head impact, compared with those with mild head impact. In a study of hockey players, Dr. Shahim and colleagues found that neurofilament light measured in the acute setting could distinguish those who would have a prolonged return to play from those who would have a quick return to play.

A Study of Professional Athletes

In their latest study, Dr. Shahim and colleagues sought to determine whether professional athletes with PCS resulting from repetitive concussive TBI have elevated CSF and plasma neurofilament light and tau, compared with controls. They also investigated whether elevated concentrations of these biomarkers are associated with persistent PCS.

Between September 2013 and September 2017, the investigators enrolled 31 athletes (ie, professional players of hockey and soccer) with PCS resulting from repetitive concussive TBI, 48 athletes with concussion but without PCS, and 30 control athletes into their study. Participants underwent CSF and plasma biomarker assessments, responded to the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), and underwent structural brain MRI. The population’s median time since the last concussion was 1.5 years. The three groups were matched on sport.

Biomarker Indicated Duration of PCS

Dr. Shahim and colleagues found “a tight correlation between plasma concentrations of neurofilament [light] and CSF neurofilament [light], while there was no correlation between plasma tau and CSF tau.”

Plasma neurofilament light concentrations were significantly increased in participants with concussion and those with PCS, compared with controls. The concentration of plasma neurofilament light was higher in patients with concussion but without PCS, compared with the PCS group. This finding was “expected, as we are comparing acute cases of concussion versus chronic cases,” said Dr. Shahim.

When they examined only participants with PCS, athletes who had had PCS for more than one year had higher concentrations of neurofilament light, compared with athletes who had had PCS for less than one year. The latter returned to play, while the former resigned, said Dr. Shahim. In addition, plasma neurofilament light concentration correlated with RPQ scores and lifetime number of concussions.

Levels of tau were lower among participants with PCS than among control athletes, and the researchers found no correlation between tau level and duration of PCS. Levels of tau also had no association with RPQ scores.

Dr. Shahim and colleagues next examined whether these biomarkers had prognostic value. They found that CSF neurofilament concentrations could distinguish between participants who had had PCS for less than a year and those who had had PCS for more than a year (area under the curve [AUC], 0.86). Plasma neurofilament light distinguished between these groups with an AUC of 0.85. Neither CSF tau nor plasma tau reliably indicated duration of PCS, however. In addition, the investigators found no correlation between CSF and plasma tau concentrations from the same individual. This finding casts doubt on the hypothesis that tau concentrations reflect axonal injury, said Dr. Shahim.

—Erik Greb

Suggested Reading

Shahim P, Tegner Y, Marklund N, et al. Neurofilament light and tau as blood biomarkers for sports-related concussion. Neurology. 2018;90(20):e1780-e1788.

Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017;88(19):1788-1794.