A few years ago I wrote a column about what promised to be an exciting development in blood testing technology. Using the money her parents had set aside for her education, a young woman dropped out of Stanford University at age 19 and started a company that she claimed would be able to offer hundreds of lab tests on just a few drops of blood. Results would be available in just minutes instead of hours or days. At the time I wrote the column, the company had just landed a contract with a large drug store chain with an arrangement that would eventually allow nearly every resident of the United States to be within a few miles of a site that would offer rapid response blood tests with nothing more than a finger prick.

It seemed a little hard to believe, but the prospect of pediatricians being able to make a diagnosis without running the risk of exsanguinating our smallest patients sounded appealing. On the other hand, I worried that a quick and easy technology might encourage some physicians to use a shotgun approach to diagnosing illness rather than a more rational and cost-effective process based on the traditional skills of history taking and physical examination. Some patients who foolishly wanted to know “everything” about themselves might be tempted to ask their physicians to order the whole smorgasbord of tests. “Hey, it’s only a few drops of blood.”

Turns out there were enough people with more money than reservations and the company quickly attracted hundreds of millions of dollars in venture capital. The company, now calling itself Theranos, has been valued at nine billion dollars. But, recently this startup star has encountered some serious bumps in the road to a full-scale launch (“Hot Startup Theranos Has Struggled With Its Blood-Test Technology” by John Carreyrou, The Wall Street Journal, updated Oct. 16, 2015). The Wall Street Journal reported that despite promises, only a few of the 240 tests offered by the company are currently performed using their proprietary microtechnique. In the days following the Journal article, the Food and Drug Administration warned Theranos that their “nanotainer” is considered a new medical device that must first clear the agency’s time consuming and costly vetting process (“Hot Startup Theranos Dials Back Lab Tests at FDA’s Behest” by John Carreyrou, The Wall Street Journal, updated Oct. 16, 2015).

The venture capitalists who had climbed on the Theranos bandwagon tempted by the just-a-few-drops promise may end up seeing their bank accounts hemorrhage. But I don’t think we should be too critical of their investment decision. It was and may still be good idea that has simply run afoul of the details. However, I recently learned about another new business that I don’t consider to have even started with a good idea, but still has managed to attract enough capital to get itself off the ground (“Should Breast Milk Be Nutritionally Analyzed?” by Laura Johannes, The Wall Street Journal, Dec. 28, 2015).

I’m sure you have seen some new mothers who were concerned that their breast milk was not enough for their babies. But how many of them would pay $150 for a start-up kit and then more than $300 to find out the nutritional content of their breast milk? What if it meant pumping and freezing three samples 2 or 3 days apart and then shipping them in a cooler to a lab? What if you told them that neither you nor anyone else could reliably interpret the results because there aren’t any published guidelines for the optimal composition of human breast milk? Even if your practice is packed to the rafters with anxiety-driven, irrational parents, I don’t think you would find many takers. But that doesn’t seem to have bothered the folks who have invested in Happy Vitals, a company in Washington that is offering a service similar to the one I have just described.

You and I might not have invested in a company whose business plan was to offer such a service. But I fear there may be enough health care “providers” practicing without the benefit of an evidence-based education that what I consider a capital misadventure may actually be able to pay back its investors.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

A few years ago I wrote a column about what promised to be an exciting development in blood testing technology. Using the money her parents had set aside for her education, a young woman dropped out of Stanford University at age 19 and started a company that she claimed would be able to offer hundreds of lab tests on just a few drops of blood. Results would be available in just minutes instead of hours or days. At the time I wrote the column, the company had just landed a contract with a large drug store chain with an arrangement that would eventually allow nearly every resident of the United States to be within a few miles of a site that would offer rapid response blood tests with nothing more than a finger prick.

It seemed a little hard to believe, but the prospect of pediatricians being able to make a diagnosis without running the risk of exsanguinating our smallest patients sounded appealing. On the other hand, I worried that a quick and easy technology might encourage some physicians to use a shotgun approach to diagnosing illness rather than a more rational and cost-effective process based on the traditional skills of history taking and physical examination. Some patients who foolishly wanted to know “everything” about themselves might be tempted to ask their physicians to order the whole smorgasbord of tests. “Hey, it’s only a few drops of blood.”

Turns out there were enough people with more money than reservations and the company quickly attracted hundreds of millions of dollars in venture capital. The company, now calling itself Theranos, has been valued at nine billion dollars. But, recently this startup star has encountered some serious bumps in the road to a full-scale launch (“Hot Startup Theranos Has Struggled With Its Blood-Test Technology” by John Carreyrou, The Wall Street Journal, updated Oct. 16, 2015). The Wall Street Journal reported that despite promises, only a few of the 240 tests offered by the company are currently performed using their proprietary microtechnique. In the days following the Journal article, the Food and Drug Administration warned Theranos that their “nanotainer” is considered a new medical device that must first clear the agency’s time consuming and costly vetting process (“Hot Startup Theranos Dials Back Lab Tests at FDA’s Behest” by John Carreyrou, The Wall Street Journal, updated Oct. 16, 2015).

The venture capitalists who had climbed on the Theranos bandwagon tempted by the just-a-few-drops promise may end up seeing their bank accounts hemorrhage. But I don’t think we should be too critical of their investment decision. It was and may still be good idea that has simply run afoul of the details. However, I recently learned about another new business that I don’t consider to have even started with a good idea, but still has managed to attract enough capital to get itself off the ground (“Should Breast Milk Be Nutritionally Analyzed?” by Laura Johannes, The Wall Street Journal, Dec. 28, 2015).

I’m sure you have seen some new mothers who were concerned that their breast milk was not enough for their babies. But how many of them would pay $150 for a start-up kit and then more than $300 to find out the nutritional content of their breast milk? What if it meant pumping and freezing three samples 2 or 3 days apart and then shipping them in a cooler to a lab? What if you told them that neither you nor anyone else could reliably interpret the results because there aren’t any published guidelines for the optimal composition of human breast milk? Even if your practice is packed to the rafters with anxiety-driven, irrational parents, I don’t think you would find many takers. But that doesn’t seem to have bothered the folks who have invested in Happy Vitals, a company in Washington that is offering a service similar to the one I have just described.

You and I might not have invested in a company whose business plan was to offer such a service. But I fear there may be enough health care “providers” practicing without the benefit of an evidence-based education that what I consider a capital misadventure may actually be able to pay back its investors.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

A few years ago I wrote a column about what promised to be an exciting development in blood testing technology. Using the money her parents had set aside for her education, a young woman dropped out of Stanford University at age 19 and started a company that she claimed would be able to offer hundreds of lab tests on just a few drops of blood. Results would be available in just minutes instead of hours or days. At the time I wrote the column, the company had just landed a contract with a large drug store chain with an arrangement that would eventually allow nearly every resident of the United States to be within a few miles of a site that would offer rapid response blood tests with nothing more than a finger prick.

It seemed a little hard to believe, but the prospect of pediatricians being able to make a diagnosis without running the risk of exsanguinating our smallest patients sounded appealing. On the other hand, I worried that a quick and easy technology might encourage some physicians to use a shotgun approach to diagnosing illness rather than a more rational and cost-effective process based on the traditional skills of history taking and physical examination. Some patients who foolishly wanted to know “everything” about themselves might be tempted to ask their physicians to order the whole smorgasbord of tests. “Hey, it’s only a few drops of blood.”

Turns out there were enough people with more money than reservations and the company quickly attracted hundreds of millions of dollars in venture capital. The company, now calling itself Theranos, has been valued at nine billion dollars. But, recently this startup star has encountered some serious bumps in the road to a full-scale launch (“Hot Startup Theranos Has Struggled With Its Blood-Test Technology” by John Carreyrou, The Wall Street Journal, updated Oct. 16, 2015). The Wall Street Journal reported that despite promises, only a few of the 240 tests offered by the company are currently performed using their proprietary microtechnique. In the days following the Journal article, the Food and Drug Administration warned Theranos that their “nanotainer” is considered a new medical device that must first clear the agency’s time consuming and costly vetting process (“Hot Startup Theranos Dials Back Lab Tests at FDA’s Behest” by John Carreyrou, The Wall Street Journal, updated Oct. 16, 2015).

The venture capitalists who had climbed on the Theranos bandwagon tempted by the just-a-few-drops promise may end up seeing their bank accounts hemorrhage. But I don’t think we should be too critical of their investment decision. It was and may still be good idea that has simply run afoul of the details. However, I recently learned about another new business that I don’t consider to have even started with a good idea, but still has managed to attract enough capital to get itself off the ground (“Should Breast Milk Be Nutritionally Analyzed?” by Laura Johannes, The Wall Street Journal, Dec. 28, 2015).

I’m sure you have seen some new mothers who were concerned that their breast milk was not enough for their babies. But how many of them would pay $150 for a start-up kit and then more than $300 to find out the nutritional content of their breast milk? What if it meant pumping and freezing three samples 2 or 3 days apart and then shipping them in a cooler to a lab? What if you told them that neither you nor anyone else could reliably interpret the results because there aren’t any published guidelines for the optimal composition of human breast milk? Even if your practice is packed to the rafters with anxiety-driven, irrational parents, I don’t think you would find many takers. But that doesn’t seem to have bothered the folks who have invested in Happy Vitals, a company in Washington that is offering a service similar to the one I have just described.

You and I might not have invested in a company whose business plan was to offer such a service. But I fear there may be enough health care “providers” practicing without the benefit of an evidence-based education that what I consider a capital misadventure may actually be able to pay back its investors.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics including “How to Say No to Your Toddler.”

Case Report

A 19-year-old man was admitted to our hospital to begin treatment for acute myeloid leukemia that had been diagnosed 2 days prior. Three days after completing a 10-day regimen of induction chemotherapy, he developed bilateral, well-demarcated erythematous patches on the palmar surfaces of the proximal phalanges of the third, fourth, and fifth fingers (Figure 1) and 2 patches on the right palm. The patient was referred to dermatology for evaluation. He recalled no trauma to these sites although he reported pushing his intravenous pole with the right hand when walking. Of note, he had become neutropenic and thrombocytopenic following chemotherapy

On physical examination, the patches measured 1- to 1.5-cm in diameter and were mildly tender to palpation. The 2 patches on the right palm were much smaller than those on the fingers but were otherwise similar in appearance.

A punch biopsy of the erythematous lesion on the left third digit was performed. Histologic examination revealed extensive epidermal denudation associated with vascular proliferation and congestion as well as hemorrhage and a sparse lymphocytic infiltrate (Figures 2–4). There was no evidence of a leukemic infiltrate, and stains for fungal elements and bacteria were negative. Eccrine ducts appeared normal with no evidence of necrosis or metaplasia. These findings were suggestive of a frictional etiology.

Due to the distribution of the skin lesions on the hands, it was suspected that the source of friction was a video game controller. Although the patient denied playing video games since his admission to the hospital, he reported heavy video game use during the weeks prior to admission. We postulated that the thrombocytopenia the patient developed following chemotherapy along with prior friction injury sustained from heavy video game play led to traumatic subcorneal hemorrhage on the hands at the points of contact with the video game controller (Figure 5). The subcorneal hematomas resolved completely over the next 2 months during which the patient abstained from video game play.

This case demonstrates the importance of obtaining a detailed patient history, as our patient’s history of video game play prior to hospitalization proved to be of major diagnostic importance. Although the location, distribution, and well-demarcated nature of the patient’s lesions suggested an external source of trauma and biopsy definitively ruled out leukemia cutis, Sweet syndrome, and eccrine hidradenitis,¹ the final diagnosis of traumatic subcorneal hematomas was only possible with specific knowledge of the patient’s video game controller use.

Comment

History of video game play has been key to the diagnosis of a variety of cutaneous lesions documented in the medical literature. Robertson et al² attributed a similar case of traumatic subcorneal hematomas of the hands in an otherwise healthy 16-year-old boy to excessive use of a video game controller. Similarly, Kasraee et al³ attributed a case of idiopathic eccrine hidradenitis in an otherwise healthy 12-year-old girl to excessive video game use. In both of these reported cases, bilateral skin lesions on the palms of the hands appeared acutely in a pattern consistent with the points of contact of a video game controller. Excessive video game play has also been associated with unilateral dermatologic lesions on the hands, such as knuckle pads,⁴ onycholysis,⁵ friction blisters,⁶ pressure ulcers,⁷ and hemorrhagic lesions.^5,6,8

Video game–related pathologies are not limited to the skin and have been implicated in a variety of clinical presentations. In 1987, Osterman et al⁹ published an early account of repetitive strain injury (RSI) related to video game use in which the investigators reported 2 cases of video game–related volar flexor tenosynovitis (or trigger finger), which they termed “joystick digit.” Since that time, video game play has greatly evolved along with the types and nature of RSI cases reported in the medical literature. In 1990, Brasington¹⁰ described acute tendinopathy of the extensor pollicis longus tendon caused by excessive video game play, which was termed “Nintendinitis.” This term has since been used in reference to any video game–related RSI and reports have increased over time, likely due to the proliferation of an increasing array of video game systems.^5,11-16 In recent years, a number of traumatic injuries including fractures, joint dislocations, head injuries, hemothorax, and lacerations have been attributed to interactive gaming systems.^6,11,17-20 In rare cases, video game play also has been associated with enuresis,²¹ encopresis,²² and epilepsy.²³

According to a 2011 report from the Entertainment Software Association, women over the age of 18 years now represent a greater proportion of the video game–playing population than boys aged 17 years and younger.²⁴ This same report also noted that the average video game player is 35 years old; 44% of all players are female; and 27% of Americans over the age of 50 years play video games. This shifting demographic data, including the fact that 80% of American households reportedly play video games, reveals the expanding depth and breadth of the market.²⁴ However, the pediatric population is still a high-volume player demographic. Average time per session peaks between 10 to 12 years of age and then falls through the teenage and adults years.²⁴ Hence, the pediatric population is at high risk for clinical pathology because of the increased repetitive movements associated with video game play. Overall, cognizance of the popularity of video games and related pathologies can be an asset for dermatologists who evaluate pediatric patients.

Case Report

A 19-year-old man was admitted to our hospital to begin treatment for acute myeloid leukemia that had been diagnosed 2 days prior. Three days after completing a 10-day regimen of induction chemotherapy, he developed bilateral, well-demarcated erythematous patches on the palmar surfaces of the proximal phalanges of the third, fourth, and fifth fingers (Figure 1) and 2 patches on the right palm. The patient was referred to dermatology for evaluation. He recalled no trauma to these sites although he reported pushing his intravenous pole with the right hand when walking. Of note, he had become neutropenic and thrombocytopenic following chemotherapy

On physical examination, the patches measured 1- to 1.5-cm in diameter and were mildly tender to palpation. The 2 patches on the right palm were much smaller than those on the fingers but were otherwise similar in appearance.

A punch biopsy of the erythematous lesion on the left third digit was performed. Histologic examination revealed extensive epidermal denudation associated with vascular proliferation and congestion as well as hemorrhage and a sparse lymphocytic infiltrate (Figures 2–4). There was no evidence of a leukemic infiltrate, and stains for fungal elements and bacteria were negative. Eccrine ducts appeared normal with no evidence of necrosis or metaplasia. These findings were suggestive of a frictional etiology.

Due to the distribution of the skin lesions on the hands, it was suspected that the source of friction was a video game controller. Although the patient denied playing video games since his admission to the hospital, he reported heavy video game use during the weeks prior to admission. We postulated that the thrombocytopenia the patient developed following chemotherapy along with prior friction injury sustained from heavy video game play led to traumatic subcorneal hemorrhage on the hands at the points of contact with the video game controller (Figure 5). The subcorneal hematomas resolved completely over the next 2 months during which the patient abstained from video game play.

This case demonstrates the importance of obtaining a detailed patient history, as our patient’s history of video game play prior to hospitalization proved to be of major diagnostic importance. Although the location, distribution, and well-demarcated nature of the patient’s lesions suggested an external source of trauma and biopsy definitively ruled out leukemia cutis, Sweet syndrome, and eccrine hidradenitis,¹ the final diagnosis of traumatic subcorneal hematomas was only possible with specific knowledge of the patient’s video game controller use.

Comment

History of video game play has been key to the diagnosis of a variety of cutaneous lesions documented in the medical literature. Robertson et al² attributed a similar case of traumatic subcorneal hematomas of the hands in an otherwise healthy 16-year-old boy to excessive use of a video game controller. Similarly, Kasraee et al³ attributed a case of idiopathic eccrine hidradenitis in an otherwise healthy 12-year-old girl to excessive video game use. In both of these reported cases, bilateral skin lesions on the palms of the hands appeared acutely in a pattern consistent with the points of contact of a video game controller. Excessive video game play has also been associated with unilateral dermatologic lesions on the hands, such as knuckle pads,⁴ onycholysis,⁵ friction blisters,⁶ pressure ulcers,⁷ and hemorrhagic lesions.^5,6,8

Video game–related pathologies are not limited to the skin and have been implicated in a variety of clinical presentations. In 1987, Osterman et al⁹ published an early account of repetitive strain injury (RSI) related to video game use in which the investigators reported 2 cases of video game–related volar flexor tenosynovitis (or trigger finger), which they termed “joystick digit.” Since that time, video game play has greatly evolved along with the types and nature of RSI cases reported in the medical literature. In 1990, Brasington¹⁰ described acute tendinopathy of the extensor pollicis longus tendon caused by excessive video game play, which was termed “Nintendinitis.” This term has since been used in reference to any video game–related RSI and reports have increased over time, likely due to the proliferation of an increasing array of video game systems.^5,11-16 In recent years, a number of traumatic injuries including fractures, joint dislocations, head injuries, hemothorax, and lacerations have been attributed to interactive gaming systems.^6,11,17-20 In rare cases, video game play also has been associated with enuresis,²¹ encopresis,²² and epilepsy.²³

According to a 2011 report from the Entertainment Software Association, women over the age of 18 years now represent a greater proportion of the video game–playing population than boys aged 17 years and younger.²⁴ This same report also noted that the average video game player is 35 years old; 44% of all players are female; and 27% of Americans over the age of 50 years play video games. This shifting demographic data, including the fact that 80% of American households reportedly play video games, reveals the expanding depth and breadth of the market.²⁴ However, the pediatric population is still a high-volume player demographic. Average time per session peaks between 10 to 12 years of age and then falls through the teenage and adults years.²⁴ Hence, the pediatric population is at high risk for clinical pathology because of the increased repetitive movements associated with video game play. Overall, cognizance of the popularity of video games and related pathologies can be an asset for dermatologists who evaluate pediatric patients.

Case Report

A 19-year-old man was admitted to our hospital to begin treatment for acute myeloid leukemia that had been diagnosed 2 days prior. Three days after completing a 10-day regimen of induction chemotherapy, he developed bilateral, well-demarcated erythematous patches on the palmar surfaces of the proximal phalanges of the third, fourth, and fifth fingers (Figure 1) and 2 patches on the right palm. The patient was referred to dermatology for evaluation. He recalled no trauma to these sites although he reported pushing his intravenous pole with the right hand when walking. Of note, he had become neutropenic and thrombocytopenic following chemotherapy

On physical examination, the patches measured 1- to 1.5-cm in diameter and were mildly tender to palpation. The 2 patches on the right palm were much smaller than those on the fingers but were otherwise similar in appearance.

A punch biopsy of the erythematous lesion on the left third digit was performed. Histologic examination revealed extensive epidermal denudation associated with vascular proliferation and congestion as well as hemorrhage and a sparse lymphocytic infiltrate (Figures 2–4). There was no evidence of a leukemic infiltrate, and stains for fungal elements and bacteria were negative. Eccrine ducts appeared normal with no evidence of necrosis or metaplasia. These findings were suggestive of a frictional etiology.

Due to the distribution of the skin lesions on the hands, it was suspected that the source of friction was a video game controller. Although the patient denied playing video games since his admission to the hospital, he reported heavy video game use during the weeks prior to admission. We postulated that the thrombocytopenia the patient developed following chemotherapy along with prior friction injury sustained from heavy video game play led to traumatic subcorneal hemorrhage on the hands at the points of contact with the video game controller (Figure 5). The subcorneal hematomas resolved completely over the next 2 months during which the patient abstained from video game play.

This case demonstrates the importance of obtaining a detailed patient history, as our patient’s history of video game play prior to hospitalization proved to be of major diagnostic importance. Although the location, distribution, and well-demarcated nature of the patient’s lesions suggested an external source of trauma and biopsy definitively ruled out leukemia cutis, Sweet syndrome, and eccrine hidradenitis,¹ the final diagnosis of traumatic subcorneal hematomas was only possible with specific knowledge of the patient’s video game controller use.

Comment

History of video game play has been key to the diagnosis of a variety of cutaneous lesions documented in the medical literature. Robertson et al² attributed a similar case of traumatic subcorneal hematomas of the hands in an otherwise healthy 16-year-old boy to excessive use of a video game controller. Similarly, Kasraee et al³ attributed a case of idiopathic eccrine hidradenitis in an otherwise healthy 12-year-old girl to excessive video game use. In both of these reported cases, bilateral skin lesions on the palms of the hands appeared acutely in a pattern consistent with the points of contact of a video game controller. Excessive video game play has also been associated with unilateral dermatologic lesions on the hands, such as knuckle pads,⁴ onycholysis,⁵ friction blisters,⁶ pressure ulcers,⁷ and hemorrhagic lesions.^5,6,8

Video game–related pathologies are not limited to the skin and have been implicated in a variety of clinical presentations. In 1987, Osterman et al⁹ published an early account of repetitive strain injury (RSI) related to video game use in which the investigators reported 2 cases of video game–related volar flexor tenosynovitis (or trigger finger), which they termed “joystick digit.” Since that time, video game play has greatly evolved along with the types and nature of RSI cases reported in the medical literature. In 1990, Brasington¹⁰ described acute tendinopathy of the extensor pollicis longus tendon caused by excessive video game play, which was termed “Nintendinitis.” This term has since been used in reference to any video game–related RSI and reports have increased over time, likely due to the proliferation of an increasing array of video game systems.^5,11-16 In recent years, a number of traumatic injuries including fractures, joint dislocations, head injuries, hemothorax, and lacerations have been attributed to interactive gaming systems.^6,11,17-20 In rare cases, video game play also has been associated with enuresis,²¹ encopresis,²² and epilepsy.²³

According to a 2011 report from the Entertainment Software Association, women over the age of 18 years now represent a greater proportion of the video game–playing population than boys aged 17 years and younger.²⁴ This same report also noted that the average video game player is 35 years old; 44% of all players are female; and 27% of Americans over the age of 50 years play video games. This shifting demographic data, including the fact that 80% of American households reportedly play video games, reveals the expanding depth and breadth of the market.²⁴ However, the pediatric population is still a high-volume player demographic. Average time per session peaks between 10 to 12 years of age and then falls through the teenage and adults years.²⁴ Hence, the pediatric population is at high risk for clinical pathology because of the increased repetitive movements associated with video game play. Overall, cognizance of the popularity of video games and related pathologies can be an asset for dermatologists who evaluate pediatric patients.

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Patients with bipolar disorder might experience more complex negative emotions in response to positive music than typical adults, even when in a euthymic state, Dr. Sabine Choppin of the University of Rennes 1 (France) and colleagues reported.

Researchers recruited 21 patients with bipolar disorder in a euthymic phase and 21 matched healthy controls for the study. First, participants rated their emotional reactivity on two self-report scales: the Emotion Reactivity Scale (ERS) and the Multidimensional Assessment of Thymic States Scale (MAThyS). Next, they used headphones to listen to a series of 12 instrumental music excerpts lasting 45 seconds each with their eyes closed. After each musical selection, they were asked to rate how strongly they had experienced each of the nine emotional categories on the Geneva Emotional Music Scale: joy, sadness, tension, wonder, peacefulness, power, tenderness, nostalgia, and transcendence.

©Zoonar/hormydesign/Thinkstock

Statistical analyses showed that patients in the bipolar disorder group had a mean score of 41.2 on the ERS, compared with a mean score of 22.9 among healthy controls. In addition, bipolar disorder patients reported experiencing more tension and sadness than did healthy controls when listening to positive musical excerpts that had been classified as inducing joy and wonder.

“This finding tallies with the negative emotional bias displayed by depressed patients, who tend to experience more negative emotions than healthy controls,” the authors wrote. “Bipolar patients struggle so much to regulate their own positive emotions that it creates a chronic source of distress, which could be experienced as a negative emotion.”

Read the article in the Journal of Affective Disorders (2016 Feb;191:15-23. doi: 10.1016/j.jad.2015.10.063).

Patients with bipolar disorder might experience more complex negative emotions in response to positive music than typical adults, even when in a euthymic state, Dr. Sabine Choppin of the University of Rennes 1 (France) and colleagues reported.

Researchers recruited 21 patients with bipolar disorder in a euthymic phase and 21 matched healthy controls for the study. First, participants rated their emotional reactivity on two self-report scales: the Emotion Reactivity Scale (ERS) and the Multidimensional Assessment of Thymic States Scale (MAThyS). Next, they used headphones to listen to a series of 12 instrumental music excerpts lasting 45 seconds each with their eyes closed. After each musical selection, they were asked to rate how strongly they had experienced each of the nine emotional categories on the Geneva Emotional Music Scale: joy, sadness, tension, wonder, peacefulness, power, tenderness, nostalgia, and transcendence.

©Zoonar/hormydesign/Thinkstock

Statistical analyses showed that patients in the bipolar disorder group had a mean score of 41.2 on the ERS, compared with a mean score of 22.9 among healthy controls. In addition, bipolar disorder patients reported experiencing more tension and sadness than did healthy controls when listening to positive musical excerpts that had been classified as inducing joy and wonder.

“This finding tallies with the negative emotional bias displayed by depressed patients, who tend to experience more negative emotions than healthy controls,” the authors wrote. “Bipolar patients struggle so much to regulate their own positive emotions that it creates a chronic source of distress, which could be experienced as a negative emotion.”

Read the article in the Journal of Affective Disorders (2016 Feb;191:15-23. doi: 10.1016/j.jad.2015.10.063).

Patients with bipolar disorder might experience more complex negative emotions in response to positive music than typical adults, even when in a euthymic state, Dr. Sabine Choppin of the University of Rennes 1 (France) and colleagues reported.

Researchers recruited 21 patients with bipolar disorder in a euthymic phase and 21 matched healthy controls for the study. First, participants rated their emotional reactivity on two self-report scales: the Emotion Reactivity Scale (ERS) and the Multidimensional Assessment of Thymic States Scale (MAThyS). Next, they used headphones to listen to a series of 12 instrumental music excerpts lasting 45 seconds each with their eyes closed. After each musical selection, they were asked to rate how strongly they had experienced each of the nine emotional categories on the Geneva Emotional Music Scale: joy, sadness, tension, wonder, peacefulness, power, tenderness, nostalgia, and transcendence.

©Zoonar/hormydesign/Thinkstock

Statistical analyses showed that patients in the bipolar disorder group had a mean score of 41.2 on the ERS, compared with a mean score of 22.9 among healthy controls. In addition, bipolar disorder patients reported experiencing more tension and sadness than did healthy controls when listening to positive musical excerpts that had been classified as inducing joy and wonder.

“This finding tallies with the negative emotional bias displayed by depressed patients, who tend to experience more negative emotions than healthy controls,” the authors wrote. “Bipolar patients struggle so much to regulate their own positive emotions that it creates a chronic source of distress, which could be experienced as a negative emotion.”

Read the article in the Journal of Affective Disorders (2016 Feb;191:15-23. doi: 10.1016/j.jad.2015.10.063).

Dear Dr. Hospitalist:

Over the past several years, we have had a problem with physician retention, especially with nocturnists, in our medium-sized hospitalist group. Do you have any suggestions (beyond the obvious “more money”) to help us retain our hospitalists?

Missing My Friends in the Midwest

Dr. Hospitalist responds:

Since its inception, hospital medicine has been a very attractive field for practicing medicine, and although growth was phenomenal for many years (especially 2000–2010), it has leveled off over the past five years. With this exceptional growth have come increased salaries, geographically diverse job locations, and more opportunities for career development.

One of the most significant changes over the past 10 years is that hospital medicine is no longer seen as a bridge from residency to fellowship or as a stopover while waiting on the ideal job. Physicians now see hospital medicine as a career choice and are more likely to search for the “ideal” hospitalist job.

Although competitive salaries are important and a necessary starting point, to attract and keep career hospitalists, HM groups (HMGs) will need to offer opportunities for professional growth and leadership as well as flexible schedules.

Many larger HMGs offer several different schedule models, from the ubiquitous seven-on/seven-off schedule (54%, according to the 2014 State of Hospital Medicine report) to the more traditional five-day workweek with vacation time. Many also choose to work part- or full-time as a nocturnist and, in doing so, earn substantially more money (15%–20% differential). The flexible schedule and the ability to work part- or full-time have been very attractive to those clinicians just starting families or attaining another degree (MBAs are becoming very popular).

While there have always been the “check-in, check-out” docs who did their seven and didn’t want to be bothered during their time off, there were typically enough gunners around to pick up the slack. With the Millennial generation’s pervasive aim for work-life balance, it might become more difficult to find even a few who are willing to go the extra mile in hopes of career advancement. Mix in a very robust job market with a proclivity to travel, and you have a recipe for high attrition.

Like any new profession or specialty, HM will have to evolve and adjust to keep these new docs anchored. We will need to consider offering vacation time, especially for those who are willing to work a traditional Monday–Friday schedule. For those in academia with an interest in promotion, there should be real opportunities for advancement instead of the traditional “time in rank” and other nebulous requirements. There should be robust mentoring for all docs and especially for those just out of residency. The clinicians who express an interest in having an office in the C-Suite should be given a clear path and guidance.

I think with some innovation and recognition, most HMGs will have little problem retaining high-quality physicians. We must also recognize a changing value system and accept that some people will change jobs just because! TH

Dear Dr. Hospitalist:

Over the past several years, we have had a problem with physician retention, especially with nocturnists, in our medium-sized hospitalist group. Do you have any suggestions (beyond the obvious “more money”) to help us retain our hospitalists?

Missing My Friends in the Midwest

Dr. Hospitalist responds:

Since its inception, hospital medicine has been a very attractive field for practicing medicine, and although growth was phenomenal for many years (especially 2000–2010), it has leveled off over the past five years. With this exceptional growth have come increased salaries, geographically diverse job locations, and more opportunities for career development.

One of the most significant changes over the past 10 years is that hospital medicine is no longer seen as a bridge from residency to fellowship or as a stopover while waiting on the ideal job. Physicians now see hospital medicine as a career choice and are more likely to search for the “ideal” hospitalist job.

Although competitive salaries are important and a necessary starting point, to attract and keep career hospitalists, HM groups (HMGs) will need to offer opportunities for professional growth and leadership as well as flexible schedules.

Many larger HMGs offer several different schedule models, from the ubiquitous seven-on/seven-off schedule (54%, according to the 2014 State of Hospital Medicine report) to the more traditional five-day workweek with vacation time. Many also choose to work part- or full-time as a nocturnist and, in doing so, earn substantially more money (15%–20% differential). The flexible schedule and the ability to work part- or full-time have been very attractive to those clinicians just starting families or attaining another degree (MBAs are becoming very popular).

While there have always been the “check-in, check-out” docs who did their seven and didn’t want to be bothered during their time off, there were typically enough gunners around to pick up the slack. With the Millennial generation’s pervasive aim for work-life balance, it might become more difficult to find even a few who are willing to go the extra mile in hopes of career advancement. Mix in a very robust job market with a proclivity to travel, and you have a recipe for high attrition.

Like any new profession or specialty, HM will have to evolve and adjust to keep these new docs anchored. We will need to consider offering vacation time, especially for those who are willing to work a traditional Monday–Friday schedule. For those in academia with an interest in promotion, there should be real opportunities for advancement instead of the traditional “time in rank” and other nebulous requirements. There should be robust mentoring for all docs and especially for those just out of residency. The clinicians who express an interest in having an office in the C-Suite should be given a clear path and guidance.

I think with some innovation and recognition, most HMGs will have little problem retaining high-quality physicians. We must also recognize a changing value system and accept that some people will change jobs just because! TH

Dear Dr. Hospitalist:

Over the past several years, we have had a problem with physician retention, especially with nocturnists, in our medium-sized hospitalist group. Do you have any suggestions (beyond the obvious “more money”) to help us retain our hospitalists?

Missing My Friends in the Midwest

Dr. Hospitalist responds:

Since its inception, hospital medicine has been a very attractive field for practicing medicine, and although growth was phenomenal for many years (especially 2000–2010), it has leveled off over the past five years. With this exceptional growth have come increased salaries, geographically diverse job locations, and more opportunities for career development.

One of the most significant changes over the past 10 years is that hospital medicine is no longer seen as a bridge from residency to fellowship or as a stopover while waiting on the ideal job. Physicians now see hospital medicine as a career choice and are more likely to search for the “ideal” hospitalist job.

Although competitive salaries are important and a necessary starting point, to attract and keep career hospitalists, HM groups (HMGs) will need to offer opportunities for professional growth and leadership as well as flexible schedules.

Many larger HMGs offer several different schedule models, from the ubiquitous seven-on/seven-off schedule (54%, according to the 2014 State of Hospital Medicine report) to the more traditional five-day workweek with vacation time. Many also choose to work part- or full-time as a nocturnist and, in doing so, earn substantially more money (15%–20% differential). The flexible schedule and the ability to work part- or full-time have been very attractive to those clinicians just starting families or attaining another degree (MBAs are becoming very popular).

While there have always been the “check-in, check-out” docs who did their seven and didn’t want to be bothered during their time off, there were typically enough gunners around to pick up the slack. With the Millennial generation’s pervasive aim for work-life balance, it might become more difficult to find even a few who are willing to go the extra mile in hopes of career advancement. Mix in a very robust job market with a proclivity to travel, and you have a recipe for high attrition.

Like any new profession or specialty, HM will have to evolve and adjust to keep these new docs anchored. We will need to consider offering vacation time, especially for those who are willing to work a traditional Monday–Friday schedule. For those in academia with an interest in promotion, there should be real opportunities for advancement instead of the traditional “time in rank” and other nebulous requirements. There should be robust mentoring for all docs and especially for those just out of residency. The clinicians who express an interest in having an office in the C-Suite should be given a clear path and guidance.

I think with some innovation and recognition, most HMGs will have little problem retaining high-quality physicians. We must also recognize a changing value system and accept that some people will change jobs just because! TH

Clinical question: Does price display impact order costs and volume as well as patient safety outcomes, and is it acceptable to providers?

Background: Up to one-third of national healthcare expenditures are wasteful, with physicians playing a central role in overall cost, purchasing almost all tests and therapies for patients. Increasing the transparency of costs for physicians is one strategy to reduce unnecessary spending.

Study design: Systematic review.

Setting: Yale School of Medicine, New Haven, Conn.

Synopsis: Nineteen publications were selected for final analysis. Thirteen studies reported the impact of price display on costs, nine of which showed a statistically significant decrease in order costs. Only three of eight studies reporting the impact of price display on order volume showed statistically significant decreases in order volume. One study showed adverse safety findings in the form of higher rates of unscheduled follow-up care in a pediatric ED. Physicians were overall satisfied with price display in the five studies reporting this.

There was high heterogeneity among studies, which did not allow for pooling of data. Furthermore, more than half of the studies were conducted more than 15 years ago, limiting their generalizability to the modern era of electronic health records (EHRs).

Overall, this review supports the conclusion that price display has a modest effect on order costs. Additional studies utilizing EHR systems are required to more definitively confirm these findings.

Bottom line: Displaying prices to physicians can have a modest effect on overall order costs.

Citation: Silvestri MT, Bongiovanni TR, Glover JG, Gross CP. Impact of price display on provider ordering: a systematic review. J Hosp Med. 2016;11(1):65-76. doi:10.1002/jhm.2500.

Clinical question: Does price display impact order costs and volume as well as patient safety outcomes, and is it acceptable to providers?

Background: Up to one-third of national healthcare expenditures are wasteful, with physicians playing a central role in overall cost, purchasing almost all tests and therapies for patients. Increasing the transparency of costs for physicians is one strategy to reduce unnecessary spending.

Study design: Systematic review.

Setting: Yale School of Medicine, New Haven, Conn.

Synopsis: Nineteen publications were selected for final analysis. Thirteen studies reported the impact of price display on costs, nine of which showed a statistically significant decrease in order costs. Only three of eight studies reporting the impact of price display on order volume showed statistically significant decreases in order volume. One study showed adverse safety findings in the form of higher rates of unscheduled follow-up care in a pediatric ED. Physicians were overall satisfied with price display in the five studies reporting this.

There was high heterogeneity among studies, which did not allow for pooling of data. Furthermore, more than half of the studies were conducted more than 15 years ago, limiting their generalizability to the modern era of electronic health records (EHRs).

Overall, this review supports the conclusion that price display has a modest effect on order costs. Additional studies utilizing EHR systems are required to more definitively confirm these findings.

Bottom line: Displaying prices to physicians can have a modest effect on overall order costs.

Citation: Silvestri MT, Bongiovanni TR, Glover JG, Gross CP. Impact of price display on provider ordering: a systematic review. J Hosp Med. 2016;11(1):65-76. doi:10.1002/jhm.2500.

Clinical question: Does price display impact order costs and volume as well as patient safety outcomes, and is it acceptable to providers?

Background: Up to one-third of national healthcare expenditures are wasteful, with physicians playing a central role in overall cost, purchasing almost all tests and therapies for patients. Increasing the transparency of costs for physicians is one strategy to reduce unnecessary spending.

Study design: Systematic review.

Setting: Yale School of Medicine, New Haven, Conn.

Synopsis: Nineteen publications were selected for final analysis. Thirteen studies reported the impact of price display on costs, nine of which showed a statistically significant decrease in order costs. Only three of eight studies reporting the impact of price display on order volume showed statistically significant decreases in order volume. One study showed adverse safety findings in the form of higher rates of unscheduled follow-up care in a pediatric ED. Physicians were overall satisfied with price display in the five studies reporting this.

There was high heterogeneity among studies, which did not allow for pooling of data. Furthermore, more than half of the studies were conducted more than 15 years ago, limiting their generalizability to the modern era of electronic health records (EHRs).

Overall, this review supports the conclusion that price display has a modest effect on order costs. Additional studies utilizing EHR systems are required to more definitively confirm these findings.

Bottom line: Displaying prices to physicians can have a modest effect on overall order costs.

Citation: Silvestri MT, Bongiovanni TR, Glover JG, Gross CP. Impact of price display on provider ordering: a systematic review. J Hosp Med. 2016;11(1):65-76. doi:10.1002/jhm.2500.

Micrograph showing AML

Two genes are critical to the development of acute myeloid leukemia (AML), according to research published in Cancer Cell.

Previous research suggested the genes, KDM4C and PRMT1, are key players in transcription regulation during both normal and disease development.

The new study showed that, during AML development, KDM4C and PRMT1 are recruited to enable the transformation of blood cells into cancer cells.

The genes work in tandem, and, if either is not fully active, AML does not develop.

The researchers made these discoveries by inhibiting KDM4C and PRMT1—either genetically or pharmacologically—in mice with AML.

When either gene was silenced via genetic means, the majority of the mice were still alive at the end of the researchers’ 60-day experiment. However, the majority of control mice died in less than 40 days.

The team observed similarly favorable results when they inhibited either gene with drugs—the PRMT1 inhibitor AMI-408 and the KDM4C inhibitor SD70.

The median disease latency was 48 days in mice that received AMI-408 and 36 days in control mice. The median disease latency was 62 days in mice that received SD70 and 55 days in control mice.

“The demonstration of how critical these genes are to cancer transformation and treatment could be highly significant for the design of new drugs,” said study author Eric So, PhD, of King’s College London in the UK.

“Further work is needed to develop and refine drugs to maximize their effects and so that they are suitable for patients. Clinical trials will then be needed to see how leukemia patients respond to these drugs and how use of them can be optimized.”

Micrograph showing AML

Two genes are critical to the development of acute myeloid leukemia (AML), according to research published in Cancer Cell.

Previous research suggested the genes, KDM4C and PRMT1, are key players in transcription regulation during both normal and disease development.

The new study showed that, during AML development, KDM4C and PRMT1 are recruited to enable the transformation of blood cells into cancer cells.

The genes work in tandem, and, if either is not fully active, AML does not develop.

The researchers made these discoveries by inhibiting KDM4C and PRMT1—either genetically or pharmacologically—in mice with AML.

When either gene was silenced via genetic means, the majority of the mice were still alive at the end of the researchers’ 60-day experiment. However, the majority of control mice died in less than 40 days.

The team observed similarly favorable results when they inhibited either gene with drugs—the PRMT1 inhibitor AMI-408 and the KDM4C inhibitor SD70.

The median disease latency was 48 days in mice that received AMI-408 and 36 days in control mice. The median disease latency was 62 days in mice that received SD70 and 55 days in control mice.

“The demonstration of how critical these genes are to cancer transformation and treatment could be highly significant for the design of new drugs,” said study author Eric So, PhD, of King’s College London in the UK.

“Further work is needed to develop and refine drugs to maximize their effects and so that they are suitable for patients. Clinical trials will then be needed to see how leukemia patients respond to these drugs and how use of them can be optimized.”

Micrograph showing AML

Two genes are critical to the development of acute myeloid leukemia (AML), according to research published in Cancer Cell.

Previous research suggested the genes, KDM4C and PRMT1, are key players in transcription regulation during both normal and disease development.

The new study showed that, during AML development, KDM4C and PRMT1 are recruited to enable the transformation of blood cells into cancer cells.

The genes work in tandem, and, if either is not fully active, AML does not develop.

The researchers made these discoveries by inhibiting KDM4C and PRMT1—either genetically or pharmacologically—in mice with AML.

When either gene was silenced via genetic means, the majority of the mice were still alive at the end of the researchers’ 60-day experiment. However, the majority of control mice died in less than 40 days.

The team observed similarly favorable results when they inhibited either gene with drugs—the PRMT1 inhibitor AMI-408 and the KDM4C inhibitor SD70.

The median disease latency was 48 days in mice that received AMI-408 and 36 days in control mice. The median disease latency was 62 days in mice that received SD70 and 55 days in control mice.

“The demonstration of how critical these genes are to cancer transformation and treatment could be highly significant for the design of new drugs,” said study author Eric So, PhD, of King’s College London in the UK.

“Further work is needed to develop and refine drugs to maximize their effects and so that they are suitable for patients. Clinical trials will then be needed to see how leukemia patients respond to these drugs and how use of them can be optimized.”

Three generations of a family

New research suggests childhood leukemias are forged by different evolutionary forces than leukemias in older adults.

Researchers used a computational model to characterize the population dynamics of hematopoietic stem cells (HSCs) that give rise to leukemias.

And they found the evolutionary force known as “drift” contributes to leukemia development in young children but not in older adults.

“Basically, leukemia risk early in life may be more dictated by chance than by the typical ‘survival of the fittest’ that characterizes leukemia formation in older adults,” explained study author James DeGregori, PhD, of the University of Colorado School of Medicine in Aurora.

He and his colleagues recounted this discovery in PNAS.

With previous work, the DeGregori lab showed that the inevitable tissue decline associated with aging benefits HSCs with mutations that allow the cells to better adapt to the new ecosystem.

In contrast, the ecosystem of young tissue favors healthy cells. Optimized by millions of years of co-evolution, most mutations make cells less fit for the ecosystem of young, healthy tissue and lead to purging of mutant cells from the tissue.

With the current study, Dr DeGregori and his colleagues made a surprising discovery. Despite the ability of young tissue to select against cells with cancer-causing mutations, the computational model showed increased proportions of specific, mutation-bearing HSCs in the first few years after birth.

And these mutated cells were not dependent on the effect of the mutation on cell fitness. In other words, the mutation-bearing cells were not more fit than cells without the mutations. Instead of the survival-of-the-fittest form of natural selection that drives the evolution of cancer in older adults, there was another force at work.

In fact, the researchers discovered 2 factors that influence the development of childhood leukemia: the small HSC pool size at birth and the high rate of cell division necessary for body growth early in life.

The high rate of cell division increases the risk of leukemia because mutations largely happen during cell divisions. More cell divisions mean more mutations, and this increases the risk that some of these mutations could contribute to leukemia development.

The small HSC pool size influences leukemia development via the evolutionary force known as drift. Drift is the role of chance—the possibility that, despite being less fit, an animal, organism, or HSC with an oncogenic mutation will survive to shift the genetic makeup of the population.

The influence of drift is greater in small populations and, in this case, small stem cell pools. In the small HSC pools of young children, drift becomes important as a lucky genotype may end up with a larger share of the total HSC pool than warranted by its fitness status.

If this lucky cell clone happens to have a mutation that can start the HSC down the path toward leukemia, this drift-driven expansion should increase the risk of leukemia by increasing the number of HSCs with this mutation.

“Thus, early somatic evolution in HSC pools is significantly impacted by drift, with selection playing a lesser role,” Dr DeGregori and his colleagues wrote.

On the other hand, the impact of drift lessens as the HSC pool grows along with an infant’s body to reach adult size. The larger HSC pool size decreases the role of drift in the success of particular cells in the tissue.

In addition, as the pool size reaches its maximum, the HSC division rate slows to a crawl (as these stem cells enter the maintenance rather than growth phase). With a landscape of healthy, youthful tissues and low rates of mutation due to low cell division rates, the odds of leukemia diminish.

“With a large population of healthy cells optimized to young, healthy tissue, the ability of mutations, including cancerous mutations, to drive uncontrolled cell proliferation is reduced,” Dr DeGregori said.

However, in old age, tissue decline promotes selection for adaptive mutations, leading to the expansion of potentially oncogenic HSC clones that will again increase the risk of leukemia.

Thus, this research shows that, in early life, leukemias are driven by mutation and drift. And in later life, leukemias are driven by mutation and selection.

“We show that leukemias of children and older adults are different diseases, forged by different evolutionary forces and propagated under different circumstances,” Dr DeGregori said.

He and his colleagues believe this understanding raises the possibility of a new approach to cancer treatment. Perhaps researchers could find a way to manipulate the parameters of cell evolution or manipulate the tissue ecosystem to decrease cancer risk.

Three generations of a family

New research suggests childhood leukemias are forged by different evolutionary forces than leukemias in older adults.

Researchers used a computational model to characterize the population dynamics of hematopoietic stem cells (HSCs) that give rise to leukemias.

And they found the evolutionary force known as “drift” contributes to leukemia development in young children but not in older adults.

“Basically, leukemia risk early in life may be more dictated by chance than by the typical ‘survival of the fittest’ that characterizes leukemia formation in older adults,” explained study author James DeGregori, PhD, of the University of Colorado School of Medicine in Aurora.

He and his colleagues recounted this discovery in PNAS.

With previous work, the DeGregori lab showed that the inevitable tissue decline associated with aging benefits HSCs with mutations that allow the cells to better adapt to the new ecosystem.

In contrast, the ecosystem of young tissue favors healthy cells. Optimized by millions of years of co-evolution, most mutations make cells less fit for the ecosystem of young, healthy tissue and lead to purging of mutant cells from the tissue.

With the current study, Dr DeGregori and his colleagues made a surprising discovery. Despite the ability of young tissue to select against cells with cancer-causing mutations, the computational model showed increased proportions of specific, mutation-bearing HSCs in the first few years after birth.

And these mutated cells were not dependent on the effect of the mutation on cell fitness. In other words, the mutation-bearing cells were not more fit than cells without the mutations. Instead of the survival-of-the-fittest form of natural selection that drives the evolution of cancer in older adults, there was another force at work.

In fact, the researchers discovered 2 factors that influence the development of childhood leukemia: the small HSC pool size at birth and the high rate of cell division necessary for body growth early in life.

The high rate of cell division increases the risk of leukemia because mutations largely happen during cell divisions. More cell divisions mean more mutations, and this increases the risk that some of these mutations could contribute to leukemia development.

The small HSC pool size influences leukemia development via the evolutionary force known as drift. Drift is the role of chance—the possibility that, despite being less fit, an animal, organism, or HSC with an oncogenic mutation will survive to shift the genetic makeup of the population.

The influence of drift is greater in small populations and, in this case, small stem cell pools. In the small HSC pools of young children, drift becomes important as a lucky genotype may end up with a larger share of the total HSC pool than warranted by its fitness status.

If this lucky cell clone happens to have a mutation that can start the HSC down the path toward leukemia, this drift-driven expansion should increase the risk of leukemia by increasing the number of HSCs with this mutation.

“Thus, early somatic evolution in HSC pools is significantly impacted by drift, with selection playing a lesser role,” Dr DeGregori and his colleagues wrote.

On the other hand, the impact of drift lessens as the HSC pool grows along with an infant’s body to reach adult size. The larger HSC pool size decreases the role of drift in the success of particular cells in the tissue.

In addition, as the pool size reaches its maximum, the HSC division rate slows to a crawl (as these stem cells enter the maintenance rather than growth phase). With a landscape of healthy, youthful tissues and low rates of mutation due to low cell division rates, the odds of leukemia diminish.

“With a large population of healthy cells optimized to young, healthy tissue, the ability of mutations, including cancerous mutations, to drive uncontrolled cell proliferation is reduced,” Dr DeGregori said.

However, in old age, tissue decline promotes selection for adaptive mutations, leading to the expansion of potentially oncogenic HSC clones that will again increase the risk of leukemia.

Thus, this research shows that, in early life, leukemias are driven by mutation and drift. And in later life, leukemias are driven by mutation and selection.

“We show that leukemias of children and older adults are different diseases, forged by different evolutionary forces and propagated under different circumstances,” Dr DeGregori said.

He and his colleagues believe this understanding raises the possibility of a new approach to cancer treatment. Perhaps researchers could find a way to manipulate the parameters of cell evolution or manipulate the tissue ecosystem to decrease cancer risk.

Three generations of a family

New research suggests childhood leukemias are forged by different evolutionary forces than leukemias in older adults.

Researchers used a computational model to characterize the population dynamics of hematopoietic stem cells (HSCs) that give rise to leukemias.

And they found the evolutionary force known as “drift” contributes to leukemia development in young children but not in older adults.

“Basically, leukemia risk early in life may be more dictated by chance than by the typical ‘survival of the fittest’ that characterizes leukemia formation in older adults,” explained study author James DeGregori, PhD, of the University of Colorado School of Medicine in Aurora.

He and his colleagues recounted this discovery in PNAS.

With previous work, the DeGregori lab showed that the inevitable tissue decline associated with aging benefits HSCs with mutations that allow the cells to better adapt to the new ecosystem.

In contrast, the ecosystem of young tissue favors healthy cells. Optimized by millions of years of co-evolution, most mutations make cells less fit for the ecosystem of young, healthy tissue and lead to purging of mutant cells from the tissue.

With the current study, Dr DeGregori and his colleagues made a surprising discovery. Despite the ability of young tissue to select against cells with cancer-causing mutations, the computational model showed increased proportions of specific, mutation-bearing HSCs in the first few years after birth.

And these mutated cells were not dependent on the effect of the mutation on cell fitness. In other words, the mutation-bearing cells were not more fit than cells without the mutations. Instead of the survival-of-the-fittest form of natural selection that drives the evolution of cancer in older adults, there was another force at work.

In fact, the researchers discovered 2 factors that influence the development of childhood leukemia: the small HSC pool size at birth and the high rate of cell division necessary for body growth early in life.

The high rate of cell division increases the risk of leukemia because mutations largely happen during cell divisions. More cell divisions mean more mutations, and this increases the risk that some of these mutations could contribute to leukemia development.

The small HSC pool size influences leukemia development via the evolutionary force known as drift. Drift is the role of chance—the possibility that, despite being less fit, an animal, organism, or HSC with an oncogenic mutation will survive to shift the genetic makeup of the population.

The influence of drift is greater in small populations and, in this case, small stem cell pools. In the small HSC pools of young children, drift becomes important as a lucky genotype may end up with a larger share of the total HSC pool than warranted by its fitness status.

If this lucky cell clone happens to have a mutation that can start the HSC down the path toward leukemia, this drift-driven expansion should increase the risk of leukemia by increasing the number of HSCs with this mutation.

“Thus, early somatic evolution in HSC pools is significantly impacted by drift, with selection playing a lesser role,” Dr DeGregori and his colleagues wrote.

On the other hand, the impact of drift lessens as the HSC pool grows along with an infant’s body to reach adult size. The larger HSC pool size decreases the role of drift in the success of particular cells in the tissue.

In addition, as the pool size reaches its maximum, the HSC division rate slows to a crawl (as these stem cells enter the maintenance rather than growth phase). With a landscape of healthy, youthful tissues and low rates of mutation due to low cell division rates, the odds of leukemia diminish.

“With a large population of healthy cells optimized to young, healthy tissue, the ability of mutations, including cancerous mutations, to drive uncontrolled cell proliferation is reduced,” Dr DeGregori said.

However, in old age, tissue decline promotes selection for adaptive mutations, leading to the expansion of potentially oncogenic HSC clones that will again increase the risk of leukemia.

Thus, this research shows that, in early life, leukemias are driven by mutation and drift. And in later life, leukemias are driven by mutation and selection.

“We show that leukemias of children and older adults are different diseases, forged by different evolutionary forces and propagated under different circumstances,” Dr DeGregori said.

He and his colleagues believe this understanding raises the possibility of a new approach to cancer treatment. Perhaps researchers could find a way to manipulate the parameters of cell evolution or manipulate the tissue ecosystem to decrease cancer risk.

Microcapsules

Image courtesy of Ronald Xu

& The Ohio State University

Researchers say they have developed a quick and controllable method for getting 2 or more ingredients into the same tiny drug capsule and having them mix only when triggered by a signal like vibrations or heat.

This work was inspired by the search for targeted drug delivery options to treat cancers.

The idea with this multi-ingredient capsule is that the ingredients must be mixed for the drug to work, and the mixing could be triggered in targeted areas of the body, thereby boosting drug efficiency while reducing side effects.

While the researchers found they could use their technique to create multi-ingredient microcapsules, they have not yet used it to encapsulate cancer treatments.

They described their work in Applied Physics Letters.

“One of the limitations of chemotherapy is that less than 5% of the drugs typically get to the tumor, while the rest can be absorbed by other organs,” said study author Ronald Xu, PhD, of The Ohio State University in Columbus.

He and his colleagues thought one possible way to address this problem could be to make the drugs non-toxic when injected into the body and trigger mixing that would produce a toxic product only near the tumor site.

The researchers knew that, for such drugs to work on a large scale, there must be a way to quickly, controllably, and cost-effectively produce capsules with 2 or more active ingredients. If the drugs are to be injected and spread through the body via the bloodstream, the capsules should also be small.

With that in mind, Dr Xu and his colleagues developed a device that can produce tiny capsules approximately 100 microns across with multiple inner ingredients.

The device works by funneling different ingredients through 2 inner needles. These needles run parallel to each other and are both enclosed in a larger outer needle, which contains an ingredient for making the outer shell of the capsule.

As all the ingredients exit the needles through a single nozzle, a high-speed gas forces the liquids into a narrow stream that breaks into individual droplets. An electric field stabilizes the flow so that uniform droplets are created.

Depending on the relative flow rates, each droplet may contain 2 or more smaller inner droplets made from the ingredients in the inner needles.

The researchers tested their device with colored paraffin wax—red in one needle and blue in the other. The outer shell was made from sodium alginate, a material extracted from seaweed that turned gelatinous when the droplets fell into a calcium chloride solution.

Depending on the experimental conditions, the team was able to produce between 1000 and 100,000 capsules per second, and nearly 100% of the inner liquids were incorporated into the capsules without any waste.

Once encapsulated, the 2 colors of wax did not mix because of surface tension. But the researchers found they could force the red and blue wax to merge by vibrating the capsules. The team also discovered they could release the inner droplets by dissolving the outer shell.

The key features of the new device are its high efficiency and yield, and the fact that the size of the droplets can be uniformly controlled, Dr Xu said.

He added that, by further fine-tuning the device’s operation, the team could make capsules that are 3-5 microns across, about the size of a red blood cell. The process can also be scaled up by building an array of nozzles and could be modified to encapsulate 3 or more active ingredients by adding additional inner needles.

While Dr Xu and his colleagues were motivated by drug delivery, they believe their device might also find wider use in a range of applications that require controlled reactions, such as regenerative medicine and nuclear and chemical engineering.

Microcapsules

Image courtesy of Ronald Xu

& The Ohio State University

Researchers say they have developed a quick and controllable method for getting 2 or more ingredients into the same tiny drug capsule and having them mix only when triggered by a signal like vibrations or heat.

This work was inspired by the search for targeted drug delivery options to treat cancers.

The idea with this multi-ingredient capsule is that the ingredients must be mixed for the drug to work, and the mixing could be triggered in targeted areas of the body, thereby boosting drug efficiency while reducing side effects.

While the researchers found they could use their technique to create multi-ingredient microcapsules, they have not yet used it to encapsulate cancer treatments.

They described their work in Applied Physics Letters.

“One of the limitations of chemotherapy is that less than 5% of the drugs typically get to the tumor, while the rest can be absorbed by other organs,” said study author Ronald Xu, PhD, of The Ohio State University in Columbus.

He and his colleagues thought one possible way to address this problem could be to make the drugs non-toxic when injected into the body and trigger mixing that would produce a toxic product only near the tumor site.

The researchers knew that, for such drugs to work on a large scale, there must be a way to quickly, controllably, and cost-effectively produce capsules with 2 or more active ingredients. If the drugs are to be injected and spread through the body via the bloodstream, the capsules should also be small.

With that in mind, Dr Xu and his colleagues developed a device that can produce tiny capsules approximately 100 microns across with multiple inner ingredients.

The device works by funneling different ingredients through 2 inner needles. These needles run parallel to each other and are both enclosed in a larger outer needle, which contains an ingredient for making the outer shell of the capsule.

As all the ingredients exit the needles through a single nozzle, a high-speed gas forces the liquids into a narrow stream that breaks into individual droplets. An electric field stabilizes the flow so that uniform droplets are created.

Depending on the relative flow rates, each droplet may contain 2 or more smaller inner droplets made from the ingredients in the inner needles.

The researchers tested their device with colored paraffin wax—red in one needle and blue in the other. The outer shell was made from sodium alginate, a material extracted from seaweed that turned gelatinous when the droplets fell into a calcium chloride solution.

Depending on the experimental conditions, the team was able to produce between 1000 and 100,000 capsules per second, and nearly 100% of the inner liquids were incorporated into the capsules without any waste.

Once encapsulated, the 2 colors of wax did not mix because of surface tension. But the researchers found they could force the red and blue wax to merge by vibrating the capsules. The team also discovered they could release the inner droplets by dissolving the outer shell.

The key features of the new device are its high efficiency and yield, and the fact that the size of the droplets can be uniformly controlled, Dr Xu said.

He added that, by further fine-tuning the device’s operation, the team could make capsules that are 3-5 microns across, about the size of a red blood cell. The process can also be scaled up by building an array of nozzles and could be modified to encapsulate 3 or more active ingredients by adding additional inner needles.

While Dr Xu and his colleagues were motivated by drug delivery, they believe their device might also find wider use in a range of applications that require controlled reactions, such as regenerative medicine and nuclear and chemical engineering.

Microcapsules

Image courtesy of Ronald Xu

& The Ohio State University

Researchers say they have developed a quick and controllable method for getting 2 or more ingredients into the same tiny drug capsule and having them mix only when triggered by a signal like vibrations or heat.

This work was inspired by the search for targeted drug delivery options to treat cancers.

The idea with this multi-ingredient capsule is that the ingredients must be mixed for the drug to work, and the mixing could be triggered in targeted areas of the body, thereby boosting drug efficiency while reducing side effects.

While the researchers found they could use their technique to create multi-ingredient microcapsules, they have not yet used it to encapsulate cancer treatments.

They described their work in Applied Physics Letters.

“One of the limitations of chemotherapy is that less than 5% of the drugs typically get to the tumor, while the rest can be absorbed by other organs,” said study author Ronald Xu, PhD, of The Ohio State University in Columbus.

He and his colleagues thought one possible way to address this problem could be to make the drugs non-toxic when injected into the body and trigger mixing that would produce a toxic product only near the tumor site.

The researchers knew that, for such drugs to work on a large scale, there must be a way to quickly, controllably, and cost-effectively produce capsules with 2 or more active ingredients. If the drugs are to be injected and spread through the body via the bloodstream, the capsules should also be small.

With that in mind, Dr Xu and his colleagues developed a device that can produce tiny capsules approximately 100 microns across with multiple inner ingredients.

The device works by funneling different ingredients through 2 inner needles. These needles run parallel to each other and are both enclosed in a larger outer needle, which contains an ingredient for making the outer shell of the capsule.

As all the ingredients exit the needles through a single nozzle, a high-speed gas forces the liquids into a narrow stream that breaks into individual droplets. An electric field stabilizes the flow so that uniform droplets are created.

Depending on the relative flow rates, each droplet may contain 2 or more smaller inner droplets made from the ingredients in the inner needles.

The researchers tested their device with colored paraffin wax—red in one needle and blue in the other. The outer shell was made from sodium alginate, a material extracted from seaweed that turned gelatinous when the droplets fell into a calcium chloride solution.

Depending on the experimental conditions, the team was able to produce between 1000 and 100,000 capsules per second, and nearly 100% of the inner liquids were incorporated into the capsules without any waste.

Once encapsulated, the 2 colors of wax did not mix because of surface tension. But the researchers found they could force the red and blue wax to merge by vibrating the capsules. The team also discovered they could release the inner droplets by dissolving the outer shell.

The key features of the new device are its high efficiency and yield, and the fact that the size of the droplets can be uniformly controlled, Dr Xu said.

He added that, by further fine-tuning the device’s operation, the team could make capsules that are 3-5 microns across, about the size of a red blood cell. The process can also be scaled up by building an array of nozzles and could be modified to encapsulate 3 or more active ingredients by adding additional inner needles.

While Dr Xu and his colleagues were motivated by drug delivery, they believe their device might also find wider use in a range of applications that require controlled reactions, such as regenerative medicine and nuclear and chemical engineering.

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

Results of a phase 3 study suggest that administering antihuman T-lymphocyte immune globulin (ATG) prior to hematopoietic stem cell transplant (HSCT) can decrease the risk and severity of chronic graft-versus-host disease (GVHD).

Study investigators included ATG in the conditioning regimens of leukemia patients receiving peripheral blood stem cells from an HLA-identical sibling donor.

Two years after HSCT, these patients had less than half the rate of chronic GVHD of patients who did not receive ATG.

In addition, patients who received ATG were less likely to have severe chronic GVHD.

Nicolaus Kroger, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and his colleagues reported these results in NEJM.

The investigators enrolled 168 patients undergoing HSCT at 27 centers. They were randomized in a 1:1 ratio to receive ATG or not.

One hundred and fifty-five patients were randomized and evaluable—83 in the ATG group and 72 in the non-ATG group.

The only significant difference in baseline characteristics was age. The median age was 39 (range, 18-64) in the ATG group and 43.5 (range, 21-61) in the non-ATG group (P=0.04).

Most patients in both groups were male (63.9% and 55.6%, respectively), and most had acute myeloid leukemia (66.3% and 76.4%, respectively) rather than acute lymphoblastic leukemia (33.8% and 23.6%, respectively).

Most patients had intermediate-risk disease (75.9% and 82.1%, respectively), and a minority had high-risk cytogenetics (37.3% and 30.6%, respectively).

The median time between diagnosis and HSCT was about 5 months in both groups. Both groups had a median of 2 courses of chemotherapy before transplant (overall range, 1-8).

Most patients in both groups received busulfan plus cyclophosphamide as conditioning—67.5% of the ATG group and 70.8% of the non-ATG group. Some received total-body irradiation plus cyclophosphamide (27.7% and 25.0%, respectively), and a few received total-body irradiation plus etoposide (4.8% and 4.2%, respectively).

Results

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was significantly lower in the ATG group than the non-ATG group—32.2% and 68.7%, respectively (P<0.001).

In addition, patients in the ATG group were significantly less likely to have severe or extensive chronic GVHD.

According to revised Seattle criteria, the rate of limited chronic GVHD was 20.5% in the ATG group and 30.6% in the non-ATG group. And the rates of extensive chronic GVHD were 6% and 33.3%, respectively (P<0.001).

According to revised NIH criteria, the rate of mild chronic GVHD was 15.7% in the ATG group and 16.7% in the non-ATG group. The rates of moderate chronic GVHD were 8.4% and 25%, respectively. And the rates of severe chronic GVHD were 2.4% and 22.2%, respectively (P<0.001).

However, all other outcomes, when assessed alone, were similar between the treatment groups.

The rate of 2-year relapse-free survival was 59.4% in the ATG group and 64.6% in the non-ATG group (P=0.21). The overall survival rates were 74.1% and 77.9%, respectively (P=0.46).

The incidence of relapse was 32.2% and 35.5%, respectively (P=0.17). Infectious complications occurred in 57.8% and 54.2%, respectively (P=0.65). And the rates of acute GVHD were 10.8% and 18.1%, respectively (P=0.13).

However, the rate of a composite endpoint of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than the non-ATG group—36.6% and 16.8%, respectively (P=0.005).

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

Results of a phase 3 study suggest that administering antihuman T-lymphocyte immune globulin (ATG) prior to hematopoietic stem cell transplant (HSCT) can decrease the risk and severity of chronic graft-versus-host disease (GVHD).

Study investigators included ATG in the conditioning regimens of leukemia patients receiving peripheral blood stem cells from an HLA-identical sibling donor.

Two years after HSCT, these patients had less than half the rate of chronic GVHD of patients who did not receive ATG.

In addition, patients who received ATG were less likely to have severe chronic GVHD.

Nicolaus Kroger, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and his colleagues reported these results in NEJM.

The investigators enrolled 168 patients undergoing HSCT at 27 centers. They were randomized in a 1:1 ratio to receive ATG or not.

One hundred and fifty-five patients were randomized and evaluable—83 in the ATG group and 72 in the non-ATG group.

The only significant difference in baseline characteristics was age. The median age was 39 (range, 18-64) in the ATG group and 43.5 (range, 21-61) in the non-ATG group (P=0.04).

Most patients in both groups were male (63.9% and 55.6%, respectively), and most had acute myeloid leukemia (66.3% and 76.4%, respectively) rather than acute lymphoblastic leukemia (33.8% and 23.6%, respectively).

Most patients had intermediate-risk disease (75.9% and 82.1%, respectively), and a minority had high-risk cytogenetics (37.3% and 30.6%, respectively).

The median time between diagnosis and HSCT was about 5 months in both groups. Both groups had a median of 2 courses of chemotherapy before transplant (overall range, 1-8).

Most patients in both groups received busulfan plus cyclophosphamide as conditioning—67.5% of the ATG group and 70.8% of the non-ATG group. Some received total-body irradiation plus cyclophosphamide (27.7% and 25.0%, respectively), and a few received total-body irradiation plus etoposide (4.8% and 4.2%, respectively).

Results

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was significantly lower in the ATG group than the non-ATG group—32.2% and 68.7%, respectively (P<0.001).

In addition, patients in the ATG group were significantly less likely to have severe or extensive chronic GVHD.

According to revised Seattle criteria, the rate of limited chronic GVHD was 20.5% in the ATG group and 30.6% in the non-ATG group. And the rates of extensive chronic GVHD were 6% and 33.3%, respectively (P<0.001).

According to revised NIH criteria, the rate of mild chronic GVHD was 15.7% in the ATG group and 16.7% in the non-ATG group. The rates of moderate chronic GVHD were 8.4% and 25%, respectively. And the rates of severe chronic GVHD were 2.4% and 22.2%, respectively (P<0.001).

However, all other outcomes, when assessed alone, were similar between the treatment groups.

The rate of 2-year relapse-free survival was 59.4% in the ATG group and 64.6% in the non-ATG group (P=0.21). The overall survival rates were 74.1% and 77.9%, respectively (P=0.46).

The incidence of relapse was 32.2% and 35.5%, respectively (P=0.17). Infectious complications occurred in 57.8% and 54.2%, respectively (P=0.65). And the rates of acute GVHD were 10.8% and 18.1%, respectively (P=0.13).

However, the rate of a composite endpoint of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than the non-ATG group—36.6% and 16.8%, respectively (P=0.005).

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

Results of a phase 3 study suggest that administering antihuman T-lymphocyte immune globulin (ATG) prior to hematopoietic stem cell transplant (HSCT) can decrease the risk and severity of chronic graft-versus-host disease (GVHD).

Study investigators included ATG in the conditioning regimens of leukemia patients receiving peripheral blood stem cells from an HLA-identical sibling donor.

Two years after HSCT, these patients had less than half the rate of chronic GVHD of patients who did not receive ATG.

In addition, patients who received ATG were less likely to have severe chronic GVHD.

Nicolaus Kroger, MD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and his colleagues reported these results in NEJM.

The investigators enrolled 168 patients undergoing HSCT at 27 centers. They were randomized in a 1:1 ratio to receive ATG or not.

One hundred and fifty-five patients were randomized and evaluable—83 in the ATG group and 72 in the non-ATG group.

The only significant difference in baseline characteristics was age. The median age was 39 (range, 18-64) in the ATG group and 43.5 (range, 21-61) in the non-ATG group (P=0.04).

Most patients in both groups were male (63.9% and 55.6%, respectively), and most had acute myeloid leukemia (66.3% and 76.4%, respectively) rather than acute lymphoblastic leukemia (33.8% and 23.6%, respectively).

Most patients had intermediate-risk disease (75.9% and 82.1%, respectively), and a minority had high-risk cytogenetics (37.3% and 30.6%, respectively).

The median time between diagnosis and HSCT was about 5 months in both groups. Both groups had a median of 2 courses of chemotherapy before transplant (overall range, 1-8).

Most patients in both groups received busulfan plus cyclophosphamide as conditioning—67.5% of the ATG group and 70.8% of the non-ATG group. Some received total-body irradiation plus cyclophosphamide (27.7% and 25.0%, respectively), and a few received total-body irradiation plus etoposide (4.8% and 4.2%, respectively).

Results

After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was significantly lower in the ATG group than the non-ATG group—32.2% and 68.7%, respectively (P<0.001).

In addition, patients in the ATG group were significantly less likely to have severe or extensive chronic GVHD.

According to revised Seattle criteria, the rate of limited chronic GVHD was 20.5% in the ATG group and 30.6% in the non-ATG group. And the rates of extensive chronic GVHD were 6% and 33.3%, respectively (P<0.001).

According to revised NIH criteria, the rate of mild chronic GVHD was 15.7% in the ATG group and 16.7% in the non-ATG group. The rates of moderate chronic GVHD were 8.4% and 25%, respectively. And the rates of severe chronic GVHD were 2.4% and 22.2%, respectively (P<0.001).

However, all other outcomes, when assessed alone, were similar between the treatment groups.

The rate of 2-year relapse-free survival was 59.4% in the ATG group and 64.6% in the non-ATG group (P=0.21). The overall survival rates were 74.1% and 77.9%, respectively (P=0.46).

The incidence of relapse was 32.2% and 35.5%, respectively (P=0.17). Infectious complications occurred in 57.8% and 54.2%, respectively (P=0.65). And the rates of acute GVHD were 10.8% and 18.1%, respectively (P=0.13).

However, the rate of a composite endpoint of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than the non-ATG group—36.6% and 16.8%, respectively (P=0.005).