To the Editor:

The shiitake mushroom (Lentinula edodes) is a popular Asian food and represents the second most consumed mushroom in the world. It is known for having a range of strong health benefits including antihypertensive, anti-inflammatory, and immunomodulatory effects. Especially in Asia, this mushroom has been used in patients with cancers of the gastrointestinal tract and also may be helpful in the treatment of human immunodeficiency virus.^1,2 The source of these effects is lentinan, a polysaccharide in the mushroom. However, lentinan also can cause a toxic reaction of the skin when the mushrooms are eaten raw or undercooked. These reactions are mainly reported in Asia, but more cases have been published in the last decade in Europe and the United States, evidence that the incidence of this adverse effect has increased in the Western world.

A 65-year-old woman with no notable medical history presented to our outpatient practice with sudden onset of a pruritic, erythematous, papular eruption on the neck. The eruption began that morning. The diagnosis of eczematous dermatitis was made and hydrocortisone cream 2.5% was started. Three days later, she returned with spread of the rash to the trunk, arms, and legs despite the topical treatment. She denied fevers, chills, or constitutional symptoms. The patient also denied recent travel or bug bites. However, she reported that she recently had started using raw shiitake mushrooms in her salad; the first time was 3 days before the symptoms appeared. Physical examination revealed erythematous skin with long flagellate streaks composed of petechiae, papules, and vesicles involving the trunk, arms, and legs (Figure). Oral and nasal mucosae were uninvolved. Dermatographism was negative. The diagnosis of flagellate dermatitis from shiitake mushrooms was made given the patient’s history and the unique clinical findings of the skin. Blood work and a biopsy were not performed. Instead, the patient was advised to avoid shiitake mushrooms and use clobetasol propionate cream 0.05% twice daily for 2 weeks on the affected areas. The symptoms resolved within 10 days.

Erythematous flagellate streaks composed of petechiae, papules, and vesicles localized on the patient’s back (A) and right upper arm (B) associated with shiitake mushroom consumption.

The first known case of toxicoderma to shiitake mushrooms was reported in Japan by Nakamura³ in 1977. Since this seminal report, numerous cases have followed. This disorder is mainly seen in Asia.

Patients usually present with linear groups of pruritic, papular, petechial, and vesicular lesions in a flagellate pattern, most commonly localized on the trunk, arms, and legs. Oral and nasal mucosae usually are not involved, and fever and malaise may be associated. All symptoms typically occur 1 to 2 days after ingestion of the mushrooms. The patient’s history and typical clinical findings lead to a diagnosis; however, blood tests may show inflammation with leukocytosis and elevated C-reactive protein levels. Biopsy of the skin shows lymphocytic dermal infiltrates with spongiosis and necrotic cells within the epidermis.⁴

Differential diagnoses include flagellate dermatitis associated with bleomycin, a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Because it causes breaks in the DNA, bleomycin is commonly used as a chemotherapeutic agent in treating Hodgkin lymphoma and other malignancies. It presents with linear postinflammatory hyperpigmentation of the skin. However, unlike shiitake dermatitis, there is a lack of papules. Another differential diagnosis includes herpes zoster virus, which should be ruled out clinically.

All symptoms in shiitake dermatitis usually resolve within 1 to 8 weeks of avoidance of the culprit food. Topical steroids and antihistamines can be given.

The underlying pathology is a toxic reaction to the polysaccharide lentinan in the mushrooms, which is known as a thermolabile agent.⁵ Therefore, it may only cause a toxic reaction when the mushrooms are consumed raw or undercooked. Prick testing is usually negative in these patients, which suggests a toxic and not an immunologic reaction of the human body.⁶ Other forms of reaction to shiitake mushrooms include contact dermatitis after skin contact and allergic alveolitis after occupational exposure to mushroom spores, mainly in individuals cultivating shiitake mushrooms (mushroom worker’s lung). In these forms of the disease, prick testing may be positive.^7,8

Flagellate dermatitis caused by shiitake mushrooms is still an uncommon dermatologic phenomenon in the Western world. Future studies and cases should be reported to increase the awareness of this disorder. Although the patients present with typical clinical findings, the diagnosis can be missed if history is not carefully considered.

To the Editor:

The shiitake mushroom (Lentinula edodes) is a popular Asian food and represents the second most consumed mushroom in the world. It is known for having a range of strong health benefits including antihypertensive, anti-inflammatory, and immunomodulatory effects. Especially in Asia, this mushroom has been used in patients with cancers of the gastrointestinal tract and also may be helpful in the treatment of human immunodeficiency virus.^1,2 The source of these effects is lentinan, a polysaccharide in the mushroom. However, lentinan also can cause a toxic reaction of the skin when the mushrooms are eaten raw or undercooked. These reactions are mainly reported in Asia, but more cases have been published in the last decade in Europe and the United States, evidence that the incidence of this adverse effect has increased in the Western world.

A 65-year-old woman with no notable medical history presented to our outpatient practice with sudden onset of a pruritic, erythematous, papular eruption on the neck. The eruption began that morning. The diagnosis of eczematous dermatitis was made and hydrocortisone cream 2.5% was started. Three days later, she returned with spread of the rash to the trunk, arms, and legs despite the topical treatment. She denied fevers, chills, or constitutional symptoms. The patient also denied recent travel or bug bites. However, she reported that she recently had started using raw shiitake mushrooms in her salad; the first time was 3 days before the symptoms appeared. Physical examination revealed erythematous skin with long flagellate streaks composed of petechiae, papules, and vesicles involving the trunk, arms, and legs (Figure). Oral and nasal mucosae were uninvolved. Dermatographism was negative. The diagnosis of flagellate dermatitis from shiitake mushrooms was made given the patient’s history and the unique clinical findings of the skin. Blood work and a biopsy were not performed. Instead, the patient was advised to avoid shiitake mushrooms and use clobetasol propionate cream 0.05% twice daily for 2 weeks on the affected areas. The symptoms resolved within 10 days.

Erythematous flagellate streaks composed of petechiae, papules, and vesicles localized on the patient’s back (A) and right upper arm (B) associated with shiitake mushroom consumption.

The first known case of toxicoderma to shiitake mushrooms was reported in Japan by Nakamura³ in 1977. Since this seminal report, numerous cases have followed. This disorder is mainly seen in Asia.

Patients usually present with linear groups of pruritic, papular, petechial, and vesicular lesions in a flagellate pattern, most commonly localized on the trunk, arms, and legs. Oral and nasal mucosae usually are not involved, and fever and malaise may be associated. All symptoms typically occur 1 to 2 days after ingestion of the mushrooms. The patient’s history and typical clinical findings lead to a diagnosis; however, blood tests may show inflammation with leukocytosis and elevated C-reactive protein levels. Biopsy of the skin shows lymphocytic dermal infiltrates with spongiosis and necrotic cells within the epidermis.⁴

Differential diagnoses include flagellate dermatitis associated with bleomycin, a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Because it causes breaks in the DNA, bleomycin is commonly used as a chemotherapeutic agent in treating Hodgkin lymphoma and other malignancies. It presents with linear postinflammatory hyperpigmentation of the skin. However, unlike shiitake dermatitis, there is a lack of papules. Another differential diagnosis includes herpes zoster virus, which should be ruled out clinically.

All symptoms in shiitake dermatitis usually resolve within 1 to 8 weeks of avoidance of the culprit food. Topical steroids and antihistamines can be given.

The underlying pathology is a toxic reaction to the polysaccharide lentinan in the mushrooms, which is known as a thermolabile agent.⁵ Therefore, it may only cause a toxic reaction when the mushrooms are consumed raw or undercooked. Prick testing is usually negative in these patients, which suggests a toxic and not an immunologic reaction of the human body.⁶ Other forms of reaction to shiitake mushrooms include contact dermatitis after skin contact and allergic alveolitis after occupational exposure to mushroom spores, mainly in individuals cultivating shiitake mushrooms (mushroom worker’s lung). In these forms of the disease, prick testing may be positive.^7,8

Flagellate dermatitis caused by shiitake mushrooms is still an uncommon dermatologic phenomenon in the Western world. Future studies and cases should be reported to increase the awareness of this disorder. Although the patients present with typical clinical findings, the diagnosis can be missed if history is not carefully considered.

To the Editor:

The shiitake mushroom (Lentinula edodes) is a popular Asian food and represents the second most consumed mushroom in the world. It is known for having a range of strong health benefits including antihypertensive, anti-inflammatory, and immunomodulatory effects. Especially in Asia, this mushroom has been used in patients with cancers of the gastrointestinal tract and also may be helpful in the treatment of human immunodeficiency virus.^1,2 The source of these effects is lentinan, a polysaccharide in the mushroom. However, lentinan also can cause a toxic reaction of the skin when the mushrooms are eaten raw or undercooked. These reactions are mainly reported in Asia, but more cases have been published in the last decade in Europe and the United States, evidence that the incidence of this adverse effect has increased in the Western world.

A 65-year-old woman with no notable medical history presented to our outpatient practice with sudden onset of a pruritic, erythematous, papular eruption on the neck. The eruption began that morning. The diagnosis of eczematous dermatitis was made and hydrocortisone cream 2.5% was started. Three days later, she returned with spread of the rash to the trunk, arms, and legs despite the topical treatment. She denied fevers, chills, or constitutional symptoms. The patient also denied recent travel or bug bites. However, she reported that she recently had started using raw shiitake mushrooms in her salad; the first time was 3 days before the symptoms appeared. Physical examination revealed erythematous skin with long flagellate streaks composed of petechiae, papules, and vesicles involving the trunk, arms, and legs (Figure). Oral and nasal mucosae were uninvolved. Dermatographism was negative. The diagnosis of flagellate dermatitis from shiitake mushrooms was made given the patient’s history and the unique clinical findings of the skin. Blood work and a biopsy were not performed. Instead, the patient was advised to avoid shiitake mushrooms and use clobetasol propionate cream 0.05% twice daily for 2 weeks on the affected areas. The symptoms resolved within 10 days.

Erythematous flagellate streaks composed of petechiae, papules, and vesicles localized on the patient’s back (A) and right upper arm (B) associated with shiitake mushroom consumption.

The first known case of toxicoderma to shiitake mushrooms was reported in Japan by Nakamura³ in 1977. Since this seminal report, numerous cases have followed. This disorder is mainly seen in Asia.

Patients usually present with linear groups of pruritic, papular, petechial, and vesicular lesions in a flagellate pattern, most commonly localized on the trunk, arms, and legs. Oral and nasal mucosae usually are not involved, and fever and malaise may be associated. All symptoms typically occur 1 to 2 days after ingestion of the mushrooms. The patient’s history and typical clinical findings lead to a diagnosis; however, blood tests may show inflammation with leukocytosis and elevated C-reactive protein levels. Biopsy of the skin shows lymphocytic dermal infiltrates with spongiosis and necrotic cells within the epidermis.⁴

Differential diagnoses include flagellate dermatitis associated with bleomycin, a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Because it causes breaks in the DNA, bleomycin is commonly used as a chemotherapeutic agent in treating Hodgkin lymphoma and other malignancies. It presents with linear postinflammatory hyperpigmentation of the skin. However, unlike shiitake dermatitis, there is a lack of papules. Another differential diagnosis includes herpes zoster virus, which should be ruled out clinically.

All symptoms in shiitake dermatitis usually resolve within 1 to 8 weeks of avoidance of the culprit food. Topical steroids and antihistamines can be given.

The underlying pathology is a toxic reaction to the polysaccharide lentinan in the mushrooms, which is known as a thermolabile agent.⁵ Therefore, it may only cause a toxic reaction when the mushrooms are consumed raw or undercooked. Prick testing is usually negative in these patients, which suggests a toxic and not an immunologic reaction of the human body.⁶ Other forms of reaction to shiitake mushrooms include contact dermatitis after skin contact and allergic alveolitis after occupational exposure to mushroom spores, mainly in individuals cultivating shiitake mushrooms (mushroom worker’s lung). In these forms of the disease, prick testing may be positive.^7,8

Flagellate dermatitis caused by shiitake mushrooms is still an uncommon dermatologic phenomenon in the Western world. Future studies and cases should be reported to increase the awareness of this disorder. Although the patients present with typical clinical findings, the diagnosis can be missed if history is not carefully considered.

Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

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Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

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Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

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In an audiocast summarizing his Sunday Lunch Talk at the Annual Clinical Meeting of the American College of Obstetricians and Gynecologists (ACOG) on May 3, 2015, Dr. Michael L. Krychman discusses new treatment options for vulvar and vaginal atrophy (VVA), including over-the-counter and prescription products and procedures. He emphasizes that a better understanding of the physical and anatomic changes in menopause has led to these improved options.

Dr. Krychman also recommends the use of "genitourinary syndrome of menopause" (GSM), new terminology for VVA suggested by the International Society for the Study of Women's Sexual Health and the North American Menopause Society.¹

Among the products Dr. Krychman details are neogyn^® Feminine Soothing Cream (neogyn, inc., Switzerland); RepHresh™ Vaginal Gel (Church & Dwight Co., Inc., Princeton, New Jersey); Replens™ Long-Lasting Vaginal Moisturizer (Church & Dwight); silicone- and water-based lubricants (Replens™ Silky Smooth Lubricant [Church & Dwight]; JuvaGyn^® Feminine Moisturizer [neogyn, inc.]); and ospemifene (Osphena^®, Shionogi Inc., Florham Park, New Jersey).

Dr. Krychman is interested in a new laser procedure for VVA/GSM, but comments that more study is needed before he can recommend its general use. He also talks about other exciting alternatives in the pipeline.

In an audiocast summarizing his Sunday Lunch Talk at the Annual Clinical Meeting of the American College of Obstetricians and Gynecologists (ACOG) on May 3, 2015, Dr. Michael L. Krychman discusses new treatment options for vulvar and vaginal atrophy (VVA), including over-the-counter and prescription products and procedures. He emphasizes that a better understanding of the physical and anatomic changes in menopause has led to these improved options.

Dr. Krychman also recommends the use of "genitourinary syndrome of menopause" (GSM), new terminology for VVA suggested by the International Society for the Study of Women's Sexual Health and the North American Menopause Society.¹

Among the products Dr. Krychman details are neogyn^® Feminine Soothing Cream (neogyn, inc., Switzerland); RepHresh™ Vaginal Gel (Church & Dwight Co., Inc., Princeton, New Jersey); Replens™ Long-Lasting Vaginal Moisturizer (Church & Dwight); silicone- and water-based lubricants (Replens™ Silky Smooth Lubricant [Church & Dwight]; JuvaGyn^® Feminine Moisturizer [neogyn, inc.]); and ospemifene (Osphena^®, Shionogi Inc., Florham Park, New Jersey).

Dr. Krychman is interested in a new laser procedure for VVA/GSM, but comments that more study is needed before he can recommend its general use. He also talks about other exciting alternatives in the pipeline.

In an audiocast summarizing his Sunday Lunch Talk at the Annual Clinical Meeting of the American College of Obstetricians and Gynecologists (ACOG) on May 3, 2015, Dr. Michael L. Krychman discusses new treatment options for vulvar and vaginal atrophy (VVA), including over-the-counter and prescription products and procedures. He emphasizes that a better understanding of the physical and anatomic changes in menopause has led to these improved options.

Dr. Krychman also recommends the use of "genitourinary syndrome of menopause" (GSM), new terminology for VVA suggested by the International Society for the Study of Women's Sexual Health and the North American Menopause Society.¹

Among the products Dr. Krychman details are neogyn^® Feminine Soothing Cream (neogyn, inc., Switzerland); RepHresh™ Vaginal Gel (Church & Dwight Co., Inc., Princeton, New Jersey); Replens™ Long-Lasting Vaginal Moisturizer (Church & Dwight); silicone- and water-based lubricants (Replens™ Silky Smooth Lubricant [Church & Dwight]; JuvaGyn^® Feminine Moisturizer [neogyn, inc.]); and ospemifene (Osphena^®, Shionogi Inc., Florham Park, New Jersey).

Dr. Krychman is interested in a new laser procedure for VVA/GSM, but comments that more study is needed before he can recommend its general use. He also talks about other exciting alternatives in the pipeline.

Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9426,9427,9428,9429,9430,9431,9432,9433,9434,9435,9436,9437,9439,9440,9441,9442,9444,9445,9447,9449,9450,9451,9452,9453,9454,9455,9457,9458,9459,9460,9461,9462,9463,9464,9465,9467,9468,9469,9471,9472,9474"]

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Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9426,9427,9428,9429,9430,9431,9432,9433,9434,9435,9436,9437,9439,9440,9441,9442,9444,9445,9447,9449,9450,9451,9452,9453,9454,9455,9457,9458,9459,9460,9461,9462,9463,9464,9465,9467,9468,9469,9471,9472,9474"]

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Photographs from Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9426,9427,9428,9429,9430,9431,9432,9433,9434,9435,9436,9437,9439,9440,9441,9442,9444,9445,9447,9449,9450,9451,9452,9453,9454,9455,9457,9458,9459,9460,9461,9462,9463,9464,9465,9467,9468,9469,9471,9472,9474"]

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WASHINGTON – An implantable device that stimulates the sphenopalatine ganglion nerve bundle either reduced or eliminated pain in 68% of more than 5,000 cluster headaches, a 3-year study has determined.

The device, which is approved in Europe, was more effective in attacks of moderate severity, with a 78% rate of pain reduction or elimination, Dr. Jose Miguel Lainez reported at the annual meeting of the American Academy of Neurology.

Courtesy Autonomic Technologies Inc.

The Pulsante System, manufactured by Autonomic Technologiesof Redwood City, Calif., consists of a neurostimulator about the size of an almond, and a lead with six electrodes. It’s inserted under local anesthetic via a small incision in the upper gum on the side in which the patient experiences symptoms. The electrodes are positioned along the sphenopalatine ganglion (SPG) nerve and the neurostimulator is affixed to the zygomatic process.

A hand-held remote controller placed against the cheek activates the device and controls the intensity of stimulation, which is thought to work by blocking signals to the postganglionic parasympathetic fibers. Those fibers innervate facial structures and the cerebral and meningeal blood vessels and are implicated in the pain and accompanying autonomic symptoms of a cluster headache attack.

Dr. Lainez, professor of neurology at Catholic University of Valencia (Spain), presented 3-year follow-up data from Pathway CH-1, a randomized, sham-controlled trial of 43 patients with cluster headache. Of these, 33 completed the 3-year follow-up period. Of the remaining 10, 1 was lost from observation, 5 violated protocol, 1 had the device implanted incorrectly, and 3 had the device explanted because of incorrect placement or lead migration.

Most of the patients were male. Mean age was 41 years. They had a mean disease duration of 10 years and averaged 17 cluster headaches per week but ranged from 4 to 70 attacks per week. Over the 3 years, 5,130 attacks were treated; the mean stimulation duration for these was 14 minutes with a mean response time of 11 minutes. Therapy was considered effective in 65% (3,354) of these attacks based on a clinically meaningful reduction in pain or pain elimination.

Dr. Lainez did not parse these results. However, in the initial 28-week phase of the Pathway CH-1 study, pain was reduced in 68% of attacks treated with the device and 7% of those treated with the sham control. Pain freedom by 15 minutes was achieved in 34% of attacks with full stimulation, compared with 1.5% of those treated with sham.

In the follow-up study, the device seemed most effective in attacks of moderate severity (78% response rate of pain reduction or elimination). The response rate was 59% in mild attacks and 51% in severe attacks. Most attacks treated with the device (77%) did not involve the use of abortive therapy.

Dr. Lainez did not mention adverse events related to the device. However, in the 28-week study, there were 92, including parasthesias and numbness; facial and tooth pain; and swelling. Others were considered mild and included dry eye, nose bleed, and facial asymmetry.

The device is currently being investigated in a U.S. study. The open-label Pathway-CH2 study aims to recruit 120 patients. For information on Pathway CH-2, contact Anthony Caparso.

The trial was sponsored by Autonomic Technologies Inc. Dr. Lainez had no financial ties with the company.

[email protected]

On Twitter @alz_gal

WASHINGTON – An implantable device that stimulates the sphenopalatine ganglion nerve bundle either reduced or eliminated pain in 68% of more than 5,000 cluster headaches, a 3-year study has determined.

The device, which is approved in Europe, was more effective in attacks of moderate severity, with a 78% rate of pain reduction or elimination, Dr. Jose Miguel Lainez reported at the annual meeting of the American Academy of Neurology.

Courtesy Autonomic Technologies Inc.

The Pulsante System, manufactured by Autonomic Technologiesof Redwood City, Calif., consists of a neurostimulator about the size of an almond, and a lead with six electrodes. It’s inserted under local anesthetic via a small incision in the upper gum on the side in which the patient experiences symptoms. The electrodes are positioned along the sphenopalatine ganglion (SPG) nerve and the neurostimulator is affixed to the zygomatic process.

A hand-held remote controller placed against the cheek activates the device and controls the intensity of stimulation, which is thought to work by blocking signals to the postganglionic parasympathetic fibers. Those fibers innervate facial structures and the cerebral and meningeal blood vessels and are implicated in the pain and accompanying autonomic symptoms of a cluster headache attack.

Dr. Lainez, professor of neurology at Catholic University of Valencia (Spain), presented 3-year follow-up data from Pathway CH-1, a randomized, sham-controlled trial of 43 patients with cluster headache. Of these, 33 completed the 3-year follow-up period. Of the remaining 10, 1 was lost from observation, 5 violated protocol, 1 had the device implanted incorrectly, and 3 had the device explanted because of incorrect placement or lead migration.

Most of the patients were male. Mean age was 41 years. They had a mean disease duration of 10 years and averaged 17 cluster headaches per week but ranged from 4 to 70 attacks per week. Over the 3 years, 5,130 attacks were treated; the mean stimulation duration for these was 14 minutes with a mean response time of 11 minutes. Therapy was considered effective in 65% (3,354) of these attacks based on a clinically meaningful reduction in pain or pain elimination.

Dr. Lainez did not parse these results. However, in the initial 28-week phase of the Pathway CH-1 study, pain was reduced in 68% of attacks treated with the device and 7% of those treated with the sham control. Pain freedom by 15 minutes was achieved in 34% of attacks with full stimulation, compared with 1.5% of those treated with sham.

In the follow-up study, the device seemed most effective in attacks of moderate severity (78% response rate of pain reduction or elimination). The response rate was 59% in mild attacks and 51% in severe attacks. Most attacks treated with the device (77%) did not involve the use of abortive therapy.

Dr. Lainez did not mention adverse events related to the device. However, in the 28-week study, there were 92, including parasthesias and numbness; facial and tooth pain; and swelling. Others were considered mild and included dry eye, nose bleed, and facial asymmetry.

The device is currently being investigated in a U.S. study. The open-label Pathway-CH2 study aims to recruit 120 patients. For information on Pathway CH-2, contact Anthony Caparso.

The trial was sponsored by Autonomic Technologies Inc. Dr. Lainez had no financial ties with the company.

[email protected]

On Twitter @alz_gal

WASHINGTON – An implantable device that stimulates the sphenopalatine ganglion nerve bundle either reduced or eliminated pain in 68% of more than 5,000 cluster headaches, a 3-year study has determined.

The device, which is approved in Europe, was more effective in attacks of moderate severity, with a 78% rate of pain reduction or elimination, Dr. Jose Miguel Lainez reported at the annual meeting of the American Academy of Neurology.

Courtesy Autonomic Technologies Inc.

The Pulsante System, manufactured by Autonomic Technologiesof Redwood City, Calif., consists of a neurostimulator about the size of an almond, and a lead with six electrodes. It’s inserted under local anesthetic via a small incision in the upper gum on the side in which the patient experiences symptoms. The electrodes are positioned along the sphenopalatine ganglion (SPG) nerve and the neurostimulator is affixed to the zygomatic process.

A hand-held remote controller placed against the cheek activates the device and controls the intensity of stimulation, which is thought to work by blocking signals to the postganglionic parasympathetic fibers. Those fibers innervate facial structures and the cerebral and meningeal blood vessels and are implicated in the pain and accompanying autonomic symptoms of a cluster headache attack.

Dr. Lainez, professor of neurology at Catholic University of Valencia (Spain), presented 3-year follow-up data from Pathway CH-1, a randomized, sham-controlled trial of 43 patients with cluster headache. Of these, 33 completed the 3-year follow-up period. Of the remaining 10, 1 was lost from observation, 5 violated protocol, 1 had the device implanted incorrectly, and 3 had the device explanted because of incorrect placement or lead migration.

Most of the patients were male. Mean age was 41 years. They had a mean disease duration of 10 years and averaged 17 cluster headaches per week but ranged from 4 to 70 attacks per week. Over the 3 years, 5,130 attacks were treated; the mean stimulation duration for these was 14 minutes with a mean response time of 11 minutes. Therapy was considered effective in 65% (3,354) of these attacks based on a clinically meaningful reduction in pain or pain elimination.

Dr. Lainez did not parse these results. However, in the initial 28-week phase of the Pathway CH-1 study, pain was reduced in 68% of attacks treated with the device and 7% of those treated with the sham control. Pain freedom by 15 minutes was achieved in 34% of attacks with full stimulation, compared with 1.5% of those treated with sham.

In the follow-up study, the device seemed most effective in attacks of moderate severity (78% response rate of pain reduction or elimination). The response rate was 59% in mild attacks and 51% in severe attacks. Most attacks treated with the device (77%) did not involve the use of abortive therapy.

Dr. Lainez did not mention adverse events related to the device. However, in the 28-week study, there were 92, including parasthesias and numbness; facial and tooth pain; and swelling. Others were considered mild and included dry eye, nose bleed, and facial asymmetry.

The device is currently being investigated in a U.S. study. The open-label Pathway-CH2 study aims to recruit 120 patients. For information on Pathway CH-2, contact Anthony Caparso.

The trial was sponsored by Autonomic Technologies Inc. Dr. Lainez had no financial ties with the company.

[email protected]

On Twitter @alz_gal

Micrograph showing MDS

WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.

The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.

Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).

The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.

“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”

Patient and dosing details

The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.

Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.

In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.

Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).

Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).

Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.

Efficacy and safety

The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.

Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.

Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.

Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.

Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.

The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).

There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.

In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.

Micrograph showing MDS

WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.

The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.

Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).

The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.

“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”

Patient and dosing details

The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.

Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.

In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.

Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).

Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).

Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.

Efficacy and safety

The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.

Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.

Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.

Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.

Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.

The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).

There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.

In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.

Micrograph showing MDS

WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.

The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.

Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).

The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.

“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”

Patient and dosing details

The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.

Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.

In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.

Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).

Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).

Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.

Efficacy and safety

The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.

Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.

Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.

Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.

Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.

The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).

There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.

In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.

Fresh whole blood

Photo by Elise Amendola

Using fresh whole blood (FWB) from single donors for cardiac procedures in children younger than 2 years of age is better than using component blood from multiple donors, researchers say.

FWB reduces the risk of getting transfusion-related illnesses by reducing donor exposures.

“Currently, whole blood is not generally made available to hospitals for use in pediatric heart surgery,” said David R. Jobes, MD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“Blood centers separate donated blood into component parts, which are then stored for use in medical transfusions as needed.”

At The Children’s Hospital of Philadelphia, the standard preoperative blood order for elective pediatric heart surgery with cariopulmonary bypass is 2 units of FWB and 2 units of packed red blood cells. The FWB is to be used during and immediately after surgery and the components thereafter, if necessary.

The researchers set out to examine the effectiveness of this protocol. They conducted a retrospective study of patient records over a period of 15 years from a surgical registry and blood bank, comparing the cohort of 4111 patients to published reports.

The team defined donor exposures as transfusion requirements for the day of operation and the next postoperative day. All blood products issued were presumed to have been tranfused, and all aliquots from a single donor were counted as a single donor exposure.

Patients were a median age of 94 days and weighed a median of 4.4 kg.

Most (3836) patients received FWB, and 252 received components exclusively when no FWB was available. Twenty-three patients did not receive any blood products. A median of 2 whole blood units was transfused, for a total of 2 donor exposures for the entire cohort.

The researchers found that the youngest patients having complex procedures were exposed to the highest number of donors, while older patients having simpler procedures were exposed to fewer donors.

For example, 72 patients who were a median of 5 days old and underwent truncus arteriosus repair had a median of 4 donor exposures (range, 1-14). And 136 older patients who were a median of 610 days old and underwent fontan completion had a median of 1 donor exposure (range, 0-8).

The researchers concluded that the protocol resulted in fewer donor exposures compared with component use reported in the literature.

Dr Jobes said the risk for disease transmission in pediatric patients is essentially the same as the risk for adults, but it may be more costly for pediatric patients in the long run because infants and young children may live longer with chronic illness stemming from transfusion.

He added, “We hope that our research helps to re-examine current blood storage practice and make whole blood more readily available for pediatric patients.”

He and his colleagues described this research in The Annals of Thoracic Surgery.

Fresh whole blood

Photo by Elise Amendola

Using fresh whole blood (FWB) from single donors for cardiac procedures in children younger than 2 years of age is better than using component blood from multiple donors, researchers say.

FWB reduces the risk of getting transfusion-related illnesses by reducing donor exposures.

“Currently, whole blood is not generally made available to hospitals for use in pediatric heart surgery,” said David R. Jobes, MD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“Blood centers separate donated blood into component parts, which are then stored for use in medical transfusions as needed.”

At The Children’s Hospital of Philadelphia, the standard preoperative blood order for elective pediatric heart surgery with cariopulmonary bypass is 2 units of FWB and 2 units of packed red blood cells. The FWB is to be used during and immediately after surgery and the components thereafter, if necessary.

The researchers set out to examine the effectiveness of this protocol. They conducted a retrospective study of patient records over a period of 15 years from a surgical registry and blood bank, comparing the cohort of 4111 patients to published reports.

The team defined donor exposures as transfusion requirements for the day of operation and the next postoperative day. All blood products issued were presumed to have been tranfused, and all aliquots from a single donor were counted as a single donor exposure.

Patients were a median age of 94 days and weighed a median of 4.4 kg.

Most (3836) patients received FWB, and 252 received components exclusively when no FWB was available. Twenty-three patients did not receive any blood products. A median of 2 whole blood units was transfused, for a total of 2 donor exposures for the entire cohort.

The researchers found that the youngest patients having complex procedures were exposed to the highest number of donors, while older patients having simpler procedures were exposed to fewer donors.

For example, 72 patients who were a median of 5 days old and underwent truncus arteriosus repair had a median of 4 donor exposures (range, 1-14). And 136 older patients who were a median of 610 days old and underwent fontan completion had a median of 1 donor exposure (range, 0-8).

The researchers concluded that the protocol resulted in fewer donor exposures compared with component use reported in the literature.

Dr Jobes said the risk for disease transmission in pediatric patients is essentially the same as the risk for adults, but it may be more costly for pediatric patients in the long run because infants and young children may live longer with chronic illness stemming from transfusion.

He added, “We hope that our research helps to re-examine current blood storage practice and make whole blood more readily available for pediatric patients.”

He and his colleagues described this research in The Annals of Thoracic Surgery.

Fresh whole blood

Photo by Elise Amendola

Using fresh whole blood (FWB) from single donors for cardiac procedures in children younger than 2 years of age is better than using component blood from multiple donors, researchers say.

FWB reduces the risk of getting transfusion-related illnesses by reducing donor exposures.

“Currently, whole blood is not generally made available to hospitals for use in pediatric heart surgery,” said David R. Jobes, MD, of The Children’s Hospital of Philadelphia in Pennsylvania.

“Blood centers separate donated blood into component parts, which are then stored for use in medical transfusions as needed.”

At The Children’s Hospital of Philadelphia, the standard preoperative blood order for elective pediatric heart surgery with cariopulmonary bypass is 2 units of FWB and 2 units of packed red blood cells. The FWB is to be used during and immediately after surgery and the components thereafter, if necessary.

The researchers set out to examine the effectiveness of this protocol. They conducted a retrospective study of patient records over a period of 15 years from a surgical registry and blood bank, comparing the cohort of 4111 patients to published reports.

The team defined donor exposures as transfusion requirements for the day of operation and the next postoperative day. All blood products issued were presumed to have been tranfused, and all aliquots from a single donor were counted as a single donor exposure.

Patients were a median age of 94 days and weighed a median of 4.4 kg.

Most (3836) patients received FWB, and 252 received components exclusively when no FWB was available. Twenty-three patients did not receive any blood products. A median of 2 whole blood units was transfused, for a total of 2 donor exposures for the entire cohort.

The researchers found that the youngest patients having complex procedures were exposed to the highest number of donors, while older patients having simpler procedures were exposed to fewer donors.

For example, 72 patients who were a median of 5 days old and underwent truncus arteriosus repair had a median of 4 donor exposures (range, 1-14). And 136 older patients who were a median of 610 days old and underwent fontan completion had a median of 1 donor exposure (range, 0-8).

The researchers concluded that the protocol resulted in fewer donor exposures compared with component use reported in the literature.

Dr Jobes said the risk for disease transmission in pediatric patients is essentially the same as the risk for adults, but it may be more costly for pediatric patients in the long run because infants and young children may live longer with chronic illness stemming from transfusion.

He added, “We hope that our research helps to re-examine current blood storage practice and make whole blood more readily available for pediatric patients.”

He and his colleagues described this research in The Annals of Thoracic Surgery.

Thrombus

Image by Kevin MacKenzie

SEATTLE—Routine screening for venous thromboembolism (VTE) may decrease morbidity and mortality among patients undergoing pneumonectomy for benign or malignant indications, according to researchers.

The group conducted a study that showed the rate of VTE diagnosis was 3 times higher for patients who underwent routine VTE screening post-pneumonectomy than for patients who were tested for VTE only after they exhibited symptoms.

Siva Raja MD, PhD, of the Cleveland Clinic in Ohio, presented this finding at the 95th Annual Meeting of the American Association for Thoracic Surgery.

He and his colleagues analyzed 112 patients who underwent pneumonectomy for benign and malignant indications and were screened for VTE. The team compared the rate of VTE diagnosis in this group to the rate in a previously published group of 336 similar patients who did not undergo VTE screening.

The rate of in-hospital VTEs in the screened group was almost 3 times higher than the rate in patients who were not screened—8.9% and 3.0%, respectively (P=0.008).

Over the 30-day post-operative period, the rate of VTE for screened patients was more than double the rate for unscreened patients—13% and 5.1%, respectively (P=0.007).

In the screened group, 10 of 112 patients had VTE detected by screening just before discharge, and 4 additional patients developed symptomatic VTE within 30 days despite a negative pre-discharge screen. In all, 20 patients in this group developed a VTE.

In both the screened and unscreened cohorts, the risk of VTE peaked 6 days after surgery and plateaued after 30 days.

“We find that a large proportion (50%) of VTEs occurred prior to the time of discharge, and the risk of developing symptomatic VTE remained elevated for 30 days,” Dr Raja said. “It is possible that the prevalence of VTE may be even higher should a comprehensive serial screening program be initiated.”

Dr Raja also noted that VTEs are a particular problem after pneumonectomy, since these patients often have low pulmonary reserve to withstand the impact of pulmonary embolism.

Indeed, this study showed that post-pneumonectomy patients who developed VTE had worse long-term survival than patients who did not develop clots, although the difference was not statistically significant (hazard ratio=2.1, P=0.08).

Still, Dr Raja said these results suggest that patients undergoing pneumonectomy receive anticoagulants for a longer duration, as well as undergo repeat screening test for VTE even after hospital discharge.

Thrombus

Image by Kevin MacKenzie

SEATTLE—Routine screening for venous thromboembolism (VTE) may decrease morbidity and mortality among patients undergoing pneumonectomy for benign or malignant indications, according to researchers.

The group conducted a study that showed the rate of VTE diagnosis was 3 times higher for patients who underwent routine VTE screening post-pneumonectomy than for patients who were tested for VTE only after they exhibited symptoms.

Siva Raja MD, PhD, of the Cleveland Clinic in Ohio, presented this finding at the 95th Annual Meeting of the American Association for Thoracic Surgery.

He and his colleagues analyzed 112 patients who underwent pneumonectomy for benign and malignant indications and were screened for VTE. The team compared the rate of VTE diagnosis in this group to the rate in a previously published group of 336 similar patients who did not undergo VTE screening.

The rate of in-hospital VTEs in the screened group was almost 3 times higher than the rate in patients who were not screened—8.9% and 3.0%, respectively (P=0.008).

Over the 30-day post-operative period, the rate of VTE for screened patients was more than double the rate for unscreened patients—13% and 5.1%, respectively (P=0.007).

In the screened group, 10 of 112 patients had VTE detected by screening just before discharge, and 4 additional patients developed symptomatic VTE within 30 days despite a negative pre-discharge screen. In all, 20 patients in this group developed a VTE.

In both the screened and unscreened cohorts, the risk of VTE peaked 6 days after surgery and plateaued after 30 days.

“We find that a large proportion (50%) of VTEs occurred prior to the time of discharge, and the risk of developing symptomatic VTE remained elevated for 30 days,” Dr Raja said. “It is possible that the prevalence of VTE may be even higher should a comprehensive serial screening program be initiated.”

Dr Raja also noted that VTEs are a particular problem after pneumonectomy, since these patients often have low pulmonary reserve to withstand the impact of pulmonary embolism.

Indeed, this study showed that post-pneumonectomy patients who developed VTE had worse long-term survival than patients who did not develop clots, although the difference was not statistically significant (hazard ratio=2.1, P=0.08).

Still, Dr Raja said these results suggest that patients undergoing pneumonectomy receive anticoagulants for a longer duration, as well as undergo repeat screening test for VTE even after hospital discharge.

Thrombus

Image by Kevin MacKenzie

SEATTLE—Routine screening for venous thromboembolism (VTE) may decrease morbidity and mortality among patients undergoing pneumonectomy for benign or malignant indications, according to researchers.

The group conducted a study that showed the rate of VTE diagnosis was 3 times higher for patients who underwent routine VTE screening post-pneumonectomy than for patients who were tested for VTE only after they exhibited symptoms.

Siva Raja MD, PhD, of the Cleveland Clinic in Ohio, presented this finding at the 95th Annual Meeting of the American Association for Thoracic Surgery.

He and his colleagues analyzed 112 patients who underwent pneumonectomy for benign and malignant indications and were screened for VTE. The team compared the rate of VTE diagnosis in this group to the rate in a previously published group of 336 similar patients who did not undergo VTE screening.

The rate of in-hospital VTEs in the screened group was almost 3 times higher than the rate in patients who were not screened—8.9% and 3.0%, respectively (P=0.008).

Over the 30-day post-operative period, the rate of VTE for screened patients was more than double the rate for unscreened patients—13% and 5.1%, respectively (P=0.007).

In the screened group, 10 of 112 patients had VTE detected by screening just before discharge, and 4 additional patients developed symptomatic VTE within 30 days despite a negative pre-discharge screen. In all, 20 patients in this group developed a VTE.

In both the screened and unscreened cohorts, the risk of VTE peaked 6 days after surgery and plateaued after 30 days.

“We find that a large proportion (50%) of VTEs occurred prior to the time of discharge, and the risk of developing symptomatic VTE remained elevated for 30 days,” Dr Raja said. “It is possible that the prevalence of VTE may be even higher should a comprehensive serial screening program be initiated.”

Dr Raja also noted that VTEs are a particular problem after pneumonectomy, since these patients often have low pulmonary reserve to withstand the impact of pulmonary embolism.

Indeed, this study showed that post-pneumonectomy patients who developed VTE had worse long-term survival than patients who did not develop clots, although the difference was not statistically significant (hazard ratio=2.1, P=0.08).

Still, Dr Raja said these results suggest that patients undergoing pneumonectomy receive anticoagulants for a longer duration, as well as undergo repeat screening test for VTE even after hospital discharge.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved an intravenous, recombinant, human coagulation factor IX product (Ixinity) for use in patients

with hemophilia B.

The drug is intended to control and prevent bleeding episodes and for perioperative management in adults and children age 12 and older.

Concurrent with the FDA’s approval, Emergent Biosolutions (the company developing Ixinity) launched the Ixinity IXperience Concierge. This resource, which consumers can access by calling 1-855-IXINITY, provides information on the drug.

About Ixinity

Ixinity contains trenonacog alfa, a purified, single-chain glycoprotein derived from Chinese hamster ovary (CHO) cells that has an amino acid sequence comparable to the Thr148 allelic form of plasma-derived factor IX.

No human or animal proteins are added during any stage of manufacturing or formulation of Ixinity. The recombinant factor IX is purified by a chromatography purification process.

The process includes 3 validated steps for virus inactivation and removal. It also includes a validated manufacturing step to reduce the presence of CHO proteins in the final drug product.

Ixinity is contraindicated in patients who have known hypersensitivity to the drug or its excipients, including CHO protein. Hypersensitivity reactions, including anaphylaxis, may occur following treatment with Ixinity. Patients who receive Ixinity are also at risk of developing nephrotic syndrome and thromboembolism.

Trial data

The FDA approved Ixinity based on results from a phase 1/3 trial of the drug in previously treated adults and children (age 12 and older) with severe to moderately severe (factor IX level < 2%) hemophilia B.

Seventy-seven patients received at least 1 dose of Ixinity. The drug was given as routine prophylaxis or on-demand treatment for bleeding episodes.

Fifty-five patients received treatment for more than 50 exposure days, and 45 received the drug for more than 100 exposure days. The median duration of treatment on study was 16.2 months (range, 2.4-39.6 months) for the routine treatment regimen and 14.1 months (range, 2.3-36.9 months) for the on-demand treatment regimen.

A total of 508 bleeding episodes were treated with Ixinity—286 bleeds for patients on routine treatment and 222 for patients receiving on-demand treatment. A majority of the bleeds (84%) were resolved by 1 or 2 infusions of the drug.

Patients rated hemostatic efficacy at the resolution of a bleed as “excellent” or “good” in 84% of all treated bleeding episodes. “Excellent” was defined as a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size. “Good” was defined as pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution.

Ixinity also induced hemostasis in patients who underwent major surgical procedures.

The drug exhibited similar pharmacokinetic behavior as nonacog alfa, another licensed recombinant coagulation factor IX product. There was no significant reduction in steady-state factor IX levels or alteration in pharmacokinetic behavior over time with Ixinity.

There were 14 adverse events reported in 6 patients. The most common event, observed in 2.6% of patients, was headache. Other adverse events were asthenia, apathy, depression, dysgeusia, influenza, injection site discomfort, lethargy, and skin rash.

None of the patients developed inhibitors to Ixinity, and there were no reports of thrombotic events or allergic reactions.

For more details on this research, see the full prescribing information for Ixinity, available at www.IXINITY.com.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved an intravenous, recombinant, human coagulation factor IX product (Ixinity) for use in patients

with hemophilia B.

The drug is intended to control and prevent bleeding episodes and for perioperative management in adults and children age 12 and older.

Concurrent with the FDA’s approval, Emergent Biosolutions (the company developing Ixinity) launched the Ixinity IXperience Concierge. This resource, which consumers can access by calling 1-855-IXINITY, provides information on the drug.

About Ixinity

Ixinity contains trenonacog alfa, a purified, single-chain glycoprotein derived from Chinese hamster ovary (CHO) cells that has an amino acid sequence comparable to the Thr148 allelic form of plasma-derived factor IX.

No human or animal proteins are added during any stage of manufacturing or formulation of Ixinity. The recombinant factor IX is purified by a chromatography purification process.

The process includes 3 validated steps for virus inactivation and removal. It also includes a validated manufacturing step to reduce the presence of CHO proteins in the final drug product.

Ixinity is contraindicated in patients who have known hypersensitivity to the drug or its excipients, including CHO protein. Hypersensitivity reactions, including anaphylaxis, may occur following treatment with Ixinity. Patients who receive Ixinity are also at risk of developing nephrotic syndrome and thromboembolism.

Trial data

The FDA approved Ixinity based on results from a phase 1/3 trial of the drug in previously treated adults and children (age 12 and older) with severe to moderately severe (factor IX level < 2%) hemophilia B.

Seventy-seven patients received at least 1 dose of Ixinity. The drug was given as routine prophylaxis or on-demand treatment for bleeding episodes.

Fifty-five patients received treatment for more than 50 exposure days, and 45 received the drug for more than 100 exposure days. The median duration of treatment on study was 16.2 months (range, 2.4-39.6 months) for the routine treatment regimen and 14.1 months (range, 2.3-36.9 months) for the on-demand treatment regimen.

A total of 508 bleeding episodes were treated with Ixinity—286 bleeds for patients on routine treatment and 222 for patients receiving on-demand treatment. A majority of the bleeds (84%) were resolved by 1 or 2 infusions of the drug.

Patients rated hemostatic efficacy at the resolution of a bleed as “excellent” or “good” in 84% of all treated bleeding episodes. “Excellent” was defined as a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size. “Good” was defined as pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution.

Ixinity also induced hemostasis in patients who underwent major surgical procedures.

The drug exhibited similar pharmacokinetic behavior as nonacog alfa, another licensed recombinant coagulation factor IX product. There was no significant reduction in steady-state factor IX levels or alteration in pharmacokinetic behavior over time with Ixinity.

There were 14 adverse events reported in 6 patients. The most common event, observed in 2.6% of patients, was headache. Other adverse events were asthenia, apathy, depression, dysgeusia, influenza, injection site discomfort, lethargy, and skin rash.

None of the patients developed inhibitors to Ixinity, and there were no reports of thrombotic events or allergic reactions.

For more details on this research, see the full prescribing information for Ixinity, available at www.IXINITY.com.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved an intravenous, recombinant, human coagulation factor IX product (Ixinity) for use in patients

with hemophilia B.

The drug is intended to control and prevent bleeding episodes and for perioperative management in adults and children age 12 and older.

Concurrent with the FDA’s approval, Emergent Biosolutions (the company developing Ixinity) launched the Ixinity IXperience Concierge. This resource, which consumers can access by calling 1-855-IXINITY, provides information on the drug.

About Ixinity

Ixinity contains trenonacog alfa, a purified, single-chain glycoprotein derived from Chinese hamster ovary (CHO) cells that has an amino acid sequence comparable to the Thr148 allelic form of plasma-derived factor IX.

No human or animal proteins are added during any stage of manufacturing or formulation of Ixinity. The recombinant factor IX is purified by a chromatography purification process.

The process includes 3 validated steps for virus inactivation and removal. It also includes a validated manufacturing step to reduce the presence of CHO proteins in the final drug product.

Ixinity is contraindicated in patients who have known hypersensitivity to the drug or its excipients, including CHO protein. Hypersensitivity reactions, including anaphylaxis, may occur following treatment with Ixinity. Patients who receive Ixinity are also at risk of developing nephrotic syndrome and thromboembolism.

Trial data

The FDA approved Ixinity based on results from a phase 1/3 trial of the drug in previously treated adults and children (age 12 and older) with severe to moderately severe (factor IX level < 2%) hemophilia B.

Seventy-seven patients received at least 1 dose of Ixinity. The drug was given as routine prophylaxis or on-demand treatment for bleeding episodes.

Fifty-five patients received treatment for more than 50 exposure days, and 45 received the drug for more than 100 exposure days. The median duration of treatment on study was 16.2 months (range, 2.4-39.6 months) for the routine treatment regimen and 14.1 months (range, 2.3-36.9 months) for the on-demand treatment regimen.

A total of 508 bleeding episodes were treated with Ixinity—286 bleeds for patients on routine treatment and 222 for patients receiving on-demand treatment. A majority of the bleeds (84%) were resolved by 1 or 2 infusions of the drug.

Patients rated hemostatic efficacy at the resolution of a bleed as “excellent” or “good” in 84% of all treated bleeding episodes. “Excellent” was defined as a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size. “Good” was defined as pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution.

Ixinity also induced hemostasis in patients who underwent major surgical procedures.

The drug exhibited similar pharmacokinetic behavior as nonacog alfa, another licensed recombinant coagulation factor IX product. There was no significant reduction in steady-state factor IX levels or alteration in pharmacokinetic behavior over time with Ixinity.

There were 14 adverse events reported in 6 patients. The most common event, observed in 2.6% of patients, was headache. Other adverse events were asthenia, apathy, depression, dysgeusia, influenza, injection site discomfort, lethargy, and skin rash.

None of the patients developed inhibitors to Ixinity, and there were no reports of thrombotic events or allergic reactions.

For more details on this research, see the full prescribing information for Ixinity, available at www.IXINITY.com.

Clinical question: Does a restrictive transfusion strategy improve outcomes following nonemergent cardiac surgery?

Bottom line: For patients undergoing cardiac surgery, using a restrictive transfusion strategy with a hemoglobin threshold of 7.5 g/dL does not decrease serious infections or ischemic events and may lead to increased all-cause mortality at 90 days. (LOE = 1b)

Reference: Murphy GJ, Pike K, Rogers CA, et al, for the TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;372(11):997-1008.

Study design: Randomized controlled trial (single-blinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location)

Synopsis

This is yet another study that compares restrictive and liberal transfusion strategies, this time in a cardiac surgery population. These investigators enrolled patients undergoing nonemergency cardiac surgery (mostly coronary artery bypass grafts or valvular procedures) who had a drop of hemoglobin level to below 9 g/dL following surgery.

Patients were randomized, using concealed allocation, to the restrictive transfusion threshold group (threshold hemoglobin 7.5 g/dL) or liberal transfusion threshold group (threshold hemoglobin 9 g/dL). Patients were masked but physicians and nurses were aware of the group assignments.

In the liberal group, patients received one unit of red cell transfusion immediately after randomization followed by an additional unit if the hemoglobin level remained below or dropped below 9 g/dL again during the hospitalization. In the restrictive group, patients received one unit of red cells only if the hemoglobin level dropped below 7.5 g/dL. An additional unit was then given if hemoglobin remained below or dropped below 7.5 g/dL again during the hospitalization. The 2 groups were similar at baseline and analysis was by intention to treat. Not surprisingly, more patients in the liberal strategy group received transfusions than did those in the restrictive strategy group (95% vs 64%).

For the primary outcome—a composite of sepsis, wound infection, stroke, myocardial infarction, gut infarction, or acute kidney injury within 3 months of randomization—there was no significant difference detected between the 2 groups. However, the restrictive group had a higher mortality rate than the liberal group (4.2% vs 2.6%; P = .045). Although this was a secondary outcome, it is possible that a restrictive strategy may be harmful in this cohort, given that they may have less cardiovascular reserve than the general patient population.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Does a restrictive transfusion strategy improve outcomes following nonemergent cardiac surgery?

Bottom line: For patients undergoing cardiac surgery, using a restrictive transfusion strategy with a hemoglobin threshold of 7.5 g/dL does not decrease serious infections or ischemic events and may lead to increased all-cause mortality at 90 days. (LOE = 1b)

Reference: Murphy GJ, Pike K, Rogers CA, et al, for the TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;372(11):997-1008.

Study design: Randomized controlled trial (single-blinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location)

Synopsis

This is yet another study that compares restrictive and liberal transfusion strategies, this time in a cardiac surgery population. These investigators enrolled patients undergoing nonemergency cardiac surgery (mostly coronary artery bypass grafts or valvular procedures) who had a drop of hemoglobin level to below 9 g/dL following surgery.

Patients were randomized, using concealed allocation, to the restrictive transfusion threshold group (threshold hemoglobin 7.5 g/dL) or liberal transfusion threshold group (threshold hemoglobin 9 g/dL). Patients were masked but physicians and nurses were aware of the group assignments.

In the liberal group, patients received one unit of red cell transfusion immediately after randomization followed by an additional unit if the hemoglobin level remained below or dropped below 9 g/dL again during the hospitalization. In the restrictive group, patients received one unit of red cells only if the hemoglobin level dropped below 7.5 g/dL. An additional unit was then given if hemoglobin remained below or dropped below 7.5 g/dL again during the hospitalization. The 2 groups were similar at baseline and analysis was by intention to treat. Not surprisingly, more patients in the liberal strategy group received transfusions than did those in the restrictive strategy group (95% vs 64%).

For the primary outcome—a composite of sepsis, wound infection, stroke, myocardial infarction, gut infarction, or acute kidney injury within 3 months of randomization—there was no significant difference detected between the 2 groups. However, the restrictive group had a higher mortality rate than the liberal group (4.2% vs 2.6%; P = .045). Although this was a secondary outcome, it is possible that a restrictive strategy may be harmful in this cohort, given that they may have less cardiovascular reserve than the general patient population.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Does a restrictive transfusion strategy improve outcomes following nonemergent cardiac surgery?

Bottom line: For patients undergoing cardiac surgery, using a restrictive transfusion strategy with a hemoglobin threshold of 7.5 g/dL does not decrease serious infections or ischemic events and may lead to increased all-cause mortality at 90 days. (LOE = 1b)

Reference: Murphy GJ, Pike K, Rogers CA, et al, for the TITRe2 Investigators. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;372(11):997-1008.

Study design: Randomized controlled trial (single-blinded)

Funding source: Government

Allocation: Concealed

Setting: Inpatient (any location)

Synopsis

This is yet another study that compares restrictive and liberal transfusion strategies, this time in a cardiac surgery population. These investigators enrolled patients undergoing nonemergency cardiac surgery (mostly coronary artery bypass grafts or valvular procedures) who had a drop of hemoglobin level to below 9 g/dL following surgery.

Patients were randomized, using concealed allocation, to the restrictive transfusion threshold group (threshold hemoglobin 7.5 g/dL) or liberal transfusion threshold group (threshold hemoglobin 9 g/dL). Patients were masked but physicians and nurses were aware of the group assignments.

In the liberal group, patients received one unit of red cell transfusion immediately after randomization followed by an additional unit if the hemoglobin level remained below or dropped below 9 g/dL again during the hospitalization. In the restrictive group, patients received one unit of red cells only if the hemoglobin level dropped below 7.5 g/dL. An additional unit was then given if hemoglobin remained below or dropped below 7.5 g/dL again during the hospitalization. The 2 groups were similar at baseline and analysis was by intention to treat. Not surprisingly, more patients in the liberal strategy group received transfusions than did those in the restrictive strategy group (95% vs 64%).

For the primary outcome—a composite of sepsis, wound infection, stroke, myocardial infarction, gut infarction, or acute kidney injury within 3 months of randomization—there was no significant difference detected between the 2 groups. However, the restrictive group had a higher mortality rate than the liberal group (4.2% vs 2.6%; P = .045). Although this was a secondary outcome, it is possible that a restrictive strategy may be harmful in this cohort, given that they may have less cardiovascular reserve than the general patient population.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.