BALTIMORE—A common molecule may prolong cell survival in patients with serious neurologic conditions, according to research presented at the 59th Annual Meeting of the Biophysical Society. “The present findings could provide a new lead compound for the development of drug therapies for necrosis-related diseases such as traumatic brain injury [TBI], stroke, and myocardial infarction—conditions for which no effective drug-based treatments are currently available [that work by blocking necrosis],” said Abraham H. Parola, MSc, a Professor of Biophysical Chemistry at Ben-Gurion University of the Negev in Beer-Sheva, Israel. Prof. Parola is a visiting professor of Biophysical Chemistry and Director of Natural Sciences at New York University Shanghai.

Stroke, heart attack, and TBI are separate diseases with certain shared pathologies that achieve a common end—cell death and human injury due to hypoxia. In these diseases, a lack of blood supply to affected tissues begins a signaling pathway that ultimately halts the production of energy-releasing adenosine triphosphate (ATP) molecules, which ultimately leads to cell death.

By employing derivatives of humanin, a naturally occurring peptide encoded in the genome of cellular mitochondria, researchers are working to interrupt this process, buying precious time for tissues whose cellular mechanisms have ceased to function.

The humanin derivatives work by counteracting the decrease in ATP levels caused by necrosis. The researchers tested the effectiveness of the humanin analogues AGA(C8R)-HNG17 and AGA-HNG by treating neuronal cells with these peptides prior to exposure to a necrotic agent. Results showed that humanin analogues reduced necrosis.

Prof. Parola’s previous work dealt with membrane dynamics and the mechanism of action of antiangiogenesis drugs, which starve malignant tumor growths by preventing the supply of nutrients and oxygen to the fast-growing tissue. Prof. Parola also has studied various other biophysical and molecular medicine and diagnostic topics.

“A recent paper published by our group suggested the involvement of cardiolipin [a phospholipid in inner mitochondrial membranes] in the necrotic process,” Prof. Parola said. “During this work, we stumbled upon humanin, were intrigued by its antiapoptotic effect, and extended it to [an] antinecrotic effect.”

Prof. Parola and his colleagues also performed in vivo studies by treating mice with TBI with an HNG17 analogue, which successfully reduced cranial fluid buildup and lowered the mice’s motor impairment severity scores.

As the peptides Prof. Parola and his colleagues used are derivatives of naturally occurring humanin, an ideal treatment might involve a drug delivery system with the HNG17 as the lead compound. The delivery process would be aided by the peptides’ ability to penetrate the cell membrane without the use of additional reagents.

Future work for this research team will include further exploration of ischemic activity in liver cirrhosis, as induced by acetaminophen activity, in addition to a search for a synergistic effect between humanin and other antinecrotic agents, such as protease inhibitors, to increase the clinical potential of humanin.

BALTIMORE—A common molecule may prolong cell survival in patients with serious neurologic conditions, according to research presented at the 59th Annual Meeting of the Biophysical Society. “The present findings could provide a new lead compound for the development of drug therapies for necrosis-related diseases such as traumatic brain injury [TBI], stroke, and myocardial infarction—conditions for which no effective drug-based treatments are currently available [that work by blocking necrosis],” said Abraham H. Parola, MSc, a Professor of Biophysical Chemistry at Ben-Gurion University of the Negev in Beer-Sheva, Israel. Prof. Parola is a visiting professor of Biophysical Chemistry and Director of Natural Sciences at New York University Shanghai.

Stroke, heart attack, and TBI are separate diseases with certain shared pathologies that achieve a common end—cell death and human injury due to hypoxia. In these diseases, a lack of blood supply to affected tissues begins a signaling pathway that ultimately halts the production of energy-releasing adenosine triphosphate (ATP) molecules, which ultimately leads to cell death.

By employing derivatives of humanin, a naturally occurring peptide encoded in the genome of cellular mitochondria, researchers are working to interrupt this process, buying precious time for tissues whose cellular mechanisms have ceased to function.

The humanin derivatives work by counteracting the decrease in ATP levels caused by necrosis. The researchers tested the effectiveness of the humanin analogues AGA(C8R)-HNG17 and AGA-HNG by treating neuronal cells with these peptides prior to exposure to a necrotic agent. Results showed that humanin analogues reduced necrosis.

Prof. Parola’s previous work dealt with membrane dynamics and the mechanism of action of antiangiogenesis drugs, which starve malignant tumor growths by preventing the supply of nutrients and oxygen to the fast-growing tissue. Prof. Parola also has studied various other biophysical and molecular medicine and diagnostic topics.

“A recent paper published by our group suggested the involvement of cardiolipin [a phospholipid in inner mitochondrial membranes] in the necrotic process,” Prof. Parola said. “During this work, we stumbled upon humanin, were intrigued by its antiapoptotic effect, and extended it to [an] antinecrotic effect.”

Prof. Parola and his colleagues also performed in vivo studies by treating mice with TBI with an HNG17 analogue, which successfully reduced cranial fluid buildup and lowered the mice’s motor impairment severity scores.

As the peptides Prof. Parola and his colleagues used are derivatives of naturally occurring humanin, an ideal treatment might involve a drug delivery system with the HNG17 as the lead compound. The delivery process would be aided by the peptides’ ability to penetrate the cell membrane without the use of additional reagents.

Future work for this research team will include further exploration of ischemic activity in liver cirrhosis, as induced by acetaminophen activity, in addition to a search for a synergistic effect between humanin and other antinecrotic agents, such as protease inhibitors, to increase the clinical potential of humanin.

BALTIMORE—A common molecule may prolong cell survival in patients with serious neurologic conditions, according to research presented at the 59th Annual Meeting of the Biophysical Society. “The present findings could provide a new lead compound for the development of drug therapies for necrosis-related diseases such as traumatic brain injury [TBI], stroke, and myocardial infarction—conditions for which no effective drug-based treatments are currently available [that work by blocking necrosis],” said Abraham H. Parola, MSc, a Professor of Biophysical Chemistry at Ben-Gurion University of the Negev in Beer-Sheva, Israel. Prof. Parola is a visiting professor of Biophysical Chemistry and Director of Natural Sciences at New York University Shanghai.

Stroke, heart attack, and TBI are separate diseases with certain shared pathologies that achieve a common end—cell death and human injury due to hypoxia. In these diseases, a lack of blood supply to affected tissues begins a signaling pathway that ultimately halts the production of energy-releasing adenosine triphosphate (ATP) molecules, which ultimately leads to cell death.

By employing derivatives of humanin, a naturally occurring peptide encoded in the genome of cellular mitochondria, researchers are working to interrupt this process, buying precious time for tissues whose cellular mechanisms have ceased to function.

The humanin derivatives work by counteracting the decrease in ATP levels caused by necrosis. The researchers tested the effectiveness of the humanin analogues AGA(C8R)-HNG17 and AGA-HNG by treating neuronal cells with these peptides prior to exposure to a necrotic agent. Results showed that humanin analogues reduced necrosis.

Prof. Parola’s previous work dealt with membrane dynamics and the mechanism of action of antiangiogenesis drugs, which starve malignant tumor growths by preventing the supply of nutrients and oxygen to the fast-growing tissue. Prof. Parola also has studied various other biophysical and molecular medicine and diagnostic topics.

“A recent paper published by our group suggested the involvement of cardiolipin [a phospholipid in inner mitochondrial membranes] in the necrotic process,” Prof. Parola said. “During this work, we stumbled upon humanin, were intrigued by its antiapoptotic effect, and extended it to [an] antinecrotic effect.”

Prof. Parola and his colleagues also performed in vivo studies by treating mice with TBI with an HNG17 analogue, which successfully reduced cranial fluid buildup and lowered the mice’s motor impairment severity scores.

As the peptides Prof. Parola and his colleagues used are derivatives of naturally occurring humanin, an ideal treatment might involve a drug delivery system with the HNG17 as the lead compound. The delivery process would be aided by the peptides’ ability to penetrate the cell membrane without the use of additional reagents.

Future work for this research team will include further exploration of ischemic activity in liver cirrhosis, as induced by acetaminophen activity, in addition to a search for a synergistic effect between humanin and other antinecrotic agents, such as protease inhibitors, to increase the clinical potential of humanin.

Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic events, and cerebrovascular disease in women, according to a study published online ahead of print February 16 in Circulation. Participants included 1.1 million women in the United Kingdom with no history of cancer, heart disease, stroke, blood clots, or diabetes who joined the Million Women study between 1996 and 2001. Their average age when they joined the study was 56. Women who performed strenuous physical activity two to three times per week were 20% less likely to develop heart disease, strokes, or blood clots, compared with participants who reported little or no activity. More frequent physical activity did not result in further reductions in the risk of heart disease.

The FDA has approved Rytary, an extended-release oral capsule formulation of carbidopa–levodopa, for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Rytary contains immediate-release and extended-release beads that contain carbidopa and levodopa in a 1:4 ratio, and provides initial and extended levodopa plasma concentrations after a single dose. In a trial of 393 randomized patients with advanced Parkinson’s disease, treatment with Rytary reduced the percentage of off time during waking hours from baseline to the end of the study, versus immediate-release carbidopa–levodopa. Rytary may be swallowed whole or opened, and the beads may be sprinkled on applesauce and consumed immediately. The drug is manufactured by Impax Pharmaceuticals (Hayward, California).

The FDA has approved Duopa, an enteral suspension of carbidopa and levodopa, as an orphan drug for the treatment of motor fluctuations in people with advanced Parkinson’s disease. The approval of Duopa is based on a phase III, 12-week, double-blind, double-placebo, active control, parallel-group, multicenter trial that compared the efficacy and safety of Duopa with that of oral, immediate-release carbidopa–levodopa tablets in patients with advanced Parkinson’s disease. Duopa significantly reduced daily mean off time at 12 weeks by four hours, which resulted in an average of 1.9 fewer hours of off time, when compared with carbidopa–levodopa tablets. Duopa is administered using a small, portable infusion pump that delivers carbidopa and levodopa directly into the small intestine continuously for 16 hours via a surgically-placed tube. The drug is manufactured by AbbVie (North Chicago, Illinois).

A link exists between brain structure and postconcussive symptoms among young male athletes who are otherwise healthy, according to a study published in the February issue of the Journal of Pediatrics. Researchers used advanced imaging technology and cognitive testing to assess 29 ice hockey players between ages 14 and 23, some of whom had a sports-related concussion. As the severity of the athletes’ concussion symptoms increased, the cortex became thinner in areas of the brain where it should be dense for players of these ages. Investigators believe that injury to a developing brain may be more severe than injury to an adult brain. “Years of playing contact sports and repeatedly getting your head knocked around probably is not good for the brain, especially in young children whose brains are still maturing,” the researchers stated.

Children whose urine drug screens tested positive for tetrahydrocannabinol (THC) met multiple sleep latency tests (MSLT) criteria for narcolepsy or had multiple sleep-onset REM periods, according to a study published January 15 in Journal of Clinical Sleep Medicine. The 10-year retrospective study included 383 children who underwent drug screens on the morning before MSLT. Of children with urine drug screens that were positive for marijuana, 43% had MSLT results consistent with narcolepsy or abnormal REM sleep patterns. Approximately 24% of children who tested negative for marijuana had MSLT results consistent with narcolepsy. No child younger than 13 had a positive urine drug screen. Males were more likely to have a positive urine drug screen and MSLT findings that were consistent with narcolepsy, compared with other groups.

Low plasma levels of APOE are associated with increased risk of future Alzheimer’s disease and all dementia in the general population, independent of ε2, ε3, and ε4 APOE genotype, according to a study published in the February issue of Annals of Neurology. The study included 75,708 participants. Multifactorially adjusted hazard ratios for lowest versus highest APOE tertile were 2.68 and 1.80 for Alzheimer’s disease and all dementia, respectively. After further adjustment for APOE genotype, plasma APOE tertiles remained associated with Alzheimer’s disease and all dementia. Researchers determined that the low level of APOE in the blood reflects a low level of APOE in the brain, indicating that β-amyloid is less effectively removed. Plasma levels of APOE may be a new, easily accessible preclinical biomarker, said the authors.

Women with Alzheimer’s disease had stable cognition for a year when they received leuprolide acetate, according to a study published in the January 1 issue of Journal of Alzheimer’s Disease. The clinical trial followed 109 women with mild to moderate Alzheimer’s disease who were randomized to low-dose leuprolide acetate, high-dose leuprolide acetate, or placebo. Among patients taking an acetylcholinesterase inhibitor, researchers saw a statistically significant benefit in the high-dose leuprolide acetate group, compared with the other groups, as determined by the Alzheimer’s Disease Assessment Scale-cognitive subscale. Mean decline was 0.18 for the high-dose group, 4.21 for the low-dose group, and 3.30 for the placebo group. “This is the first time any therapy has been shown to stabilize memory loss over a year,” the researchers said.

The rate of favorable seizure outcome or seizure freedom after resective epilepsy surgery is significant and remains stable for more than 15 years, according to a study published online ahead of print January 19 in Epilepsy & Behavior. The findings were based on a telephone survey of 253 patients who underwent resection to treat localization-related epilepsy during an 18-year period. The mean age at the time of surgery was 35.4, with a range from five months to 71. Investigators found that 92% of patients surveyed considered epilepsy surgery worthwhile, 32% were seizure-free, and 75% had favorable results. Favorable and seizure-free outcome rates remained stable after surgery over long-term follow-up. Compared with baseline, patients were more likely to be driving and taking antidepressant medication, but less likely to be employed full-time after surgery.

Nearly one in five adults with epilepsy has symptoms of attention deficit hyperactivity disorder (ADHD), which are associated with increased psychosocial morbidity and lowered quality of life, according to a study published online ahead of print January 15 in Epilepsia. In the study, researchers mailed a survey to a national sample of adult patients with epilepsy, as part of the Epilepsy Comorbidities and Health study. The relationship of ADHD symptoms to quality of life outcomes was examined using statistical analyses, which also looked at sociodemographics, depression, anxiety, seizure frequency, and number of antiepileptic drugs. Nearly one-fifth (18.4%) of 1,361 respondents with active epilepsy were classified as experiencing significant ADHD symptoms. “This study reinforces the fact that we have to broaden our view of what epilepsy entails,” said the investigators.

Triheptanoin corrects the bioenergetic profile in the brain of patients with Huntington’s disease early in the course of the disease, according to a study published online ahead of print January 7 in Neurology. Researchers used MRI brain scans to analyze the energy profile before, during, and after the brain was visually stimulated in nine people in the early stages of Huntington’s disease and 13 people without the disease. In the people without the disease, the brain’s metabolism increased during the stimulation, then returned to the normal level. In people with Huntington’s disease, there was no change in metabolism. For the second part of the study, participants with Huntington’s disease received triheptanoin. When these participants underwent the visual stimulation test again, their brain metabolism was normal.

A common gut microbe may curb the risk of developing multiple sclerosis (MS) in women, according to a study published online ahead of print January 19 in the Journal of Neurology, Neurosurgery & Psychiatry. Researchers tested 550 people with confirmed MS and a comparison group of 299 healthy people, matched for age and sex, for antibodies to H. pylori between 2007 and 2011. The prevalence of the infection was significantly lower in participants with MS than in the comparison group, but only among women, in whom it was 30% lower. Among men, a positive test result was linked to higher rates of disability, but a positive test was associated with lower disability among women. The researchers found no evidence of any link between the presence of the infection and relapse rate.

Among patients with relapsing-remitting multiple sclerosis (MS), nonmyeloablative hematopoietic stem cell transplantation is associated with improvement in neurologic disability and other clinical outcomes, according to a study published January 20 in JAMA. In a case series of patients with relapsing-remitting MS or secondary progressive MS, participants received transplantation and were followed up for five years. In all, 41 patients (50%) had significant improvement in Expanded Disability Status Scale score at two years, and 23 patients (64%) had significant improvement at four years. Receipt of hematopoietic stem cell transplantation was associated with improvement in physical function, cognitive function, and quality of life. In addition, treatment was associated with a reduction in the volume of brain lesions associated with MS seen on MRI.

Insomnia in childhood and adolescence partially results from genetic factors, according to a study published in the January issue of Sleep. The study group included 1,412 twin pairs between the ages of 8 and 18. Participants were followed-up at three time points. The average ages at each of the four stages of the study were 8, 10, 14, and 15. The results showed that clinically significant insomnia was moderately heritable at all stages of the longitudinal study. Genetic factors contributed 33% to 38% of the insomnia ratings at the first two stages of the study, when participants were an average age of 8 to 10. “Insomnia in youth is moderately related to genetic factors, but the specific genetic factors may change with age,” stated the investigators.

People with epilepsy who sleep on their stomach may be at a higher risk of sudden unexpected death, according to a literature review published online ahead of print January 21 in Neurology. Researchers found that 73% of the deaths occurred while individuals were sleeping on their stomachs, compared with 27% of deaths that occurred during other sleep positions. In a subgroup of 88 people, researchers found that people younger than 40 were four times more likely to be found on their stomach at the time of sudden death than people older than 40. A total of 86% of those under 40 slept on their stomach, compared with 60% of people older than 40. Eleven sudden deaths occurred while the participants were being monitored with video EEG.

—Kimberly D. Williams

Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic events, and cerebrovascular disease in women, according to a study published online ahead of print February 16 in Circulation. Participants included 1.1 million women in the United Kingdom with no history of cancer, heart disease, stroke, blood clots, or diabetes who joined the Million Women study between 1996 and 2001. Their average age when they joined the study was 56. Women who performed strenuous physical activity two to three times per week were 20% less likely to develop heart disease, strokes, or blood clots, compared with participants who reported little or no activity. More frequent physical activity did not result in further reductions in the risk of heart disease.

The FDA has approved Rytary, an extended-release oral capsule formulation of carbidopa–levodopa, for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Rytary contains immediate-release and extended-release beads that contain carbidopa and levodopa in a 1:4 ratio, and provides initial and extended levodopa plasma concentrations after a single dose. In a trial of 393 randomized patients with advanced Parkinson’s disease, treatment with Rytary reduced the percentage of off time during waking hours from baseline to the end of the study, versus immediate-release carbidopa–levodopa. Rytary may be swallowed whole or opened, and the beads may be sprinkled on applesauce and consumed immediately. The drug is manufactured by Impax Pharmaceuticals (Hayward, California).

The FDA has approved Duopa, an enteral suspension of carbidopa and levodopa, as an orphan drug for the treatment of motor fluctuations in people with advanced Parkinson’s disease. The approval of Duopa is based on a phase III, 12-week, double-blind, double-placebo, active control, parallel-group, multicenter trial that compared the efficacy and safety of Duopa with that of oral, immediate-release carbidopa–levodopa tablets in patients with advanced Parkinson’s disease. Duopa significantly reduced daily mean off time at 12 weeks by four hours, which resulted in an average of 1.9 fewer hours of off time, when compared with carbidopa–levodopa tablets. Duopa is administered using a small, portable infusion pump that delivers carbidopa and levodopa directly into the small intestine continuously for 16 hours via a surgically-placed tube. The drug is manufactured by AbbVie (North Chicago, Illinois).

A link exists between brain structure and postconcussive symptoms among young male athletes who are otherwise healthy, according to a study published in the February issue of the Journal of Pediatrics. Researchers used advanced imaging technology and cognitive testing to assess 29 ice hockey players between ages 14 and 23, some of whom had a sports-related concussion. As the severity of the athletes’ concussion symptoms increased, the cortex became thinner in areas of the brain where it should be dense for players of these ages. Investigators believe that injury to a developing brain may be more severe than injury to an adult brain. “Years of playing contact sports and repeatedly getting your head knocked around probably is not good for the brain, especially in young children whose brains are still maturing,” the researchers stated.

Children whose urine drug screens tested positive for tetrahydrocannabinol (THC) met multiple sleep latency tests (MSLT) criteria for narcolepsy or had multiple sleep-onset REM periods, according to a study published January 15 in Journal of Clinical Sleep Medicine. The 10-year retrospective study included 383 children who underwent drug screens on the morning before MSLT. Of children with urine drug screens that were positive for marijuana, 43% had MSLT results consistent with narcolepsy or abnormal REM sleep patterns. Approximately 24% of children who tested negative for marijuana had MSLT results consistent with narcolepsy. No child younger than 13 had a positive urine drug screen. Males were more likely to have a positive urine drug screen and MSLT findings that were consistent with narcolepsy, compared with other groups.

Low plasma levels of APOE are associated with increased risk of future Alzheimer’s disease and all dementia in the general population, independent of ε2, ε3, and ε4 APOE genotype, according to a study published in the February issue of Annals of Neurology. The study included 75,708 participants. Multifactorially adjusted hazard ratios for lowest versus highest APOE tertile were 2.68 and 1.80 for Alzheimer’s disease and all dementia, respectively. After further adjustment for APOE genotype, plasma APOE tertiles remained associated with Alzheimer’s disease and all dementia. Researchers determined that the low level of APOE in the blood reflects a low level of APOE in the brain, indicating that β-amyloid is less effectively removed. Plasma levels of APOE may be a new, easily accessible preclinical biomarker, said the authors.

Women with Alzheimer’s disease had stable cognition for a year when they received leuprolide acetate, according to a study published in the January 1 issue of Journal of Alzheimer’s Disease. The clinical trial followed 109 women with mild to moderate Alzheimer’s disease who were randomized to low-dose leuprolide acetate, high-dose leuprolide acetate, or placebo. Among patients taking an acetylcholinesterase inhibitor, researchers saw a statistically significant benefit in the high-dose leuprolide acetate group, compared with the other groups, as determined by the Alzheimer’s Disease Assessment Scale-cognitive subscale. Mean decline was 0.18 for the high-dose group, 4.21 for the low-dose group, and 3.30 for the placebo group. “This is the first time any therapy has been shown to stabilize memory loss over a year,” the researchers said.

The rate of favorable seizure outcome or seizure freedom after resective epilepsy surgery is significant and remains stable for more than 15 years, according to a study published online ahead of print January 19 in Epilepsy & Behavior. The findings were based on a telephone survey of 253 patients who underwent resection to treat localization-related epilepsy during an 18-year period. The mean age at the time of surgery was 35.4, with a range from five months to 71. Investigators found that 92% of patients surveyed considered epilepsy surgery worthwhile, 32% were seizure-free, and 75% had favorable results. Favorable and seizure-free outcome rates remained stable after surgery over long-term follow-up. Compared with baseline, patients were more likely to be driving and taking antidepressant medication, but less likely to be employed full-time after surgery.

Nearly one in five adults with epilepsy has symptoms of attention deficit hyperactivity disorder (ADHD), which are associated with increased psychosocial morbidity and lowered quality of life, according to a study published online ahead of print January 15 in Epilepsia. In the study, researchers mailed a survey to a national sample of adult patients with epilepsy, as part of the Epilepsy Comorbidities and Health study. The relationship of ADHD symptoms to quality of life outcomes was examined using statistical analyses, which also looked at sociodemographics, depression, anxiety, seizure frequency, and number of antiepileptic drugs. Nearly one-fifth (18.4%) of 1,361 respondents with active epilepsy were classified as experiencing significant ADHD symptoms. “This study reinforces the fact that we have to broaden our view of what epilepsy entails,” said the investigators.

Triheptanoin corrects the bioenergetic profile in the brain of patients with Huntington’s disease early in the course of the disease, according to a study published online ahead of print January 7 in Neurology. Researchers used MRI brain scans to analyze the energy profile before, during, and after the brain was visually stimulated in nine people in the early stages of Huntington’s disease and 13 people without the disease. In the people without the disease, the brain’s metabolism increased during the stimulation, then returned to the normal level. In people with Huntington’s disease, there was no change in metabolism. For the second part of the study, participants with Huntington’s disease received triheptanoin. When these participants underwent the visual stimulation test again, their brain metabolism was normal.

A common gut microbe may curb the risk of developing multiple sclerosis (MS) in women, according to a study published online ahead of print January 19 in the Journal of Neurology, Neurosurgery & Psychiatry. Researchers tested 550 people with confirmed MS and a comparison group of 299 healthy people, matched for age and sex, for antibodies to H. pylori between 2007 and 2011. The prevalence of the infection was significantly lower in participants with MS than in the comparison group, but only among women, in whom it was 30% lower. Among men, a positive test result was linked to higher rates of disability, but a positive test was associated with lower disability among women. The researchers found no evidence of any link between the presence of the infection and relapse rate.

Among patients with relapsing-remitting multiple sclerosis (MS), nonmyeloablative hematopoietic stem cell transplantation is associated with improvement in neurologic disability and other clinical outcomes, according to a study published January 20 in JAMA. In a case series of patients with relapsing-remitting MS or secondary progressive MS, participants received transplantation and were followed up for five years. In all, 41 patients (50%) had significant improvement in Expanded Disability Status Scale score at two years, and 23 patients (64%) had significant improvement at four years. Receipt of hematopoietic stem cell transplantation was associated with improvement in physical function, cognitive function, and quality of life. In addition, treatment was associated with a reduction in the volume of brain lesions associated with MS seen on MRI.

Insomnia in childhood and adolescence partially results from genetic factors, according to a study published in the January issue of Sleep. The study group included 1,412 twin pairs between the ages of 8 and 18. Participants were followed-up at three time points. The average ages at each of the four stages of the study were 8, 10, 14, and 15. The results showed that clinically significant insomnia was moderately heritable at all stages of the longitudinal study. Genetic factors contributed 33% to 38% of the insomnia ratings at the first two stages of the study, when participants were an average age of 8 to 10. “Insomnia in youth is moderately related to genetic factors, but the specific genetic factors may change with age,” stated the investigators.

People with epilepsy who sleep on their stomach may be at a higher risk of sudden unexpected death, according to a literature review published online ahead of print January 21 in Neurology. Researchers found that 73% of the deaths occurred while individuals were sleeping on their stomachs, compared with 27% of deaths that occurred during other sleep positions. In a subgroup of 88 people, researchers found that people younger than 40 were four times more likely to be found on their stomach at the time of sudden death than people older than 40. A total of 86% of those under 40 slept on their stomach, compared with 60% of people older than 40. Eleven sudden deaths occurred while the participants were being monitored with video EEG.

—Kimberly D. Williams

Moderate physical activity is associated with a lower risk of coronary heart disease, venous thromboembolic events, and cerebrovascular disease in women, according to a study published online ahead of print February 16 in Circulation. Participants included 1.1 million women in the United Kingdom with no history of cancer, heart disease, stroke, blood clots, or diabetes who joined the Million Women study between 1996 and 2001. Their average age when they joined the study was 56. Women who performed strenuous physical activity two to three times per week were 20% less likely to develop heart disease, strokes, or blood clots, compared with participants who reported little or no activity. More frequent physical activity did not result in further reductions in the risk of heart disease.

The FDA has approved Rytary, an extended-release oral capsule formulation of carbidopa–levodopa, for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Rytary contains immediate-release and extended-release beads that contain carbidopa and levodopa in a 1:4 ratio, and provides initial and extended levodopa plasma concentrations after a single dose. In a trial of 393 randomized patients with advanced Parkinson’s disease, treatment with Rytary reduced the percentage of off time during waking hours from baseline to the end of the study, versus immediate-release carbidopa–levodopa. Rytary may be swallowed whole or opened, and the beads may be sprinkled on applesauce and consumed immediately. The drug is manufactured by Impax Pharmaceuticals (Hayward, California).

The FDA has approved Duopa, an enteral suspension of carbidopa and levodopa, as an orphan drug for the treatment of motor fluctuations in people with advanced Parkinson’s disease. The approval of Duopa is based on a phase III, 12-week, double-blind, double-placebo, active control, parallel-group, multicenter trial that compared the efficacy and safety of Duopa with that of oral, immediate-release carbidopa–levodopa tablets in patients with advanced Parkinson’s disease. Duopa significantly reduced daily mean off time at 12 weeks by four hours, which resulted in an average of 1.9 fewer hours of off time, when compared with carbidopa–levodopa tablets. Duopa is administered using a small, portable infusion pump that delivers carbidopa and levodopa directly into the small intestine continuously for 16 hours via a surgically-placed tube. The drug is manufactured by AbbVie (North Chicago, Illinois).

A link exists between brain structure and postconcussive symptoms among young male athletes who are otherwise healthy, according to a study published in the February issue of the Journal of Pediatrics. Researchers used advanced imaging technology and cognitive testing to assess 29 ice hockey players between ages 14 and 23, some of whom had a sports-related concussion. As the severity of the athletes’ concussion symptoms increased, the cortex became thinner in areas of the brain where it should be dense for players of these ages. Investigators believe that injury to a developing brain may be more severe than injury to an adult brain. “Years of playing contact sports and repeatedly getting your head knocked around probably is not good for the brain, especially in young children whose brains are still maturing,” the researchers stated.

Children whose urine drug screens tested positive for tetrahydrocannabinol (THC) met multiple sleep latency tests (MSLT) criteria for narcolepsy or had multiple sleep-onset REM periods, according to a study published January 15 in Journal of Clinical Sleep Medicine. The 10-year retrospective study included 383 children who underwent drug screens on the morning before MSLT. Of children with urine drug screens that were positive for marijuana, 43% had MSLT results consistent with narcolepsy or abnormal REM sleep patterns. Approximately 24% of children who tested negative for marijuana had MSLT results consistent with narcolepsy. No child younger than 13 had a positive urine drug screen. Males were more likely to have a positive urine drug screen and MSLT findings that were consistent with narcolepsy, compared with other groups.

Low plasma levels of APOE are associated with increased risk of future Alzheimer’s disease and all dementia in the general population, independent of ε2, ε3, and ε4 APOE genotype, according to a study published in the February issue of Annals of Neurology. The study included 75,708 participants. Multifactorially adjusted hazard ratios for lowest versus highest APOE tertile were 2.68 and 1.80 for Alzheimer’s disease and all dementia, respectively. After further adjustment for APOE genotype, plasma APOE tertiles remained associated with Alzheimer’s disease and all dementia. Researchers determined that the low level of APOE in the blood reflects a low level of APOE in the brain, indicating that β-amyloid is less effectively removed. Plasma levels of APOE may be a new, easily accessible preclinical biomarker, said the authors.

Women with Alzheimer’s disease had stable cognition for a year when they received leuprolide acetate, according to a study published in the January 1 issue of Journal of Alzheimer’s Disease. The clinical trial followed 109 women with mild to moderate Alzheimer’s disease who were randomized to low-dose leuprolide acetate, high-dose leuprolide acetate, or placebo. Among patients taking an acetylcholinesterase inhibitor, researchers saw a statistically significant benefit in the high-dose leuprolide acetate group, compared with the other groups, as determined by the Alzheimer’s Disease Assessment Scale-cognitive subscale. Mean decline was 0.18 for the high-dose group, 4.21 for the low-dose group, and 3.30 for the placebo group. “This is the first time any therapy has been shown to stabilize memory loss over a year,” the researchers said.

The rate of favorable seizure outcome or seizure freedom after resective epilepsy surgery is significant and remains stable for more than 15 years, according to a study published online ahead of print January 19 in Epilepsy & Behavior. The findings were based on a telephone survey of 253 patients who underwent resection to treat localization-related epilepsy during an 18-year period. The mean age at the time of surgery was 35.4, with a range from five months to 71. Investigators found that 92% of patients surveyed considered epilepsy surgery worthwhile, 32% were seizure-free, and 75% had favorable results. Favorable and seizure-free outcome rates remained stable after surgery over long-term follow-up. Compared with baseline, patients were more likely to be driving and taking antidepressant medication, but less likely to be employed full-time after surgery.

Nearly one in five adults with epilepsy has symptoms of attention deficit hyperactivity disorder (ADHD), which are associated with increased psychosocial morbidity and lowered quality of life, according to a study published online ahead of print January 15 in Epilepsia. In the study, researchers mailed a survey to a national sample of adult patients with epilepsy, as part of the Epilepsy Comorbidities and Health study. The relationship of ADHD symptoms to quality of life outcomes was examined using statistical analyses, which also looked at sociodemographics, depression, anxiety, seizure frequency, and number of antiepileptic drugs. Nearly one-fifth (18.4%) of 1,361 respondents with active epilepsy were classified as experiencing significant ADHD symptoms. “This study reinforces the fact that we have to broaden our view of what epilepsy entails,” said the investigators.

Triheptanoin corrects the bioenergetic profile in the brain of patients with Huntington’s disease early in the course of the disease, according to a study published online ahead of print January 7 in Neurology. Researchers used MRI brain scans to analyze the energy profile before, during, and after the brain was visually stimulated in nine people in the early stages of Huntington’s disease and 13 people without the disease. In the people without the disease, the brain’s metabolism increased during the stimulation, then returned to the normal level. In people with Huntington’s disease, there was no change in metabolism. For the second part of the study, participants with Huntington’s disease received triheptanoin. When these participants underwent the visual stimulation test again, their brain metabolism was normal.

A common gut microbe may curb the risk of developing multiple sclerosis (MS) in women, according to a study published online ahead of print January 19 in the Journal of Neurology, Neurosurgery & Psychiatry. Researchers tested 550 people with confirmed MS and a comparison group of 299 healthy people, matched for age and sex, for antibodies to H. pylori between 2007 and 2011. The prevalence of the infection was significantly lower in participants with MS than in the comparison group, but only among women, in whom it was 30% lower. Among men, a positive test result was linked to higher rates of disability, but a positive test was associated with lower disability among women. The researchers found no evidence of any link between the presence of the infection and relapse rate.

Among patients with relapsing-remitting multiple sclerosis (MS), nonmyeloablative hematopoietic stem cell transplantation is associated with improvement in neurologic disability and other clinical outcomes, according to a study published January 20 in JAMA. In a case series of patients with relapsing-remitting MS or secondary progressive MS, participants received transplantation and were followed up for five years. In all, 41 patients (50%) had significant improvement in Expanded Disability Status Scale score at two years, and 23 patients (64%) had significant improvement at four years. Receipt of hematopoietic stem cell transplantation was associated with improvement in physical function, cognitive function, and quality of life. In addition, treatment was associated with a reduction in the volume of brain lesions associated with MS seen on MRI.

Insomnia in childhood and adolescence partially results from genetic factors, according to a study published in the January issue of Sleep. The study group included 1,412 twin pairs between the ages of 8 and 18. Participants were followed-up at three time points. The average ages at each of the four stages of the study were 8, 10, 14, and 15. The results showed that clinically significant insomnia was moderately heritable at all stages of the longitudinal study. Genetic factors contributed 33% to 38% of the insomnia ratings at the first two stages of the study, when participants were an average age of 8 to 10. “Insomnia in youth is moderately related to genetic factors, but the specific genetic factors may change with age,” stated the investigators.

People with epilepsy who sleep on their stomach may be at a higher risk of sudden unexpected death, according to a literature review published online ahead of print January 21 in Neurology. Researchers found that 73% of the deaths occurred while individuals were sleeping on their stomachs, compared with 27% of deaths that occurred during other sleep positions. In a subgroup of 88 people, researchers found that people younger than 40 were four times more likely to be found on their stomach at the time of sudden death than people older than 40. A total of 86% of those under 40 slept on their stomach, compared with 60% of people older than 40. Eleven sudden deaths occurred while the participants were being monitored with video EEG.

—Kimberly D. Williams

Click here to download the PDF.

Click here to download the PDF.

Click here to download the PDF.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Anopheles gambiae mosquito

Photo courtesy of CDC

Sexual biology may be the key to uncovering why Anopheles mosquitoes are unique in their ability to transmit malaria to humans, according to research published in Science.

By analyzing 16 Anopheles genomes, investigators found these mosquitoes’ reproductive traits evolved along with their capacity to transmit the Plasmodium parasite.

The team believes these findings may provide a new target for malaria control, particularly in regions hardest hit by the disease.

“Our study is the first to reveal the evolutionary dynamics between the sexes that are likely responsible for shaping the ability of Anopheles mosquitoes to transmit malaria to humans,” said study author Flaminia Catteruccia, PhD, of the University of Perugia in Italy.

She and her colleagues analyzed 9 globally dispersed Anopheles species, enabling reconstruction of the evolutionary history of the mosquitoes’ reproductive traits and capacity to transmit malaria.

Results showed that 2 key male reproductive traits in Anopheles are acquired and evolved together over time. The first is transferring ejaculate as a gelatinous, rod-shaped structure called the mating plug. And the second is the ability to synthesize a steroid hormone known as 20-hydroxyecdysone (20E), which is contained in the mating plug.

The investigators also demonstrated that the evolution of these male traits drove reciprocal adaptations in females that are strongly linked to the mosquitoes’ capacity to transmit malaria.

With prior research, the team had shown that sexual transfer of 20E induces a series of dramatic changes in the female mosquito, fundamentally altering her physiology and behavior. These changes affect a female’s reproductive output, longevity, and immune response to Plasmodium parasites, all key factors in malaria transmission.

All 4 species of Anopheles mosquitoes that transfer large levels of 20E are major malaria vectors originating from Africa and India, the regions of highest malaria burden.

The investigators believe that, by identifying factors important for malaria transmission, they have paved the way for the development of compounds to specifically target those factors. Such compounds could be incorporated into existing mosquito control technologies, boosting their overall effectiveness.

The team also thinks their findings might be applicable to Dengue and West Nile virus, which are transmitted by the Aedes and Culex mosquitoes, respectively. In these species, some aspects of reproductive biology are similar to Anopheles.

Anopheles gambiae mosquito

Photo courtesy of CDC

Sexual biology may be the key to uncovering why Anopheles mosquitoes are unique in their ability to transmit malaria to humans, according to research published in Science.

By analyzing 16 Anopheles genomes, investigators found these mosquitoes’ reproductive traits evolved along with their capacity to transmit the Plasmodium parasite.

The team believes these findings may provide a new target for malaria control, particularly in regions hardest hit by the disease.

“Our study is the first to reveal the evolutionary dynamics between the sexes that are likely responsible for shaping the ability of Anopheles mosquitoes to transmit malaria to humans,” said study author Flaminia Catteruccia, PhD, of the University of Perugia in Italy.

She and her colleagues analyzed 9 globally dispersed Anopheles species, enabling reconstruction of the evolutionary history of the mosquitoes’ reproductive traits and capacity to transmit malaria.

Results showed that 2 key male reproductive traits in Anopheles are acquired and evolved together over time. The first is transferring ejaculate as a gelatinous, rod-shaped structure called the mating plug. And the second is the ability to synthesize a steroid hormone known as 20-hydroxyecdysone (20E), which is contained in the mating plug.

The investigators also demonstrated that the evolution of these male traits drove reciprocal adaptations in females that are strongly linked to the mosquitoes’ capacity to transmit malaria.

With prior research, the team had shown that sexual transfer of 20E induces a series of dramatic changes in the female mosquito, fundamentally altering her physiology and behavior. These changes affect a female’s reproductive output, longevity, and immune response to Plasmodium parasites, all key factors in malaria transmission.

All 4 species of Anopheles mosquitoes that transfer large levels of 20E are major malaria vectors originating from Africa and India, the regions of highest malaria burden.

The investigators believe that, by identifying factors important for malaria transmission, they have paved the way for the development of compounds to specifically target those factors. Such compounds could be incorporated into existing mosquito control technologies, boosting their overall effectiveness.

The team also thinks their findings might be applicable to Dengue and West Nile virus, which are transmitted by the Aedes and Culex mosquitoes, respectively. In these species, some aspects of reproductive biology are similar to Anopheles.

Anopheles gambiae mosquito

Photo courtesy of CDC

Sexual biology may be the key to uncovering why Anopheles mosquitoes are unique in their ability to transmit malaria to humans, according to research published in Science.

By analyzing 16 Anopheles genomes, investigators found these mosquitoes’ reproductive traits evolved along with their capacity to transmit the Plasmodium parasite.

The team believes these findings may provide a new target for malaria control, particularly in regions hardest hit by the disease.

“Our study is the first to reveal the evolutionary dynamics between the sexes that are likely responsible for shaping the ability of Anopheles mosquitoes to transmit malaria to humans,” said study author Flaminia Catteruccia, PhD, of the University of Perugia in Italy.

She and her colleagues analyzed 9 globally dispersed Anopheles species, enabling reconstruction of the evolutionary history of the mosquitoes’ reproductive traits and capacity to transmit malaria.

Results showed that 2 key male reproductive traits in Anopheles are acquired and evolved together over time. The first is transferring ejaculate as a gelatinous, rod-shaped structure called the mating plug. And the second is the ability to synthesize a steroid hormone known as 20-hydroxyecdysone (20E), which is contained in the mating plug.

The investigators also demonstrated that the evolution of these male traits drove reciprocal adaptations in females that are strongly linked to the mosquitoes’ capacity to transmit malaria.

With prior research, the team had shown that sexual transfer of 20E induces a series of dramatic changes in the female mosquito, fundamentally altering her physiology and behavior. These changes affect a female’s reproductive output, longevity, and immune response to Plasmodium parasites, all key factors in malaria transmission.

All 4 species of Anopheles mosquitoes that transfer large levels of 20E are major malaria vectors originating from Africa and India, the regions of highest malaria burden.

The investigators believe that, by identifying factors important for malaria transmission, they have paved the way for the development of compounds to specifically target those factors. Such compounds could be incorporated into existing mosquito control technologies, boosting their overall effectiveness.

The team also thinks their findings might be applicable to Dengue and West Nile virus, which are transmitted by the Aedes and Culex mosquitoes, respectively. In these species, some aspects of reproductive biology are similar to Anopheles.

The Centers for Disease Control and Prevention (CDC) has published its 2015 immunization schedules for adults and for children and adolescents.^1,2 There are very few changes from 2014 recommendations; most are alterations in the footnotes to clarify complex and confusing catch-up schedules. The 2 substantive changes have been discussed in previous Practice Alerts:

• the addition of the 13-valent pneumococcal conjugate vaccine (PCV13)  to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the routine older-adult recommendations;³
• a stated preference for live attenuated influenza vaccine (LAIV) for children ages 2 through 8 years.⁴

The LAIV statement came under criticism at the recent meeting of the Advisory Committee on Immunization Practices (ACIP). A prospective case-control study conducted at 5 sites in the US Flu Vaccine Effectiveness Network looked at the effectiveness of LAIV and inactivated influenza vaccine (IIV) against medically-attended influenza in 3 flu seasons: 2011-2012, 2012-2013, and 2013-2014.⁵ The results differed by age.

In patients ages 9 to 18 years, the vaccines were equally effective in all 3 seasons, with effectiveness ranging between 32% and 67% depending on the year and the vaccine. In children ages 2 to 8 years, LAIV appeared to be more effective than IIV in the 2011-2012 and 2012-2013 seasons, with odds ratios of .54 and .74, respectively (although not statistically significant). In the 2013-2014 season, however, IIV was the more effective vaccine, with a statistically significant odds ratio of 5.17.

In the immediate past season, the predominant influenza strain circulating was H1N1 pdm09, against which the LAIV appeared to be minimally, if at all, effective. These results were replicated in a study conducted by the LAIV producer, MedImmune, and in a study conducted by the United States Air Force.⁵ Based on the predominant circulating strains in the 2014-2015 flu season, ACIP has not changed its preference for LAIV for ages 2 through 8 years.

Typhoid fever vaccines

Late last year, ACIP updated its recommendations on the use of typhoid vaccines. They had last been reviewed with the recommendations in 1994, and surprisingly few changes were needed. Roughly 400 cases of typhoid fever occur in the United States each year, mostly in travelers returning from India, Bangladesh, or Pakistan. Each year, worldwide, there are an estimated 20 million cases of typhoid and 200,000 related deaths.⁶

ACIP recommends typhoid vaccine for travelers to areas within Asia, Africa, and Latin America that present a risk of exposure to Salmonella typhi. Country-specific recommendations can be found on the CDC travel Web site (http://wwwnc.cdc.gov/travel). Others for whom the vaccine is recommended: those who have a household contact with S. typhi or who have had other intimate exposure to a chronic S. typhi carrier (eg, someone who has excreted S. typhi in stool or urine for a year or more); and microbiologists and lab workers who might be exposed to S. typhi.

Two typhoid vaccines are available and neither is listed as preferred. One is a live vaccine (Ty21a) taken orally in 4 doses, one dose every other day over 7 days. The other is a killed vaccine (Vi capsular polysaccharide vaccine [ViCPS]), given intramuscularly in a single dose (TABLE).^6,7 Ty21a is approved for individuals ages 6 years and older; ViCPS for ages 2 years and older.

Anticipated changes this year

HPV vaccine

Two human papillomavirus (HPV) vaccines are available in the United States: Gardasil, a quadrivalent vaccine (HPV4) that protects against types 6, 11, 16, and 18, and Cervarix, a bivalent product (HPV2) protecting against types 16 and 18. Both vaccines contain antigens of HPV subtypes 16 and 18, which cause 70% of cervical cancers in the United States and the rest of the world. The HPV4 is soon to be replaced with a 9-valent product that will contain antigens for types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which are responsible for 90% of cervical cancers worldwide.⁸

A 9-valent HPV vaccine, anticipated for release in 2015, will target 9 types of HPV that are responsible for 90% of cervical cancers worldwide. Many countries now allow a 2-dose schedule for both HPV2 and HPV4. For girls younger than 15 years, the World Health Organization recommends a 2-dose schedule for HPV vaccines, 6 to 12 months apart.⁹ A 3-dose schedule is still recommended for those ages 15 years or older and for those who are immunocompromised.

ACIP will assess studies on the effectiveness of 2-dose schedules of HPV2, HPV4, and HPV9, and will make recommendations within the next year. Although the manufacturers of the HPV vaccines have not applied to the US Food and Drug Administration (FDA) for approval of a 2-dose schedule, ACIP will still consider the possibility of recommending it. The current 3-dose schedule is seen as a barrier to HPV vaccination and one reason why the rate of vaccination in girls in the United States remains at a disappointing 37.6% for 3 doses, 47.7% for at least 2 doses, and 57.3% for 1 dose.¹⁰

ACIP will attempt to address multiple issues in the next year regarding HPV vaccination: HPV9 use in men and women, including the possibility of catch-up schedules for those who have received HPV4 or HPV2; the possibility of using a 2-dose schedule for all HPV vaccines; and ways to increase uptake of this cancer-preventing vaccine.

Meningococcus type B

With the widespread use of quadrivalent meningococcal vaccines (MCV4), meningococcal meningitis has declined markedly in all age groups. The incidence of disease caused by meningococcal serotype B, which MCV4 does not protect against, has also declined from 0.3 to less than 0.1 cases per 100,000 between 1994 and 2013.¹¹ The highest incidence occurs in infants under the age of 1 year, at 1.5/100,000, with 67% of cases attributable to serotype B. A slight bump in risk is seen with those ages 19 to 22 years (0.2/100,000) compared with other adolescents and adults.

While serotype B accounts for a larger proportion of all meningococcal disease than it did before, it is still relatively rare. In the United States between 2010 and 2012, annual cases totaled 48 to 56.¹¹ Groups that are at higher risk of infection include those with complement deficiencies or asplenia (functional or anatomical), microbiologists and lab personnel who work with the organism, and those who have close contact with infected individuals.

In the past few years, well-publicized outbreaks of meningococcus B have occurred on some university campuses. Princeton had 9 cases, and the University of California at Santa Barbara had 4.¹¹ This led to the use of meningococcal B vaccine as an outbreak control measure, with permission from the FDA before the vaccine was licensed. While these outbreaks created an impression of increased risks on college campuses, college students are actually at lower risk of type B meningococcal disease than others of the same age.¹¹

This year, meningococcal B vaccines Trumenba (a 3-dose series) and Bexsero (a 2-dose series) will be available for individuals ages 10 to 25 years. This year, 2 meningococcal B vaccines will be available in the United States. The first, rLP2086, Trumenba (Pfizer) is a 3-dose series that was licensed in late 2014. The second, 4CMenB, Bexsero (Novartis) is a 2-dose series that received FDA approval in January 2015. Both are licensed for individuals ages 10 to 25 years. Formulating a recommendation for the use of these vaccines will be challenging because of several factors: the multiple dose schedules, the low rate of meningococcal B disease, and the age group for whom the vaccines are licensed.

The Centers for Disease Control and Prevention (CDC) has published its 2015 immunization schedules for adults and for children and adolescents.^1,2 There are very few changes from 2014 recommendations; most are alterations in the footnotes to clarify complex and confusing catch-up schedules. The 2 substantive changes have been discussed in previous Practice Alerts:

• the addition of the 13-valent pneumococcal conjugate vaccine (PCV13)  to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the routine older-adult recommendations;³
• a stated preference for live attenuated influenza vaccine (LAIV) for children ages 2 through 8 years.⁴

The LAIV statement came under criticism at the recent meeting of the Advisory Committee on Immunization Practices (ACIP). A prospective case-control study conducted at 5 sites in the US Flu Vaccine Effectiveness Network looked at the effectiveness of LAIV and inactivated influenza vaccine (IIV) against medically-attended influenza in 3 flu seasons: 2011-2012, 2012-2013, and 2013-2014.⁵ The results differed by age.

In patients ages 9 to 18 years, the vaccines were equally effective in all 3 seasons, with effectiveness ranging between 32% and 67% depending on the year and the vaccine. In children ages 2 to 8 years, LAIV appeared to be more effective than IIV in the 2011-2012 and 2012-2013 seasons, with odds ratios of .54 and .74, respectively (although not statistically significant). In the 2013-2014 season, however, IIV was the more effective vaccine, with a statistically significant odds ratio of 5.17.

In the immediate past season, the predominant influenza strain circulating was H1N1 pdm09, against which the LAIV appeared to be minimally, if at all, effective. These results were replicated in a study conducted by the LAIV producer, MedImmune, and in a study conducted by the United States Air Force.⁵ Based on the predominant circulating strains in the 2014-2015 flu season, ACIP has not changed its preference for LAIV for ages 2 through 8 years.

Typhoid fever vaccines

Late last year, ACIP updated its recommendations on the use of typhoid vaccines. They had last been reviewed with the recommendations in 1994, and surprisingly few changes were needed. Roughly 400 cases of typhoid fever occur in the United States each year, mostly in travelers returning from India, Bangladesh, or Pakistan. Each year, worldwide, there are an estimated 20 million cases of typhoid and 200,000 related deaths.⁶

ACIP recommends typhoid vaccine for travelers to areas within Asia, Africa, and Latin America that present a risk of exposure to Salmonella typhi. Country-specific recommendations can be found on the CDC travel Web site (http://wwwnc.cdc.gov/travel). Others for whom the vaccine is recommended: those who have a household contact with S. typhi or who have had other intimate exposure to a chronic S. typhi carrier (eg, someone who has excreted S. typhi in stool or urine for a year or more); and microbiologists and lab workers who might be exposed to S. typhi.

Two typhoid vaccines are available and neither is listed as preferred. One is a live vaccine (Ty21a) taken orally in 4 doses, one dose every other day over 7 days. The other is a killed vaccine (Vi capsular polysaccharide vaccine [ViCPS]), given intramuscularly in a single dose (TABLE).^6,7 Ty21a is approved for individuals ages 6 years and older; ViCPS for ages 2 years and older.

Anticipated changes this year

HPV vaccine

Two human papillomavirus (HPV) vaccines are available in the United States: Gardasil, a quadrivalent vaccine (HPV4) that protects against types 6, 11, 16, and 18, and Cervarix, a bivalent product (HPV2) protecting against types 16 and 18. Both vaccines contain antigens of HPV subtypes 16 and 18, which cause 70% of cervical cancers in the United States and the rest of the world. The HPV4 is soon to be replaced with a 9-valent product that will contain antigens for types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which are responsible for 90% of cervical cancers worldwide.⁸

A 9-valent HPV vaccine, anticipated for release in 2015, will target 9 types of HPV that are responsible for 90% of cervical cancers worldwide. Many countries now allow a 2-dose schedule for both HPV2 and HPV4. For girls younger than 15 years, the World Health Organization recommends a 2-dose schedule for HPV vaccines, 6 to 12 months apart.⁹ A 3-dose schedule is still recommended for those ages 15 years or older and for those who are immunocompromised.

ACIP will assess studies on the effectiveness of 2-dose schedules of HPV2, HPV4, and HPV9, and will make recommendations within the next year. Although the manufacturers of the HPV vaccines have not applied to the US Food and Drug Administration (FDA) for approval of a 2-dose schedule, ACIP will still consider the possibility of recommending it. The current 3-dose schedule is seen as a barrier to HPV vaccination and one reason why the rate of vaccination in girls in the United States remains at a disappointing 37.6% for 3 doses, 47.7% for at least 2 doses, and 57.3% for 1 dose.¹⁰

ACIP will attempt to address multiple issues in the next year regarding HPV vaccination: HPV9 use in men and women, including the possibility of catch-up schedules for those who have received HPV4 or HPV2; the possibility of using a 2-dose schedule for all HPV vaccines; and ways to increase uptake of this cancer-preventing vaccine.

Meningococcus type B

With the widespread use of quadrivalent meningococcal vaccines (MCV4), meningococcal meningitis has declined markedly in all age groups. The incidence of disease caused by meningococcal serotype B, which MCV4 does not protect against, has also declined from 0.3 to less than 0.1 cases per 100,000 between 1994 and 2013.¹¹ The highest incidence occurs in infants under the age of 1 year, at 1.5/100,000, with 67% of cases attributable to serotype B. A slight bump in risk is seen with those ages 19 to 22 years (0.2/100,000) compared with other adolescents and adults.

While serotype B accounts for a larger proportion of all meningococcal disease than it did before, it is still relatively rare. In the United States between 2010 and 2012, annual cases totaled 48 to 56.¹¹ Groups that are at higher risk of infection include those with complement deficiencies or asplenia (functional or anatomical), microbiologists and lab personnel who work with the organism, and those who have close contact with infected individuals.

In the past few years, well-publicized outbreaks of meningococcus B have occurred on some university campuses. Princeton had 9 cases, and the University of California at Santa Barbara had 4.¹¹ This led to the use of meningococcal B vaccine as an outbreak control measure, with permission from the FDA before the vaccine was licensed. While these outbreaks created an impression of increased risks on college campuses, college students are actually at lower risk of type B meningococcal disease than others of the same age.¹¹

This year, meningococcal B vaccines Trumenba (a 3-dose series) and Bexsero (a 2-dose series) will be available for individuals ages 10 to 25 years. This year, 2 meningococcal B vaccines will be available in the United States. The first, rLP2086, Trumenba (Pfizer) is a 3-dose series that was licensed in late 2014. The second, 4CMenB, Bexsero (Novartis) is a 2-dose series that received FDA approval in January 2015. Both are licensed for individuals ages 10 to 25 years. Formulating a recommendation for the use of these vaccines will be challenging because of several factors: the multiple dose schedules, the low rate of meningococcal B disease, and the age group for whom the vaccines are licensed.

The Centers for Disease Control and Prevention (CDC) has published its 2015 immunization schedules for adults and for children and adolescents.^1,2 There are very few changes from 2014 recommendations; most are alterations in the footnotes to clarify complex and confusing catch-up schedules. The 2 substantive changes have been discussed in previous Practice Alerts:

• the addition of the 13-valent pneumococcal conjugate vaccine (PCV13)  to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the routine older-adult recommendations;³
• a stated preference for live attenuated influenza vaccine (LAIV) for children ages 2 through 8 years.⁴

The LAIV statement came under criticism at the recent meeting of the Advisory Committee on Immunization Practices (ACIP). A prospective case-control study conducted at 5 sites in the US Flu Vaccine Effectiveness Network looked at the effectiveness of LAIV and inactivated influenza vaccine (IIV) against medically-attended influenza in 3 flu seasons: 2011-2012, 2012-2013, and 2013-2014.⁵ The results differed by age.

In patients ages 9 to 18 years, the vaccines were equally effective in all 3 seasons, with effectiveness ranging between 32% and 67% depending on the year and the vaccine. In children ages 2 to 8 years, LAIV appeared to be more effective than IIV in the 2011-2012 and 2012-2013 seasons, with odds ratios of .54 and .74, respectively (although not statistically significant). In the 2013-2014 season, however, IIV was the more effective vaccine, with a statistically significant odds ratio of 5.17.

In the immediate past season, the predominant influenza strain circulating was H1N1 pdm09, against which the LAIV appeared to be minimally, if at all, effective. These results were replicated in a study conducted by the LAIV producer, MedImmune, and in a study conducted by the United States Air Force.⁵ Based on the predominant circulating strains in the 2014-2015 flu season, ACIP has not changed its preference for LAIV for ages 2 through 8 years.

Typhoid fever vaccines

Late last year, ACIP updated its recommendations on the use of typhoid vaccines. They had last been reviewed with the recommendations in 1994, and surprisingly few changes were needed. Roughly 400 cases of typhoid fever occur in the United States each year, mostly in travelers returning from India, Bangladesh, or Pakistan. Each year, worldwide, there are an estimated 20 million cases of typhoid and 200,000 related deaths.⁶

ACIP recommends typhoid vaccine for travelers to areas within Asia, Africa, and Latin America that present a risk of exposure to Salmonella typhi. Country-specific recommendations can be found on the CDC travel Web site (http://wwwnc.cdc.gov/travel). Others for whom the vaccine is recommended: those who have a household contact with S. typhi or who have had other intimate exposure to a chronic S. typhi carrier (eg, someone who has excreted S. typhi in stool or urine for a year or more); and microbiologists and lab workers who might be exposed to S. typhi.

Two typhoid vaccines are available and neither is listed as preferred. One is a live vaccine (Ty21a) taken orally in 4 doses, one dose every other day over 7 days. The other is a killed vaccine (Vi capsular polysaccharide vaccine [ViCPS]), given intramuscularly in a single dose (TABLE).^6,7 Ty21a is approved for individuals ages 6 years and older; ViCPS for ages 2 years and older.

Anticipated changes this year

HPV vaccine

Two human papillomavirus (HPV) vaccines are available in the United States: Gardasil, a quadrivalent vaccine (HPV4) that protects against types 6, 11, 16, and 18, and Cervarix, a bivalent product (HPV2) protecting against types 16 and 18. Both vaccines contain antigens of HPV subtypes 16 and 18, which cause 70% of cervical cancers in the United States and the rest of the world. The HPV4 is soon to be replaced with a 9-valent product that will contain antigens for types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which are responsible for 90% of cervical cancers worldwide.⁸

A 9-valent HPV vaccine, anticipated for release in 2015, will target 9 types of HPV that are responsible for 90% of cervical cancers worldwide. Many countries now allow a 2-dose schedule for both HPV2 and HPV4. For girls younger than 15 years, the World Health Organization recommends a 2-dose schedule for HPV vaccines, 6 to 12 months apart.⁹ A 3-dose schedule is still recommended for those ages 15 years or older and for those who are immunocompromised.

ACIP will assess studies on the effectiveness of 2-dose schedules of HPV2, HPV4, and HPV9, and will make recommendations within the next year. Although the manufacturers of the HPV vaccines have not applied to the US Food and Drug Administration (FDA) for approval of a 2-dose schedule, ACIP will still consider the possibility of recommending it. The current 3-dose schedule is seen as a barrier to HPV vaccination and one reason why the rate of vaccination in girls in the United States remains at a disappointing 37.6% for 3 doses, 47.7% for at least 2 doses, and 57.3% for 1 dose.¹⁰

ACIP will attempt to address multiple issues in the next year regarding HPV vaccination: HPV9 use in men and women, including the possibility of catch-up schedules for those who have received HPV4 or HPV2; the possibility of using a 2-dose schedule for all HPV vaccines; and ways to increase uptake of this cancer-preventing vaccine.

Meningococcus type B

With the widespread use of quadrivalent meningococcal vaccines (MCV4), meningococcal meningitis has declined markedly in all age groups. The incidence of disease caused by meningococcal serotype B, which MCV4 does not protect against, has also declined from 0.3 to less than 0.1 cases per 100,000 between 1994 and 2013.¹¹ The highest incidence occurs in infants under the age of 1 year, at 1.5/100,000, with 67% of cases attributable to serotype B. A slight bump in risk is seen with those ages 19 to 22 years (0.2/100,000) compared with other adolescents and adults.

While serotype B accounts for a larger proportion of all meningococcal disease than it did before, it is still relatively rare. In the United States between 2010 and 2012, annual cases totaled 48 to 56.¹¹ Groups that are at higher risk of infection include those with complement deficiencies or asplenia (functional or anatomical), microbiologists and lab personnel who work with the organism, and those who have close contact with infected individuals.

In the past few years, well-publicized outbreaks of meningococcus B have occurred on some university campuses. Princeton had 9 cases, and the University of California at Santa Barbara had 4.¹¹ This led to the use of meningococcal B vaccine as an outbreak control measure, with permission from the FDA before the vaccine was licensed. While these outbreaks created an impression of increased risks on college campuses, college students are actually at lower risk of type B meningococcal disease than others of the same age.¹¹

This year, meningococcal B vaccines Trumenba (a 3-dose series) and Bexsero (a 2-dose series) will be available for individuals ages 10 to 25 years. This year, 2 meningococcal B vaccines will be available in the United States. The first, rLP2086, Trumenba (Pfizer) is a 3-dose series that was licensed in late 2014. The second, 4CMenB, Bexsero (Novartis) is a 2-dose series that received FDA approval in January 2015. Both are licensed for individuals ages 10 to 25 years. Formulating a recommendation for the use of these vaccines will be challenging because of several factors: the multiple dose schedules, the low rate of meningococcal B disease, and the age group for whom the vaccines are licensed.

THE CASE

A 31-year-old man came to an internal medicine clinic because he’d been losing weight over the past 2 years and hadn’t been able to regain any weight despite eating properly. Our patient was born in Ethiopia, but had been living in Canada for 6 years. He reported a remote history of 2 episodes of diarrhea.

His physical exam was normal and laboratory results revealed mild eosinophilia of 0.6 × 10⁹/L (normal range, <0.45 × 10⁹/L). Additional tests (including complete blood count, electrolytes, liver panel, thyrotropin, and blood smear) revealed no apparent metabolic causes of the patient’s weight loss. Stool analysis (3 exams) was negative for ova and parasites.

THE DIAGNOSIS

Because our patient was born in Ethiopia, we did serologic testing for Strongyloides, which was positive (enzyme-linked immunosorbent assay for immunoglobulin G antibodies [IgG-ELISA] was 2.9; positive is >2.1). We diagnosed strongyloidiasis in this patient.

DISCUSSION

Strongyloidiasis is an infection caused by the parasite Strongyloides stercoralis.¹ It affects an estimated 30 to 100 million people worldwide, mainly in Africa, Southeast Asia, Central America, and South America, but it also can occur in temperate climates.²Strongyloides is a soil-transmitted helminth (parasitic worm). The prevalence of Strongyloides infection among refugee groups in the United States is 1% to 4.3%.^3-5

Although patients with strongyloidiasis are often asymptomatic, they can present with a wide range of nonspecific symptoms. In the acute stage, patients may develop signs and symptoms including cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens.² Respiratory symptoms, including tracheal irritation and a dry cough, are often confused with asthma. In the generally asymptomatic chronic stage, patients may develop gastrointestinal complaints, such as epigastric pain and heartburn.⁶

Hyperinfection syndrome can occur when patients with subclinical infection receive high doses of corticosteroids for asthma or chronic obstructive pulmonary disease exacerbations. Risk of hyperinfection is increased among immunocompromised patients with human T lymphotropic virus type-1 (HTLV-1),⁷ as well as in patients with malignancies, malnutrition, and alcohol use disorder. Eosinophilia is often absent in patients with hyperinfection, and stool examination results are almost always positive.⁸

Who to screen, how to make the diagnosis

Suspect strongyloidiasis infection in immigrants, refugees, and travelers from endemic regions who have eosinophilia. The presence of eosinophilia in immigrants, refugees, and travelers from endemic regions should alert clinicians to the possibility of an underlying helminth infection. However, because eosinophilia occurs intermittently in response to tissue invasion, absence of eosinophilia does not exclude strongyloidiasis.

The Canadian Collaboration for Immigrants and Refugee Health (CCIRH) recommends using serologic testing to screen for Strongyloides in all newly arrived refugees from low-income countries in Southeast Asia and Africa.⁹ The CCIRH also advises that while data on the burden of strongyloidiasis in non-refugee immigrant populations is limited, you should consider screening foreign-born individuals who have lived in endemic areas, have symptoms and/or signs of Strongyloides infection, and/or have evidence of eosinophilia.⁹ Because the risk of hyperinfection is increased in immunocompromised individuals, screening should be done to detect Strongyloides infection before starting chemotherapy and before initiating corticosteroids in patients from endemic areas.¹⁰

Diagnostic methods. Stool examination⁶ and IgG-ELISA² are the main methods used to diagnose strongyloidiasis. However, traditional stool examinations have low sensitivity, and it may require up to 7 stool exams to reach a sensitivity of 100%,⁶ which could explain why our patient’s stool analysis was negative for parasites. In our experience, a positive serology result should always be assumed to indicate an active infection unless there is a well documented history of prior therapy. (In such cases, a positive serology result could represent persistent antibodies following therapy.)

First-line therapy and alternative treatment

All patients with strongyloidiasis, regardless of whether they are symptomatic, must be treated to prevent possible late-onset disseminated disease and hyperinfection.⁹ The Centers for Disease Control and Prevention recommends one to 2 doses of ivermectin 200 mcg/kg as first-line therapy or albendazole 400 mg twice daily for 3 days as an alternative treatment (TABLE).¹¹ Ivermectin cures more than 95% of cases.¹² Albendazole has lower efficacy (78%).¹³ Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for the parasite to migrate to the gut.⁴

Consider referral to an infectious disease specialist for patients coinfected with HTLV-1, as well as those who are immunocompromised. Coinfection with HTLV-1 (which is endemic in areas where Strongyloides also is
endemic) modifies patients’ immune response and can complicate treatment.⁹ Clinicians should screen strongyloidiasis patients for HTLV-1 if they come from high-prevalence areas and/or have persistent strongyloidiasis that responds poorly to antiparasitic treatment.⁹

Consider referral to an infectious disease specialist for patients coinfected with
HTLV-1, as well as those who are immunocompromised. Such referral also may be appropriate for patients from countries where loa loa is endemic, because encephalopathy has occurred in patients coinfected with loa loa who were treated with ivermectin.¹⁰

Our patient was treated with 2 doses of ivermectin 200 mcg/kg, 2 weeks apart. Four months later, his eosinophilia had resolved, his IgG-ELISA dropped to 0.37, and he had gained 2.5 pounds.

THE TAKEAWAY

Strongyloidiasis is an infection caused by the parasitic worm Strongyloides stercoralis that is most common in tropical or subtropical areas. It can be asymptomatic or present with a wide range of nonspecific signs and symptoms, such as eosinophilia, cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens. It is diagnosed by stool examination and serologic testing. Ivermectin is first-line therapy; albendazole is an alternative.

THE CASE

A 31-year-old man came to an internal medicine clinic because he’d been losing weight over the past 2 years and hadn’t been able to regain any weight despite eating properly. Our patient was born in Ethiopia, but had been living in Canada for 6 years. He reported a remote history of 2 episodes of diarrhea.

His physical exam was normal and laboratory results revealed mild eosinophilia of 0.6 × 10⁹/L (normal range, <0.45 × 10⁹/L). Additional tests (including complete blood count, electrolytes, liver panel, thyrotropin, and blood smear) revealed no apparent metabolic causes of the patient’s weight loss. Stool analysis (3 exams) was negative for ova and parasites.

THE DIAGNOSIS

Because our patient was born in Ethiopia, we did serologic testing for Strongyloides, which was positive (enzyme-linked immunosorbent assay for immunoglobulin G antibodies [IgG-ELISA] was 2.9; positive is >2.1). We diagnosed strongyloidiasis in this patient.

DISCUSSION

Strongyloidiasis is an infection caused by the parasite Strongyloides stercoralis.¹ It affects an estimated 30 to 100 million people worldwide, mainly in Africa, Southeast Asia, Central America, and South America, but it also can occur in temperate climates.²Strongyloides is a soil-transmitted helminth (parasitic worm). The prevalence of Strongyloides infection among refugee groups in the United States is 1% to 4.3%.^3-5

Although patients with strongyloidiasis are often asymptomatic, they can present with a wide range of nonspecific symptoms. In the acute stage, patients may develop signs and symptoms including cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens.² Respiratory symptoms, including tracheal irritation and a dry cough, are often confused with asthma. In the generally asymptomatic chronic stage, patients may develop gastrointestinal complaints, such as epigastric pain and heartburn.⁶

Hyperinfection syndrome can occur when patients with subclinical infection receive high doses of corticosteroids for asthma or chronic obstructive pulmonary disease exacerbations. Risk of hyperinfection is increased among immunocompromised patients with human T lymphotropic virus type-1 (HTLV-1),⁷ as well as in patients with malignancies, malnutrition, and alcohol use disorder. Eosinophilia is often absent in patients with hyperinfection, and stool examination results are almost always positive.⁸

Who to screen, how to make the diagnosis

Suspect strongyloidiasis infection in immigrants, refugees, and travelers from endemic regions who have eosinophilia. The presence of eosinophilia in immigrants, refugees, and travelers from endemic regions should alert clinicians to the possibility of an underlying helminth infection. However, because eosinophilia occurs intermittently in response to tissue invasion, absence of eosinophilia does not exclude strongyloidiasis.

The Canadian Collaboration for Immigrants and Refugee Health (CCIRH) recommends using serologic testing to screen for Strongyloides in all newly arrived refugees from low-income countries in Southeast Asia and Africa.⁹ The CCIRH also advises that while data on the burden of strongyloidiasis in non-refugee immigrant populations is limited, you should consider screening foreign-born individuals who have lived in endemic areas, have symptoms and/or signs of Strongyloides infection, and/or have evidence of eosinophilia.⁹ Because the risk of hyperinfection is increased in immunocompromised individuals, screening should be done to detect Strongyloides infection before starting chemotherapy and before initiating corticosteroids in patients from endemic areas.¹⁰

Diagnostic methods. Stool examination⁶ and IgG-ELISA² are the main methods used to diagnose strongyloidiasis. However, traditional stool examinations have low sensitivity, and it may require up to 7 stool exams to reach a sensitivity of 100%,⁶ which could explain why our patient’s stool analysis was negative for parasites. In our experience, a positive serology result should always be assumed to indicate an active infection unless there is a well documented history of prior therapy. (In such cases, a positive serology result could represent persistent antibodies following therapy.)

First-line therapy and alternative treatment

All patients with strongyloidiasis, regardless of whether they are symptomatic, must be treated to prevent possible late-onset disseminated disease and hyperinfection.⁹ The Centers for Disease Control and Prevention recommends one to 2 doses of ivermectin 200 mcg/kg as first-line therapy or albendazole 400 mg twice daily for 3 days as an alternative treatment (TABLE).¹¹ Ivermectin cures more than 95% of cases.¹² Albendazole has lower efficacy (78%).¹³ Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for the parasite to migrate to the gut.⁴

Consider referral to an infectious disease specialist for patients coinfected with HTLV-1, as well as those who are immunocompromised. Coinfection with HTLV-1 (which is endemic in areas where Strongyloides also is
endemic) modifies patients’ immune response and can complicate treatment.⁹ Clinicians should screen strongyloidiasis patients for HTLV-1 if they come from high-prevalence areas and/or have persistent strongyloidiasis that responds poorly to antiparasitic treatment.⁹

Consider referral to an infectious disease specialist for patients coinfected with
HTLV-1, as well as those who are immunocompromised. Such referral also may be appropriate for patients from countries where loa loa is endemic, because encephalopathy has occurred in patients coinfected with loa loa who were treated with ivermectin.¹⁰

Our patient was treated with 2 doses of ivermectin 200 mcg/kg, 2 weeks apart. Four months later, his eosinophilia had resolved, his IgG-ELISA dropped to 0.37, and he had gained 2.5 pounds.

THE TAKEAWAY

Strongyloidiasis is an infection caused by the parasitic worm Strongyloides stercoralis that is most common in tropical or subtropical areas. It can be asymptomatic or present with a wide range of nonspecific signs and symptoms, such as eosinophilia, cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens. It is diagnosed by stool examination and serologic testing. Ivermectin is first-line therapy; albendazole is an alternative.

THE CASE

A 31-year-old man came to an internal medicine clinic because he’d been losing weight over the past 2 years and hadn’t been able to regain any weight despite eating properly. Our patient was born in Ethiopia, but had been living in Canada for 6 years. He reported a remote history of 2 episodes of diarrhea.

His physical exam was normal and laboratory results revealed mild eosinophilia of 0.6 × 10⁹/L (normal range, <0.45 × 10⁹/L). Additional tests (including complete blood count, electrolytes, liver panel, thyrotropin, and blood smear) revealed no apparent metabolic causes of the patient’s weight loss. Stool analysis (3 exams) was negative for ova and parasites.

THE DIAGNOSIS

Because our patient was born in Ethiopia, we did serologic testing for Strongyloides, which was positive (enzyme-linked immunosorbent assay for immunoglobulin G antibodies [IgG-ELISA] was 2.9; positive is >2.1). We diagnosed strongyloidiasis in this patient.

DISCUSSION

Strongyloidiasis is an infection caused by the parasite Strongyloides stercoralis.¹ It affects an estimated 30 to 100 million people worldwide, mainly in Africa, Southeast Asia, Central America, and South America, but it also can occur in temperate climates.²Strongyloides is a soil-transmitted helminth (parasitic worm). The prevalence of Strongyloides infection among refugee groups in the United States is 1% to 4.3%.^3-5

Although patients with strongyloidiasis are often asymptomatic, they can present with a wide range of nonspecific symptoms. In the acute stage, patients may develop signs and symptoms including cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens.² Respiratory symptoms, including tracheal irritation and a dry cough, are often confused with asthma. In the generally asymptomatic chronic stage, patients may develop gastrointestinal complaints, such as epigastric pain and heartburn.⁶

Hyperinfection syndrome can occur when patients with subclinical infection receive high doses of corticosteroids for asthma or chronic obstructive pulmonary disease exacerbations. Risk of hyperinfection is increased among immunocompromised patients with human T lymphotropic virus type-1 (HTLV-1),⁷ as well as in patients with malignancies, malnutrition, and alcohol use disorder. Eosinophilia is often absent in patients with hyperinfection, and stool examination results are almost always positive.⁸

Who to screen, how to make the diagnosis

Suspect strongyloidiasis infection in immigrants, refugees, and travelers from endemic regions who have eosinophilia. The presence of eosinophilia in immigrants, refugees, and travelers from endemic regions should alert clinicians to the possibility of an underlying helminth infection. However, because eosinophilia occurs intermittently in response to tissue invasion, absence of eosinophilia does not exclude strongyloidiasis.

The Canadian Collaboration for Immigrants and Refugee Health (CCIRH) recommends using serologic testing to screen for Strongyloides in all newly arrived refugees from low-income countries in Southeast Asia and Africa.⁹ The CCIRH also advises that while data on the burden of strongyloidiasis in non-refugee immigrant populations is limited, you should consider screening foreign-born individuals who have lived in endemic areas, have symptoms and/or signs of Strongyloides infection, and/or have evidence of eosinophilia.⁹ Because the risk of hyperinfection is increased in immunocompromised individuals, screening should be done to detect Strongyloides infection before starting chemotherapy and before initiating corticosteroids in patients from endemic areas.¹⁰

Diagnostic methods. Stool examination⁶ and IgG-ELISA² are the main methods used to diagnose strongyloidiasis. However, traditional stool examinations have low sensitivity, and it may require up to 7 stool exams to reach a sensitivity of 100%,⁶ which could explain why our patient’s stool analysis was negative for parasites. In our experience, a positive serology result should always be assumed to indicate an active infection unless there is a well documented history of prior therapy. (In such cases, a positive serology result could represent persistent antibodies following therapy.)

First-line therapy and alternative treatment

All patients with strongyloidiasis, regardless of whether they are symptomatic, must be treated to prevent possible late-onset disseminated disease and hyperinfection.⁹ The Centers for Disease Control and Prevention recommends one to 2 doses of ivermectin 200 mcg/kg as first-line therapy or albendazole 400 mg twice daily for 3 days as an alternative treatment (TABLE).¹¹ Ivermectin cures more than 95% of cases.¹² Albendazole has lower efficacy (78%).¹³ Some experts recommend administering the 2 doses of ivermectin 2 weeks apart to allow enough time for the parasite to migrate to the gut.⁴

Consider referral to an infectious disease specialist for patients coinfected with HTLV-1, as well as those who are immunocompromised. Coinfection with HTLV-1 (which is endemic in areas where Strongyloides also is
endemic) modifies patients’ immune response and can complicate treatment.⁹ Clinicians should screen strongyloidiasis patients for HTLV-1 if they come from high-prevalence areas and/or have persistent strongyloidiasis that responds poorly to antiparasitic treatment.⁹

Consider referral to an infectious disease specialist for patients coinfected with
HTLV-1, as well as those who are immunocompromised. Such referral also may be appropriate for patients from countries where loa loa is endemic, because encephalopathy has occurred in patients coinfected with loa loa who were treated with ivermectin.¹⁰

Our patient was treated with 2 doses of ivermectin 200 mcg/kg, 2 weeks apart. Four months later, his eosinophilia had resolved, his IgG-ELISA dropped to 0.37, and he had gained 2.5 pounds.

THE TAKEAWAY

Strongyloidiasis is an infection caused by the parasitic worm Strongyloides stercoralis that is most common in tropical or subtropical areas. It can be asymptomatic or present with a wide range of nonspecific signs and symptoms, such as eosinophilia, cough, wheeze, abdominal pain, weight loss, diarrhea, pruritus ani, and larva currens. It is diagnosed by stool examination and serologic testing. Ivermectin is first-line therapy; albendazole is an alternative.

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Case

A previously healthy 10-month-old girl was brought to the ED by her mother, who noted that the child had been excessively drowsy throughout the day. She reported that her husband had dropped an unknown amount of his morphine sulfate extended-release 60-mg tablets and oxycodone 10-mg/acetaminophen 325-mg tablets on the floor 5 days earlier. Although unsure of how many tablets he had dropped, the father believed he had located all of them. The mother, however, found some of the tablets around the crib in their daughter’s room.

When the child arrived to the ED, her vital signs were: blood pressure, 95/60 mm Hg; heart rate, 102 beats/minute; respiratory rate (RR), 18 breaths/minute; and temperature, 98.4°F. Oxygen saturation was 98% on room air. On physical examination, the child was lethargic, her pupils were less than 1 mm in diameter, and her bowel sounds were absent. After the administration of intravenous (IV) naloxone 0.4 mg, the patient became less drowsy and her RR normalized. Approximately 1 hour later, though, the child again became lethargic; she was given a repeat dose of IV naloxone 0.4 mg, and a naloxone infusion was initiated at 0.3 mg/h. Over approximately 20 hours, the infusion was tapered and discontinued. Three hours after the infusion was stopped, the child’s vital signs and behavior were both normal. After a social worker and representative from the Administration for Children’s Services reviewed the patient’s case, she was discharged home with her parents.

Less than 1 hour later, however, the mother returned to the ED with the child, who was again unresponsive. Although the girl’s RR was normal, she had pinpoint pupils. After she was given IV naloxone 0.4 mg, the child awoke and remained responsive for 20 minutes before returning to a somnolent state. Another IV dose of naloxone 0.4 mg was administered, which showed partial improvement in responsiveness. A naloxone infusion was then initiated and titrated up to 1 mg/h to maintain wakefulness and ventilation. In the pediatric intensive care unit, the child required titration of the naloxone infusion to 2 mg/h to which she responded well. Over the next 12 hours, the infusion was tapered off and the child was discharged home with her parents.

Blood samples from both the initial visit and the return visit were sent for toxicologic analysis by gas chromatography-mass spectrometry (GC-MS). Serum from the first visit contained morphine at a concentration of 3,000 ng/mL; serum from the second visit contained morphine at 420 ng/mL. Both samples were negative for oxycodone or any of the other substances checked on the extended GC-MS screen.

What is the toxicologic differential?

Although this patient’s extreme somnolence was suspected to be opioid-induced, and was confirmed by an appropriate response to naloxone, children may present to the ED somnolent for a variety of unknown reasons. Even with a fairly clear history, the clinician should also consider metabolic, neurological, infectious, traumatic, and psychiatric causes of altered mental status.¹ The toxicologic causes of altered mental status are expansive and include the effects of many medications used therapeutically or in overdose. Opioids, benzodiazepines, barbiturates, α-2 agonists (eg, clonidine), sleep aids (eg, zolpidem, diphenhydramine), and ethanol are common causes of induced an altered mental status. When taking a toxicologic history, it is important to inquire not only about the patient’s medications but also the medications of other members of the household to which the patient may have access. This includes not only prescription medications but also over-the-counter, complementary, and herbal preparations.

Why did this child have delayed recurrent opioid toxicity?

When used as directed, opioids cause analgesia and euphoria. Analgesia is mediated by agonism at the μ- , κ-, and δ-opioid receptors throughout the brain and spinal cord. The majority of morphine’s analgesic activity comes from activation of the μ-opioid receptors.² In overdose, opioids classically cause a toxidrome characterized by miosis, coma, decreased bowel sounds, and respiratory depression. These signs can give clues to a patient’s exposure.

Supportive care is the cornerstone of treatment for patients with opioid toxicity, and maintaining the airway and monitoring the respiratory status are extremely important. When ventilation decreases due to the actions of opioids (typically denoted by a RR of <12 breaths/minute in adults, but may be marked by a reduction in depth of breathing as well), the use of an opioid antagonist is appropriate.⁴ The most commonly used antagonist is naloxone, an antidote with antagonism at all opioid receptor subtypes.⁵

In patients who are not dependent on opioids, IV naloxone 0.4 mg is an appropriate initial dose—regardless of patient size or specifics of the exposure. Patients with opioid dependency (eg, patients taking opioids for chronic pain or palliative care, or in those with suspected or confirmed opioid abuse), should receive smaller initial doses of naloxone (eg, 0.04 mg); the dose should be titrated up to effect to avoid precipitating acute opioid withdrawal. The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. The duration of action of naloxone is 20 to 90 minutes in adults.

Patients presenting with heroin overdose should be monitored for at least 2 hours after naloxone administration (some suggest 3 hours) to determine whether or not additional dosing will be necessary. After oral opioid exposures, particularly with extended-release or long-acting formulations, longer periods of observation are required (this is unrelated to the naloxone pharmacokinetics, but rather to the slow rise in blood levels from some of these formulations). If repeated opioid toxicity occurs in adults, a naloxone infusion may be helpful to reduce the need for repetitive re-dosing. Initially, an hourly infusion equal to two-thirds of the dose of naloxone that reversed the patient’s respiratory depression is suggested⁶

Naloxone is eliminated by conjugation with glucuronic acid before is it excreted from the body. Due to decreased hepatic conjugation and prolonged metabolization of drugs in pediatric patients, naloxone may have a longer half-life in children—especially neonates and infants⁷; in children, the half-life of naloxone may extend up to three times that of adults.⁸ This extended half-life can lead to a false sense of assurance that a child is free of opioid effects 120 minutes after receiving naloxone—the time by which an adult patient would likely be without significant systemic effects of naloxone—when in fact the effect of naloxone has not yet sufficiently waned. This in turn may prompt discharge before sufficient time has passed to exclude recrudescence of opioid toxicity: The presence of persistent opioid agonist concentrations in the blood, even at consequential amounts, remains masked by the persistent presence of naloxone.

The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. In this patient, it is not surprising that the the ingestion of an extended-relief form of morphine should produce a prolonged opioid effect. At therapeutic concentrations in children (~10 ng/mL), the half-life of morphine is slightly longer than in adults (~3 hours vs 2 hours) and is likely even longer with very high serum concentrations. It is metabolized to morphine 6-glucuronide, which is active and longer lasting than the parent compound. This may account for additional clinical effects beyond the time that the serum morphine concentration falls, and is particularly relevant following immediate-release morphine overdose.

In this case it is also important to consider whether or not the patient was re-exposed to an opioid between the first and second ED visit. The dramatically elevated initial serum morphine concentrations and the relatively appropriate fall in magnitude of the second sample suggest that the recurrence of respiratory depression was not the result of re-exposure. The patient’s recurrent effects, even a day out from exposure, can be explained by the immediate-release morphine exposure and the discharge prior to waning of the naloxone. In children with opioid toxicity, another potential option, though not directly studied, is to administer the long-acting opioid antagonist naltrexone to the patient prior to discharge.

Case Conclusion

When used appropriately and under the correct circumstances, naloxone is safe and effective for the reversal of opioid toxicity. As with any antidote, patients must be appropriately monitored for any adverse effects or recurrence of toxicity. Moreover, the clinician should be mindful of the pharmacokinetic differences between adults and young children and the possibility of a later-than-expected recurrence of opioid toxicity in pediatric patients.

This case is a reminder of the importance of safe medication storage. Infants and young children who are crawling and exploring their environment are especially vulnerable to toxicity from medications found on the floor. Regardless of age, quick recognition of opioid-induced respiratory depression and appropriate use of naloxone can help to decrease the morbidity associated with excessive opioid exposures in all patients.

Dr Berman is a senior medical toxicology fellow at North Shore-Long Island Jewish Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Majlesi is the director of medical toxicology at Staten Island University Hospital, New York.

Case

A previously healthy 10-month-old girl was brought to the ED by her mother, who noted that the child had been excessively drowsy throughout the day. She reported that her husband had dropped an unknown amount of his morphine sulfate extended-release 60-mg tablets and oxycodone 10-mg/acetaminophen 325-mg tablets on the floor 5 days earlier. Although unsure of how many tablets he had dropped, the father believed he had located all of them. The mother, however, found some of the tablets around the crib in their daughter’s room.

When the child arrived to the ED, her vital signs were: blood pressure, 95/60 mm Hg; heart rate, 102 beats/minute; respiratory rate (RR), 18 breaths/minute; and temperature, 98.4°F. Oxygen saturation was 98% on room air. On physical examination, the child was lethargic, her pupils were less than 1 mm in diameter, and her bowel sounds were absent. After the administration of intravenous (IV) naloxone 0.4 mg, the patient became less drowsy and her RR normalized. Approximately 1 hour later, though, the child again became lethargic; she was given a repeat dose of IV naloxone 0.4 mg, and a naloxone infusion was initiated at 0.3 mg/h. Over approximately 20 hours, the infusion was tapered and discontinued. Three hours after the infusion was stopped, the child’s vital signs and behavior were both normal. After a social worker and representative from the Administration for Children’s Services reviewed the patient’s case, she was discharged home with her parents.

Less than 1 hour later, however, the mother returned to the ED with the child, who was again unresponsive. Although the girl’s RR was normal, she had pinpoint pupils. After she was given IV naloxone 0.4 mg, the child awoke and remained responsive for 20 minutes before returning to a somnolent state. Another IV dose of naloxone 0.4 mg was administered, which showed partial improvement in responsiveness. A naloxone infusion was then initiated and titrated up to 1 mg/h to maintain wakefulness and ventilation. In the pediatric intensive care unit, the child required titration of the naloxone infusion to 2 mg/h to which she responded well. Over the next 12 hours, the infusion was tapered off and the child was discharged home with her parents.

Blood samples from both the initial visit and the return visit were sent for toxicologic analysis by gas chromatography-mass spectrometry (GC-MS). Serum from the first visit contained morphine at a concentration of 3,000 ng/mL; serum from the second visit contained morphine at 420 ng/mL. Both samples were negative for oxycodone or any of the other substances checked on the extended GC-MS screen.

What is the toxicologic differential?

Although this patient’s extreme somnolence was suspected to be opioid-induced, and was confirmed by an appropriate response to naloxone, children may present to the ED somnolent for a variety of unknown reasons. Even with a fairly clear history, the clinician should also consider metabolic, neurological, infectious, traumatic, and psychiatric causes of altered mental status.¹ The toxicologic causes of altered mental status are expansive and include the effects of many medications used therapeutically or in overdose. Opioids, benzodiazepines, barbiturates, α-2 agonists (eg, clonidine), sleep aids (eg, zolpidem, diphenhydramine), and ethanol are common causes of induced an altered mental status. When taking a toxicologic history, it is important to inquire not only about the patient’s medications but also the medications of other members of the household to which the patient may have access. This includes not only prescription medications but also over-the-counter, complementary, and herbal preparations.

Why did this child have delayed recurrent opioid toxicity?

When used as directed, opioids cause analgesia and euphoria. Analgesia is mediated by agonism at the μ- , κ-, and δ-opioid receptors throughout the brain and spinal cord. The majority of morphine’s analgesic activity comes from activation of the μ-opioid receptors.² In overdose, opioids classically cause a toxidrome characterized by miosis, coma, decreased bowel sounds, and respiratory depression. These signs can give clues to a patient’s exposure.

Supportive care is the cornerstone of treatment for patients with opioid toxicity, and maintaining the airway and monitoring the respiratory status are extremely important. When ventilation decreases due to the actions of opioids (typically denoted by a RR of <12 breaths/minute in adults, but may be marked by a reduction in depth of breathing as well), the use of an opioid antagonist is appropriate.⁴ The most commonly used antagonist is naloxone, an antidote with antagonism at all opioid receptor subtypes.⁵

In patients who are not dependent on opioids, IV naloxone 0.4 mg is an appropriate initial dose—regardless of patient size or specifics of the exposure. Patients with opioid dependency (eg, patients taking opioids for chronic pain or palliative care, or in those with suspected or confirmed opioid abuse), should receive smaller initial doses of naloxone (eg, 0.04 mg); the dose should be titrated up to effect to avoid precipitating acute opioid withdrawal. The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. The duration of action of naloxone is 20 to 90 minutes in adults.

Patients presenting with heroin overdose should be monitored for at least 2 hours after naloxone administration (some suggest 3 hours) to determine whether or not additional dosing will be necessary. After oral opioid exposures, particularly with extended-release or long-acting formulations, longer periods of observation are required (this is unrelated to the naloxone pharmacokinetics, but rather to the slow rise in blood levels from some of these formulations). If repeated opioid toxicity occurs in adults, a naloxone infusion may be helpful to reduce the need for repetitive re-dosing. Initially, an hourly infusion equal to two-thirds of the dose of naloxone that reversed the patient’s respiratory depression is suggested⁶

Naloxone is eliminated by conjugation with glucuronic acid before is it excreted from the body. Due to decreased hepatic conjugation and prolonged metabolization of drugs in pediatric patients, naloxone may have a longer half-life in children—especially neonates and infants⁷; in children, the half-life of naloxone may extend up to three times that of adults.⁸ This extended half-life can lead to a false sense of assurance that a child is free of opioid effects 120 minutes after receiving naloxone—the time by which an adult patient would likely be without significant systemic effects of naloxone—when in fact the effect of naloxone has not yet sufficiently waned. This in turn may prompt discharge before sufficient time has passed to exclude recrudescence of opioid toxicity: The presence of persistent opioid agonist concentrations in the blood, even at consequential amounts, remains masked by the persistent presence of naloxone.

The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. In this patient, it is not surprising that the the ingestion of an extended-relief form of morphine should produce a prolonged opioid effect. At therapeutic concentrations in children (~10 ng/mL), the half-life of morphine is slightly longer than in adults (~3 hours vs 2 hours) and is likely even longer with very high serum concentrations. It is metabolized to morphine 6-glucuronide, which is active and longer lasting than the parent compound. This may account for additional clinical effects beyond the time that the serum morphine concentration falls, and is particularly relevant following immediate-release morphine overdose.

In this case it is also important to consider whether or not the patient was re-exposed to an opioid between the first and second ED visit. The dramatically elevated initial serum morphine concentrations and the relatively appropriate fall in magnitude of the second sample suggest that the recurrence of respiratory depression was not the result of re-exposure. The patient’s recurrent effects, even a day out from exposure, can be explained by the immediate-release morphine exposure and the discharge prior to waning of the naloxone. In children with opioid toxicity, another potential option, though not directly studied, is to administer the long-acting opioid antagonist naltrexone to the patient prior to discharge.

Case Conclusion

When used appropriately and under the correct circumstances, naloxone is safe and effective for the reversal of opioid toxicity. As with any antidote, patients must be appropriately monitored for any adverse effects or recurrence of toxicity. Moreover, the clinician should be mindful of the pharmacokinetic differences between adults and young children and the possibility of a later-than-expected recurrence of opioid toxicity in pediatric patients.

This case is a reminder of the importance of safe medication storage. Infants and young children who are crawling and exploring their environment are especially vulnerable to toxicity from medications found on the floor. Regardless of age, quick recognition of opioid-induced respiratory depression and appropriate use of naloxone can help to decrease the morbidity associated with excessive opioid exposures in all patients.

Dr Berman is a senior medical toxicology fellow at North Shore-Long Island Jewish Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Majlesi is the director of medical toxicology at Staten Island University Hospital, New York.

Case

A previously healthy 10-month-old girl was brought to the ED by her mother, who noted that the child had been excessively drowsy throughout the day. She reported that her husband had dropped an unknown amount of his morphine sulfate extended-release 60-mg tablets and oxycodone 10-mg/acetaminophen 325-mg tablets on the floor 5 days earlier. Although unsure of how many tablets he had dropped, the father believed he had located all of them. The mother, however, found some of the tablets around the crib in their daughter’s room.

When the child arrived to the ED, her vital signs were: blood pressure, 95/60 mm Hg; heart rate, 102 beats/minute; respiratory rate (RR), 18 breaths/minute; and temperature, 98.4°F. Oxygen saturation was 98% on room air. On physical examination, the child was lethargic, her pupils were less than 1 mm in diameter, and her bowel sounds were absent. After the administration of intravenous (IV) naloxone 0.4 mg, the patient became less drowsy and her RR normalized. Approximately 1 hour later, though, the child again became lethargic; she was given a repeat dose of IV naloxone 0.4 mg, and a naloxone infusion was initiated at 0.3 mg/h. Over approximately 20 hours, the infusion was tapered and discontinued. Three hours after the infusion was stopped, the child’s vital signs and behavior were both normal. After a social worker and representative from the Administration for Children’s Services reviewed the patient’s case, she was discharged home with her parents.

Less than 1 hour later, however, the mother returned to the ED with the child, who was again unresponsive. Although the girl’s RR was normal, she had pinpoint pupils. After she was given IV naloxone 0.4 mg, the child awoke and remained responsive for 20 minutes before returning to a somnolent state. Another IV dose of naloxone 0.4 mg was administered, which showed partial improvement in responsiveness. A naloxone infusion was then initiated and titrated up to 1 mg/h to maintain wakefulness and ventilation. In the pediatric intensive care unit, the child required titration of the naloxone infusion to 2 mg/h to which she responded well. Over the next 12 hours, the infusion was tapered off and the child was discharged home with her parents.

Blood samples from both the initial visit and the return visit were sent for toxicologic analysis by gas chromatography-mass spectrometry (GC-MS). Serum from the first visit contained morphine at a concentration of 3,000 ng/mL; serum from the second visit contained morphine at 420 ng/mL. Both samples were negative for oxycodone or any of the other substances checked on the extended GC-MS screen.

What is the toxicologic differential?

Although this patient’s extreme somnolence was suspected to be opioid-induced, and was confirmed by an appropriate response to naloxone, children may present to the ED somnolent for a variety of unknown reasons. Even with a fairly clear history, the clinician should also consider metabolic, neurological, infectious, traumatic, and psychiatric causes of altered mental status.¹ The toxicologic causes of altered mental status are expansive and include the effects of many medications used therapeutically or in overdose. Opioids, benzodiazepines, barbiturates, α-2 agonists (eg, clonidine), sleep aids (eg, zolpidem, diphenhydramine), and ethanol are common causes of induced an altered mental status. When taking a toxicologic history, it is important to inquire not only about the patient’s medications but also the medications of other members of the household to which the patient may have access. This includes not only prescription medications but also over-the-counter, complementary, and herbal preparations.

Why did this child have delayed recurrent opioid toxicity?

When used as directed, opioids cause analgesia and euphoria. Analgesia is mediated by agonism at the μ- , κ-, and δ-opioid receptors throughout the brain and spinal cord. The majority of morphine’s analgesic activity comes from activation of the μ-opioid receptors.² In overdose, opioids classically cause a toxidrome characterized by miosis, coma, decreased bowel sounds, and respiratory depression. These signs can give clues to a patient’s exposure.

Supportive care is the cornerstone of treatment for patients with opioid toxicity, and maintaining the airway and monitoring the respiratory status are extremely important. When ventilation decreases due to the actions of opioids (typically denoted by a RR of <12 breaths/minute in adults, but may be marked by a reduction in depth of breathing as well), the use of an opioid antagonist is appropriate.⁴ The most commonly used antagonist is naloxone, an antidote with antagonism at all opioid receptor subtypes.⁵

In patients who are not dependent on opioids, IV naloxone 0.4 mg is an appropriate initial dose—regardless of patient size or specifics of the exposure. Patients with opioid dependency (eg, patients taking opioids for chronic pain or palliative care, or in those with suspected or confirmed opioid abuse), should receive smaller initial doses of naloxone (eg, 0.04 mg); the dose should be titrated up to effect to avoid precipitating acute opioid withdrawal. The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. The duration of action of naloxone is 20 to 90 minutes in adults.

Patients presenting with heroin overdose should be monitored for at least 2 hours after naloxone administration (some suggest 3 hours) to determine whether or not additional dosing will be necessary. After oral opioid exposures, particularly with extended-release or long-acting formulations, longer periods of observation are required (this is unrelated to the naloxone pharmacokinetics, but rather to the slow rise in blood levels from some of these formulations). If repeated opioid toxicity occurs in adults, a naloxone infusion may be helpful to reduce the need for repetitive re-dosing. Initially, an hourly infusion equal to two-thirds of the dose of naloxone that reversed the patient’s respiratory depression is suggested⁶

Naloxone is eliminated by conjugation with glucuronic acid before is it excreted from the body. Due to decreased hepatic conjugation and prolonged metabolization of drugs in pediatric patients, naloxone may have a longer half-life in children—especially neonates and infants⁷; in children, the half-life of naloxone may extend up to three times that of adults.⁸ This extended half-life can lead to a false sense of assurance that a child is free of opioid effects 120 minutes after receiving naloxone—the time by which an adult patient would likely be without significant systemic effects of naloxone—when in fact the effect of naloxone has not yet sufficiently waned. This in turn may prompt discharge before sufficient time has passed to exclude recrudescence of opioid toxicity: The presence of persistent opioid agonist concentrations in the blood, even at consequential amounts, remains masked by the persistent presence of naloxone.

The goal of opioid antagonism is to allow the patient to breathe spontaneously and at an appropriate rate and depth without precipitating withdrawal. In this patient, it is not surprising that the the ingestion of an extended-relief form of morphine should produce a prolonged opioid effect. At therapeutic concentrations in children (~10 ng/mL), the half-life of morphine is slightly longer than in adults (~3 hours vs 2 hours) and is likely even longer with very high serum concentrations. It is metabolized to morphine 6-glucuronide, which is active and longer lasting than the parent compound. This may account for additional clinical effects beyond the time that the serum morphine concentration falls, and is particularly relevant following immediate-release morphine overdose.

In this case it is also important to consider whether or not the patient was re-exposed to an opioid between the first and second ED visit. The dramatically elevated initial serum morphine concentrations and the relatively appropriate fall in magnitude of the second sample suggest that the recurrence of respiratory depression was not the result of re-exposure. The patient’s recurrent effects, even a day out from exposure, can be explained by the immediate-release morphine exposure and the discharge prior to waning of the naloxone. In children with opioid toxicity, another potential option, though not directly studied, is to administer the long-acting opioid antagonist naltrexone to the patient prior to discharge.

Case Conclusion

When used appropriately and under the correct circumstances, naloxone is safe and effective for the reversal of opioid toxicity. As with any antidote, patients must be appropriately monitored for any adverse effects or recurrence of toxicity. Moreover, the clinician should be mindful of the pharmacokinetic differences between adults and young children and the possibility of a later-than-expected recurrence of opioid toxicity in pediatric patients.

This case is a reminder of the importance of safe medication storage. Infants and young children who are crawling and exploring their environment are especially vulnerable to toxicity from medications found on the floor. Regardless of age, quick recognition of opioid-induced respiratory depression and appropriate use of naloxone can help to decrease the morbidity associated with excessive opioid exposures in all patients.

Dr Berman is a senior medical toxicology fellow at North Shore-Long Island Jewish Medical Center, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Majlesi is the director of medical toxicology at Staten Island University Hospital, New York.

The year 2014 marked a sea change in our approach to tissue extraction during minimally invasive surgery. The US Food and Drug Administration (FDA) initiated this transformation in April, when it issued a safety warning on the use of open power morcellation.¹ A flurry of statements on the practice followed from professional societies, capped, in late November, with another statement from the FDA.^2–4 The new bottom line: The use of open electromechanical (“power”) morcellation is contraindicated in perimenopausal and postmenopausal women, as well as in those who are known or suspected to have a malignancy.⁴

Most of the concern to date has centered on the risk that an occult leiomyosarcoma could be morcellated inadvertently during uterine surgery, an event that may worsen the prognosis for the patient. To get a gynecologic oncologist’s take on the controversy, OBG Management caught up with Amanda Nickles Fader, MD, director of the Kelly Gynecologic Oncology Service at Johns Hopkins University. Dr. Fader’s perspective is unique in that she treats a relatively high number of patients who have leiomyosarcoma and other uterine cancers.

In this Q&A, we discuss the patient population at Johns Hopkins; why Dr. Fader is especially qualified to speak to the future of electromechanical morcellation in gynecologic surgery; the benefits and risks of minimally invasive surgery, including tissue extraction; her recommendations for preoperative evaluation and counseling of patients undergoing uterine surgery; and guidance on how the specialty of gynecologic surgery should proceed in the future.

OBG Management: Dr. Fader, by way of introduction, could you characterize your patient population?

Amanda Nickles Fader, MD: Like most gynecologic oncologists, I primarily treat women with cancers of the uterus, ovary, cervix, and vulva. Many of us also have the opportunity to treat a number of women each year with complex benign gynecologic conditions that require surgery. As someone who is extremely interested in rare gynecologic tumors, I also treat a relatively high volume of women diagnosed with uterine sarcoma.

Approximately 75% of the women I see in my practice have preinvasive or invasive cancer, and 25% have a benign condition, such as enlarged fibroids or advanced-stage endometriosis.

OBG Management: How many cases of uterine sarcoma do you encounter on an annual basis?

Dr. Fader: Uterine sarcomas are very rare. They represent only 2% of all uterine cancers. Put into perspective, that means that about 0.4 cases of leiomyosarcoma occur in every 100,000 US women—most commonly postmenopausal women. Leiomyosarcoma is a biologically aggressive, high-grade malignancy that often is lethal.⁵

Endometrial stroma sarcoma is even less common—only 0.3 cases occur in every 100,000 US women. However, this tumor type is more indolent, often diagnosed at an earlier stage, and potentially curable with surgery (with or without hormonal therapy).⁶

As a referral center for rare uterine tumors, the Kelly Gynecologic Oncology Service and the Sarcoma Center at Johns Hopkins see approximately 35 to 40 new cases of uterine sarcoma annually for treatment of primary disease or recurrence. An additional 15 to 20 consult cases are reviewed from outside hospitals each year by our gynecologic pathology department.

Why a minimally invasive approach is vital
OBG Management: When it comes to uterine surgery for presumed benign conditions, why is a minimally invasive approach important?

Dr. Fader: Minimally invasive surgery clearly benefits women and is one of the greatest advances of the past half-century within our field. Randomized controlled trials and meta-analyses have demonstrated without question that women who undergo minimally invasive surgery for benign conditions or early-stage cancerous gynecologic conditions have superior clinical outcomes, compared with women who undergo surgery via laparotomy.^7,8 These outcomes include fewer perioperative complications (including fewer cases of surgical site infection, venous thromboembolism, wound dehiscence, and hospital readmission), shorter hospital stays, less pain, faster recovery, and fewer adhesions. And when women with early-stage cancers undergo minimally invasive surgery, randomized controlled trials show, they have a stage-specific survival rate similar to that observed in women treated with laparotomy.⁹

Benefits and risks of tissue extraction in minimally invasive surgery
OBG Management: What are the main benefits of tissue extraction, including morcellation?

Dr. Fader: Tissue extraction is a practice that has allowed us to offer minimally invasive surgery to countless more women than we could have in the recent past. It is a technique in which a large specimen (typically a uterus or fibroid) is fragmented into smaller parts in order to remove it through a small laparoscopic incision or orifice (vagina, umbilicus). Without tissue-extraction practices, thousands of women who undergo myomectomy each year to conserve their fertility and hundreds of thousands of women who require hysterectomy potentially would have to undergo a more painful and risky surgery through a larger abdominal incision. That would not be desirable, as we know conclusively that laparotomy is associated with worse outcomes—and even an increased risk of mortality—compared with minimally invasive surgery performed by experienced surgeons.¹⁰

Tissue extraction can be approached in a variety of ways. It can be performed with a scalpel, with a resectoscope, or with an electromechanical morcellator. Tissue extraction can be performed within the uterine cavity, through the vagina, within the abdominal compartment, or within a containment system in any of those compartments.

OBG Management: What are the risks of tissue extraction?

Dr. Fader: The risks of tissue extraction with electromechanical morcellation include potential injury to intra-abdominal organs and vasculature and risk of dissemination of an occult (ie, undiagnosed) uterine cancer. A report by our research group also demonstrated the risks of dissemination of benign uterine tissue requiring subsequent surgery in the setting of open electromechanical morcellation.¹¹ The risk of these events occurring in the hands of a thoughtful and experienced surgeon who conducts comprehensive preoperative patient evaluations is extremely low. However, recent evidence demonstrates that a handful of women worldwide are diagnosed with an occult uterine cancer each year during a morcellation procedure.^12–14 Although it is a very rare event (given that most women undergoing hysterectomy and myomectomy procedures are of reproductive age and unlikely to have uterine cancer), this risk is a serious issue. There is an exigent need for the gynecologic surgical community to develop better approaches to tissue extraction that minimize preventable harm in women.

Needed: high-quality data on the risks of morcellation
OBG Management: How does the recent FDA statement urging caution with the use of open power morcellation factor into this equation? The most recent FDA statement noted that open power morcellation is contraindicated in perimenopausal and postmenopausal women.⁴

Dr. Fader: The FDA’s concern is legitimate. However, the magnitude of the risk of occult uterine sarcoma in women undergoing presumed benign gynecologic surgery has been scrutinized and debated. The FDA panel quoted a risk that roughly 1 in 350 women undergoing presumed benign gynecologic surgery for fibroids will have an occult leiomyosarcoma diagnosed. However, more recent systematic reviews and a review of the prospective published literature demonstrate that the risk is more likely on the order of 1 in 1,700 to 1 in 8,333 women.¹⁵ The risk may be even lower in gynecologic surgery practices that see a high volume of ­hysterectomy/myomectomy cases and utilize meticulous preoperative patient selection criteria to establish a woman’s ­candidacy for tissue-extraction procedures.

I am concerned with how “occult sarcoma” discovered during surgery for “presumed benign gynecologic disease is being defined in the literature. There is no uniform definition being used. A cancer in this setting is only truly occult or undiagnosed if the physician was thinking about it and made every effort to rule out cancer preoperatively, and the morcellation procedure was performed in a low-risk population (but cancer was still diagnosed on final pathology in this population). However, in the majority of the morcellation studies in the literature, it is not clear that thorough preoperative evaluations occurred in patients to rule out uterine malignancy—in fact, there is a paucity of published information regarding establishing appropriate patient candidacy for morcellation procedures. So we can’t derive any conclusions regarding whether “occult” sarcomas were truly undetectable or not in the published literature.

In addition, the literature is very clear that advancing age and postmenopausal status are risk factors for uterine malignancy.¹⁶ The vast majority of uterine sarcoma cases are diagnosed in postmenopausal women. Yet, in one large US population-based hysterectomy study, 20% of the morcellated cases (and the overwhelming majority of the “occult” morcellated uterine cancers) occurred in postmenopausal women!¹⁷

Further, in a more recent study by the same authors, again the risks of morcellating a uterine cancer in a population undergoing myomectomy was significantly higher in a postmenopausal population and occurred only rarely in women younger than age 40. But it should come as no surprise that a greater incidence of uterine cancer was identified in these older cohorts—cancer risk increases precipitously with age. That’s not “occult”; that’s basic cancer epidemiology.

In other words, we cannot assume from population-based administrative claims data that morcellation performed in inappropriate populations at higher risk of uterine malignancy (in which we do not know whether patients were properly screened for the procedure preoperatively or whether they had risk factors for uterine cancer but were presumably poor candidates for morcellation due to age alone) helps us define the true incidence of “occult” sarcoma or cancer in a population.

These studies are provocative, however, and do inform us that, as women get older, we are apt to see a greater incidence of uterine cancer. We cannot safely assume that a postmenopausal or elderly woman with symptomatic or enlarging fibroids has “presumed benign disease”—it is cancer until proven otherwise, and we need to be looking for it preoperatively. Therefore, we need to be particularly careful with our surgical practices in this population—ie, the basis for the FDA’s recommendation to avoid morcellation in older women. And I agree with the FDA that open electromechanical morcellation generally is contraindicated in postmenopausal women. However, we need better data from large prospective studies to inform our understanding of the true incidence of undiagnosed or “occult” uterine sarcoma in women undergoing surgery for presumed benign disease. These future studies are likely to demonstrate what we already know—that in young, well-screened, well-selected candidates for minimally invasive hysterectomy or myomectomy, the risk of occult cancer is going to be exceptionally low.

OBG Management: Which is greater—the risks or benefits of tissue extraction?

Dr. Fader: Assessment of risks and benefits in medicine has everything to do with the intervention in question as applied to an individual patient. At the end of the day, there are risks and benefits to every medical or surgical treatment offered to patients in every medical and surgical discipline. But the risk of an occult uterine sarcoma is extremely low in a woman of reproductive age who has been properly selected and comprehensively evaluated for minimally invasive surgery and tissue extraction prior to surgery. And this small—though not negligible—risk must be weighed against the much higher risk of harm that may be incurred with an open abdominal procedure, compared with minimally invasive surgery.

However, in many elderly women, the risks of tissue extraction with an electromechanical morcellator may outweigh the benefits. Even so, there are exceptions in which tissue extraction may be acceptable in postmenopausal women (ie, using alternative tissue-extraction methods in those undergoing minimally invasive supracervical hysterectomy and sacral colpopexy for pelvic organ prolapse).

Few of the data published on the risks of morcellation are of very high quality in terms of scientific rigor or methodology. The best thing we can do as a gynecologic surgical community is conduct sound quality-­improvement (QI) programs, disseminate our QI results, publish our data, establish guidelines for best practices in uterine tissue extraction, and collaborate readily to increase the scholarly output on this issue so that national societies and government regulatory agencies have better-quality data to inform future policy on this issue.

A case-based approach
OBG Management: How would you approach tissue extraction in the following case?

CASE: A desire for myomectomy
A 35-year-old woman (G1P1) who delivered by cesarean has an 8-cm symptomatic ­intramural fibroid. She has regular heavy periods that have led to anemia (hemoglobin level = 10 mg/dL). Her medical history is negative for malignancy, pelvic radiation, or tamoxifen use, and she wants to preserve her fertility. Magnetic resonance imaging (MRI) confirms an 8-cm fibroid. Endometrial biopsy results are negative.

Dr. Fader: At Johns Hopkins, as at many other centers, we use well-defined criteria to determine whether a minimally invasive approach (and tissue extraction) might be appropriate. We also individualize treatment and surgical decision-making on a case-by-case basis. Any candidate for minimally invasive surgery and tissue extraction for uterine fibroids must undergo a thorough preoperative assessment.

Johns Hopkins preoperative assessment criteria include:

Our top priority is patient safety, so until more data are available, we no longer perform open electromechanical morcellation. We perform all tissue extraction within a containment system and under institutional review board protocol. We primarily perform tissue extraction via scalpel ­morcellation.

OBG Management: How do the patient’s wishes factor into the decision to perform minimally invasive surgery with morcellation?

Dr. Fader: Our patients make their own decisions regarding surgical approach and procedure after undergoing extensive counseling about the risks and benefits of the proposed procedures. I certainly would offer a patient like the one described in this case the opportunity for a minimally invasive approach (if, after thorough preoperative evaluation, she were deemed to be at very low risk for uterine malignancy). In my experience, most women opt for the minimally invasive approach in this setting; however, if a patient declines minimally invasive surgery, I respect her decision.

Tissue extraction in perimenopause

CASE: A desire for myomectomy at age 48
OBG Management: How would you approach the same case if the patient were a 48-year-old perimenopausal woman?

Dr. Fader: In perimenopausal women, we are more selective about performing morcellation, given the recent FDA safety statement, and because the incidence of occult cancer starts to increase slightly in this patient cohort (although it doesn’t precipitously increase until well into the postmenopausal period).

In addition, myomectomy may have less value in a 48-year-old, given the lower likelihood of achieving successful fertility, although there are exceptions. US  cancer statistics and studies on morcellation demonstrate that the vast majority of women in their 30s and 40s have an extremely low risk for sarcomas and other uterine malignancies.²

In select cases in which a woman has undergone a comprehensive preoperative work-up, has a stable-appearing fibroid(s), and is well-educated and counseled about the pros and cons of morcellation, we would consider performing a procedure with contained tissue extraction. As a general matter, however, I would be more inclined to offer a 48-year-old in this situation a uterine artery embolization or minimally invasive hysterectomy than a myomectomy procedure, especially given the recent study by Wright and colleagues demonstrating the significantly increased risks of uterine cancer at myomectomy surgery for a woman in her late 40s or early 50s.¹⁸

Preoperative assessment should be comprehensive
OBG Management: What preoperative evaluation do you perform when tissue extraction, including morcellation, is an issue?

Dr. Fader: It is the policy at Johns Hopkins that all women being considered for minimally invasive surgery and tissue extraction must undergo a rigorous preoperative work-up that includes:

We have separate conferences for the gynecology and gynecologic oncology services and have employed this practice for many years at Hopkins. We are also studying the role of serum lactate dehydrogenase (LDH) isoenzyme levels in stratifying women with uterine fibroids versus cancer/sarcoma.¹⁹

OBG Management: Which patients would you exclude from the electromechanical morcellation option?

Dr. Fader: As the American College of Obstetricians and Gynecologists, the AAGL, the Society of Gynecologic Oncology, and the Society of Gynecologic Surgeons appear to agree:

At our institution, we have significantly ­curtailed the use of electromechanical morcellation at this time and especially do not perform it in women aged 50 or older or in those with confirmed postmenopausal status. We also do not perform electromechanical morcellation in women with a personal history of uterine, cervical, or ovarian preinvasive or invasive cancer, or in women with a strong family history of gynecologic malignancy.

Other populations we exclude are women with:

Counseling the patient
OBG Management: If tissue extraction is an issue, and morcellation will be necessary for a minimally invasive approach, how do you counsel the patient?

Dr. Fader: We have an informed consent protocol we use at Hopkins in this regard. We speak extensively to our patients about the fact that every procedure or intervention performed in medicine carries a benefit/risk ratio. We inform patients of the FDA morcellation safety statement—that their fibroid or fibroids may contain unexpected cancerous tissue and that laparoscopic electromechanical morcellation may spread the cancer and possibly worsen their prognosis. We also explain that, while the FDA quotes a risk of approximately 1 in 350 for occult sarcoma, that this data review was somewhat limited in scope and included postmenopausal women in the estimates. Based on the best available published systematic reviews and internal Hopkins data, we believe the risk of morcellating an occult uterine malignancy in a woman of reproductive age is more likely on the order of approximately 1 in 1,700 to 1 in 8,333.

We discuss our institution’s approach to tissue extraction (ie, that we no longer perform open electromechanical morcellation but instead perform contained tissue extraction on an institutional review board protocol). We tell patients that contained tissue-extraction practices are still experimental, although there is published literature preliminarily supporting the safety of the practice. In addition, we discuss the fact that contained tissue extraction has been used for years to safely remove large intra-abdominal specimens from laparoscopic incisions, from adnexal tissue to gallbladder, spleen, kidney, intestinal, and appendiceal specimens.

We also explain that, as physicians, we do our best to ensure that risks are minimized and reasonable in relation to anticipated benefits but that, even when we use the very best diagnostic measures, no test is 100% sensitive or specific to rule out malignancy in this setting (or in any setting, ­actually).

Finally, we discuss the fact that minimally invasive surgery and tissue extraction practices performed in appropriate patients by skilled surgeons conclusively benefit hundreds of thousands of women each year around the world. That is a narrative that has been somewhat lacking in the recent dialogue about tissue-extraction practices.
 

OBG Management: What do we know about outcomes when a leiomyosarcoma is inadvertently morcellated?

Dr. Fader: This is considered a “cut-through” procedure, in that a cancerous tumor that is potentially contained to an organ is not removed intact or with clean margins. The morcellation procedure effectively cuts through the occult cancer, which is not desirable. Intact surgical removal of uterine cancers or sarcomas is the mainstay of therapy for these malignancies, based on NCCN guidelines.²²

OBG Management: Does a morcellated leiomyosarcoma carry a worse prognosis than an unmorcellated leiomyosarcoma?

Dr. Fader: When it comes to morcellated versus “intact” uterine leiomyosarcoma, we enter a largely data-free zone. We don’t know with certainty whether the outcome is worsened. If we’re being intellectually honest, we must admit the possibility that a morcellated cancer is more likely to be disseminated, rendering it potentially more difficult to treat. However, sarcomas primarily spread by hematogenous dissemination. It is quite possible that even the act of incising an intact fibroid in an open abdominal procedure or performing a supracervical or total hysterectomy without morcellation may still result in hematogenous cancer dissemination. So there is no indication yet that electromechanical morcellation poses a unique and higher risk of cancer upstaging or worse prognosis compared with techniques such as open myomectomy, supracervical hysterectomy, or hysteroscopic myomectomy.

In addition, the prognosis associated with even early-stage uterine leiomyosarcoma is uniformly poor. A published study from Hopkins that included 108 patients with uterine leiomyosarcoma suggests that the recurrence rate and survival of patients with early-stage, “intact” leiomyosarcoma are very poor and comparable to the survival rate documented in the literature for women with morcellated sarcomas.²³

The few retrospective studies that exist suggesting worse outcomes with morcellation have limitations that preclude any definitive conclusions.² These studies are marred by small numbers, heterogeneity in morcellation practices, poor follow-up times, and a lack of detail regarding how patients with morcellated versus unmorcellated sarcomas were treated. Nevertheless, a couple of these small retrospective reports indicate the possibility of worse outcomes in women with morcellated uterine sarcomas, compared with historical controls with intact sarcoma removal.

Is the morcellator at fault—or the user?
OBG Management: Some would argue that even one case of a morcellated uterine sarcoma is too many. How would you respond?

Dr. Fader: There is no doubt that a handful of women each year have been harmed by morcellation practices. Those women deserve our dedication and best efforts to learn how to better treat morcellated sarcomas—and more importantly—how to mitigate the risks associated with morcellation practices and reduce the risk of preventable harm for all women undergoing minimally invasive fibroid procedures. I think the single best thing we can do to mitigate risk is to be more ­conscientious about selecting our patients for tissue-extraction procedures (ie, strict selection criteria, appropriate preoperative work-ups). If we did this, we likely would reduce the number of oncologic morcellator mishaps by 50% to 80% without changing anything else.

When we closely scrutinize the ­literature, and when I reflect on the women with morcellated cancers that we have cared for at Hopkins, we observe that some (but not all) “occult” uterine cancers were not that hidden after all and may have been detected preoperatively if an effort had been made.

We have noted a number of patients in this setting who experienced harm not because a specific device was used to cut up their uterus but because they were never appropriate candidates for the procedure in the first place. For instance, I recently cared for an elderly woman with a morcellated uterine cancer who underwent a laparoscopic supracervical hysterectomy without an appropriate preoperative work-up (ie, no endometrial biopsy or imaging) or informed consent about the possibility that she might have cancer. If an elderly woman presents with concerning symptoms related to her uterus (ie, enlargement, bleeding), she must be evaluated and counseled regarding the considerable risk of potential malignancy. Even in the setting of a normal work-up, I don’t believe it is a good idea to perform electromechanical morcellation in higher-risk women, including elderly women. That does not mean that select, well-screened women cannot be considered for alternative tissue-extraction techniques, but the risks and benefits must be carefully weighed in each patient, and informed consent must be obtained.

By continuing to refine the safety features of the electromechanical morcellator devices and choosing patients more carefully for minimally invasive procedures and tissue extraction, we likely will reduce the risk of preventable harm in women undergoing gynecologic surgery.

Can leiomyosarcoma be detected preoperatively?
OBG Management: How can we improve preoperative detection of uterine malignancy, particularly leiomyosarcoma?

Dr. Fader: For starters, we can improve detection of uterine cancers by simply looking for them. Almost all epithelial uterine cancers will be detectable by endometrial sampling. A comprehensive history and physical and uterine imaging also may be helpful. And although they are more difficult to detect than epithelial uterine cancers, it is a myth that sarcomas cannot be diagnosed preoperatively. Investigators from Columbia University retrospectively evaluated the ability to preoperatively detect epithelial uterine cancers and uterine sarcomas on final pathology. In 72 women who were ultimately diagnosed with a sarcoma, preoperative endometrial sampling suggested an invasive tumor in 86% and predicted the correct histology in 64%. In fact, the rate of detection of invasive cancer by preoperative sampling was not statistically different among sarcomas than it was among epithelial uterine cancers, although there was less of a correlation with appropriate histology seen with endometrial biopsy.²⁰

That being said, sarcomas can be missed, especially in younger women who have extremely large, degenerated, or necrotic-appearing fibroids. Improvements in diagnostic testing are desperately needed to help distinguish benign fibroids from sarcomas, as there are no reliable modalities to exclude a sarcoma at this time. MRI appears to be the most useful imaging modality, although it cannot definitively distinguish a fibroid from a sarcoma. However, a fairly constant finding in leiomyosarcomas is the absence of calcifications. Further, some studies also suggest that ill-defined margins are consistent with a sarcoma. Finally, several centers, including our own, are studying novel biologic markers and revisiting the utility of previously described markers such as LDH in the preoperative detection of uterine sarcoma.²¹

The way forward
OBG Management: You have said, “Keep patients informed and safe but avoid being too reactionary.” Could you expand on this statement?

Dr. Fader: Certainly. There are many examples throughout the history of medicine in which treatments have brought benefit to thousands or millions of individuals but may cause harm in a select few. We know that when controversial medical issues have arisen in the past, the pendulum has swung widely in terms of societal response.

For example, the landmark Women’s Health Initiative had an immediate and adverse impact on hormone replacement therapy (HRT) administration. The increased risk of cardiovascular disease and breast cancer ­observed with use of long-term combination therapy with conjugated equine estrogen and medroxyprogesterone acetate prompted many US health-care providers to abandon use of HRT—until more contemporary data demonstrated that, in younger, healthier postmenopausal women, these adverse events were very rare and the benefits of HRT outweighed the risks.

Can we avoid stroke, heart attack, and breast cancer in all younger women taking HRT? Of course not. But we counsel women about the benefit/risk ratio of the therapy and advise them that the likelihood of these events is rare.

Similarly, as with the HRT analogy, younger women have lower risks associated with surgery and morcellation, compared with older women, and are more likely to derive benefit from the procedure (after ­ensuring appropriate candidacy with a comprehensive preoperative evaluation and informed consent).

However, if the expectation is that no cases of harm will ever occur with a surgical device or procedure in order for it to be deemed acceptable and safe to use in practice, then that is simply an impossible standard to uphold. There is no device, medication, or intervention I know of in ­medicine that is completely risk-free.

OBG Management: Are there other examples of this type of benefit/risk assessment?

Dr. Fader: Yes. For instance, tamoxifen is a nonsteroidal anti-estrogen agent approved by the FDA for adjuvant treatment of breast cancer, treatment of metastatic breast cancer, and reduction of breast cancer incidence in high-risk women. Tamoxifen has effectively reduced breast cancer rates and significantly improved survival in select breast cancer patients. Yet, it is well known that long-term use of tamoxifen is associated with a twofold increased risk of uterine cancer and uterine sarcoma—a likely far more commonly occurring adverse event than an occult, morcellated uterine sarcoma during a minimally invasive gynecologic procedure.

Should the FDA ban or significantly curtail the use of tamoxifen? No, not likely, because the benefits far outweigh the risks in previvors and hormone-positive breast cancer survivors. “Keep patients informed and safe but avoid being too reactionary” means that we must do our due diligence as physicians by comprehensively counseling and obtaining informed consent from our patients before performing medical ­interventions. We also must closely scrutinize and improve upon practices that may cause harm.

However, what this also means is that while it may be prudent to restrict or limit a surgical practice in select higher-risk populations or modify it in some way to make it safer, we shouldn’t necessarily completely abandon or ban a practice that has benefited hundreds of thousands of patients at low risk of harm until we have objectively reviewed all of the available science and fully ­understand the implications of a practice change (ie, would the risks of preventable harm be even greater for women if more of them had to undergo open abdominal surgery?). We need continued cool heads and sound scientific reasoning to decide upon health-care policy changes or treatment paradigm shifts.

At the end of the day, however, it is paramount that we mitigate patient harm. The subject of tissue extraction during minimally invasive surgery is a complex and nuanced issue that merits continued study and open-minded and intelligent dialogue between patient stakeholders, clinicians, scientists, industry, ethicists, regulatory agencies, and the press. I think we can all appreciate how humbling and challenging the morcellation issue has been for many of us, especially our patients—particularly the unfortunate women who have been diagnosed with a uterine sarcoma.

Like many of my colleagues, I have been privileged to care for a number of women with uterine leiomyosarcoma. It is a devastating disease, and the prognosis is very poor, whether it is morcellated or removed intact. We are fortunate that the vast majority of women who undergo a minimally invasive procedure for fibroids or other presumed benign indications will not be at risk for an occult malignancy. But what can we do now to continue to offer the benefits of minimally invasive surgery and tissue extraction to women while simultaneously reducing the risk to the select few who will develop a rare uterine cancer?

We can all make a greater effort to more carefully select our patients for minimally invasive surgery and tissue extraction, to limit the performance of open electromechanical morcellation and collaborate in studying the role of refined tissue-extraction techniques and containment systems, to enhance the informed consent process, to develop improved diagnostic tests for preoperative cancer detection, and to conduct higher-quality studies on minimally invasive tissue-extraction techniques for regulatory agencies to review in the near future. It also goes without saying that we need more federal funding to study rare tumors (and gynecologic cancers in general) and develop better sarcoma treatments.

Although there is no medical treatment or surgical procedure that is completely risk-free, interventions such as HRT, tamoxifen, and uterine morcellation—when used in appropriate patients and for appropriate indications—will allow preventable harm to be minimized and make it possible for countless women to continue to derive tremendous benefit.
 

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The year 2014 marked a sea change in our approach to tissue extraction during minimally invasive surgery. The US Food and Drug Administration (FDA) initiated this transformation in April, when it issued a safety warning on the use of open power morcellation.¹ A flurry of statements on the practice followed from professional societies, capped, in late November, with another statement from the FDA.^2–4 The new bottom line: The use of open electromechanical (“power”) morcellation is contraindicated in perimenopausal and postmenopausal women, as well as in those who are known or suspected to have a malignancy.⁴

Most of the concern to date has centered on the risk that an occult leiomyosarcoma could be morcellated inadvertently during uterine surgery, an event that may worsen the prognosis for the patient. To get a gynecologic oncologist’s take on the controversy, OBG Management caught up with Amanda Nickles Fader, MD, director of the Kelly Gynecologic Oncology Service at Johns Hopkins University. Dr. Fader’s perspective is unique in that she treats a relatively high number of patients who have leiomyosarcoma and other uterine cancers.

In this Q&A, we discuss the patient population at Johns Hopkins; why Dr. Fader is especially qualified to speak to the future of electromechanical morcellation in gynecologic surgery; the benefits and risks of minimally invasive surgery, including tissue extraction; her recommendations for preoperative evaluation and counseling of patients undergoing uterine surgery; and guidance on how the specialty of gynecologic surgery should proceed in the future.

OBG Management: Dr. Fader, by way of introduction, could you characterize your patient population?

Amanda Nickles Fader, MD: Like most gynecologic oncologists, I primarily treat women with cancers of the uterus, ovary, cervix, and vulva. Many of us also have the opportunity to treat a number of women each year with complex benign gynecologic conditions that require surgery. As someone who is extremely interested in rare gynecologic tumors, I also treat a relatively high volume of women diagnosed with uterine sarcoma.

Approximately 75% of the women I see in my practice have preinvasive or invasive cancer, and 25% have a benign condition, such as enlarged fibroids or advanced-stage endometriosis.

OBG Management: How many cases of uterine sarcoma do you encounter on an annual basis?

Dr. Fader: Uterine sarcomas are very rare. They represent only 2% of all uterine cancers. Put into perspective, that means that about 0.4 cases of leiomyosarcoma occur in every 100,000 US women—most commonly postmenopausal women. Leiomyosarcoma is a biologically aggressive, high-grade malignancy that often is lethal.⁵

Endometrial stroma sarcoma is even less common—only 0.3 cases occur in every 100,000 US women. However, this tumor type is more indolent, often diagnosed at an earlier stage, and potentially curable with surgery (with or without hormonal therapy).⁶

As a referral center for rare uterine tumors, the Kelly Gynecologic Oncology Service and the Sarcoma Center at Johns Hopkins see approximately 35 to 40 new cases of uterine sarcoma annually for treatment of primary disease or recurrence. An additional 15 to 20 consult cases are reviewed from outside hospitals each year by our gynecologic pathology department.

Why a minimally invasive approach is vital
OBG Management: When it comes to uterine surgery for presumed benign conditions, why is a minimally invasive approach important?

Dr. Fader: Minimally invasive surgery clearly benefits women and is one of the greatest advances of the past half-century within our field. Randomized controlled trials and meta-analyses have demonstrated without question that women who undergo minimally invasive surgery for benign conditions or early-stage cancerous gynecologic conditions have superior clinical outcomes, compared with women who undergo surgery via laparotomy.^7,8 These outcomes include fewer perioperative complications (including fewer cases of surgical site infection, venous thromboembolism, wound dehiscence, and hospital readmission), shorter hospital stays, less pain, faster recovery, and fewer adhesions. And when women with early-stage cancers undergo minimally invasive surgery, randomized controlled trials show, they have a stage-specific survival rate similar to that observed in women treated with laparotomy.⁹

Benefits and risks of tissue extraction in minimally invasive surgery
OBG Management: What are the main benefits of tissue extraction, including morcellation?

Dr. Fader: Tissue extraction is a practice that has allowed us to offer minimally invasive surgery to countless more women than we could have in the recent past. It is a technique in which a large specimen (typically a uterus or fibroid) is fragmented into smaller parts in order to remove it through a small laparoscopic incision or orifice (vagina, umbilicus). Without tissue-extraction practices, thousands of women who undergo myomectomy each year to conserve their fertility and hundreds of thousands of women who require hysterectomy potentially would have to undergo a more painful and risky surgery through a larger abdominal incision. That would not be desirable, as we know conclusively that laparotomy is associated with worse outcomes—and even an increased risk of mortality—compared with minimally invasive surgery performed by experienced surgeons.¹⁰

Tissue extraction can be approached in a variety of ways. It can be performed with a scalpel, with a resectoscope, or with an electromechanical morcellator. Tissue extraction can be performed within the uterine cavity, through the vagina, within the abdominal compartment, or within a containment system in any of those compartments.

OBG Management: What are the risks of tissue extraction?

Dr. Fader: The risks of tissue extraction with electromechanical morcellation include potential injury to intra-abdominal organs and vasculature and risk of dissemination of an occult (ie, undiagnosed) uterine cancer. A report by our research group also demonstrated the risks of dissemination of benign uterine tissue requiring subsequent surgery in the setting of open electromechanical morcellation.¹¹ The risk of these events occurring in the hands of a thoughtful and experienced surgeon who conducts comprehensive preoperative patient evaluations is extremely low. However, recent evidence demonstrates that a handful of women worldwide are diagnosed with an occult uterine cancer each year during a morcellation procedure.^12–14 Although it is a very rare event (given that most women undergoing hysterectomy and myomectomy procedures are of reproductive age and unlikely to have uterine cancer), this risk is a serious issue. There is an exigent need for the gynecologic surgical community to develop better approaches to tissue extraction that minimize preventable harm in women.

Needed: high-quality data on the risks of morcellation
OBG Management: How does the recent FDA statement urging caution with the use of open power morcellation factor into this equation? The most recent FDA statement noted that open power morcellation is contraindicated in perimenopausal and postmenopausal women.⁴

Dr. Fader: The FDA’s concern is legitimate. However, the magnitude of the risk of occult uterine sarcoma in women undergoing presumed benign gynecologic surgery has been scrutinized and debated. The FDA panel quoted a risk that roughly 1 in 350 women undergoing presumed benign gynecologic surgery for fibroids will have an occult leiomyosarcoma diagnosed. However, more recent systematic reviews and a review of the prospective published literature demonstrate that the risk is more likely on the order of 1 in 1,700 to 1 in 8,333 women.¹⁵ The risk may be even lower in gynecologic surgery practices that see a high volume of ­hysterectomy/myomectomy cases and utilize meticulous preoperative patient selection criteria to establish a woman’s ­candidacy for tissue-extraction procedures.

I am concerned with how “occult sarcoma” discovered during surgery for “presumed benign gynecologic disease is being defined in the literature. There is no uniform definition being used. A cancer in this setting is only truly occult or undiagnosed if the physician was thinking about it and made every effort to rule out cancer preoperatively, and the morcellation procedure was performed in a low-risk population (but cancer was still diagnosed on final pathology in this population). However, in the majority of the morcellation studies in the literature, it is not clear that thorough preoperative evaluations occurred in patients to rule out uterine malignancy—in fact, there is a paucity of published information regarding establishing appropriate patient candidacy for morcellation procedures. So we can’t derive any conclusions regarding whether “occult” sarcomas were truly undetectable or not in the published literature.

In addition, the literature is very clear that advancing age and postmenopausal status are risk factors for uterine malignancy.¹⁶ The vast majority of uterine sarcoma cases are diagnosed in postmenopausal women. Yet, in one large US population-based hysterectomy study, 20% of the morcellated cases (and the overwhelming majority of the “occult” morcellated uterine cancers) occurred in postmenopausal women!¹⁷

Further, in a more recent study by the same authors, again the risks of morcellating a uterine cancer in a population undergoing myomectomy was significantly higher in a postmenopausal population and occurred only rarely in women younger than age 40. But it should come as no surprise that a greater incidence of uterine cancer was identified in these older cohorts—cancer risk increases precipitously with age. That’s not “occult”; that’s basic cancer epidemiology.

In other words, we cannot assume from population-based administrative claims data that morcellation performed in inappropriate populations at higher risk of uterine malignancy (in which we do not know whether patients were properly screened for the procedure preoperatively or whether they had risk factors for uterine cancer but were presumably poor candidates for morcellation due to age alone) helps us define the true incidence of “occult” sarcoma or cancer in a population.

These studies are provocative, however, and do inform us that, as women get older, we are apt to see a greater incidence of uterine cancer. We cannot safely assume that a postmenopausal or elderly woman with symptomatic or enlarging fibroids has “presumed benign disease”—it is cancer until proven otherwise, and we need to be looking for it preoperatively. Therefore, we need to be particularly careful with our surgical practices in this population—ie, the basis for the FDA’s recommendation to avoid morcellation in older women. And I agree with the FDA that open electromechanical morcellation generally is contraindicated in postmenopausal women. However, we need better data from large prospective studies to inform our understanding of the true incidence of undiagnosed or “occult” uterine sarcoma in women undergoing surgery for presumed benign disease. These future studies are likely to demonstrate what we already know—that in young, well-screened, well-selected candidates for minimally invasive hysterectomy or myomectomy, the risk of occult cancer is going to be exceptionally low.

OBG Management: Which is greater—the risks or benefits of tissue extraction?

Dr. Fader: Assessment of risks and benefits in medicine has everything to do with the intervention in question as applied to an individual patient. At the end of the day, there are risks and benefits to every medical or surgical treatment offered to patients in every medical and surgical discipline. But the risk of an occult uterine sarcoma is extremely low in a woman of reproductive age who has been properly selected and comprehensively evaluated for minimally invasive surgery and tissue extraction prior to surgery. And this small—though not negligible—risk must be weighed against the much higher risk of harm that may be incurred with an open abdominal procedure, compared with minimally invasive surgery.

However, in many elderly women, the risks of tissue extraction with an electromechanical morcellator may outweigh the benefits. Even so, there are exceptions in which tissue extraction may be acceptable in postmenopausal women (ie, using alternative tissue-extraction methods in those undergoing minimally invasive supracervical hysterectomy and sacral colpopexy for pelvic organ prolapse).

Few of the data published on the risks of morcellation are of very high quality in terms of scientific rigor or methodology. The best thing we can do as a gynecologic surgical community is conduct sound quality-­improvement (QI) programs, disseminate our QI results, publish our data, establish guidelines for best practices in uterine tissue extraction, and collaborate readily to increase the scholarly output on this issue so that national societies and government regulatory agencies have better-quality data to inform future policy on this issue.

A case-based approach
OBG Management: How would you approach tissue extraction in the following case?

CASE: A desire for myomectomy
A 35-year-old woman (G1P1) who delivered by cesarean has an 8-cm symptomatic ­intramural fibroid. She has regular heavy periods that have led to anemia (hemoglobin level = 10 mg/dL). Her medical history is negative for malignancy, pelvic radiation, or tamoxifen use, and she wants to preserve her fertility. Magnetic resonance imaging (MRI) confirms an 8-cm fibroid. Endometrial biopsy results are negative.

Dr. Fader: At Johns Hopkins, as at many other centers, we use well-defined criteria to determine whether a minimally invasive approach (and tissue extraction) might be appropriate. We also individualize treatment and surgical decision-making on a case-by-case basis. Any candidate for minimally invasive surgery and tissue extraction for uterine fibroids must undergo a thorough preoperative assessment.

Johns Hopkins preoperative assessment criteria include:

Our top priority is patient safety, so until more data are available, we no longer perform open electromechanical morcellation. We perform all tissue extraction within a containment system and under institutional review board protocol. We primarily perform tissue extraction via scalpel ­morcellation.

OBG Management: How do the patient’s wishes factor into the decision to perform minimally invasive surgery with morcellation?

Dr. Fader: Our patients make their own decisions regarding surgical approach and procedure after undergoing extensive counseling about the risks and benefits of the proposed procedures. I certainly would offer a patient like the one described in this case the opportunity for a minimally invasive approach (if, after thorough preoperative evaluation, she were deemed to be at very low risk for uterine malignancy). In my experience, most women opt for the minimally invasive approach in this setting; however, if a patient declines minimally invasive surgery, I respect her decision.

Tissue extraction in perimenopause

CASE: A desire for myomectomy at age 48
OBG Management: How would you approach the same case if the patient were a 48-year-old perimenopausal woman?

Dr. Fader: In perimenopausal women, we are more selective about performing morcellation, given the recent FDA safety statement, and because the incidence of occult cancer starts to increase slightly in this patient cohort (although it doesn’t precipitously increase until well into the postmenopausal period).

In addition, myomectomy may have less value in a 48-year-old, given the lower likelihood of achieving successful fertility, although there are exceptions. US  cancer statistics and studies on morcellation demonstrate that the vast majority of women in their 30s and 40s have an extremely low risk for sarcomas and other uterine malignancies.²

In select cases in which a woman has undergone a comprehensive preoperative work-up, has a stable-appearing fibroid(s), and is well-educated and counseled about the pros and cons of morcellation, we would consider performing a procedure with contained tissue extraction. As a general matter, however, I would be more inclined to offer a 48-year-old in this situation a uterine artery embolization or minimally invasive hysterectomy than a myomectomy procedure, especially given the recent study by Wright and colleagues demonstrating the significantly increased risks of uterine cancer at myomectomy surgery for a woman in her late 40s or early 50s.¹⁸

Preoperative assessment should be comprehensive
OBG Management: What preoperative evaluation do you perform when tissue extraction, including morcellation, is an issue?

Dr. Fader: It is the policy at Johns Hopkins that all women being considered for minimally invasive surgery and tissue extraction must undergo a rigorous preoperative work-up that includes:

We have separate conferences for the gynecology and gynecologic oncology services and have employed this practice for many years at Hopkins. We are also studying the role of serum lactate dehydrogenase (LDH) isoenzyme levels in stratifying women with uterine fibroids versus cancer/sarcoma.¹⁹

OBG Management: Which patients would you exclude from the electromechanical morcellation option?

Dr. Fader: As the American College of Obstetricians and Gynecologists, the AAGL, the Society of Gynecologic Oncology, and the Society of Gynecologic Surgeons appear to agree:

At our institution, we have significantly ­curtailed the use of electromechanical morcellation at this time and especially do not perform it in women aged 50 or older or in those with confirmed postmenopausal status. We also do not perform electromechanical morcellation in women with a personal history of uterine, cervical, or ovarian preinvasive or invasive cancer, or in women with a strong family history of gynecologic malignancy.

Other populations we exclude are women with:

Counseling the patient
OBG Management: If tissue extraction is an issue, and morcellation will be necessary for a minimally invasive approach, how do you counsel the patient?

Dr. Fader: We have an informed consent protocol we use at Hopkins in this regard. We speak extensively to our patients about the fact that every procedure or intervention performed in medicine carries a benefit/risk ratio. We inform patients of the FDA morcellation safety statement—that their fibroid or fibroids may contain unexpected cancerous tissue and that laparoscopic electromechanical morcellation may spread the cancer and possibly worsen their prognosis. We also explain that, while the FDA quotes a risk of approximately 1 in 350 for occult sarcoma, that this data review was somewhat limited in scope and included postmenopausal women in the estimates. Based on the best available published systematic reviews and internal Hopkins data, we believe the risk of morcellating an occult uterine malignancy in a woman of reproductive age is more likely on the order of approximately 1 in 1,700 to 1 in 8,333.

We discuss our institution’s approach to tissue extraction (ie, that we no longer perform open electromechanical morcellation but instead perform contained tissue extraction on an institutional review board protocol). We tell patients that contained tissue-extraction practices are still experimental, although there is published literature preliminarily supporting the safety of the practice. In addition, we discuss the fact that contained tissue extraction has been used for years to safely remove large intra-abdominal specimens from laparoscopic incisions, from adnexal tissue to gallbladder, spleen, kidney, intestinal, and appendiceal specimens.

We also explain that, as physicians, we do our best to ensure that risks are minimized and reasonable in relation to anticipated benefits but that, even when we use the very best diagnostic measures, no test is 100% sensitive or specific to rule out malignancy in this setting (or in any setting, ­actually).

Finally, we discuss the fact that minimally invasive surgery and tissue extraction practices performed in appropriate patients by skilled surgeons conclusively benefit hundreds of thousands of women each year around the world. That is a narrative that has been somewhat lacking in the recent dialogue about tissue-extraction practices.
 

OBG Management: What do we know about outcomes when a leiomyosarcoma is inadvertently morcellated?

Dr. Fader: This is considered a “cut-through” procedure, in that a cancerous tumor that is potentially contained to an organ is not removed intact or with clean margins. The morcellation procedure effectively cuts through the occult cancer, which is not desirable. Intact surgical removal of uterine cancers or sarcomas is the mainstay of therapy for these malignancies, based on NCCN guidelines.²²

OBG Management: Does a morcellated leiomyosarcoma carry a worse prognosis than an unmorcellated leiomyosarcoma?

Dr. Fader: When it comes to morcellated versus “intact” uterine leiomyosarcoma, we enter a largely data-free zone. We don’t know with certainty whether the outcome is worsened. If we’re being intellectually honest, we must admit the possibility that a morcellated cancer is more likely to be disseminated, rendering it potentially more difficult to treat. However, sarcomas primarily spread by hematogenous dissemination. It is quite possible that even the act of incising an intact fibroid in an open abdominal procedure or performing a supracervical or total hysterectomy without morcellation may still result in hematogenous cancer dissemination. So there is no indication yet that electromechanical morcellation poses a unique and higher risk of cancer upstaging or worse prognosis compared with techniques such as open myomectomy, supracervical hysterectomy, or hysteroscopic myomectomy.

In addition, the prognosis associated with even early-stage uterine leiomyosarcoma is uniformly poor. A published study from Hopkins that included 108 patients with uterine leiomyosarcoma suggests that the recurrence rate and survival of patients with early-stage, “intact” leiomyosarcoma are very poor and comparable to the survival rate documented in the literature for women with morcellated sarcomas.²³

The few retrospective studies that exist suggesting worse outcomes with morcellation have limitations that preclude any definitive conclusions.² These studies are marred by small numbers, heterogeneity in morcellation practices, poor follow-up times, and a lack of detail regarding how patients with morcellated versus unmorcellated sarcomas were treated. Nevertheless, a couple of these small retrospective reports indicate the possibility of worse outcomes in women with morcellated uterine sarcomas, compared with historical controls with intact sarcoma removal.

Is the morcellator at fault—or the user?
OBG Management: Some would argue that even one case of a morcellated uterine sarcoma is too many. How would you respond?

Dr. Fader: There is no doubt that a handful of women each year have been harmed by morcellation practices. Those women deserve our dedication and best efforts to learn how to better treat morcellated sarcomas—and more importantly—how to mitigate the risks associated with morcellation practices and reduce the risk of preventable harm for all women undergoing minimally invasive fibroid procedures. I think the single best thing we can do to mitigate risk is to be more ­conscientious about selecting our patients for tissue-extraction procedures (ie, strict selection criteria, appropriate preoperative work-ups). If we did this, we likely would reduce the number of oncologic morcellator mishaps by 50% to 80% without changing anything else.

When we closely scrutinize the ­literature, and when I reflect on the women with morcellated cancers that we have cared for at Hopkins, we observe that some (but not all) “occult” uterine cancers were not that hidden after all and may have been detected preoperatively if an effort had been made.

We have noted a number of patients in this setting who experienced harm not because a specific device was used to cut up their uterus but because they were never appropriate candidates for the procedure in the first place. For instance, I recently cared for an elderly woman with a morcellated uterine cancer who underwent a laparoscopic supracervical hysterectomy without an appropriate preoperative work-up (ie, no endometrial biopsy or imaging) or informed consent about the possibility that she might have cancer. If an elderly woman presents with concerning symptoms related to her uterus (ie, enlargement, bleeding), she must be evaluated and counseled regarding the considerable risk of potential malignancy. Even in the setting of a normal work-up, I don’t believe it is a good idea to perform electromechanical morcellation in higher-risk women, including elderly women. That does not mean that select, well-screened women cannot be considered for alternative tissue-extraction techniques, but the risks and benefits must be carefully weighed in each patient, and informed consent must be obtained.

By continuing to refine the safety features of the electromechanical morcellator devices and choosing patients more carefully for minimally invasive procedures and tissue extraction, we likely will reduce the risk of preventable harm in women undergoing gynecologic surgery.

Can leiomyosarcoma be detected preoperatively?
OBG Management: How can we improve preoperative detection of uterine malignancy, particularly leiomyosarcoma?

Dr. Fader: For starters, we can improve detection of uterine cancers by simply looking for them. Almost all epithelial uterine cancers will be detectable by endometrial sampling. A comprehensive history and physical and uterine imaging also may be helpful. And although they are more difficult to detect than epithelial uterine cancers, it is a myth that sarcomas cannot be diagnosed preoperatively. Investigators from Columbia University retrospectively evaluated the ability to preoperatively detect epithelial uterine cancers and uterine sarcomas on final pathology. In 72 women who were ultimately diagnosed with a sarcoma, preoperative endometrial sampling suggested an invasive tumor in 86% and predicted the correct histology in 64%. In fact, the rate of detection of invasive cancer by preoperative sampling was not statistically different among sarcomas than it was among epithelial uterine cancers, although there was less of a correlation with appropriate histology seen with endometrial biopsy.²⁰

That being said, sarcomas can be missed, especially in younger women who have extremely large, degenerated, or necrotic-appearing fibroids. Improvements in diagnostic testing are desperately needed to help distinguish benign fibroids from sarcomas, as there are no reliable modalities to exclude a sarcoma at this time. MRI appears to be the most useful imaging modality, although it cannot definitively distinguish a fibroid from a sarcoma. However, a fairly constant finding in leiomyosarcomas is the absence of calcifications. Further, some studies also suggest that ill-defined margins are consistent with a sarcoma. Finally, several centers, including our own, are studying novel biologic markers and revisiting the utility of previously described markers such as LDH in the preoperative detection of uterine sarcoma.²¹

The way forward
OBG Management: You have said, “Keep patients informed and safe but avoid being too reactionary.” Could you expand on this statement?

Dr. Fader: Certainly. There are many examples throughout the history of medicine in which treatments have brought benefit to thousands or millions of individuals but may cause harm in a select few. We know that when controversial medical issues have arisen in the past, the pendulum has swung widely in terms of societal response.

For example, the landmark Women’s Health Initiative had an immediate and adverse impact on hormone replacement therapy (HRT) administration. The increased risk of cardiovascular disease and breast cancer ­observed with use of long-term combination therapy with conjugated equine estrogen and medroxyprogesterone acetate prompted many US health-care providers to abandon use of HRT—until more contemporary data demonstrated that, in younger, healthier postmenopausal women, these adverse events were very rare and the benefits of HRT outweighed the risks.

Can we avoid stroke, heart attack, and breast cancer in all younger women taking HRT? Of course not. But we counsel women about the benefit/risk ratio of the therapy and advise them that the likelihood of these events is rare.

Similarly, as with the HRT analogy, younger women have lower risks associated with surgery and morcellation, compared with older women, and are more likely to derive benefit from the procedure (after ­ensuring appropriate candidacy with a comprehensive preoperative evaluation and informed consent).

However, if the expectation is that no cases of harm will ever occur with a surgical device or procedure in order for it to be deemed acceptable and safe to use in practice, then that is simply an impossible standard to uphold. There is no device, medication, or intervention I know of in ­medicine that is completely risk-free.

OBG Management: Are there other examples of this type of benefit/risk assessment?

Dr. Fader: Yes. For instance, tamoxifen is a nonsteroidal anti-estrogen agent approved by the FDA for adjuvant treatment of breast cancer, treatment of metastatic breast cancer, and reduction of breast cancer incidence in high-risk women. Tamoxifen has effectively reduced breast cancer rates and significantly improved survival in select breast cancer patients. Yet, it is well known that long-term use of tamoxifen is associated with a twofold increased risk of uterine cancer and uterine sarcoma—a likely far more commonly occurring adverse event than an occult, morcellated uterine sarcoma during a minimally invasive gynecologic procedure.

Should the FDA ban or significantly curtail the use of tamoxifen? No, not likely, because the benefits far outweigh the risks in previvors and hormone-positive breast cancer survivors. “Keep patients informed and safe but avoid being too reactionary” means that we must do our due diligence as physicians by comprehensively counseling and obtaining informed consent from our patients before performing medical ­interventions. We also must closely scrutinize and improve upon practices that may cause harm.

However, what this also means is that while it may be prudent to restrict or limit a surgical practice in select higher-risk populations or modify it in some way to make it safer, we shouldn’t necessarily completely abandon or ban a practice that has benefited hundreds of thousands of patients at low risk of harm until we have objectively reviewed all of the available science and fully ­understand the implications of a practice change (ie, would the risks of preventable harm be even greater for women if more of them had to undergo open abdominal surgery?). We need continued cool heads and sound scientific reasoning to decide upon health-care policy changes or treatment paradigm shifts.

At the end of the day, however, it is paramount that we mitigate patient harm. The subject of tissue extraction during minimally invasive surgery is a complex and nuanced issue that merits continued study and open-minded and intelligent dialogue between patient stakeholders, clinicians, scientists, industry, ethicists, regulatory agencies, and the press. I think we can all appreciate how humbling and challenging the morcellation issue has been for many of us, especially our patients—particularly the unfortunate women who have been diagnosed with a uterine sarcoma.

Like many of my colleagues, I have been privileged to care for a number of women with uterine leiomyosarcoma. It is a devastating disease, and the prognosis is very poor, whether it is morcellated or removed intact. We are fortunate that the vast majority of women who undergo a minimally invasive procedure for fibroids or other presumed benign indications will not be at risk for an occult malignancy. But what can we do now to continue to offer the benefits of minimally invasive surgery and tissue extraction to women while simultaneously reducing the risk to the select few who will develop a rare uterine cancer?

We can all make a greater effort to more carefully select our patients for minimally invasive surgery and tissue extraction, to limit the performance of open electromechanical morcellation and collaborate in studying the role of refined tissue-extraction techniques and containment systems, to enhance the informed consent process, to develop improved diagnostic tests for preoperative cancer detection, and to conduct higher-quality studies on minimally invasive tissue-extraction techniques for regulatory agencies to review in the near future. It also goes without saying that we need more federal funding to study rare tumors (and gynecologic cancers in general) and develop better sarcoma treatments.

Although there is no medical treatment or surgical procedure that is completely risk-free, interventions such as HRT, tamoxifen, and uterine morcellation—when used in appropriate patients and for appropriate indications—will allow preventable harm to be minimized and make it possible for countless women to continue to derive tremendous benefit.
 

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The year 2014 marked a sea change in our approach to tissue extraction during minimally invasive surgery. The US Food and Drug Administration (FDA) initiated this transformation in April, when it issued a safety warning on the use of open power morcellation.¹ A flurry of statements on the practice followed from professional societies, capped, in late November, with another statement from the FDA.^2–4 The new bottom line: The use of open electromechanical (“power”) morcellation is contraindicated in perimenopausal and postmenopausal women, as well as in those who are known or suspected to have a malignancy.⁴

Most of the concern to date has centered on the risk that an occult leiomyosarcoma could be morcellated inadvertently during uterine surgery, an event that may worsen the prognosis for the patient. To get a gynecologic oncologist’s take on the controversy, OBG Management caught up with Amanda Nickles Fader, MD, director of the Kelly Gynecologic Oncology Service at Johns Hopkins University. Dr. Fader’s perspective is unique in that she treats a relatively high number of patients who have leiomyosarcoma and other uterine cancers.

In this Q&A, we discuss the patient population at Johns Hopkins; why Dr. Fader is especially qualified to speak to the future of electromechanical morcellation in gynecologic surgery; the benefits and risks of minimally invasive surgery, including tissue extraction; her recommendations for preoperative evaluation and counseling of patients undergoing uterine surgery; and guidance on how the specialty of gynecologic surgery should proceed in the future.

OBG Management: Dr. Fader, by way of introduction, could you characterize your patient population?

Amanda Nickles Fader, MD: Like most gynecologic oncologists, I primarily treat women with cancers of the uterus, ovary, cervix, and vulva. Many of us also have the opportunity to treat a number of women each year with complex benign gynecologic conditions that require surgery. As someone who is extremely interested in rare gynecologic tumors, I also treat a relatively high volume of women diagnosed with uterine sarcoma.

Approximately 75% of the women I see in my practice have preinvasive or invasive cancer, and 25% have a benign condition, such as enlarged fibroids or advanced-stage endometriosis.

OBG Management: How many cases of uterine sarcoma do you encounter on an annual basis?

Dr. Fader: Uterine sarcomas are very rare. They represent only 2% of all uterine cancers. Put into perspective, that means that about 0.4 cases of leiomyosarcoma occur in every 100,000 US women—most commonly postmenopausal women. Leiomyosarcoma is a biologically aggressive, high-grade malignancy that often is lethal.⁵

Endometrial stroma sarcoma is even less common—only 0.3 cases occur in every 100,000 US women. However, this tumor type is more indolent, often diagnosed at an earlier stage, and potentially curable with surgery (with or without hormonal therapy).⁶

As a referral center for rare uterine tumors, the Kelly Gynecologic Oncology Service and the Sarcoma Center at Johns Hopkins see approximately 35 to 40 new cases of uterine sarcoma annually for treatment of primary disease or recurrence. An additional 15 to 20 consult cases are reviewed from outside hospitals each year by our gynecologic pathology department.

Why a minimally invasive approach is vital
OBG Management: When it comes to uterine surgery for presumed benign conditions, why is a minimally invasive approach important?

Dr. Fader: Minimally invasive surgery clearly benefits women and is one of the greatest advances of the past half-century within our field. Randomized controlled trials and meta-analyses have demonstrated without question that women who undergo minimally invasive surgery for benign conditions or early-stage cancerous gynecologic conditions have superior clinical outcomes, compared with women who undergo surgery via laparotomy.^7,8 These outcomes include fewer perioperative complications (including fewer cases of surgical site infection, venous thromboembolism, wound dehiscence, and hospital readmission), shorter hospital stays, less pain, faster recovery, and fewer adhesions. And when women with early-stage cancers undergo minimally invasive surgery, randomized controlled trials show, they have a stage-specific survival rate similar to that observed in women treated with laparotomy.⁹

Benefits and risks of tissue extraction in minimally invasive surgery
OBG Management: What are the main benefits of tissue extraction, including morcellation?

Dr. Fader: Tissue extraction is a practice that has allowed us to offer minimally invasive surgery to countless more women than we could have in the recent past. It is a technique in which a large specimen (typically a uterus or fibroid) is fragmented into smaller parts in order to remove it through a small laparoscopic incision or orifice (vagina, umbilicus). Without tissue-extraction practices, thousands of women who undergo myomectomy each year to conserve their fertility and hundreds of thousands of women who require hysterectomy potentially would have to undergo a more painful and risky surgery through a larger abdominal incision. That would not be desirable, as we know conclusively that laparotomy is associated with worse outcomes—and even an increased risk of mortality—compared with minimally invasive surgery performed by experienced surgeons.¹⁰

Tissue extraction can be approached in a variety of ways. It can be performed with a scalpel, with a resectoscope, or with an electromechanical morcellator. Tissue extraction can be performed within the uterine cavity, through the vagina, within the abdominal compartment, or within a containment system in any of those compartments.

OBG Management: What are the risks of tissue extraction?

Dr. Fader: The risks of tissue extraction with electromechanical morcellation include potential injury to intra-abdominal organs and vasculature and risk of dissemination of an occult (ie, undiagnosed) uterine cancer. A report by our research group also demonstrated the risks of dissemination of benign uterine tissue requiring subsequent surgery in the setting of open electromechanical morcellation.¹¹ The risk of these events occurring in the hands of a thoughtful and experienced surgeon who conducts comprehensive preoperative patient evaluations is extremely low. However, recent evidence demonstrates that a handful of women worldwide are diagnosed with an occult uterine cancer each year during a morcellation procedure.^12–14 Although it is a very rare event (given that most women undergoing hysterectomy and myomectomy procedures are of reproductive age and unlikely to have uterine cancer), this risk is a serious issue. There is an exigent need for the gynecologic surgical community to develop better approaches to tissue extraction that minimize preventable harm in women.

Needed: high-quality data on the risks of morcellation
OBG Management: How does the recent FDA statement urging caution with the use of open power morcellation factor into this equation? The most recent FDA statement noted that open power morcellation is contraindicated in perimenopausal and postmenopausal women.⁴

Dr. Fader: The FDA’s concern is legitimate. However, the magnitude of the risk of occult uterine sarcoma in women undergoing presumed benign gynecologic surgery has been scrutinized and debated. The FDA panel quoted a risk that roughly 1 in 350 women undergoing presumed benign gynecologic surgery for fibroids will have an occult leiomyosarcoma diagnosed. However, more recent systematic reviews and a review of the prospective published literature demonstrate that the risk is more likely on the order of 1 in 1,700 to 1 in 8,333 women.¹⁵ The risk may be even lower in gynecologic surgery practices that see a high volume of ­hysterectomy/myomectomy cases and utilize meticulous preoperative patient selection criteria to establish a woman’s ­candidacy for tissue-extraction procedures.

I am concerned with how “occult sarcoma” discovered during surgery for “presumed benign gynecologic disease is being defined in the literature. There is no uniform definition being used. A cancer in this setting is only truly occult or undiagnosed if the physician was thinking about it and made every effort to rule out cancer preoperatively, and the morcellation procedure was performed in a low-risk population (but cancer was still diagnosed on final pathology in this population). However, in the majority of the morcellation studies in the literature, it is not clear that thorough preoperative evaluations occurred in patients to rule out uterine malignancy—in fact, there is a paucity of published information regarding establishing appropriate patient candidacy for morcellation procedures. So we can’t derive any conclusions regarding whether “occult” sarcomas were truly undetectable or not in the published literature.

In addition, the literature is very clear that advancing age and postmenopausal status are risk factors for uterine malignancy.¹⁶ The vast majority of uterine sarcoma cases are diagnosed in postmenopausal women. Yet, in one large US population-based hysterectomy study, 20% of the morcellated cases (and the overwhelming majority of the “occult” morcellated uterine cancers) occurred in postmenopausal women!¹⁷

Further, in a more recent study by the same authors, again the risks of morcellating a uterine cancer in a population undergoing myomectomy was significantly higher in a postmenopausal population and occurred only rarely in women younger than age 40. But it should come as no surprise that a greater incidence of uterine cancer was identified in these older cohorts—cancer risk increases precipitously with age. That’s not “occult”; that’s basic cancer epidemiology.

In other words, we cannot assume from population-based administrative claims data that morcellation performed in inappropriate populations at higher risk of uterine malignancy (in which we do not know whether patients were properly screened for the procedure preoperatively or whether they had risk factors for uterine cancer but were presumably poor candidates for morcellation due to age alone) helps us define the true incidence of “occult” sarcoma or cancer in a population.

These studies are provocative, however, and do inform us that, as women get older, we are apt to see a greater incidence of uterine cancer. We cannot safely assume that a postmenopausal or elderly woman with symptomatic or enlarging fibroids has “presumed benign disease”—it is cancer until proven otherwise, and we need to be looking for it preoperatively. Therefore, we need to be particularly careful with our surgical practices in this population—ie, the basis for the FDA’s recommendation to avoid morcellation in older women. And I agree with the FDA that open electromechanical morcellation generally is contraindicated in postmenopausal women. However, we need better data from large prospective studies to inform our understanding of the true incidence of undiagnosed or “occult” uterine sarcoma in women undergoing surgery for presumed benign disease. These future studies are likely to demonstrate what we already know—that in young, well-screened, well-selected candidates for minimally invasive hysterectomy or myomectomy, the risk of occult cancer is going to be exceptionally low.

OBG Management: Which is greater—the risks or benefits of tissue extraction?

Dr. Fader: Assessment of risks and benefits in medicine has everything to do with the intervention in question as applied to an individual patient. At the end of the day, there are risks and benefits to every medical or surgical treatment offered to patients in every medical and surgical discipline. But the risk of an occult uterine sarcoma is extremely low in a woman of reproductive age who has been properly selected and comprehensively evaluated for minimally invasive surgery and tissue extraction prior to surgery. And this small—though not negligible—risk must be weighed against the much higher risk of harm that may be incurred with an open abdominal procedure, compared with minimally invasive surgery.

However, in many elderly women, the risks of tissue extraction with an electromechanical morcellator may outweigh the benefits. Even so, there are exceptions in which tissue extraction may be acceptable in postmenopausal women (ie, using alternative tissue-extraction methods in those undergoing minimally invasive supracervical hysterectomy and sacral colpopexy for pelvic organ prolapse).

Few of the data published on the risks of morcellation are of very high quality in terms of scientific rigor or methodology. The best thing we can do as a gynecologic surgical community is conduct sound quality-­improvement (QI) programs, disseminate our QI results, publish our data, establish guidelines for best practices in uterine tissue extraction, and collaborate readily to increase the scholarly output on this issue so that national societies and government regulatory agencies have better-quality data to inform future policy on this issue.

A case-based approach
OBG Management: How would you approach tissue extraction in the following case?

CASE: A desire for myomectomy
A 35-year-old woman (G1P1) who delivered by cesarean has an 8-cm symptomatic ­intramural fibroid. She has regular heavy periods that have led to anemia (hemoglobin level = 10 mg/dL). Her medical history is negative for malignancy, pelvic radiation, or tamoxifen use, and she wants to preserve her fertility. Magnetic resonance imaging (MRI) confirms an 8-cm fibroid. Endometrial biopsy results are negative.

Dr. Fader: At Johns Hopkins, as at many other centers, we use well-defined criteria to determine whether a minimally invasive approach (and tissue extraction) might be appropriate. We also individualize treatment and surgical decision-making on a case-by-case basis. Any candidate for minimally invasive surgery and tissue extraction for uterine fibroids must undergo a thorough preoperative assessment.

Johns Hopkins preoperative assessment criteria include:

Our top priority is patient safety, so until more data are available, we no longer perform open electromechanical morcellation. We perform all tissue extraction within a containment system and under institutional review board protocol. We primarily perform tissue extraction via scalpel ­morcellation.

OBG Management: How do the patient’s wishes factor into the decision to perform minimally invasive surgery with morcellation?

Dr. Fader: Our patients make their own decisions regarding surgical approach and procedure after undergoing extensive counseling about the risks and benefits of the proposed procedures. I certainly would offer a patient like the one described in this case the opportunity for a minimally invasive approach (if, after thorough preoperative evaluation, she were deemed to be at very low risk for uterine malignancy). In my experience, most women opt for the minimally invasive approach in this setting; however, if a patient declines minimally invasive surgery, I respect her decision.

Tissue extraction in perimenopause

CASE: A desire for myomectomy at age 48
OBG Management: How would you approach the same case if the patient were a 48-year-old perimenopausal woman?

Dr. Fader: In perimenopausal women, we are more selective about performing morcellation, given the recent FDA safety statement, and because the incidence of occult cancer starts to increase slightly in this patient cohort (although it doesn’t precipitously increase until well into the postmenopausal period).

In addition, myomectomy may have less value in a 48-year-old, given the lower likelihood of achieving successful fertility, although there are exceptions. US  cancer statistics and studies on morcellation demonstrate that the vast majority of women in their 30s and 40s have an extremely low risk for sarcomas and other uterine malignancies.²

In select cases in which a woman has undergone a comprehensive preoperative work-up, has a stable-appearing fibroid(s), and is well-educated and counseled about the pros and cons of morcellation, we would consider performing a procedure with contained tissue extraction. As a general matter, however, I would be more inclined to offer a 48-year-old in this situation a uterine artery embolization or minimally invasive hysterectomy than a myomectomy procedure, especially given the recent study by Wright and colleagues demonstrating the significantly increased risks of uterine cancer at myomectomy surgery for a woman in her late 40s or early 50s.¹⁸

Preoperative assessment should be comprehensive
OBG Management: What preoperative evaluation do you perform when tissue extraction, including morcellation, is an issue?

Dr. Fader: It is the policy at Johns Hopkins that all women being considered for minimally invasive surgery and tissue extraction must undergo a rigorous preoperative work-up that includes:

We have separate conferences for the gynecology and gynecologic oncology services and have employed this practice for many years at Hopkins. We are also studying the role of serum lactate dehydrogenase (LDH) isoenzyme levels in stratifying women with uterine fibroids versus cancer/sarcoma.¹⁹

OBG Management: Which patients would you exclude from the electromechanical morcellation option?

Dr. Fader: As the American College of Obstetricians and Gynecologists, the AAGL, the Society of Gynecologic Oncology, and the Society of Gynecologic Surgeons appear to agree:

At our institution, we have significantly ­curtailed the use of electromechanical morcellation at this time and especially do not perform it in women aged 50 or older or in those with confirmed postmenopausal status. We also do not perform electromechanical morcellation in women with a personal history of uterine, cervical, or ovarian preinvasive or invasive cancer, or in women with a strong family history of gynecologic malignancy.

Other populations we exclude are women with:

Counseling the patient
OBG Management: If tissue extraction is an issue, and morcellation will be necessary for a minimally invasive approach, how do you counsel the patient?

Dr. Fader: We have an informed consent protocol we use at Hopkins in this regard. We speak extensively to our patients about the fact that every procedure or intervention performed in medicine carries a benefit/risk ratio. We inform patients of the FDA morcellation safety statement—that their fibroid or fibroids may contain unexpected cancerous tissue and that laparoscopic electromechanical morcellation may spread the cancer and possibly worsen their prognosis. We also explain that, while the FDA quotes a risk of approximately 1 in 350 for occult sarcoma, that this data review was somewhat limited in scope and included postmenopausal women in the estimates. Based on the best available published systematic reviews and internal Hopkins data, we believe the risk of morcellating an occult uterine malignancy in a woman of reproductive age is more likely on the order of approximately 1 in 1,700 to 1 in 8,333.

We discuss our institution’s approach to tissue extraction (ie, that we no longer perform open electromechanical morcellation but instead perform contained tissue extraction on an institutional review board protocol). We tell patients that contained tissue-extraction practices are still experimental, although there is published literature preliminarily supporting the safety of the practice. In addition, we discuss the fact that contained tissue extraction has been used for years to safely remove large intra-abdominal specimens from laparoscopic incisions, from adnexal tissue to gallbladder, spleen, kidney, intestinal, and appendiceal specimens.

We also explain that, as physicians, we do our best to ensure that risks are minimized and reasonable in relation to anticipated benefits but that, even when we use the very best diagnostic measures, no test is 100% sensitive or specific to rule out malignancy in this setting (or in any setting, ­actually).

Finally, we discuss the fact that minimally invasive surgery and tissue extraction practices performed in appropriate patients by skilled surgeons conclusively benefit hundreds of thousands of women each year around the world. That is a narrative that has been somewhat lacking in the recent dialogue about tissue-extraction practices.
 

OBG Management: What do we know about outcomes when a leiomyosarcoma is inadvertently morcellated?

Dr. Fader: This is considered a “cut-through” procedure, in that a cancerous tumor that is potentially contained to an organ is not removed intact or with clean margins. The morcellation procedure effectively cuts through the occult cancer, which is not desirable. Intact surgical removal of uterine cancers or sarcomas is the mainstay of therapy for these malignancies, based on NCCN guidelines.²²

OBG Management: Does a morcellated leiomyosarcoma carry a worse prognosis than an unmorcellated leiomyosarcoma?

Dr. Fader: When it comes to morcellated versus “intact” uterine leiomyosarcoma, we enter a largely data-free zone. We don’t know with certainty whether the outcome is worsened. If we’re being intellectually honest, we must admit the possibility that a morcellated cancer is more likely to be disseminated, rendering it potentially more difficult to treat. However, sarcomas primarily spread by hematogenous dissemination. It is quite possible that even the act of incising an intact fibroid in an open abdominal procedure or performing a supracervical or total hysterectomy without morcellation may still result in hematogenous cancer dissemination. So there is no indication yet that electromechanical morcellation poses a unique and higher risk of cancer upstaging or worse prognosis compared with techniques such as open myomectomy, supracervical hysterectomy, or hysteroscopic myomectomy.

In addition, the prognosis associated with even early-stage uterine leiomyosarcoma is uniformly poor. A published study from Hopkins that included 108 patients with uterine leiomyosarcoma suggests that the recurrence rate and survival of patients with early-stage, “intact” leiomyosarcoma are very poor and comparable to the survival rate documented in the literature for women with morcellated sarcomas.²³

The few retrospective studies that exist suggesting worse outcomes with morcellation have limitations that preclude any definitive conclusions.² These studies are marred by small numbers, heterogeneity in morcellation practices, poor follow-up times, and a lack of detail regarding how patients with morcellated versus unmorcellated sarcomas were treated. Nevertheless, a couple of these small retrospective reports indicate the possibility of worse outcomes in women with morcellated uterine sarcomas, compared with historical controls with intact sarcoma removal.

Is the morcellator at fault—or the user?
OBG Management: Some would argue that even one case of a morcellated uterine sarcoma is too many. How would you respond?

Dr. Fader: There is no doubt that a handful of women each year have been harmed by morcellation practices. Those women deserve our dedication and best efforts to learn how to better treat morcellated sarcomas—and more importantly—how to mitigate the risks associated with morcellation practices and reduce the risk of preventable harm for all women undergoing minimally invasive fibroid procedures. I think the single best thing we can do to mitigate risk is to be more ­conscientious about selecting our patients for tissue-extraction procedures (ie, strict selection criteria, appropriate preoperative work-ups). If we did this, we likely would reduce the number of oncologic morcellator mishaps by 50% to 80% without changing anything else.

When we closely scrutinize the ­literature, and when I reflect on the women with morcellated cancers that we have cared for at Hopkins, we observe that some (but not all) “occult” uterine cancers were not that hidden after all and may have been detected preoperatively if an effort had been made.

We have noted a number of patients in this setting who experienced harm not because a specific device was used to cut up their uterus but because they were never appropriate candidates for the procedure in the first place. For instance, I recently cared for an elderly woman with a morcellated uterine cancer who underwent a laparoscopic supracervical hysterectomy without an appropriate preoperative work-up (ie, no endometrial biopsy or imaging) or informed consent about the possibility that she might have cancer. If an elderly woman presents with concerning symptoms related to her uterus (ie, enlargement, bleeding), she must be evaluated and counseled regarding the considerable risk of potential malignancy. Even in the setting of a normal work-up, I don’t believe it is a good idea to perform electromechanical morcellation in higher-risk women, including elderly women. That does not mean that select, well-screened women cannot be considered for alternative tissue-extraction techniques, but the risks and benefits must be carefully weighed in each patient, and informed consent must be obtained.

By continuing to refine the safety features of the electromechanical morcellator devices and choosing patients more carefully for minimally invasive procedures and tissue extraction, we likely will reduce the risk of preventable harm in women undergoing gynecologic surgery.

Can leiomyosarcoma be detected preoperatively?
OBG Management: How can we improve preoperative detection of uterine malignancy, particularly leiomyosarcoma?

Dr. Fader: For starters, we can improve detection of uterine cancers by simply looking for them. Almost all epithelial uterine cancers will be detectable by endometrial sampling. A comprehensive history and physical and uterine imaging also may be helpful. And although they are more difficult to detect than epithelial uterine cancers, it is a myth that sarcomas cannot be diagnosed preoperatively. Investigators from Columbia University retrospectively evaluated the ability to preoperatively detect epithelial uterine cancers and uterine sarcomas on final pathology. In 72 women who were ultimately diagnosed with a sarcoma, preoperative endometrial sampling suggested an invasive tumor in 86% and predicted the correct histology in 64%. In fact, the rate of detection of invasive cancer by preoperative sampling was not statistically different among sarcomas than it was among epithelial uterine cancers, although there was less of a correlation with appropriate histology seen with endometrial biopsy.²⁰

That being said, sarcomas can be missed, especially in younger women who have extremely large, degenerated, or necrotic-appearing fibroids. Improvements in diagnostic testing are desperately needed to help distinguish benign fibroids from sarcomas, as there are no reliable modalities to exclude a sarcoma at this time. MRI appears to be the most useful imaging modality, although it cannot definitively distinguish a fibroid from a sarcoma. However, a fairly constant finding in leiomyosarcomas is the absence of calcifications. Further, some studies also suggest that ill-defined margins are consistent with a sarcoma. Finally, several centers, including our own, are studying novel biologic markers and revisiting the utility of previously described markers such as LDH in the preoperative detection of uterine sarcoma.²¹

The way forward
OBG Management: You have said, “Keep patients informed and safe but avoid being too reactionary.” Could you expand on this statement?

Dr. Fader: Certainly. There are many examples throughout the history of medicine in which treatments have brought benefit to thousands or millions of individuals but may cause harm in a select few. We know that when controversial medical issues have arisen in the past, the pendulum has swung widely in terms of societal response.

For example, the landmark Women’s Health Initiative had an immediate and adverse impact on hormone replacement therapy (HRT) administration. The increased risk of cardiovascular disease and breast cancer ­observed with use of long-term combination therapy with conjugated equine estrogen and medroxyprogesterone acetate prompted many US health-care providers to abandon use of HRT—until more contemporary data demonstrated that, in younger, healthier postmenopausal women, these adverse events were very rare and the benefits of HRT outweighed the risks.

Can we avoid stroke, heart attack, and breast cancer in all younger women taking HRT? Of course not. But we counsel women about the benefit/risk ratio of the therapy and advise them that the likelihood of these events is rare.

Similarly, as with the HRT analogy, younger women have lower risks associated with surgery and morcellation, compared with older women, and are more likely to derive benefit from the procedure (after ­ensuring appropriate candidacy with a comprehensive preoperative evaluation and informed consent).

However, if the expectation is that no cases of harm will ever occur with a surgical device or procedure in order for it to be deemed acceptable and safe to use in practice, then that is simply an impossible standard to uphold. There is no device, medication, or intervention I know of in ­medicine that is completely risk-free.

OBG Management: Are there other examples of this type of benefit/risk assessment?

Dr. Fader: Yes. For instance, tamoxifen is a nonsteroidal anti-estrogen agent approved by the FDA for adjuvant treatment of breast cancer, treatment of metastatic breast cancer, and reduction of breast cancer incidence in high-risk women. Tamoxifen has effectively reduced breast cancer rates and significantly improved survival in select breast cancer patients. Yet, it is well known that long-term use of tamoxifen is associated with a twofold increased risk of uterine cancer and uterine sarcoma—a likely far more commonly occurring adverse event than an occult, morcellated uterine sarcoma during a minimally invasive gynecologic procedure.

Should the FDA ban or significantly curtail the use of tamoxifen? No, not likely, because the benefits far outweigh the risks in previvors and hormone-positive breast cancer survivors. “Keep patients informed and safe but avoid being too reactionary” means that we must do our due diligence as physicians by comprehensively counseling and obtaining informed consent from our patients before performing medical ­interventions. We also must closely scrutinize and improve upon practices that may cause harm.

However, what this also means is that while it may be prudent to restrict or limit a surgical practice in select higher-risk populations or modify it in some way to make it safer, we shouldn’t necessarily completely abandon or ban a practice that has benefited hundreds of thousands of patients at low risk of harm until we have objectively reviewed all of the available science and fully ­understand the implications of a practice change (ie, would the risks of preventable harm be even greater for women if more of them had to undergo open abdominal surgery?). We need continued cool heads and sound scientific reasoning to decide upon health-care policy changes or treatment paradigm shifts.

At the end of the day, however, it is paramount that we mitigate patient harm. The subject of tissue extraction during minimally invasive surgery is a complex and nuanced issue that merits continued study and open-minded and intelligent dialogue between patient stakeholders, clinicians, scientists, industry, ethicists, regulatory agencies, and the press. I think we can all appreciate how humbling and challenging the morcellation issue has been for many of us, especially our patients—particularly the unfortunate women who have been diagnosed with a uterine sarcoma.

Like many of my colleagues, I have been privileged to care for a number of women with uterine leiomyosarcoma. It is a devastating disease, and the prognosis is very poor, whether it is morcellated or removed intact. We are fortunate that the vast majority of women who undergo a minimally invasive procedure for fibroids or other presumed benign indications will not be at risk for an occult malignancy. But what can we do now to continue to offer the benefits of minimally invasive surgery and tissue extraction to women while simultaneously reducing the risk to the select few who will develop a rare uterine cancer?

We can all make a greater effort to more carefully select our patients for minimally invasive surgery and tissue extraction, to limit the performance of open electromechanical morcellation and collaborate in studying the role of refined tissue-extraction techniques and containment systems, to enhance the informed consent process, to develop improved diagnostic tests for preoperative cancer detection, and to conduct higher-quality studies on minimally invasive tissue-extraction techniques for regulatory agencies to review in the near future. It also goes without saying that we need more federal funding to study rare tumors (and gynecologic cancers in general) and develop better sarcoma treatments.

Although there is no medical treatment or surgical procedure that is completely risk-free, interventions such as HRT, tamoxifen, and uterine morcellation—when used in appropriate patients and for appropriate indications—will allow preventable harm to be minimized and make it possible for countless women to continue to derive tremendous benefit.
 

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