Conference Coverage

A new type of laser therapy is safe and effective for children with drug-resistant epilepsy, new research suggests. In a study of nearly 150 children, more than half of those who received MRI-guided laser interstitial thermal therapy (MRgLITT) were seizure free at 1 year.

Results show that this “is a new and promising therapy” for children for whom drug therapy has failed, said study investigator Elysa Widjaja, MD, a pediatric neuroradiologist at the Hospital for Sick Children and professor in the department of medical imaging, University of Toronto.

In addition, the procedure is less invasive and requires a shorter hospital stay than does open epilepsy surgery, Dr. Widjaja said.

The findings were presented at the annual meeting of the American Epilepsy Society, which was held online this year because of the COVID-19 pandemic.
 

Registry study

To date, most published studies on the laser procedure have had a small number of participants from only a few centers, Dr. Widjaja noted. “The aim of our registry is to collect data from multiple centers in both Canada and the U.S. to try to get a better understanding of the outcomes following laser therapy and the complications associated with this treatment,” she said.

In the procedure, a surgeon drills a tiny hole through the skull and, guided by MRI, inserts a very thin laser fiber into the center of the lesion. Heat then ablates the affected brain region.

From the dedicated registry, researchers recruited 182 children who were treated with MRgLITT at seven pediatric centers in the United States and two centers in Canada. The youngest patient was aged 14 months, and the oldest was aged 21 years (mean age, 11.2 years). Some pediatric hospitals treat patients up to age 21, Dr. Widjaja noted.

All of the study participants had focal epilepsy, “so the seizures are coming from a defined area of the brain,” she added. In addition, study participants’ conditions were drug-resistant, defined as conditions in which two antiseizure medications had previously failed.

The mean age at seizure onset was 5.4 years, and the mean number of antiepileptic drugs that were taken was 2.3.

Before receiving the therapy, children typically undergo extensive analyses, including MRI and video electroencephalography, to pinpoint where in the brain the seizures originate. Dr. Widjaja noted that the specific area of the brain that is affected varies widely from child to child.

The investigators collected baseline clinical characteristic and procedural data, including ablation site, type of lesion, length of stay, complications, number of MRgLITT procedures, and seizure outcome. To gather this information, they used a secure electronic platform designed to collect and store research data.
 

Seizure freedom

Among 137 patients for whom 1-year seizure outcomes were available, seizure freedom was reported for 74 patients (54%). In a recent meta-analysis conducted by the investigators, the rate of seizure-free outcomes following epilepsy surgery was about 65%. Although this rate is higher than with the laser therapy, Dr. Widjaja pointed out that the laser intervention is less invasive and the hospital stay of a mean of 3.3 days is shorter than the week or so needed after surgery. This, she said, makes the procedure cost-effective.

Unlike surgery, laser therapy is also “particularly good” at reaching lesions deep in the brain without damaging surrounding tissue, Dr. Widjaja said.

Although the researchers have not evaluated seizure outcomes with respect to age, Dr. Widjaja believes age is not a major factor in outcomes. “I suspect it’s the type of lesion and how big the lesion is that mainly influences the outcome, rather than actual age,” she said.

Complications related to the laser therapy, including infections and bleeding, occurred in 15% of patients. Neurologic deficits affected about 8% of patients; however, these tended to be transient, Dr. Widjaja noted. There were two cases (1%) of permanent neurologic deficits, both of which involved weakness of arms or legs. This, said Dr. Widjaja, is less than the 5% rate of permanent neurologic deficits that occur following surgery, as reported in the literature.

There were no cases of major intracranial hemorrhage among the participants. At 30 days, there was one reported death.

Laser therapy is limited to relatively small lesions of no more than about 2 cm on average, Dr. Widjaja said. “We normally can’t treat huge lesions using laser therapy; they would need surgery.” However, it is possible to treat the same area twice. In the current study, 20 patients (11%) underwent laser therapy on one region on two occasions. Of these participants, 12 (60%) achieved freedom from seizures.

Dr. Widjaja noted that two additional epilepsy centers will soon be providing laser therapy and will expand the registry. In addition, the investigators are building a surgery registry that will enable them to compare outcomes of laser treatment with surgery.

Currently, laser therapy is available only at specialized epilepsy centers that perform surgery.
 

‘Very important’ research

Commenting on the study, Daniel Goldenholz, MD, PhD, division of epilepsy, department of neurology, Beth Israel Deaconess Medical Center, Boston, called this is “a very important study.”

Laser therapy “offers the opportunity for very rapid recovery from a minimally invasive, targeted technique while simultaneously offering promising outcomes,” said Dr. Goldenholz, who was not involved with the research.

He noted the importance of the investigators’ choosing freedom from seizures as the outcome of interest. In addition, the 54% seizure-freedom rate in the study is “substantially better” than rates from other interventions, he said.

“To put the results into perspective, other work has found that these same patients would have a less than 10% chance of seizure freedom if many different drug combinations were tried,” said Dr. Goldenholz.

He noted that the 1-year outcomes “are a good first time point” but that it is very important to assess longer-term outcomes. “Often, postsurgical outcomes are worse when looking at 2 or 5 years postoperatively,” he added. These longer-term data will be important “to fully inform our patients about long-term prognosis,” Dr. Goldenholz said.

Still, given the overall favorable results so far, “I think more centers will be likely to explore this newer technology,” he said.

The study was funded by the Pediatric Epilepsy Research Foundation. The study authors and Dr. Goldenholz report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A new type of laser therapy is safe and effective for children with drug-resistant epilepsy, new research suggests. In a study of nearly 150 children, more than half of those who received MRI-guided laser interstitial thermal therapy (MRgLITT) were seizure free at 1 year.

Results show that this “is a new and promising therapy” for children for whom drug therapy has failed, said study investigator Elysa Widjaja, MD, a pediatric neuroradiologist at the Hospital for Sick Children and professor in the department of medical imaging, University of Toronto.

In addition, the procedure is less invasive and requires a shorter hospital stay than does open epilepsy surgery, Dr. Widjaja said.

The findings were presented at the annual meeting of the American Epilepsy Society, which was held online this year because of the COVID-19 pandemic.
 

Registry study

To date, most published studies on the laser procedure have had a small number of participants from only a few centers, Dr. Widjaja noted. “The aim of our registry is to collect data from multiple centers in both Canada and the U.S. to try to get a better understanding of the outcomes following laser therapy and the complications associated with this treatment,” she said.

In the procedure, a surgeon drills a tiny hole through the skull and, guided by MRI, inserts a very thin laser fiber into the center of the lesion. Heat then ablates the affected brain region.

From the dedicated registry, researchers recruited 182 children who were treated with MRgLITT at seven pediatric centers in the United States and two centers in Canada. The youngest patient was aged 14 months, and the oldest was aged 21 years (mean age, 11.2 years). Some pediatric hospitals treat patients up to age 21, Dr. Widjaja noted.

All of the study participants had focal epilepsy, “so the seizures are coming from a defined area of the brain,” she added. In addition, study participants’ conditions were drug-resistant, defined as conditions in which two antiseizure medications had previously failed.

The mean age at seizure onset was 5.4 years, and the mean number of antiepileptic drugs that were taken was 2.3.

Before receiving the therapy, children typically undergo extensive analyses, including MRI and video electroencephalography, to pinpoint where in the brain the seizures originate. Dr. Widjaja noted that the specific area of the brain that is affected varies widely from child to child.

The investigators collected baseline clinical characteristic and procedural data, including ablation site, type of lesion, length of stay, complications, number of MRgLITT procedures, and seizure outcome. To gather this information, they used a secure electronic platform designed to collect and store research data.
 

Seizure freedom

Among 137 patients for whom 1-year seizure outcomes were available, seizure freedom was reported for 74 patients (54%). In a recent meta-analysis conducted by the investigators, the rate of seizure-free outcomes following epilepsy surgery was about 65%. Although this rate is higher than with the laser therapy, Dr. Widjaja pointed out that the laser intervention is less invasive and the hospital stay of a mean of 3.3 days is shorter than the week or so needed after surgery. This, she said, makes the procedure cost-effective.

Unlike surgery, laser therapy is also “particularly good” at reaching lesions deep in the brain without damaging surrounding tissue, Dr. Widjaja said.

Although the researchers have not evaluated seizure outcomes with respect to age, Dr. Widjaja believes age is not a major factor in outcomes. “I suspect it’s the type of lesion and how big the lesion is that mainly influences the outcome, rather than actual age,” she said.

Complications related to the laser therapy, including infections and bleeding, occurred in 15% of patients. Neurologic deficits affected about 8% of patients; however, these tended to be transient, Dr. Widjaja noted. There were two cases (1%) of permanent neurologic deficits, both of which involved weakness of arms or legs. This, said Dr. Widjaja, is less than the 5% rate of permanent neurologic deficits that occur following surgery, as reported in the literature.

There were no cases of major intracranial hemorrhage among the participants. At 30 days, there was one reported death.

Laser therapy is limited to relatively small lesions of no more than about 2 cm on average, Dr. Widjaja said. “We normally can’t treat huge lesions using laser therapy; they would need surgery.” However, it is possible to treat the same area twice. In the current study, 20 patients (11%) underwent laser therapy on one region on two occasions. Of these participants, 12 (60%) achieved freedom from seizures.

Dr. Widjaja noted that two additional epilepsy centers will soon be providing laser therapy and will expand the registry. In addition, the investigators are building a surgery registry that will enable them to compare outcomes of laser treatment with surgery.

Currently, laser therapy is available only at specialized epilepsy centers that perform surgery.
 

‘Very important’ research

Commenting on the study, Daniel Goldenholz, MD, PhD, division of epilepsy, department of neurology, Beth Israel Deaconess Medical Center, Boston, called this is “a very important study.”

Laser therapy “offers the opportunity for very rapid recovery from a minimally invasive, targeted technique while simultaneously offering promising outcomes,” said Dr. Goldenholz, who was not involved with the research.

He noted the importance of the investigators’ choosing freedom from seizures as the outcome of interest. In addition, the 54% seizure-freedom rate in the study is “substantially better” than rates from other interventions, he said.

“To put the results into perspective, other work has found that these same patients would have a less than 10% chance of seizure freedom if many different drug combinations were tried,” said Dr. Goldenholz.

He noted that the 1-year outcomes “are a good first time point” but that it is very important to assess longer-term outcomes. “Often, postsurgical outcomes are worse when looking at 2 or 5 years postoperatively,” he added. These longer-term data will be important “to fully inform our patients about long-term prognosis,” Dr. Goldenholz said.

Still, given the overall favorable results so far, “I think more centers will be likely to explore this newer technology,” he said.

The study was funded by the Pediatric Epilepsy Research Foundation. The study authors and Dr. Goldenholz report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A new type of laser therapy is safe and effective for children with drug-resistant epilepsy, new research suggests. In a study of nearly 150 children, more than half of those who received MRI-guided laser interstitial thermal therapy (MRgLITT) were seizure free at 1 year.

Results show that this “is a new and promising therapy” for children for whom drug therapy has failed, said study investigator Elysa Widjaja, MD, a pediatric neuroradiologist at the Hospital for Sick Children and professor in the department of medical imaging, University of Toronto.

In addition, the procedure is less invasive and requires a shorter hospital stay than does open epilepsy surgery, Dr. Widjaja said.

The findings were presented at the annual meeting of the American Epilepsy Society, which was held online this year because of the COVID-19 pandemic.
 

Registry study

To date, most published studies on the laser procedure have had a small number of participants from only a few centers, Dr. Widjaja noted. “The aim of our registry is to collect data from multiple centers in both Canada and the U.S. to try to get a better understanding of the outcomes following laser therapy and the complications associated with this treatment,” she said.

In the procedure, a surgeon drills a tiny hole through the skull and, guided by MRI, inserts a very thin laser fiber into the center of the lesion. Heat then ablates the affected brain region.

From the dedicated registry, researchers recruited 182 children who were treated with MRgLITT at seven pediatric centers in the United States and two centers in Canada. The youngest patient was aged 14 months, and the oldest was aged 21 years (mean age, 11.2 years). Some pediatric hospitals treat patients up to age 21, Dr. Widjaja noted.

All of the study participants had focal epilepsy, “so the seizures are coming from a defined area of the brain,” she added. In addition, study participants’ conditions were drug-resistant, defined as conditions in which two antiseizure medications had previously failed.

The mean age at seizure onset was 5.4 years, and the mean number of antiepileptic drugs that were taken was 2.3.

Before receiving the therapy, children typically undergo extensive analyses, including MRI and video electroencephalography, to pinpoint where in the brain the seizures originate. Dr. Widjaja noted that the specific area of the brain that is affected varies widely from child to child.

The investigators collected baseline clinical characteristic and procedural data, including ablation site, type of lesion, length of stay, complications, number of MRgLITT procedures, and seizure outcome. To gather this information, they used a secure electronic platform designed to collect and store research data.
 

Seizure freedom

Among 137 patients for whom 1-year seizure outcomes were available, seizure freedom was reported for 74 patients (54%). In a recent meta-analysis conducted by the investigators, the rate of seizure-free outcomes following epilepsy surgery was about 65%. Although this rate is higher than with the laser therapy, Dr. Widjaja pointed out that the laser intervention is less invasive and the hospital stay of a mean of 3.3 days is shorter than the week or so needed after surgery. This, she said, makes the procedure cost-effective.

Unlike surgery, laser therapy is also “particularly good” at reaching lesions deep in the brain without damaging surrounding tissue, Dr. Widjaja said.

Although the researchers have not evaluated seizure outcomes with respect to age, Dr. Widjaja believes age is not a major factor in outcomes. “I suspect it’s the type of lesion and how big the lesion is that mainly influences the outcome, rather than actual age,” she said.

Complications related to the laser therapy, including infections and bleeding, occurred in 15% of patients. Neurologic deficits affected about 8% of patients; however, these tended to be transient, Dr. Widjaja noted. There were two cases (1%) of permanent neurologic deficits, both of which involved weakness of arms or legs. This, said Dr. Widjaja, is less than the 5% rate of permanent neurologic deficits that occur following surgery, as reported in the literature.

There were no cases of major intracranial hemorrhage among the participants. At 30 days, there was one reported death.

Laser therapy is limited to relatively small lesions of no more than about 2 cm on average, Dr. Widjaja said. “We normally can’t treat huge lesions using laser therapy; they would need surgery.” However, it is possible to treat the same area twice. In the current study, 20 patients (11%) underwent laser therapy on one region on two occasions. Of these participants, 12 (60%) achieved freedom from seizures.

Dr. Widjaja noted that two additional epilepsy centers will soon be providing laser therapy and will expand the registry. In addition, the investigators are building a surgery registry that will enable them to compare outcomes of laser treatment with surgery.

Currently, laser therapy is available only at specialized epilepsy centers that perform surgery.
 

‘Very important’ research

Commenting on the study, Daniel Goldenholz, MD, PhD, division of epilepsy, department of neurology, Beth Israel Deaconess Medical Center, Boston, called this is “a very important study.”

Laser therapy “offers the opportunity for very rapid recovery from a minimally invasive, targeted technique while simultaneously offering promising outcomes,” said Dr. Goldenholz, who was not involved with the research.

He noted the importance of the investigators’ choosing freedom from seizures as the outcome of interest. In addition, the 54% seizure-freedom rate in the study is “substantially better” than rates from other interventions, he said.

“To put the results into perspective, other work has found that these same patients would have a less than 10% chance of seizure freedom if many different drug combinations were tried,” said Dr. Goldenholz.

He noted that the 1-year outcomes “are a good first time point” but that it is very important to assess longer-term outcomes. “Often, postsurgical outcomes are worse when looking at 2 or 5 years postoperatively,” he added. These longer-term data will be important “to fully inform our patients about long-term prognosis,” Dr. Goldenholz said.

Still, given the overall favorable results so far, “I think more centers will be likely to explore this newer technology,” he said.

The study was funded by the Pediatric Epilepsy Research Foundation. The study authors and Dr. Goldenholz report no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Sudden unexpected death in epilepsy (SUDEP) may explain 3% of all sudden deaths in children – a prevalence rate that is at least three times greater than previously reported estimates – new research shows.

Just a few years ago, the message regarding SUDEP was that “it’s very rare in children so you don’t need to worry about it,” said study investigator Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke.

These new study results should refocus the message that “the condition is rare, but not as rare as we thought it was,” she said.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Population-based study

Most of the research examining the pediatric SUDEP rate in the United States is based on convenience samples, with few population-based studies.

The investigators used data from the National Institutes of Health/Centers for Disease Control and Prevention Sudden Death in the Young Case Registry. The CDC set up the registry several years ago to record cases of sudden infant death syndrome and sudden deaths in children resulting from violence, trauma, and abuse. Its mandate has since expanded, and the registry now includes data on sudden cardiac death and SUDEP in children.

The current study included children with SUDEP or cardiac/SUDEP who were aged 0-17 years from several states or jurisdictions from 2015 to 2017. Cases were deemed to be SUDEP if the patient had a history of epilepsy, with or without evidence of seizure at the time of death, but excluding status epilepticus.

Criteria for cardiac/SUDEP cases included having a family history of a heritable cardiac condition or sudden death before age 50 years, a personal history of cardiac disease, or a clinical history suggestive of a cardiac disorder, such as death during exertion.

This second category, said Dr. Whittemore, might capture children with Dravet syndrome, a type of epilepsy caused by a genetic mutation that affects both the heart and the brain. “In these cases, it’s sometimes difficult to tell if the child died due to a heart complication or due to epilepsy,” she said.

The analysis included 1,776 cases. Of these, 3% were categorized as SUDEP, and 1% were categorized as cardiac/SUDEP.

The relatively high prevalence of SUDEP was somewhat unexpected, inasmuch as previous reports estimated the rate to be 0.5%-1%, said Dr. Whittemore.

She noted that the current study is population based and included all cases of child death, whereas past reports relied on death certificates. “That probably missed a lot of deaths because they weren’t recorded accurately on the death certificate or weren’t reported in a way that anyone could ascertain that it was a death in someone that had epilepsy.”
 

Racial differences

Autopsy rates were lower for SUDEP (70%), compared with other categories of death in the registry (81%-100%).

In most jurisdictions, parents must give consent for an autopsy to be performed for a child, and many parents who have suffered such a sudden loss don’t want further investigation, said Dr. Whittemore. “If you know your child had epilepsy, doing an autopsy really isn’t going to tell you very much. You already know they had epilepsy; you may not know the cause of the epilepsy, but an autopsy isn’t going to reveal as much as it would in children with sudden cardiac death.”

SUDEP was equally common in boys and girls. However, the SUDEP mortality rate was higher in Black children (0.32/100,000) than in White children (0.22/100,000). It’s unclear from this study why this is so, but another study that examined SUDEP rates by ZIP code suggested that the higher rate may be caused by socioeconomic factors, said Dr. Whittemore. “Black children from a lower-income family who don’t have access to care may not be getting as good treatment and so have more uncontrolled seizures, which may lead to higher incidence of SUDEP.”

SUDEP occurred at all ages, but mortality rates were highest among patients aged 0-1 year (0.53/100,000) and in those aged 14-17 years (0.31/100,000). Dr. Whittemore speculated that SUDEP rates were higher among the youngest patients because their seizures have just started, and it may be more difficult to bring them under control. In the past, some of these cases may have been classified as sudden infant death syndrome but are now recognized as SUDEP.

As for the older group, research shows that puberty can result in poorer seizure control, which may put teens at elevated risk for SUDEP, said Dr. Whittemore. She added that, as teens continue to age, SUDEP risk may continue to increase. Dr. Whittemore suggested that young adults who head off to college may stop taking their antiseizure medications or consume alcohol while taking these drugs.
 

Failure of arousal

The study results revealed that most SUDEP cases occurred during sleep without a witness. Dr. Whittemore believes that sleeping with one’s face in a pillow may prevent the reflex required to turn the head to breathe. “It’s sort of a failure of arousal that is potentially the underlying mechanism.”

In some cases, there are signs children had a seizure just prior to death, said Dr. Whittemore.

The researchers have now collected information for 2018 and 2019 and plan to add these data to the current 3-year results. “We will now expand our analysis to include these new numbers to make sure the trends we saw in those 3 years are continuing,” said Dr. Whittemore. The new results should help raise awareness that SUDEP is not as rare as previously believed.

Parents of children with epilepsy can take steps to help reduce the risk for SUDEP, she added. For example, they can use night monitors, and for the children at highest risk (e.g., those with Dravet syndrome), they can use an “alarm blanket” that alerts them when the child moves.
 

Much is still unknown

Commenting on the study, Daniel Goldenholz, MD, PhD, division of epilepsy, department of neurology, Beth Israel Deaconess Medical Center, New York, who has participated in SUDEP research, said it “raises important questions about SUDEP in children and about racial disparities in SUDEP.”

The understanding of SUDEP so far “leaves much to be desired,” said Dr. Goldenholz. “We don’t yet know why it happens, and we don’t yet know how to prevent it.” The current study “brings a couple of new data points to the table which need further validation, confirmation, and explanation.”

The Sudden Death in Young Case Registry is supported by the National Heart, Lung, and Blood Institute; the National Institute of Neurological Disorders and Stroke; and the CDC. The investigators and Dr. Goldenholz disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Sudden unexpected death in epilepsy (SUDEP) may explain 3% of all sudden deaths in children – a prevalence rate that is at least three times greater than previously reported estimates – new research shows.

Just a few years ago, the message regarding SUDEP was that “it’s very rare in children so you don’t need to worry about it,” said study investigator Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke.

These new study results should refocus the message that “the condition is rare, but not as rare as we thought it was,” she said.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Population-based study

Most of the research examining the pediatric SUDEP rate in the United States is based on convenience samples, with few population-based studies.

The investigators used data from the National Institutes of Health/Centers for Disease Control and Prevention Sudden Death in the Young Case Registry. The CDC set up the registry several years ago to record cases of sudden infant death syndrome and sudden deaths in children resulting from violence, trauma, and abuse. Its mandate has since expanded, and the registry now includes data on sudden cardiac death and SUDEP in children.

The current study included children with SUDEP or cardiac/SUDEP who were aged 0-17 years from several states or jurisdictions from 2015 to 2017. Cases were deemed to be SUDEP if the patient had a history of epilepsy, with or without evidence of seizure at the time of death, but excluding status epilepticus.

Criteria for cardiac/SUDEP cases included having a family history of a heritable cardiac condition or sudden death before age 50 years, a personal history of cardiac disease, or a clinical history suggestive of a cardiac disorder, such as death during exertion.

This second category, said Dr. Whittemore, might capture children with Dravet syndrome, a type of epilepsy caused by a genetic mutation that affects both the heart and the brain. “In these cases, it’s sometimes difficult to tell if the child died due to a heart complication or due to epilepsy,” she said.

The analysis included 1,776 cases. Of these, 3% were categorized as SUDEP, and 1% were categorized as cardiac/SUDEP.

The relatively high prevalence of SUDEP was somewhat unexpected, inasmuch as previous reports estimated the rate to be 0.5%-1%, said Dr. Whittemore.

She noted that the current study is population based and included all cases of child death, whereas past reports relied on death certificates. “That probably missed a lot of deaths because they weren’t recorded accurately on the death certificate or weren’t reported in a way that anyone could ascertain that it was a death in someone that had epilepsy.”
 

Racial differences

Autopsy rates were lower for SUDEP (70%), compared with other categories of death in the registry (81%-100%).

In most jurisdictions, parents must give consent for an autopsy to be performed for a child, and many parents who have suffered such a sudden loss don’t want further investigation, said Dr. Whittemore. “If you know your child had epilepsy, doing an autopsy really isn’t going to tell you very much. You already know they had epilepsy; you may not know the cause of the epilepsy, but an autopsy isn’t going to reveal as much as it would in children with sudden cardiac death.”

SUDEP was equally common in boys and girls. However, the SUDEP mortality rate was higher in Black children (0.32/100,000) than in White children (0.22/100,000). It’s unclear from this study why this is so, but another study that examined SUDEP rates by ZIP code suggested that the higher rate may be caused by socioeconomic factors, said Dr. Whittemore. “Black children from a lower-income family who don’t have access to care may not be getting as good treatment and so have more uncontrolled seizures, which may lead to higher incidence of SUDEP.”

SUDEP occurred at all ages, but mortality rates were highest among patients aged 0-1 year (0.53/100,000) and in those aged 14-17 years (0.31/100,000). Dr. Whittemore speculated that SUDEP rates were higher among the youngest patients because their seizures have just started, and it may be more difficult to bring them under control. In the past, some of these cases may have been classified as sudden infant death syndrome but are now recognized as SUDEP.

As for the older group, research shows that puberty can result in poorer seizure control, which may put teens at elevated risk for SUDEP, said Dr. Whittemore. She added that, as teens continue to age, SUDEP risk may continue to increase. Dr. Whittemore suggested that young adults who head off to college may stop taking their antiseizure medications or consume alcohol while taking these drugs.
 

Failure of arousal

The study results revealed that most SUDEP cases occurred during sleep without a witness. Dr. Whittemore believes that sleeping with one’s face in a pillow may prevent the reflex required to turn the head to breathe. “It’s sort of a failure of arousal that is potentially the underlying mechanism.”

In some cases, there are signs children had a seizure just prior to death, said Dr. Whittemore.

The researchers have now collected information for 2018 and 2019 and plan to add these data to the current 3-year results. “We will now expand our analysis to include these new numbers to make sure the trends we saw in those 3 years are continuing,” said Dr. Whittemore. The new results should help raise awareness that SUDEP is not as rare as previously believed.

Parents of children with epilepsy can take steps to help reduce the risk for SUDEP, she added. For example, they can use night monitors, and for the children at highest risk (e.g., those with Dravet syndrome), they can use an “alarm blanket” that alerts them when the child moves.
 

Much is still unknown

Commenting on the study, Daniel Goldenholz, MD, PhD, division of epilepsy, department of neurology, Beth Israel Deaconess Medical Center, New York, who has participated in SUDEP research, said it “raises important questions about SUDEP in children and about racial disparities in SUDEP.”

The understanding of SUDEP so far “leaves much to be desired,” said Dr. Goldenholz. “We don’t yet know why it happens, and we don’t yet know how to prevent it.” The current study “brings a couple of new data points to the table which need further validation, confirmation, and explanation.”

The Sudden Death in Young Case Registry is supported by the National Heart, Lung, and Blood Institute; the National Institute of Neurological Disorders and Stroke; and the CDC. The investigators and Dr. Goldenholz disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Sudden unexpected death in epilepsy (SUDEP) may explain 3% of all sudden deaths in children – a prevalence rate that is at least three times greater than previously reported estimates – new research shows.

Just a few years ago, the message regarding SUDEP was that “it’s very rare in children so you don’t need to worry about it,” said study investigator Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke.

These new study results should refocus the message that “the condition is rare, but not as rare as we thought it was,” she said.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Population-based study

Most of the research examining the pediatric SUDEP rate in the United States is based on convenience samples, with few population-based studies.

The investigators used data from the National Institutes of Health/Centers for Disease Control and Prevention Sudden Death in the Young Case Registry. The CDC set up the registry several years ago to record cases of sudden infant death syndrome and sudden deaths in children resulting from violence, trauma, and abuse. Its mandate has since expanded, and the registry now includes data on sudden cardiac death and SUDEP in children.

The current study included children with SUDEP or cardiac/SUDEP who were aged 0-17 years from several states or jurisdictions from 2015 to 2017. Cases were deemed to be SUDEP if the patient had a history of epilepsy, with or without evidence of seizure at the time of death, but excluding status epilepticus.

Criteria for cardiac/SUDEP cases included having a family history of a heritable cardiac condition or sudden death before age 50 years, a personal history of cardiac disease, or a clinical history suggestive of a cardiac disorder, such as death during exertion.

This second category, said Dr. Whittemore, might capture children with Dravet syndrome, a type of epilepsy caused by a genetic mutation that affects both the heart and the brain. “In these cases, it’s sometimes difficult to tell if the child died due to a heart complication or due to epilepsy,” she said.

The analysis included 1,776 cases. Of these, 3% were categorized as SUDEP, and 1% were categorized as cardiac/SUDEP.

The relatively high prevalence of SUDEP was somewhat unexpected, inasmuch as previous reports estimated the rate to be 0.5%-1%, said Dr. Whittemore.

She noted that the current study is population based and included all cases of child death, whereas past reports relied on death certificates. “That probably missed a lot of deaths because they weren’t recorded accurately on the death certificate or weren’t reported in a way that anyone could ascertain that it was a death in someone that had epilepsy.”
 

Racial differences

Autopsy rates were lower for SUDEP (70%), compared with other categories of death in the registry (81%-100%).

In most jurisdictions, parents must give consent for an autopsy to be performed for a child, and many parents who have suffered such a sudden loss don’t want further investigation, said Dr. Whittemore. “If you know your child had epilepsy, doing an autopsy really isn’t going to tell you very much. You already know they had epilepsy; you may not know the cause of the epilepsy, but an autopsy isn’t going to reveal as much as it would in children with sudden cardiac death.”

SUDEP was equally common in boys and girls. However, the SUDEP mortality rate was higher in Black children (0.32/100,000) than in White children (0.22/100,000). It’s unclear from this study why this is so, but another study that examined SUDEP rates by ZIP code suggested that the higher rate may be caused by socioeconomic factors, said Dr. Whittemore. “Black children from a lower-income family who don’t have access to care may not be getting as good treatment and so have more uncontrolled seizures, which may lead to higher incidence of SUDEP.”

SUDEP occurred at all ages, but mortality rates were highest among patients aged 0-1 year (0.53/100,000) and in those aged 14-17 years (0.31/100,000). Dr. Whittemore speculated that SUDEP rates were higher among the youngest patients because their seizures have just started, and it may be more difficult to bring them under control. In the past, some of these cases may have been classified as sudden infant death syndrome but are now recognized as SUDEP.

As for the older group, research shows that puberty can result in poorer seizure control, which may put teens at elevated risk for SUDEP, said Dr. Whittemore. She added that, as teens continue to age, SUDEP risk may continue to increase. Dr. Whittemore suggested that young adults who head off to college may stop taking their antiseizure medications or consume alcohol while taking these drugs.
 

Failure of arousal

The study results revealed that most SUDEP cases occurred during sleep without a witness. Dr. Whittemore believes that sleeping with one’s face in a pillow may prevent the reflex required to turn the head to breathe. “It’s sort of a failure of arousal that is potentially the underlying mechanism.”

In some cases, there are signs children had a seizure just prior to death, said Dr. Whittemore.

The researchers have now collected information for 2018 and 2019 and plan to add these data to the current 3-year results. “We will now expand our analysis to include these new numbers to make sure the trends we saw in those 3 years are continuing,” said Dr. Whittemore. The new results should help raise awareness that SUDEP is not as rare as previously believed.

Parents of children with epilepsy can take steps to help reduce the risk for SUDEP, she added. For example, they can use night monitors, and for the children at highest risk (e.g., those with Dravet syndrome), they can use an “alarm blanket” that alerts them when the child moves.
 

Much is still unknown

Commenting on the study, Daniel Goldenholz, MD, PhD, division of epilepsy, department of neurology, Beth Israel Deaconess Medical Center, New York, who has participated in SUDEP research, said it “raises important questions about SUDEP in children and about racial disparities in SUDEP.”

The understanding of SUDEP so far “leaves much to be desired,” said Dr. Goldenholz. “We don’t yet know why it happens, and we don’t yet know how to prevent it.” The current study “brings a couple of new data points to the table which need further validation, confirmation, and explanation.”

The Sudden Death in Young Case Registry is supported by the National Heart, Lung, and Blood Institute; the National Institute of Neurological Disorders and Stroke; and the CDC. The investigators and Dr. Goldenholz disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Children with epilepsy with no previous psychiatric diagnosis have alarmingly high rates of suicidal thoughts and behaviors, new research suggests. In a study of more than 100 youth with the disorder, more than 40% had depression, 30% had anxiety, and about 1 in 10 exhibited signs of suicidal thoughts and behaviors.

These rates “are really worrisome” and highlight the need to screen all children and young adults with epilepsy for psychiatric disorders, said study author Tatiana Falcone, MD, assistant professor of neurology and child and adolescent psychiatry at the Cleveland Clinic.

“It’s very important to screen for suicidality and for depression and anxiety, even when patients aren’t reporting symptoms,” said Dr. Falcone.

Previous research shows children with epilepsy will attend the emergency room with symptoms such as headache or stomachache “when the main reason for the visit was the kid was suicidal,” Dr. Falcone said. “Unless you ask the specific question: ‘Are you having thoughts about hurting yourself?’ this will go unreported,” she added.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Red flag

Not much is known about suicidality in children and youth with epilepsy except that depression and anxiety – the most common psychiatric comorbidities in this population – appear to contribute to suicidal thoughts.

Dr. Falcone said that she and her colleagues often see children and adolescents with epilepsy in their clinic who have attempted suicide. In recent years, the clinicians have increased efforts to try to identify them before they carry out a successful suicide attempt, said lead investigator Anjali Dagar, MD, clinical research psychiatry fellow at Cleveland Clinic.

The study included 119 patients aged 10-24 years (mean age, 15.8 years; 54.6% female). All attended an epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and did not have a psychiatric diagnosis.

Epilepsy severity ranged among study participants. About half were drug resistant and were at the center for surgical evaluation and the others were newly diagnosed.

Participants filled out questionnaires to self-report psychiatric conditions. The validated screening tools included the Center for Epidemiological Studies Depression Scale for Children (CES-DC), the Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Ask Suicide–Screening Questions (ASQ).

A score of 15 or higher on the CES-DC indicates a risk for depression. On the SCARED test, a score higher than 32 indicates anxiety. Recent research has shown that anxiety is a main risk factor “in moving people from contemplating suicide to actually carrying it out,” Dr. Falcone said.

The ASQ includes four questions about suicidal thoughts and whether respondents have tried to hurt themselves. Dr. Dagar noted that a positive response to any of these questions should raise a red flag.
 

Very high rates

Results showed that almost one-third (30.2%) of the participants scored positive for anxiety on SCARED and 41.2% scored positive for depression on the CSE-DC. These are “very high” rates, Dr. Falcone said. For comparison, the rate of reported anxiety is less than 10% in school surveys.

In addition, the Centers for Disease Control and Prevention reports about 3% of 2- to 17-year-olds in the general population have depression. Even compared with other chronic illnesses (including diabetes, heart disease, and cancer), children with epilepsy have a higher rate of depression, said Dr. Falcone.

More than 1 in 10 (10.9%) participants in the study exhibited signs of suicidality, as shown by having at least one positive response on the ASQ. “That’s a lot,” and much higher than the estimated rate in the general teen population, Dr. Falcone noted.

She noted that “these are just general kids with epilepsy” who had not been previously diagnosed with a psychiatric disorder.

“Depression, anxiety, and suicidality are very frequent comorbidities in patients with epilepsy; and even if a patient is not reporting any symptoms, we should be asking these questions to help them,” she said.

Study participants who had at least one positive response on the ASQ had a mean score of 32.1 on the SCARED, compared with a mean score of 18.3 for those who did not have a positive response on the ASQ (P = .003).

“We wanted to see if there was a direct association in our sample between anxiety and suicidal thoughts, and we found [that] yes there was,” Dr. Falcone said. There was also an association with depression. More than 26% of participants who scored 16 or higher on the CES-DC indicated at least one positive response on the ASQ. This is significantly higher than those who scored 15 or below on the CES-DC (P < .0001).
 

Bidirectional relationship

The findings suggest that either depression or anxiety may contribute to suicidal thoughts or behaviors, Dr. Dagar said. “It’s like two hands. It could be anxiety leading to suicidality, or it could be depression, or it could be both.”

Dr. Falcone noted that children with epilepsy who aren’t sure when they’ll get their next seizure, or who are bullied at school for being different, may be especially prone to anxiety or depression.

There’s a bit of a “chicken-and-egg” relationship between depression and epilepsy, a disorder affecting electrical signals in the brain, she said. Previous research has shown that a “bidirectional relationship” is involved.

“Even in patients with depression who are not diagnosed with epilepsy, the incidence of epilepsy is 3% higher just because you have depression,” Dr. Falcone said.

Suicidal youth tend to attempt suicide more than once. Dr. Falcone and colleagues are trying to intervene “at different levels,” be that in the hospital or as an outpatient, to prevent this from happening. “We want to find out what different things we can do to engage them and improve the probability they don’t reattempt,” she said.

All children and youth with epilepsy should be screened for anxiety, depression, and suicidal thoughts and behaviors. From age 10 years, children with epilepsy should be screened at least once a year, but those with a psychiatric disorder should be screened more often, Dr. Falcone added. The investigators note their findings need to be confirmed in larger, more diverse studies.
 

Importance of screening

Michael Privitera, MD, director of the Epilepsy Center and professor of neurology at the University of Cincinnati Gardner Neuroscience Institute, said the findings reinforce that, as with adults, depression and anxiety are common in children with epilepsy.

“Neurologists should take advantage of the many psychiatric screening tools available to identify these problems in their pediatric and adult patients,” Dr. Privitera said. Even more importantly, screening may help identify those who may be at highest risk of suicide.

The study was funded by the Health Resources Services Administration. The investigators and Dr. Privitera have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Children with epilepsy with no previous psychiatric diagnosis have alarmingly high rates of suicidal thoughts and behaviors, new research suggests. In a study of more than 100 youth with the disorder, more than 40% had depression, 30% had anxiety, and about 1 in 10 exhibited signs of suicidal thoughts and behaviors.

These rates “are really worrisome” and highlight the need to screen all children and young adults with epilepsy for psychiatric disorders, said study author Tatiana Falcone, MD, assistant professor of neurology and child and adolescent psychiatry at the Cleveland Clinic.

“It’s very important to screen for suicidality and for depression and anxiety, even when patients aren’t reporting symptoms,” said Dr. Falcone.

Previous research shows children with epilepsy will attend the emergency room with symptoms such as headache or stomachache “when the main reason for the visit was the kid was suicidal,” Dr. Falcone said. “Unless you ask the specific question: ‘Are you having thoughts about hurting yourself?’ this will go unreported,” she added.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Red flag

Not much is known about suicidality in children and youth with epilepsy except that depression and anxiety – the most common psychiatric comorbidities in this population – appear to contribute to suicidal thoughts.

Dr. Falcone said that she and her colleagues often see children and adolescents with epilepsy in their clinic who have attempted suicide. In recent years, the clinicians have increased efforts to try to identify them before they carry out a successful suicide attempt, said lead investigator Anjali Dagar, MD, clinical research psychiatry fellow at Cleveland Clinic.

The study included 119 patients aged 10-24 years (mean age, 15.8 years; 54.6% female). All attended an epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and did not have a psychiatric diagnosis.

Epilepsy severity ranged among study participants. About half were drug resistant and were at the center for surgical evaluation and the others were newly diagnosed.

Participants filled out questionnaires to self-report psychiatric conditions. The validated screening tools included the Center for Epidemiological Studies Depression Scale for Children (CES-DC), the Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Ask Suicide–Screening Questions (ASQ).

A score of 15 or higher on the CES-DC indicates a risk for depression. On the SCARED test, a score higher than 32 indicates anxiety. Recent research has shown that anxiety is a main risk factor “in moving people from contemplating suicide to actually carrying it out,” Dr. Falcone said.

The ASQ includes four questions about suicidal thoughts and whether respondents have tried to hurt themselves. Dr. Dagar noted that a positive response to any of these questions should raise a red flag.
 

Very high rates

Results showed that almost one-third (30.2%) of the participants scored positive for anxiety on SCARED and 41.2% scored positive for depression on the CSE-DC. These are “very high” rates, Dr. Falcone said. For comparison, the rate of reported anxiety is less than 10% in school surveys.

In addition, the Centers for Disease Control and Prevention reports about 3% of 2- to 17-year-olds in the general population have depression. Even compared with other chronic illnesses (including diabetes, heart disease, and cancer), children with epilepsy have a higher rate of depression, said Dr. Falcone.

More than 1 in 10 (10.9%) participants in the study exhibited signs of suicidality, as shown by having at least one positive response on the ASQ. “That’s a lot,” and much higher than the estimated rate in the general teen population, Dr. Falcone noted.

She noted that “these are just general kids with epilepsy” who had not been previously diagnosed with a psychiatric disorder.

“Depression, anxiety, and suicidality are very frequent comorbidities in patients with epilepsy; and even if a patient is not reporting any symptoms, we should be asking these questions to help them,” she said.

Study participants who had at least one positive response on the ASQ had a mean score of 32.1 on the SCARED, compared with a mean score of 18.3 for those who did not have a positive response on the ASQ (P = .003).

“We wanted to see if there was a direct association in our sample between anxiety and suicidal thoughts, and we found [that] yes there was,” Dr. Falcone said. There was also an association with depression. More than 26% of participants who scored 16 or higher on the CES-DC indicated at least one positive response on the ASQ. This is significantly higher than those who scored 15 or below on the CES-DC (P < .0001).
 

Bidirectional relationship

The findings suggest that either depression or anxiety may contribute to suicidal thoughts or behaviors, Dr. Dagar said. “It’s like two hands. It could be anxiety leading to suicidality, or it could be depression, or it could be both.”

Dr. Falcone noted that children with epilepsy who aren’t sure when they’ll get their next seizure, or who are bullied at school for being different, may be especially prone to anxiety or depression.

There’s a bit of a “chicken-and-egg” relationship between depression and epilepsy, a disorder affecting electrical signals in the brain, she said. Previous research has shown that a “bidirectional relationship” is involved.

“Even in patients with depression who are not diagnosed with epilepsy, the incidence of epilepsy is 3% higher just because you have depression,” Dr. Falcone said.

Suicidal youth tend to attempt suicide more than once. Dr. Falcone and colleagues are trying to intervene “at different levels,” be that in the hospital or as an outpatient, to prevent this from happening. “We want to find out what different things we can do to engage them and improve the probability they don’t reattempt,” she said.

All children and youth with epilepsy should be screened for anxiety, depression, and suicidal thoughts and behaviors. From age 10 years, children with epilepsy should be screened at least once a year, but those with a psychiatric disorder should be screened more often, Dr. Falcone added. The investigators note their findings need to be confirmed in larger, more diverse studies.
 

Importance of screening

Michael Privitera, MD, director of the Epilepsy Center and professor of neurology at the University of Cincinnati Gardner Neuroscience Institute, said the findings reinforce that, as with adults, depression and anxiety are common in children with epilepsy.

“Neurologists should take advantage of the many psychiatric screening tools available to identify these problems in their pediatric and adult patients,” Dr. Privitera said. Even more importantly, screening may help identify those who may be at highest risk of suicide.

The study was funded by the Health Resources Services Administration. The investigators and Dr. Privitera have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Children with epilepsy with no previous psychiatric diagnosis have alarmingly high rates of suicidal thoughts and behaviors, new research suggests. In a study of more than 100 youth with the disorder, more than 40% had depression, 30% had anxiety, and about 1 in 10 exhibited signs of suicidal thoughts and behaviors.

These rates “are really worrisome” and highlight the need to screen all children and young adults with epilepsy for psychiatric disorders, said study author Tatiana Falcone, MD, assistant professor of neurology and child and adolescent psychiatry at the Cleveland Clinic.

“It’s very important to screen for suicidality and for depression and anxiety, even when patients aren’t reporting symptoms,” said Dr. Falcone.

Previous research shows children with epilepsy will attend the emergency room with symptoms such as headache or stomachache “when the main reason for the visit was the kid was suicidal,” Dr. Falcone said. “Unless you ask the specific question: ‘Are you having thoughts about hurting yourself?’ this will go unreported,” she added.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Red flag

Not much is known about suicidality in children and youth with epilepsy except that depression and anxiety – the most common psychiatric comorbidities in this population – appear to contribute to suicidal thoughts.

Dr. Falcone said that she and her colleagues often see children and adolescents with epilepsy in their clinic who have attempted suicide. In recent years, the clinicians have increased efforts to try to identify them before they carry out a successful suicide attempt, said lead investigator Anjali Dagar, MD, clinical research psychiatry fellow at Cleveland Clinic.

The study included 119 patients aged 10-24 years (mean age, 15.8 years; 54.6% female). All attended an epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and did not have a psychiatric diagnosis.

Epilepsy severity ranged among study participants. About half were drug resistant and were at the center for surgical evaluation and the others were newly diagnosed.

Participants filled out questionnaires to self-report psychiatric conditions. The validated screening tools included the Center for Epidemiological Studies Depression Scale for Children (CES-DC), the Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Ask Suicide–Screening Questions (ASQ).

A score of 15 or higher on the CES-DC indicates a risk for depression. On the SCARED test, a score higher than 32 indicates anxiety. Recent research has shown that anxiety is a main risk factor “in moving people from contemplating suicide to actually carrying it out,” Dr. Falcone said.

The ASQ includes four questions about suicidal thoughts and whether respondents have tried to hurt themselves. Dr. Dagar noted that a positive response to any of these questions should raise a red flag.
 

Very high rates

Results showed that almost one-third (30.2%) of the participants scored positive for anxiety on SCARED and 41.2% scored positive for depression on the CSE-DC. These are “very high” rates, Dr. Falcone said. For comparison, the rate of reported anxiety is less than 10% in school surveys.

In addition, the Centers for Disease Control and Prevention reports about 3% of 2- to 17-year-olds in the general population have depression. Even compared with other chronic illnesses (including diabetes, heart disease, and cancer), children with epilepsy have a higher rate of depression, said Dr. Falcone.

More than 1 in 10 (10.9%) participants in the study exhibited signs of suicidality, as shown by having at least one positive response on the ASQ. “That’s a lot,” and much higher than the estimated rate in the general teen population, Dr. Falcone noted.

She noted that “these are just general kids with epilepsy” who had not been previously diagnosed with a psychiatric disorder.

“Depression, anxiety, and suicidality are very frequent comorbidities in patients with epilepsy; and even if a patient is not reporting any symptoms, we should be asking these questions to help them,” she said.

Study participants who had at least one positive response on the ASQ had a mean score of 32.1 on the SCARED, compared with a mean score of 18.3 for those who did not have a positive response on the ASQ (P = .003).

“We wanted to see if there was a direct association in our sample between anxiety and suicidal thoughts, and we found [that] yes there was,” Dr. Falcone said. There was also an association with depression. More than 26% of participants who scored 16 or higher on the CES-DC indicated at least one positive response on the ASQ. This is significantly higher than those who scored 15 or below on the CES-DC (P < .0001).
 

Bidirectional relationship

The findings suggest that either depression or anxiety may contribute to suicidal thoughts or behaviors, Dr. Dagar said. “It’s like two hands. It could be anxiety leading to suicidality, or it could be depression, or it could be both.”

Dr. Falcone noted that children with epilepsy who aren’t sure when they’ll get their next seizure, or who are bullied at school for being different, may be especially prone to anxiety or depression.

There’s a bit of a “chicken-and-egg” relationship between depression and epilepsy, a disorder affecting electrical signals in the brain, she said. Previous research has shown that a “bidirectional relationship” is involved.

“Even in patients with depression who are not diagnosed with epilepsy, the incidence of epilepsy is 3% higher just because you have depression,” Dr. Falcone said.

Suicidal youth tend to attempt suicide more than once. Dr. Falcone and colleagues are trying to intervene “at different levels,” be that in the hospital or as an outpatient, to prevent this from happening. “We want to find out what different things we can do to engage them and improve the probability they don’t reattempt,” she said.

All children and youth with epilepsy should be screened for anxiety, depression, and suicidal thoughts and behaviors. From age 10 years, children with epilepsy should be screened at least once a year, but those with a psychiatric disorder should be screened more often, Dr. Falcone added. The investigators note their findings need to be confirmed in larger, more diverse studies.
 

Importance of screening

Michael Privitera, MD, director of the Epilepsy Center and professor of neurology at the University of Cincinnati Gardner Neuroscience Institute, said the findings reinforce that, as with adults, depression and anxiety are common in children with epilepsy.

“Neurologists should take advantage of the many psychiatric screening tools available to identify these problems in their pediatric and adult patients,” Dr. Privitera said. Even more importantly, screening may help identify those who may be at highest risk of suicide.

The study was funded by the Health Resources Services Administration. The investigators and Dr. Privitera have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Osteoarthritis patients report significant pain relief after treatment with cooled radiofrequency ablation, a new technique that “stuns” sensory nerves in shoulder and hip joints to reduce – and sometimes eliminate – pain.

“We send a small current to the sensory nerve to heat up the tissue and disrupt the fibers,” study lead author Felix Gonzalez, MD, of Emory University, Atlanta, said in an interview. “The effect is that the transmission of pain is significantly slowed or halted altogether.

“We damage something to fix something,” Dr. Gonzalez continued. “We target only the problematic nerve and get a very localized effect.”
 

Two-phase treatment

The treatment is performed in two phases. First, patients with shoulder pain are given an anesthetic to block their suprascapular, lateral pectoral, and axillary sensory articular nerves. Patients with hip pain have their obturator and femoral sensory articular nerves blocked.

A week or two later, the same nerves are treated with cooled radiofrequency ablation. Guided by x-ray imaging, a clinician heats up the affected nerve tissue using the tip of a needle, which is pointed at the nerve. “It’s a 22-gauge needle, slightly thicker than an acupuncture needle,” Dr. Gonzalez explained. “We heat up the nerve for about 2 minutes to about 60 degrees Celsius – it stuns the nerve,” he said.

“The result disrupts or slows down pain transmission while leaving the nerve intact.”

To test the efficacy of the technique, researchers treated 12 shoulders in patients with an average age of 61 years, and 11 hips in patients with an average age of 62 years.

Three months after treatment, patients with hip pain reported improvement in Hip Disability and Osteoarthritis Outcome Score (HOOS) from a baseline of 17.0 to 52.9 (P < .0001).

Shoulder pain was also reduced significantly. Using the American Shoulder and Elbow Surgeons (ASES) score, researchers reported an improvement from 17.2 (±6.6) at baseline to 65.7 (±5.9) at 3 months (P < .0001).

“We are targeting a subset of patients for this that don’t qualify for surgery,” Dr. Gonzalez noted. For patients with a body mass index above 35, or a history of hypertension, heart disease, or multiple strokes, opioids are the most common treatment, he said.

These patients “fall through the cracks,” he explained. Those who have mild to moderate pain are managed with physical therapy and injections, and those with severe pain go into surgery. “But what about the ones in the middle ... who are not eligible for surgery? They are at risk for opioid overuse,” he said. “So this treatment is a good option for them.”
 

Treats the symptoms, not the cause

“This study shows the efficacy of this method in taking care of shoulder and hip pain,” Luca Maria Sconfienza, MD, PhD, of Galeazzi Orthopedic Hospital in Milan, said in an interview. Dr. Sconfienza was not involved in Dr. Gonzalez’s study.

However, like corticosteroid injections, “the drawback of radiofrequency ablation is the fact that it only treats the symptoms and not the cause, and efficacy is usually limited over time,” she said.

Dr. Sconfienza said this study leaves her with three pertinent questions. “First, whether pain control extends beyond the 3-month follow-up reported by authors in the abstract; second, [what] is the efficacy of this method compared to other interventions (e.g., physical therapy, injections) or to doing nothing; and last, radiofrequency ablation is usually not a cheap treatment, thus a cost-efficacy analysis would be desirable, especially in comparison to other procedures.”

Dr. Gonzalez and Dr. Sconfienza have nothing relevant to disclose.

A version of this article originally appeared on Medscape.com.

Osteoarthritis patients report significant pain relief after treatment with cooled radiofrequency ablation, a new technique that “stuns” sensory nerves in shoulder and hip joints to reduce – and sometimes eliminate – pain.

“We send a small current to the sensory nerve to heat up the tissue and disrupt the fibers,” study lead author Felix Gonzalez, MD, of Emory University, Atlanta, said in an interview. “The effect is that the transmission of pain is significantly slowed or halted altogether.

“We damage something to fix something,” Dr. Gonzalez continued. “We target only the problematic nerve and get a very localized effect.”
 

Two-phase treatment

The treatment is performed in two phases. First, patients with shoulder pain are given an anesthetic to block their suprascapular, lateral pectoral, and axillary sensory articular nerves. Patients with hip pain have their obturator and femoral sensory articular nerves blocked.

A week or two later, the same nerves are treated with cooled radiofrequency ablation. Guided by x-ray imaging, a clinician heats up the affected nerve tissue using the tip of a needle, which is pointed at the nerve. “It’s a 22-gauge needle, slightly thicker than an acupuncture needle,” Dr. Gonzalez explained. “We heat up the nerve for about 2 minutes to about 60 degrees Celsius – it stuns the nerve,” he said.

“The result disrupts or slows down pain transmission while leaving the nerve intact.”

To test the efficacy of the technique, researchers treated 12 shoulders in patients with an average age of 61 years, and 11 hips in patients with an average age of 62 years.

Three months after treatment, patients with hip pain reported improvement in Hip Disability and Osteoarthritis Outcome Score (HOOS) from a baseline of 17.0 to 52.9 (P < .0001).

Shoulder pain was also reduced significantly. Using the American Shoulder and Elbow Surgeons (ASES) score, researchers reported an improvement from 17.2 (±6.6) at baseline to 65.7 (±5.9) at 3 months (P < .0001).

“We are targeting a subset of patients for this that don’t qualify for surgery,” Dr. Gonzalez noted. For patients with a body mass index above 35, or a history of hypertension, heart disease, or multiple strokes, opioids are the most common treatment, he said.

These patients “fall through the cracks,” he explained. Those who have mild to moderate pain are managed with physical therapy and injections, and those with severe pain go into surgery. “But what about the ones in the middle ... who are not eligible for surgery? They are at risk for opioid overuse,” he said. “So this treatment is a good option for them.”
 

Treats the symptoms, not the cause

“This study shows the efficacy of this method in taking care of shoulder and hip pain,” Luca Maria Sconfienza, MD, PhD, of Galeazzi Orthopedic Hospital in Milan, said in an interview. Dr. Sconfienza was not involved in Dr. Gonzalez’s study.

However, like corticosteroid injections, “the drawback of radiofrequency ablation is the fact that it only treats the symptoms and not the cause, and efficacy is usually limited over time,” she said.

Dr. Sconfienza said this study leaves her with three pertinent questions. “First, whether pain control extends beyond the 3-month follow-up reported by authors in the abstract; second, [what] is the efficacy of this method compared to other interventions (e.g., physical therapy, injections) or to doing nothing; and last, radiofrequency ablation is usually not a cheap treatment, thus a cost-efficacy analysis would be desirable, especially in comparison to other procedures.”

Dr. Gonzalez and Dr. Sconfienza have nothing relevant to disclose.

A version of this article originally appeared on Medscape.com.

Osteoarthritis patients report significant pain relief after treatment with cooled radiofrequency ablation, a new technique that “stuns” sensory nerves in shoulder and hip joints to reduce – and sometimes eliminate – pain.

“We send a small current to the sensory nerve to heat up the tissue and disrupt the fibers,” study lead author Felix Gonzalez, MD, of Emory University, Atlanta, said in an interview. “The effect is that the transmission of pain is significantly slowed or halted altogether.

“We damage something to fix something,” Dr. Gonzalez continued. “We target only the problematic nerve and get a very localized effect.”
 

Two-phase treatment

The treatment is performed in two phases. First, patients with shoulder pain are given an anesthetic to block their suprascapular, lateral pectoral, and axillary sensory articular nerves. Patients with hip pain have their obturator and femoral sensory articular nerves blocked.

A week or two later, the same nerves are treated with cooled radiofrequency ablation. Guided by x-ray imaging, a clinician heats up the affected nerve tissue using the tip of a needle, which is pointed at the nerve. “It’s a 22-gauge needle, slightly thicker than an acupuncture needle,” Dr. Gonzalez explained. “We heat up the nerve for about 2 minutes to about 60 degrees Celsius – it stuns the nerve,” he said.

“The result disrupts or slows down pain transmission while leaving the nerve intact.”

To test the efficacy of the technique, researchers treated 12 shoulders in patients with an average age of 61 years, and 11 hips in patients with an average age of 62 years.

Three months after treatment, patients with hip pain reported improvement in Hip Disability and Osteoarthritis Outcome Score (HOOS) from a baseline of 17.0 to 52.9 (P < .0001).

Shoulder pain was also reduced significantly. Using the American Shoulder and Elbow Surgeons (ASES) score, researchers reported an improvement from 17.2 (±6.6) at baseline to 65.7 (±5.9) at 3 months (P < .0001).

“We are targeting a subset of patients for this that don’t qualify for surgery,” Dr. Gonzalez noted. For patients with a body mass index above 35, or a history of hypertension, heart disease, or multiple strokes, opioids are the most common treatment, he said.

These patients “fall through the cracks,” he explained. Those who have mild to moderate pain are managed with physical therapy and injections, and those with severe pain go into surgery. “But what about the ones in the middle ... who are not eligible for surgery? They are at risk for opioid overuse,” he said. “So this treatment is a good option for them.”
 

Treats the symptoms, not the cause

“This study shows the efficacy of this method in taking care of shoulder and hip pain,” Luca Maria Sconfienza, MD, PhD, of Galeazzi Orthopedic Hospital in Milan, said in an interview. Dr. Sconfienza was not involved in Dr. Gonzalez’s study.

However, like corticosteroid injections, “the drawback of radiofrequency ablation is the fact that it only treats the symptoms and not the cause, and efficacy is usually limited over time,” she said.

Dr. Sconfienza said this study leaves her with three pertinent questions. “First, whether pain control extends beyond the 3-month follow-up reported by authors in the abstract; second, [what] is the efficacy of this method compared to other interventions (e.g., physical therapy, injections) or to doing nothing; and last, radiofrequency ablation is usually not a cheap treatment, thus a cost-efficacy analysis would be desirable, especially in comparison to other procedures.”

Dr. Gonzalez and Dr. Sconfienza have nothing relevant to disclose.

A version of this article originally appeared on Medscape.com.

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Three genes that could predict susceptibility to congenital Zika virus (ZIKV) infection have been identified, Dr. Irene Rivero-Calle, MD, shared at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

ZIKV, an emerging flavivirus, is responsible for one the most critical pandemic emergencies of the last decade and has been associated with severe neonatal brain disabilities, declared Dr. Rivero-Calle, of the Hospital Clínico Universitario de Santiago de Compostela in Santiago de Compostela, Spain. “We think that understanding the genomic background could explain some of the most relevant symptoms of congenital Zika syndrome (CZS) and could be essential to better comprehend this disease.”

To achieve this understanding, Dr. Rivero-Calle and her colleagues conducted a study aiming to analyze any genetic factors that could explain the variation in phenotypes in newborns from mothers who had a Zika infection during their pregnancy. Additionally, they strove to “elucidate if the possible genetic association is specific to mothers or their newborns, and to check if this genomic background or any genomic ancestry pattern could be related with the phenotype,” she explained.

In their study, Dr. Rivero-Calle and her team analyzed 80 samples, comprising 40 samples from mothers who had been infected by ZIKV during their pregnancy and 40 from their newborns. Of those descendants, 20 were asymptomatic and 20 were symptomatic (13 had CZS, 3 had microcephaly, 2 had a pathologic MRI, 1 had hearing loss, and 1 was born preterm).

Population stratification, which Dr. Rivero-Calle explained “lets us know if the population is African, European, or Native American looking at the genes,” did not show any relation with the phenotype. We had a mixture of population genomics among all samples.”

Dr. Rivero-Calle and her team then performed three analyses: genotype analysis, an allelic test, and gene analysis. The allelic test and gene-collapsing method highlighted three genes (PANO1, PIDD1, and SLC25A22) as potential determinants of the varying phenotypes in the newborns from ZIKV-infected mothers. Overrepresentation analysis of gene ontology terms shows that PIDD1 and PANO1 are related to apoptosis and cell death, which is closely related to early infantile epilepsy. This could explain the most severe complications of CZS: seizures, brain damage, microcephaly, and detrimental neurodevelopmental growth. Regarding reactome and KEGG analysis, gene PIID1 is related with p53 pathway, which correlates with cell’s death and apoptosis, and with microcephaly, a typical phenotypic feature of CZS.

“So, in conclusion, we found three genes which could predict susceptibility to congenital Zika infection; we saw that the functionality of these genes seems to be deeply related with mechanisms which could explain the different phenotypes; and we saw that these three genes only appear in the children’s cohort, so there is no candidate gene in the mother’s genomic background which can help predict the phenotype of the newborn,” Dr. Rivero-Calle declared. “Finally, there is no ancestry pattern associated with disabilities caused by Zika infection.”

Dr. Rivero-Calle reported that this project (ZikAction) has received funding from the European Union’s Horizon 2020 research and innovation program, under grant agreement 734857.

Three genes that could predict susceptibility to congenital Zika virus (ZIKV) infection have been identified, Dr. Irene Rivero-Calle, MD, shared at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

ZIKV, an emerging flavivirus, is responsible for one the most critical pandemic emergencies of the last decade and has been associated with severe neonatal brain disabilities, declared Dr. Rivero-Calle, of the Hospital Clínico Universitario de Santiago de Compostela in Santiago de Compostela, Spain. “We think that understanding the genomic background could explain some of the most relevant symptoms of congenital Zika syndrome (CZS) and could be essential to better comprehend this disease.”

To achieve this understanding, Dr. Rivero-Calle and her colleagues conducted a study aiming to analyze any genetic factors that could explain the variation in phenotypes in newborns from mothers who had a Zika infection during their pregnancy. Additionally, they strove to “elucidate if the possible genetic association is specific to mothers or their newborns, and to check if this genomic background or any genomic ancestry pattern could be related with the phenotype,” she explained.

In their study, Dr. Rivero-Calle and her team analyzed 80 samples, comprising 40 samples from mothers who had been infected by ZIKV during their pregnancy and 40 from their newborns. Of those descendants, 20 were asymptomatic and 20 were symptomatic (13 had CZS, 3 had microcephaly, 2 had a pathologic MRI, 1 had hearing loss, and 1 was born preterm).

Population stratification, which Dr. Rivero-Calle explained “lets us know if the population is African, European, or Native American looking at the genes,” did not show any relation with the phenotype. We had a mixture of population genomics among all samples.”

Dr. Rivero-Calle and her team then performed three analyses: genotype analysis, an allelic test, and gene analysis. The allelic test and gene-collapsing method highlighted three genes (PANO1, PIDD1, and SLC25A22) as potential determinants of the varying phenotypes in the newborns from ZIKV-infected mothers. Overrepresentation analysis of gene ontology terms shows that PIDD1 and PANO1 are related to apoptosis and cell death, which is closely related to early infantile epilepsy. This could explain the most severe complications of CZS: seizures, brain damage, microcephaly, and detrimental neurodevelopmental growth. Regarding reactome and KEGG analysis, gene PIID1 is related with p53 pathway, which correlates with cell’s death and apoptosis, and with microcephaly, a typical phenotypic feature of CZS.

“So, in conclusion, we found three genes which could predict susceptibility to congenital Zika infection; we saw that the functionality of these genes seems to be deeply related with mechanisms which could explain the different phenotypes; and we saw that these three genes only appear in the children’s cohort, so there is no candidate gene in the mother’s genomic background which can help predict the phenotype of the newborn,” Dr. Rivero-Calle declared. “Finally, there is no ancestry pattern associated with disabilities caused by Zika infection.”

Dr. Rivero-Calle reported that this project (ZikAction) has received funding from the European Union’s Horizon 2020 research and innovation program, under grant agreement 734857.

Three genes that could predict susceptibility to congenital Zika virus (ZIKV) infection have been identified, Dr. Irene Rivero-Calle, MD, shared at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

ZIKV, an emerging flavivirus, is responsible for one the most critical pandemic emergencies of the last decade and has been associated with severe neonatal brain disabilities, declared Dr. Rivero-Calle, of the Hospital Clínico Universitario de Santiago de Compostela in Santiago de Compostela, Spain. “We think that understanding the genomic background could explain some of the most relevant symptoms of congenital Zika syndrome (CZS) and could be essential to better comprehend this disease.”

To achieve this understanding, Dr. Rivero-Calle and her colleagues conducted a study aiming to analyze any genetic factors that could explain the variation in phenotypes in newborns from mothers who had a Zika infection during their pregnancy. Additionally, they strove to “elucidate if the possible genetic association is specific to mothers or their newborns, and to check if this genomic background or any genomic ancestry pattern could be related with the phenotype,” she explained.

In their study, Dr. Rivero-Calle and her team analyzed 80 samples, comprising 40 samples from mothers who had been infected by ZIKV during their pregnancy and 40 from their newborns. Of those descendants, 20 were asymptomatic and 20 were symptomatic (13 had CZS, 3 had microcephaly, 2 had a pathologic MRI, 1 had hearing loss, and 1 was born preterm).

Population stratification, which Dr. Rivero-Calle explained “lets us know if the population is African, European, or Native American looking at the genes,” did not show any relation with the phenotype. We had a mixture of population genomics among all samples.”

Dr. Rivero-Calle and her team then performed three analyses: genotype analysis, an allelic test, and gene analysis. The allelic test and gene-collapsing method highlighted three genes (PANO1, PIDD1, and SLC25A22) as potential determinants of the varying phenotypes in the newborns from ZIKV-infected mothers. Overrepresentation analysis of gene ontology terms shows that PIDD1 and PANO1 are related to apoptosis and cell death, which is closely related to early infantile epilepsy. This could explain the most severe complications of CZS: seizures, brain damage, microcephaly, and detrimental neurodevelopmental growth. Regarding reactome and KEGG analysis, gene PIID1 is related with p53 pathway, which correlates with cell’s death and apoptosis, and with microcephaly, a typical phenotypic feature of CZS.

“So, in conclusion, we found three genes which could predict susceptibility to congenital Zika infection; we saw that the functionality of these genes seems to be deeply related with mechanisms which could explain the different phenotypes; and we saw that these three genes only appear in the children’s cohort, so there is no candidate gene in the mother’s genomic background which can help predict the phenotype of the newborn,” Dr. Rivero-Calle declared. “Finally, there is no ancestry pattern associated with disabilities caused by Zika infection.”

Dr. Rivero-Calle reported that this project (ZikAction) has received funding from the European Union’s Horizon 2020 research and innovation program, under grant agreement 734857.

There was a low prevalence of meningococcal colonization in health care professionals working in pediatrics and adolescent medicine at a university – lower than expected for all age groups, Lisa-Maria Steurer, MD, said regarding study findings reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

CDC/Sarah Bailey Cutchin/Illustrator Dan Higgins

“This implicates that the risk of horizontal meningococcal transmission via this health care professional cohort seems to be low,” said Dr. Steurer, of the Medical University of Vienna.

Her data were based on a survey conducted between April and October 2018 at the department of paediatrics and adolescent medicine at the tertiary university pediatric hospital. The study aimed to determine colonization rates of Neisseria meningitidis and the serogroup distribution of carried meningococcal isolates in asymptomatic health care professionals employed there, reported Dr. Steurer. Her research team also sought to identify what factors increased risk of N. meningitidis carriage.

“We who work in pediatrics and adolescent medicine are exposed to those patient cohorts with the highest risk for meningococcal carriage, but also to those patients who have the highest risk for serious, invasive meningococcal disease, which peaks at the extremities of age,” declared Dr. Steurer. “But currently, there is no surveillance of asymptomatic carriers in this health care professional cohort.”

A total of 437 oropharyngeal swabs were collected from enrolled nurses, pediatricians, and medical students working in the department and immediately plated onto selective agar plates. Conventional culture was used to identify bacteria, and meningococcal isolates were characterized further through whole-genome sequencing. Sociodemographic data and information on participants’ vaccination status were collected via questionnaire.

The main finding was an overall meningococcal prevalence of 1.14%. Among the participants, the median age was 33 years, and the highest rate of carriage, 4.4%, was observed in those aged 18-25 years. None of the carriers were older than 35 years. There was a negative association found between carriage and participants’ age and time employed in the field, Dr. Steurer said.

“Risk-factor analysis found an inverse correlation with meningococcal carriage for age and timespan working in pediatrics. On the contrary, no correlations with carriage could be found for all other factors evaluated,” she said. These factors included recent contact with an immunodeficient patient, respiratory tract infection, smoking, vaccination against any meningococcal serogroup, different professions, main work settings, month of swab collection, and living with children or adolescents in the same household.

Of the study population, 29% reported that they had been vaccinated against at least one meningococcal serogroup. “Interestingly, while more than 50% of doctors and medical students had a vaccination against at least one meningococcal serogroup, only 17% of nurses were vaccinated,” Dr. Steurer remarked.

The study was financially supported by Pfizer. Dr. Steurer had no other relevant financial disclosures.

There was a low prevalence of meningococcal colonization in health care professionals working in pediatrics and adolescent medicine at a university – lower than expected for all age groups, Lisa-Maria Steurer, MD, said regarding study findings reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

CDC/Sarah Bailey Cutchin/Illustrator Dan Higgins

“This implicates that the risk of horizontal meningococcal transmission via this health care professional cohort seems to be low,” said Dr. Steurer, of the Medical University of Vienna.

Her data were based on a survey conducted between April and October 2018 at the department of paediatrics and adolescent medicine at the tertiary university pediatric hospital. The study aimed to determine colonization rates of Neisseria meningitidis and the serogroup distribution of carried meningococcal isolates in asymptomatic health care professionals employed there, reported Dr. Steurer. Her research team also sought to identify what factors increased risk of N. meningitidis carriage.

“We who work in pediatrics and adolescent medicine are exposed to those patient cohorts with the highest risk for meningococcal carriage, but also to those patients who have the highest risk for serious, invasive meningococcal disease, which peaks at the extremities of age,” declared Dr. Steurer. “But currently, there is no surveillance of asymptomatic carriers in this health care professional cohort.”

A total of 437 oropharyngeal swabs were collected from enrolled nurses, pediatricians, and medical students working in the department and immediately plated onto selective agar plates. Conventional culture was used to identify bacteria, and meningococcal isolates were characterized further through whole-genome sequencing. Sociodemographic data and information on participants’ vaccination status were collected via questionnaire.

The main finding was an overall meningococcal prevalence of 1.14%. Among the participants, the median age was 33 years, and the highest rate of carriage, 4.4%, was observed in those aged 18-25 years. None of the carriers were older than 35 years. There was a negative association found between carriage and participants’ age and time employed in the field, Dr. Steurer said.

“Risk-factor analysis found an inverse correlation with meningococcal carriage for age and timespan working in pediatrics. On the contrary, no correlations with carriage could be found for all other factors evaluated,” she said. These factors included recent contact with an immunodeficient patient, respiratory tract infection, smoking, vaccination against any meningococcal serogroup, different professions, main work settings, month of swab collection, and living with children or adolescents in the same household.

Of the study population, 29% reported that they had been vaccinated against at least one meningococcal serogroup. “Interestingly, while more than 50% of doctors and medical students had a vaccination against at least one meningococcal serogroup, only 17% of nurses were vaccinated,” Dr. Steurer remarked.

The study was financially supported by Pfizer. Dr. Steurer had no other relevant financial disclosures.

There was a low prevalence of meningococcal colonization in health care professionals working in pediatrics and adolescent medicine at a university – lower than expected for all age groups, Lisa-Maria Steurer, MD, said regarding study findings reported at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year.

CDC/Sarah Bailey Cutchin/Illustrator Dan Higgins

“This implicates that the risk of horizontal meningococcal transmission via this health care professional cohort seems to be low,” said Dr. Steurer, of the Medical University of Vienna.

Her data were based on a survey conducted between April and October 2018 at the department of paediatrics and adolescent medicine at the tertiary university pediatric hospital. The study aimed to determine colonization rates of Neisseria meningitidis and the serogroup distribution of carried meningococcal isolates in asymptomatic health care professionals employed there, reported Dr. Steurer. Her research team also sought to identify what factors increased risk of N. meningitidis carriage.

“We who work in pediatrics and adolescent medicine are exposed to those patient cohorts with the highest risk for meningococcal carriage, but also to those patients who have the highest risk for serious, invasive meningococcal disease, which peaks at the extremities of age,” declared Dr. Steurer. “But currently, there is no surveillance of asymptomatic carriers in this health care professional cohort.”

A total of 437 oropharyngeal swabs were collected from enrolled nurses, pediatricians, and medical students working in the department and immediately plated onto selective agar plates. Conventional culture was used to identify bacteria, and meningococcal isolates were characterized further through whole-genome sequencing. Sociodemographic data and information on participants’ vaccination status were collected via questionnaire.

The main finding was an overall meningococcal prevalence of 1.14%. Among the participants, the median age was 33 years, and the highest rate of carriage, 4.4%, was observed in those aged 18-25 years. None of the carriers were older than 35 years. There was a negative association found between carriage and participants’ age and time employed in the field, Dr. Steurer said.

“Risk-factor analysis found an inverse correlation with meningococcal carriage for age and timespan working in pediatrics. On the contrary, no correlations with carriage could be found for all other factors evaluated,” she said. These factors included recent contact with an immunodeficient patient, respiratory tract infection, smoking, vaccination against any meningococcal serogroup, different professions, main work settings, month of swab collection, and living with children or adolescents in the same household.

Of the study population, 29% reported that they had been vaccinated against at least one meningococcal serogroup. “Interestingly, while more than 50% of doctors and medical students had a vaccination against at least one meningococcal serogroup, only 17% of nurses were vaccinated,” Dr. Steurer remarked.

The study was financially supported by Pfizer. Dr. Steurer had no other relevant financial disclosures.

Countries across the world are in the process of closing and reopening schools to contain the spread of COVID-19. Should there be universal testing and quarantining of sick school children and their classmates?

miodrag ignjatovic/E+

In a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Andreea M. Panciu, MD, from the National Institute of Infectious Diseases in Bucharest, argued for routine testing and quarantining of all school children. Her opposite number, Danilo Buonsenso, MD, from the Centre for Global Health Research and Studies, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, made the case for a more selective approach.
 

Should children be sent to school?

“Risk-reduction strategies and detection of cases must be in place to allow children to return safely to school,” stated Dr. Panciu as she started the debate by explaining the challenges faced by schools in adhering to key mitigation strategies. The U.S. Centers for Disease Control and Prevention recommends that students keep 1.8 m (6 feet) distance from one another. “In many school settings this is not feasible without drastically limiting the number of students,” she explained. “This is a massive challenge for many schools that are already overcrowded.”

The use of facemasks also is a challenge in classrooms. Children have a lower tolerance or may not be able to use the mask properly. There also are concerns regarding impaired learning, speech development, social development, and facial recognition. “We need to look at the evidence; preventive measures work,” responded Dr. Buonsenso. If distance can be implemented, the more distance the lower the transmission of infection, with 1.5-2 meters having the best effects. “Distance can be difficult when school buildings do not allow it, however, governments have had time to plan, and this should not be a limitation to education for kids.”

A recent review clearly showed that children and adolescents aged under 20 years have a much lower risk of susceptibility to COVID-19 infection, compared with adults. This is especially the case for children younger than 14 years. “There is no excuse, let’s bring the children back to school,” argued Dr. Buonsenso.

Dr. Panciu responded with several studies that have tried to quantify the amount of SARS-CoV-2 virus that is carried by infected children. Viral load in the nasopharynx in children under 5 years with mild to moderate COVID-19 symptoms was higher than that of both children over 5 as well as adults. The viral load in young children did not seem to differ by age or symptom severity. “There doesn’t appear to be a significant difference in viral load between symptomatic children and symptomatic adults,” she stated.

“But the question is: ‘How infectious are children?’ ” reacted Dr. Buonsenso. Data from South Korea showed that, for children, particularly those under 10 years, the number of secondary cases of contacts was very low, suggesting that children are rarely spreading the virus.

Dr. Buonsenso and colleagues assessed 30 households containing children aged under 18 years where an adult had been infected with COVID-19 in Rome during the peak of the pandemic. In no cases was it found that a child was the index case. This was supported by data from China, also obtained during the peak of the pandemic, which showed that the number of children infected was very low, but more importantly the number of secondary attacks from contact with children was also very low.
 

What about children who are sick at school?

The debate moved to discussing what should be done when a child is sick at school. Dr. Panciu clarified recommendations by the CDC regarding what steps to take if a student displays signs of infection consistent with COVID-19: Should they test positive, they are to stay at home for 10 days from the time signs and symptoms first appeared. Further, any teachers or students identified as close contacts are advised to stay at home for 14 days. (Since the ESPID meeting, the CDC has made changes in quarantine times for COVID-19. People can now quarantine for 10 days without a COVID-19 test if they have no symptoms. Alternatively, a quarantine can end after 7 days for someone with a negative test and no symptoms. The agency recommends a polymerase chain reaction test or an antigen assay within 48 hours before the end of a quarantine.)

A significant problem is the overlap between COVID-19 symptoms and those associated with other common illnesses because of a range of viruses. This is particularly true in younger children who often suffer from viral infections. “It is common for children to have up to eight respiratory illnesses a year,” explained Dr. Panciu, “and some may have symptoms so mild that they don’t notice them.”

“We need to be a little bit more children focused, otherwise we are going to be isolating children all the time,” said Dr. Buonsenso. The Royal College of Paediatrics and Child Health state that a child with a simple runny nose or sporadic cough without a fever, who would have attended school in other times, should not be tested for COVID-19. He moved on to then cite several studies that show little or no evidence of COVID-19 transmission between school children. This included a prospective cohort study in Australia showing that child-to-child transmission occurred in 0.3%. “To date, the advantages from routine quarantine and over testing seem too low to balance the social consequences on children and families,” he concluded.

As the debate drew to a close, Dr. Panciu reported several studies that did demonstrate transmission between school-age children. Data from an overnight camp in Georgia where the median age was 12 years showed the attack rate was 44% for ages 11-17 years and 51% for ages 6-10 years. Similar conclusions were reached in an Israeli study looking at a large COVID-19 outbreak in a school. This occurred 10 days after reopening, in spite of preventive measures being in place. “Opening safely isn’t just about the adjustments a school makes,” she said, “it’s also about how much of the virus is circulating in the community, which affects the likelihood that students and staff will bring COVID-19 into their classrooms.”

Damian Roland, consultant and honorary associate professor in pediatric emergency medicine at the University of Leicester (England), commented: “Maximizing educational potential while reducing the spread of COVID19 is a challenge laden with scientific equipoise while simultaneously infused with emotion. The evidence of transmission between, and infectivity from, children is not complete, as this debate has demonstrated. It is important scientists, clinicians, educators, and policy makers make collaborative decisions, aware there is not one perfect answer, and willing to understand and incorporate others views and objectives rather than holding onto single beliefs or approaches.”

No financial conflicts of interest were declared.

Countries across the world are in the process of closing and reopening schools to contain the spread of COVID-19. Should there be universal testing and quarantining of sick school children and their classmates?

miodrag ignjatovic/E+

In a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Andreea M. Panciu, MD, from the National Institute of Infectious Diseases in Bucharest, argued for routine testing and quarantining of all school children. Her opposite number, Danilo Buonsenso, MD, from the Centre for Global Health Research and Studies, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, made the case for a more selective approach.
 

Should children be sent to school?

“Risk-reduction strategies and detection of cases must be in place to allow children to return safely to school,” stated Dr. Panciu as she started the debate by explaining the challenges faced by schools in adhering to key mitigation strategies. The U.S. Centers for Disease Control and Prevention recommends that students keep 1.8 m (6 feet) distance from one another. “In many school settings this is not feasible without drastically limiting the number of students,” she explained. “This is a massive challenge for many schools that are already overcrowded.”

The use of facemasks also is a challenge in classrooms. Children have a lower tolerance or may not be able to use the mask properly. There also are concerns regarding impaired learning, speech development, social development, and facial recognition. “We need to look at the evidence; preventive measures work,” responded Dr. Buonsenso. If distance can be implemented, the more distance the lower the transmission of infection, with 1.5-2 meters having the best effects. “Distance can be difficult when school buildings do not allow it, however, governments have had time to plan, and this should not be a limitation to education for kids.”

A recent review clearly showed that children and adolescents aged under 20 years have a much lower risk of susceptibility to COVID-19 infection, compared with adults. This is especially the case for children younger than 14 years. “There is no excuse, let’s bring the children back to school,” argued Dr. Buonsenso.

Dr. Panciu responded with several studies that have tried to quantify the amount of SARS-CoV-2 virus that is carried by infected children. Viral load in the nasopharynx in children under 5 years with mild to moderate COVID-19 symptoms was higher than that of both children over 5 as well as adults. The viral load in young children did not seem to differ by age or symptom severity. “There doesn’t appear to be a significant difference in viral load between symptomatic children and symptomatic adults,” she stated.

“But the question is: ‘How infectious are children?’ ” reacted Dr. Buonsenso. Data from South Korea showed that, for children, particularly those under 10 years, the number of secondary cases of contacts was very low, suggesting that children are rarely spreading the virus.

Dr. Buonsenso and colleagues assessed 30 households containing children aged under 18 years where an adult had been infected with COVID-19 in Rome during the peak of the pandemic. In no cases was it found that a child was the index case. This was supported by data from China, also obtained during the peak of the pandemic, which showed that the number of children infected was very low, but more importantly the number of secondary attacks from contact with children was also very low.
 

What about children who are sick at school?

The debate moved to discussing what should be done when a child is sick at school. Dr. Panciu clarified recommendations by the CDC regarding what steps to take if a student displays signs of infection consistent with COVID-19: Should they test positive, they are to stay at home for 10 days from the time signs and symptoms first appeared. Further, any teachers or students identified as close contacts are advised to stay at home for 14 days. (Since the ESPID meeting, the CDC has made changes in quarantine times for COVID-19. People can now quarantine for 10 days without a COVID-19 test if they have no symptoms. Alternatively, a quarantine can end after 7 days for someone with a negative test and no symptoms. The agency recommends a polymerase chain reaction test or an antigen assay within 48 hours before the end of a quarantine.)

A significant problem is the overlap between COVID-19 symptoms and those associated with other common illnesses because of a range of viruses. This is particularly true in younger children who often suffer from viral infections. “It is common for children to have up to eight respiratory illnesses a year,” explained Dr. Panciu, “and some may have symptoms so mild that they don’t notice them.”

“We need to be a little bit more children focused, otherwise we are going to be isolating children all the time,” said Dr. Buonsenso. The Royal College of Paediatrics and Child Health state that a child with a simple runny nose or sporadic cough without a fever, who would have attended school in other times, should not be tested for COVID-19. He moved on to then cite several studies that show little or no evidence of COVID-19 transmission between school children. This included a prospective cohort study in Australia showing that child-to-child transmission occurred in 0.3%. “To date, the advantages from routine quarantine and over testing seem too low to balance the social consequences on children and families,” he concluded.

As the debate drew to a close, Dr. Panciu reported several studies that did demonstrate transmission between school-age children. Data from an overnight camp in Georgia where the median age was 12 years showed the attack rate was 44% for ages 11-17 years and 51% for ages 6-10 years. Similar conclusions were reached in an Israeli study looking at a large COVID-19 outbreak in a school. This occurred 10 days after reopening, in spite of preventive measures being in place. “Opening safely isn’t just about the adjustments a school makes,” she said, “it’s also about how much of the virus is circulating in the community, which affects the likelihood that students and staff will bring COVID-19 into their classrooms.”

Damian Roland, consultant and honorary associate professor in pediatric emergency medicine at the University of Leicester (England), commented: “Maximizing educational potential while reducing the spread of COVID19 is a challenge laden with scientific equipoise while simultaneously infused with emotion. The evidence of transmission between, and infectivity from, children is not complete, as this debate has demonstrated. It is important scientists, clinicians, educators, and policy makers make collaborative decisions, aware there is not one perfect answer, and willing to understand and incorporate others views and objectives rather than holding onto single beliefs or approaches.”

No financial conflicts of interest were declared.

Countries across the world are in the process of closing and reopening schools to contain the spread of COVID-19. Should there be universal testing and quarantining of sick school children and their classmates?

miodrag ignjatovic/E+

In a lively debate at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year, Andreea M. Panciu, MD, from the National Institute of Infectious Diseases in Bucharest, argued for routine testing and quarantining of all school children. Her opposite number, Danilo Buonsenso, MD, from the Centre for Global Health Research and Studies, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, made the case for a more selective approach.
 

Should children be sent to school?

“Risk-reduction strategies and detection of cases must be in place to allow children to return safely to school,” stated Dr. Panciu as she started the debate by explaining the challenges faced by schools in adhering to key mitigation strategies. The U.S. Centers for Disease Control and Prevention recommends that students keep 1.8 m (6 feet) distance from one another. “In many school settings this is not feasible without drastically limiting the number of students,” she explained. “This is a massive challenge for many schools that are already overcrowded.”

The use of facemasks also is a challenge in classrooms. Children have a lower tolerance or may not be able to use the mask properly. There also are concerns regarding impaired learning, speech development, social development, and facial recognition. “We need to look at the evidence; preventive measures work,” responded Dr. Buonsenso. If distance can be implemented, the more distance the lower the transmission of infection, with 1.5-2 meters having the best effects. “Distance can be difficult when school buildings do not allow it, however, governments have had time to plan, and this should not be a limitation to education for kids.”

A recent review clearly showed that children and adolescents aged under 20 years have a much lower risk of susceptibility to COVID-19 infection, compared with adults. This is especially the case for children younger than 14 years. “There is no excuse, let’s bring the children back to school,” argued Dr. Buonsenso.

Dr. Panciu responded with several studies that have tried to quantify the amount of SARS-CoV-2 virus that is carried by infected children. Viral load in the nasopharynx in children under 5 years with mild to moderate COVID-19 symptoms was higher than that of both children over 5 as well as adults. The viral load in young children did not seem to differ by age or symptom severity. “There doesn’t appear to be a significant difference in viral load between symptomatic children and symptomatic adults,” she stated.

“But the question is: ‘How infectious are children?’ ” reacted Dr. Buonsenso. Data from South Korea showed that, for children, particularly those under 10 years, the number of secondary cases of contacts was very low, suggesting that children are rarely spreading the virus.

Dr. Buonsenso and colleagues assessed 30 households containing children aged under 18 years where an adult had been infected with COVID-19 in Rome during the peak of the pandemic. In no cases was it found that a child was the index case. This was supported by data from China, also obtained during the peak of the pandemic, which showed that the number of children infected was very low, but more importantly the number of secondary attacks from contact with children was also very low.
 

What about children who are sick at school?

The debate moved to discussing what should be done when a child is sick at school. Dr. Panciu clarified recommendations by the CDC regarding what steps to take if a student displays signs of infection consistent with COVID-19: Should they test positive, they are to stay at home for 10 days from the time signs and symptoms first appeared. Further, any teachers or students identified as close contacts are advised to stay at home for 14 days. (Since the ESPID meeting, the CDC has made changes in quarantine times for COVID-19. People can now quarantine for 10 days without a COVID-19 test if they have no symptoms. Alternatively, a quarantine can end after 7 days for someone with a negative test and no symptoms. The agency recommends a polymerase chain reaction test or an antigen assay within 48 hours before the end of a quarantine.)

A significant problem is the overlap between COVID-19 symptoms and those associated with other common illnesses because of a range of viruses. This is particularly true in younger children who often suffer from viral infections. “It is common for children to have up to eight respiratory illnesses a year,” explained Dr. Panciu, “and some may have symptoms so mild that they don’t notice them.”

“We need to be a little bit more children focused, otherwise we are going to be isolating children all the time,” said Dr. Buonsenso. The Royal College of Paediatrics and Child Health state that a child with a simple runny nose or sporadic cough without a fever, who would have attended school in other times, should not be tested for COVID-19. He moved on to then cite several studies that show little or no evidence of COVID-19 transmission between school children. This included a prospective cohort study in Australia showing that child-to-child transmission occurred in 0.3%. “To date, the advantages from routine quarantine and over testing seem too low to balance the social consequences on children and families,” he concluded.

As the debate drew to a close, Dr. Panciu reported several studies that did demonstrate transmission between school-age children. Data from an overnight camp in Georgia where the median age was 12 years showed the attack rate was 44% for ages 11-17 years and 51% for ages 6-10 years. Similar conclusions were reached in an Israeli study looking at a large COVID-19 outbreak in a school. This occurred 10 days after reopening, in spite of preventive measures being in place. “Opening safely isn’t just about the adjustments a school makes,” she said, “it’s also about how much of the virus is circulating in the community, which affects the likelihood that students and staff will bring COVID-19 into their classrooms.”

Damian Roland, consultant and honorary associate professor in pediatric emergency medicine at the University of Leicester (England), commented: “Maximizing educational potential while reducing the spread of COVID19 is a challenge laden with scientific equipoise while simultaneously infused with emotion. The evidence of transmission between, and infectivity from, children is not complete, as this debate has demonstrated. It is important scientists, clinicians, educators, and policy makers make collaborative decisions, aware there is not one perfect answer, and willing to understand and incorporate others views and objectives rather than holding onto single beliefs or approaches.”

No financial conflicts of interest were declared.