In a cautiously optimistic report, researchers described pregnancy outcomes in 25 women living with HIV in clinical trials of a new long-acting injectable antiretroviral regimen of cabotegravir and rilpivirine (CAB + RPV).

Among 10 live births, there was one birth defect (congenital ptosis, or droopy eyelid), which was not attributed to the trial drugs. There were no instances of perinatal HIV transmission at delivery or during the 1-year follow-up.

“Long-acting cabotegravir-rilpivirine is the first and only complete injectable regimen potentially available for pregnant women,” first author Parul Patel, PharmD, global medical affairs director for cabotegravir at ViiV Healthcare, said in an interview. The regimen was approved by the U.S. Food and Drug Administration in January 2021 for injections every 4 weeks and in February 2022 for injections every 8 weeks.

“Importantly, it can be dosed monthly or every 2 months,” Patel said. “This could be advantageous for women who are experiencing constant change during pregnancy. This could be a consideration for women who might have problems tolerating oral pills during pregnancy or might have problems with emesis.”

The study was published in HIV Medicine.

“We are really pursuing the development of the long-acting version of cabotegravir in combination with rilpivirine,” Dr. Patel said. “It’s an industry standard during initial development that you start very conservatively and not allow a woman who is pregnant to continue dosing of a drug while still evaluating its overall safety profile. We really want to understand the use of this agent in nonpregnant adults before exposing pregnant women to active treatment.”
 

Pregnancies in trials excluding pregnant women

In the paper, Dr. Patel and her coauthors noted the limited data on pregnant women exposed to CAB + RPV. They analyzed pregnancies in four phase 2b/3/3b clinical trials sponsored by ViiV Healthcare and a compassionate use program. All clinical trial participants first received oral CAB + RPV daily for 4 weeks to assess individual tolerance before the experimental long-acting injection of CAB + RPV every 4 weeks or every 8 weeks.

Women participants were required to use highly effective contraception during the trials and for at least 52 weeks after the last injection. Urine pregnancy tests were given at baseline, before each injection, and when pregnancy was suspected. If a pregnancy was detected, CAB + RPV (oral or long-acting injections) was discontinued and the woman switched to an alternative oral antiretroviral, unless she and her physician decided to continue with injections in the compassionate use program.
 

Pregnancy outcomes

Among 25 reported pregnancies in 22 women during the trial, there were 10 live births. Nine of the mothers who delivered their babies at term had switched to an alternative antiretroviral regimen and maintained virologic suppression throughout pregnancy and post partum, or the last available viral load assessment.

The 10th participant remained on long-acting CAB + RPV during her pregnancy and had a live birth with congenital ptosis that was resolving without treatment at the 4-month ophthalmology consult, the authors wrote. The mother experienced persistent low-level viremia before and throughout her pregnancy.

Two of the pregnancies occurred after the last monthly injection, during the washout period. Other studies have reported that each long-acting drug, CAB and RPV, can be detected more than 1 year after the last injection. In the new report, plasma CAB and RPV washout concentrations during pregnancy were within the range of those in nonpregnant women, the authors wrote.

Among the 14 participants with non–live birth outcomes, 13 switched to an alternative antiretroviral regimen during pregnancy and maintained virologic suppression through pregnancy and post partum, or until their last viral assessment. The remaining participant received long-acting CAB + RPV and continued this treatment for the duration of their pregnancy.

“It’s a very limited data set, so we’re not in a position to be able to make definitive conclusions around long-acting cabotegravir-rilpivirine in pregnancy,” Dr. Patel acknowledged. “But the data that we presented among the 25 women who were exposed to cabotegravir-rilpivirine looks reassuring.”
 

Planned studies during pregnancy

Vani Vannappagari, MBBS, MPH, PhD, global head of epidemiology and real-world evidence at ViiV Healthcare and study coauthor, said in an interview that the initial results are spurring promising new research.

“We are working with an external IMPAACT [International Maternal Pediatric Adolescent AIDS Clinical Trials Network] group on a clinical trial ... to try to determine the appropriate dose of long-acting cabotegravir-rilpivirine during pregnancy,” Dr. Vannappagari said. “The clinical trial will give us the immediate safety, dose information, and viral suppression rates for both the mother and the infant. But long-term safety, especially birth defects and any adverse pregnancy and neonatal outcomes, will come from our antiretroviral pregnancy registry and other noninterventional studies.

“In the very small cohort studied, [in] pregnancies that were continued after exposure to long-acting cabotegravir and rilpivirine in the first trimester, there were no significant adverse fetal outcomes identified,” he said. “That’s reassuring, as is the fact that at the time these patients were switched in early pregnancy, their viral loads were all undetectable at the time that their pregnancies were diagnosed.”

Neil Silverman, MD, professor of clinical obstetrics and gynecology and director of the Infections in Pregnancy Program at the University of California, Los Angeles, Medical Center, who was not associated with the study, provided a comment to this news organization.

“The larger question still remains why pregnant women were so actively excluded from the original study design when this trial was evaluating a newer long-acting preparation of two anti-HIV medications that otherwise would be perfectly fine to use during pregnancy?”

Dr. Silverman continued, “In this case, it’s particularly frustrating since the present study was simply evaluating established medications currently being used to manage HIV infection, but in a newer longer-acting mode of administration by an injection every 2 months. If a patient had already been successfully managed on an oral antiviral regimen containing an integrase inhibitor and a non-nucleoside reverse transcriptase inhibitor, like the two drugs studied here, it would not be considered reasonable to switch that regimen simply because she was found to be pregnant.”

Dr. Patel and Dr. Vannappagari are employees of ViiV Healthcare and stockholders of GlaxoSmithKline.

This analysis was funded by ViiV Healthcare, and all studies were cofunded by ViiV Healthcare and Janssen Research & Development. Dr. Silverman reported no relevant financial relationships.

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

In a cautiously optimistic report, researchers described pregnancy outcomes in 25 women living with HIV in clinical trials of a new long-acting injectable antiretroviral regimen of cabotegravir and rilpivirine (CAB + RPV).

Among 10 live births, there was one birth defect (congenital ptosis, or droopy eyelid), which was not attributed to the trial drugs. There were no instances of perinatal HIV transmission at delivery or during the 1-year follow-up.

“Long-acting cabotegravir-rilpivirine is the first and only complete injectable regimen potentially available for pregnant women,” first author Parul Patel, PharmD, global medical affairs director for cabotegravir at ViiV Healthcare, said in an interview. The regimen was approved by the U.S. Food and Drug Administration in January 2021 for injections every 4 weeks and in February 2022 for injections every 8 weeks.

“Importantly, it can be dosed monthly or every 2 months,” Patel said. “This could be advantageous for women who are experiencing constant change during pregnancy. This could be a consideration for women who might have problems tolerating oral pills during pregnancy or might have problems with emesis.”

The study was published in HIV Medicine.

“We are really pursuing the development of the long-acting version of cabotegravir in combination with rilpivirine,” Dr. Patel said. “It’s an industry standard during initial development that you start very conservatively and not allow a woman who is pregnant to continue dosing of a drug while still evaluating its overall safety profile. We really want to understand the use of this agent in nonpregnant adults before exposing pregnant women to active treatment.”
 

Pregnancies in trials excluding pregnant women

In the paper, Dr. Patel and her coauthors noted the limited data on pregnant women exposed to CAB + RPV. They analyzed pregnancies in four phase 2b/3/3b clinical trials sponsored by ViiV Healthcare and a compassionate use program. All clinical trial participants first received oral CAB + RPV daily for 4 weeks to assess individual tolerance before the experimental long-acting injection of CAB + RPV every 4 weeks or every 8 weeks.

Women participants were required to use highly effective contraception during the trials and for at least 52 weeks after the last injection. Urine pregnancy tests were given at baseline, before each injection, and when pregnancy was suspected. If a pregnancy was detected, CAB + RPV (oral or long-acting injections) was discontinued and the woman switched to an alternative oral antiretroviral, unless she and her physician decided to continue with injections in the compassionate use program.
 

Pregnancy outcomes

Among 25 reported pregnancies in 22 women during the trial, there were 10 live births. Nine of the mothers who delivered their babies at term had switched to an alternative antiretroviral regimen and maintained virologic suppression throughout pregnancy and post partum, or the last available viral load assessment.

The 10th participant remained on long-acting CAB + RPV during her pregnancy and had a live birth with congenital ptosis that was resolving without treatment at the 4-month ophthalmology consult, the authors wrote. The mother experienced persistent low-level viremia before and throughout her pregnancy.

Two of the pregnancies occurred after the last monthly injection, during the washout period. Other studies have reported that each long-acting drug, CAB and RPV, can be detected more than 1 year after the last injection. In the new report, plasma CAB and RPV washout concentrations during pregnancy were within the range of those in nonpregnant women, the authors wrote.

Among the 14 participants with non–live birth outcomes, 13 switched to an alternative antiretroviral regimen during pregnancy and maintained virologic suppression through pregnancy and post partum, or until their last viral assessment. The remaining participant received long-acting CAB + RPV and continued this treatment for the duration of their pregnancy.

“It’s a very limited data set, so we’re not in a position to be able to make definitive conclusions around long-acting cabotegravir-rilpivirine in pregnancy,” Dr. Patel acknowledged. “But the data that we presented among the 25 women who were exposed to cabotegravir-rilpivirine looks reassuring.”
 

Planned studies during pregnancy

Vani Vannappagari, MBBS, MPH, PhD, global head of epidemiology and real-world evidence at ViiV Healthcare and study coauthor, said in an interview that the initial results are spurring promising new research.

“We are working with an external IMPAACT [International Maternal Pediatric Adolescent AIDS Clinical Trials Network] group on a clinical trial ... to try to determine the appropriate dose of long-acting cabotegravir-rilpivirine during pregnancy,” Dr. Vannappagari said. “The clinical trial will give us the immediate safety, dose information, and viral suppression rates for both the mother and the infant. But long-term safety, especially birth defects and any adverse pregnancy and neonatal outcomes, will come from our antiretroviral pregnancy registry and other noninterventional studies.

“In the very small cohort studied, [in] pregnancies that were continued after exposure to long-acting cabotegravir and rilpivirine in the first trimester, there were no significant adverse fetal outcomes identified,” he said. “That’s reassuring, as is the fact that at the time these patients were switched in early pregnancy, their viral loads were all undetectable at the time that their pregnancies were diagnosed.”

Neil Silverman, MD, professor of clinical obstetrics and gynecology and director of the Infections in Pregnancy Program at the University of California, Los Angeles, Medical Center, who was not associated with the study, provided a comment to this news organization.

“The larger question still remains why pregnant women were so actively excluded from the original study design when this trial was evaluating a newer long-acting preparation of two anti-HIV medications that otherwise would be perfectly fine to use during pregnancy?”

Dr. Silverman continued, “In this case, it’s particularly frustrating since the present study was simply evaluating established medications currently being used to manage HIV infection, but in a newer longer-acting mode of administration by an injection every 2 months. If a patient had already been successfully managed on an oral antiviral regimen containing an integrase inhibitor and a non-nucleoside reverse transcriptase inhibitor, like the two drugs studied here, it would not be considered reasonable to switch that regimen simply because she was found to be pregnant.”

Dr. Patel and Dr. Vannappagari are employees of ViiV Healthcare and stockholders of GlaxoSmithKline.

This analysis was funded by ViiV Healthcare, and all studies were cofunded by ViiV Healthcare and Janssen Research & Development. Dr. Silverman reported no relevant financial relationships.

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

In a cautiously optimistic report, researchers described pregnancy outcomes in 25 women living with HIV in clinical trials of a new long-acting injectable antiretroviral regimen of cabotegravir and rilpivirine (CAB + RPV).

Among 10 live births, there was one birth defect (congenital ptosis, or droopy eyelid), which was not attributed to the trial drugs. There were no instances of perinatal HIV transmission at delivery or during the 1-year follow-up.

“Long-acting cabotegravir-rilpivirine is the first and only complete injectable regimen potentially available for pregnant women,” first author Parul Patel, PharmD, global medical affairs director for cabotegravir at ViiV Healthcare, said in an interview. The regimen was approved by the U.S. Food and Drug Administration in January 2021 for injections every 4 weeks and in February 2022 for injections every 8 weeks.

“Importantly, it can be dosed monthly or every 2 months,” Patel said. “This could be advantageous for women who are experiencing constant change during pregnancy. This could be a consideration for women who might have problems tolerating oral pills during pregnancy or might have problems with emesis.”

The study was published in HIV Medicine.

“We are really pursuing the development of the long-acting version of cabotegravir in combination with rilpivirine,” Dr. Patel said. “It’s an industry standard during initial development that you start very conservatively and not allow a woman who is pregnant to continue dosing of a drug while still evaluating its overall safety profile. We really want to understand the use of this agent in nonpregnant adults before exposing pregnant women to active treatment.”
 

Pregnancies in trials excluding pregnant women

In the paper, Dr. Patel and her coauthors noted the limited data on pregnant women exposed to CAB + RPV. They analyzed pregnancies in four phase 2b/3/3b clinical trials sponsored by ViiV Healthcare and a compassionate use program. All clinical trial participants first received oral CAB + RPV daily for 4 weeks to assess individual tolerance before the experimental long-acting injection of CAB + RPV every 4 weeks or every 8 weeks.

Women participants were required to use highly effective contraception during the trials and for at least 52 weeks after the last injection. Urine pregnancy tests were given at baseline, before each injection, and when pregnancy was suspected. If a pregnancy was detected, CAB + RPV (oral or long-acting injections) was discontinued and the woman switched to an alternative oral antiretroviral, unless she and her physician decided to continue with injections in the compassionate use program.
 

Pregnancy outcomes

Among 25 reported pregnancies in 22 women during the trial, there were 10 live births. Nine of the mothers who delivered their babies at term had switched to an alternative antiretroviral regimen and maintained virologic suppression throughout pregnancy and post partum, or the last available viral load assessment.

The 10th participant remained on long-acting CAB + RPV during her pregnancy and had a live birth with congenital ptosis that was resolving without treatment at the 4-month ophthalmology consult, the authors wrote. The mother experienced persistent low-level viremia before and throughout her pregnancy.

Two of the pregnancies occurred after the last monthly injection, during the washout period. Other studies have reported that each long-acting drug, CAB and RPV, can be detected more than 1 year after the last injection. In the new report, plasma CAB and RPV washout concentrations during pregnancy were within the range of those in nonpregnant women, the authors wrote.

Among the 14 participants with non–live birth outcomes, 13 switched to an alternative antiretroviral regimen during pregnancy and maintained virologic suppression through pregnancy and post partum, or until their last viral assessment. The remaining participant received long-acting CAB + RPV and continued this treatment for the duration of their pregnancy.

“It’s a very limited data set, so we’re not in a position to be able to make definitive conclusions around long-acting cabotegravir-rilpivirine in pregnancy,” Dr. Patel acknowledged. “But the data that we presented among the 25 women who were exposed to cabotegravir-rilpivirine looks reassuring.”
 

Planned studies during pregnancy

Vani Vannappagari, MBBS, MPH, PhD, global head of epidemiology and real-world evidence at ViiV Healthcare and study coauthor, said in an interview that the initial results are spurring promising new research.

“We are working with an external IMPAACT [International Maternal Pediatric Adolescent AIDS Clinical Trials Network] group on a clinical trial ... to try to determine the appropriate dose of long-acting cabotegravir-rilpivirine during pregnancy,” Dr. Vannappagari said. “The clinical trial will give us the immediate safety, dose information, and viral suppression rates for both the mother and the infant. But long-term safety, especially birth defects and any adverse pregnancy and neonatal outcomes, will come from our antiretroviral pregnancy registry and other noninterventional studies.

“In the very small cohort studied, [in] pregnancies that were continued after exposure to long-acting cabotegravir and rilpivirine in the first trimester, there were no significant adverse fetal outcomes identified,” he said. “That’s reassuring, as is the fact that at the time these patients were switched in early pregnancy, their viral loads were all undetectable at the time that their pregnancies were diagnosed.”

Neil Silverman, MD, professor of clinical obstetrics and gynecology and director of the Infections in Pregnancy Program at the University of California, Los Angeles, Medical Center, who was not associated with the study, provided a comment to this news organization.

“The larger question still remains why pregnant women were so actively excluded from the original study design when this trial was evaluating a newer long-acting preparation of two anti-HIV medications that otherwise would be perfectly fine to use during pregnancy?”

Dr. Silverman continued, “In this case, it’s particularly frustrating since the present study was simply evaluating established medications currently being used to manage HIV infection, but in a newer longer-acting mode of administration by an injection every 2 months. If a patient had already been successfully managed on an oral antiviral regimen containing an integrase inhibitor and a non-nucleoside reverse transcriptase inhibitor, like the two drugs studied here, it would not be considered reasonable to switch that regimen simply because she was found to be pregnant.”

Dr. Patel and Dr. Vannappagari are employees of ViiV Healthcare and stockholders of GlaxoSmithKline.

This analysis was funded by ViiV Healthcare, and all studies were cofunded by ViiV Healthcare and Janssen Research & Development. Dr. Silverman reported no relevant financial relationships.

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

Regular readers of Federal Practitioner may recall that I have had a tradition of dedicating the last column of the year to an ethics rendition of the popular trope of the annual best and worst. This year we will examine the stories of 2 military physicians through the lens of virtue ethics. Aristotle (384-322 bce), arguably the most famous Western philosopher, is the acknowledged founder of virtue ethics.

Virtue ethics is among the oldest of ethical theories, and Aristotle articulates this school of thought in his work Nicomachean Ethics.² It is a good fit for Federal Practitioner as it has been constructively applied to the moral development of both military³ and medical professionals.⁴

Here is a Reader’s Digest version of virtue theory with apologizes to all the real philosophers out there. There are different ways to categorize ethical theories. One approach is to distinguish them based on the aspects of primary interest. Consequentialist ethics theories are concerned with the outcomes of actions. Deontologic theories emphasize the intention of the moral agent. In contrast, virtue ethics theories focus on the character of a person. The virtuous individual is one who has practiced the habits of moral excellence and embodies the good life. They are honored as heroes and revered as saints; they are the exemplars we imitate in our aspirations.³

The epigraph sums up one of Aristotle’s central philosophical doctrines: the close relationship of ethics and politics.¹ Personal virtue is intelligible only in the context of community and aim, and the goal of virtue is to contribute to human happiness.⁵ War, whether in ancient Greece or modern Europe, is among the forces most inimical to human flourishing. The current war in Ukraine that has united much of the Western world in opposition to tyranny has divided the 2 physicians in our story along the normative lines of virtue ethics.

The doctor of virtue: Michael Siclari, MD. A 71-year-old US Department of Veterans Affairs physician, Siclari had previously served in the military as a National Guard physician during Operation Enduring Freedom (2001-2014) in Afghanistan. He decided to serve again in Ukraine. Siclari expressed his reasons for going to Ukraine in the language of what Aristotle thought was among the highest virtues: justice. “In retrospect, as I think about why I wanted to go to Ukraine, I think it’s more of a sense that I thought an injustice was happening.”⁷

Echoing the great Rabbi Hillel, Siclari saw the Russian invasion of Ukraine as a personal call to use his experience and training as a trauma and emergency medicine physician to help the Ukrainian people. “If not me, then who?” Siclari demonstrated another virtue: generosity in taking 10 days of personal leave in August 2022 to make the trip to Ukraine, hoping to work in a combat zone tending to wounded soldiers as he had in Afghanistan. When due to logistics he instead was assigned to care for refugees and assist with evacuations from the battlefield, he humbly and compassionately cared for those in his charge. Even now, back home, he speaks to audiences of health care professionals encouraging them to consider similar acts of altruism.⁵

Virtue for Aristotle is technically defined as the mean between 2 extremes of disposition or temperament. The virtue of courage is found in the moral middle ground between the deficiency of bravery that is cowardice and the vice of excess of reckless abandon. The former person fears too much and the latter too little and both thus exhibit vicious behavior.

The doctor of vice: James Lee Henry. Henry is a major and internal medicine physician in the United States Army stationed at Fort Bragg, headquarters of the US Army Special Operations Command. Along with his wife Anna Gabrielian, a civilian anesthesiologist, he was charged in September with conspiring to divulge the protected health information of American military and government employees to the Russian government.⁸ According to the Grand Jury indictment, Henry delivered into the hands of an undercover Federal Bureau of Investigation (FBI) agent, the medical records of a US Army officer, Department of Defense employee, and the spouses of 3 Army veterans, 2 of whom were deceased.⁹ In a gross twisting of virtue language, Gabrielian explained her motivation for the couple’s espionage in terms of sacrifice and loyalty. In an antipode of Siclari’s service, Henry purportedly wanted to join the Russian army but did not have the requisite combat experience. For his part, Henry’s abysmal defense of his betrayal of his country and his oath speaks for itself, if the United States were to declare war on Russia, Henry told the FBI agent, “at that point, I’ll have some ethical issues I have to work through.”⁸

We become virtuous people through imitating the example of those who have perfected the habits of moral excellence. During 2022, 2 federal practitioners responded to the challenge of war: one displayed the zenith of virtue, the other exhibited the nadir of vice. Seldom does a single year present us with such clear choices of who and how we want to be in 2023. American culture has so trivialized New Year’s resolutions that they are no longer substantive enough for the weight of the profound question of what constitutes the good life. Rather let us make a commitment in keeping with such morally serious matters. All of us live as mixed creatures, drawn to virtue and prone to vice. May we all strive this coming year to help each other meet the high bar another great man of virtue Abraham Lincoln set in his first inaugural address, to be the “better angels of our natures.”¹⁰

Regular readers of Federal Practitioner may recall that I have had a tradition of dedicating the last column of the year to an ethics rendition of the popular trope of the annual best and worst. This year we will examine the stories of 2 military physicians through the lens of virtue ethics. Aristotle (384-322 bce), arguably the most famous Western philosopher, is the acknowledged founder of virtue ethics.

Virtue ethics is among the oldest of ethical theories, and Aristotle articulates this school of thought in his work Nicomachean Ethics.² It is a good fit for Federal Practitioner as it has been constructively applied to the moral development of both military³ and medical professionals.⁴

Here is a Reader’s Digest version of virtue theory with apologizes to all the real philosophers out there. There are different ways to categorize ethical theories. One approach is to distinguish them based on the aspects of primary interest. Consequentialist ethics theories are concerned with the outcomes of actions. Deontologic theories emphasize the intention of the moral agent. In contrast, virtue ethics theories focus on the character of a person. The virtuous individual is one who has practiced the habits of moral excellence and embodies the good life. They are honored as heroes and revered as saints; they are the exemplars we imitate in our aspirations.³

The epigraph sums up one of Aristotle’s central philosophical doctrines: the close relationship of ethics and politics.¹ Personal virtue is intelligible only in the context of community and aim, and the goal of virtue is to contribute to human happiness.⁵ War, whether in ancient Greece or modern Europe, is among the forces most inimical to human flourishing. The current war in Ukraine that has united much of the Western world in opposition to tyranny has divided the 2 physicians in our story along the normative lines of virtue ethics.

The doctor of virtue: Michael Siclari, MD. A 71-year-old US Department of Veterans Affairs physician, Siclari had previously served in the military as a National Guard physician during Operation Enduring Freedom (2001-2014) in Afghanistan. He decided to serve again in Ukraine. Siclari expressed his reasons for going to Ukraine in the language of what Aristotle thought was among the highest virtues: justice. “In retrospect, as I think about why I wanted to go to Ukraine, I think it’s more of a sense that I thought an injustice was happening.”⁷

Echoing the great Rabbi Hillel, Siclari saw the Russian invasion of Ukraine as a personal call to use his experience and training as a trauma and emergency medicine physician to help the Ukrainian people. “If not me, then who?” Siclari demonstrated another virtue: generosity in taking 10 days of personal leave in August 2022 to make the trip to Ukraine, hoping to work in a combat zone tending to wounded soldiers as he had in Afghanistan. When due to logistics he instead was assigned to care for refugees and assist with evacuations from the battlefield, he humbly and compassionately cared for those in his charge. Even now, back home, he speaks to audiences of health care professionals encouraging them to consider similar acts of altruism.⁵

Virtue for Aristotle is technically defined as the mean between 2 extremes of disposition or temperament. The virtue of courage is found in the moral middle ground between the deficiency of bravery that is cowardice and the vice of excess of reckless abandon. The former person fears too much and the latter too little and both thus exhibit vicious behavior.

The doctor of vice: James Lee Henry. Henry is a major and internal medicine physician in the United States Army stationed at Fort Bragg, headquarters of the US Army Special Operations Command. Along with his wife Anna Gabrielian, a civilian anesthesiologist, he was charged in September with conspiring to divulge the protected health information of American military and government employees to the Russian government.⁸ According to the Grand Jury indictment, Henry delivered into the hands of an undercover Federal Bureau of Investigation (FBI) agent, the medical records of a US Army officer, Department of Defense employee, and the spouses of 3 Army veterans, 2 of whom were deceased.⁹ In a gross twisting of virtue language, Gabrielian explained her motivation for the couple’s espionage in terms of sacrifice and loyalty. In an antipode of Siclari’s service, Henry purportedly wanted to join the Russian army but did not have the requisite combat experience. For his part, Henry’s abysmal defense of his betrayal of his country and his oath speaks for itself, if the United States were to declare war on Russia, Henry told the FBI agent, “at that point, I’ll have some ethical issues I have to work through.”⁸

We become virtuous people through imitating the example of those who have perfected the habits of moral excellence. During 2022, 2 federal practitioners responded to the challenge of war: one displayed the zenith of virtue, the other exhibited the nadir of vice. Seldom does a single year present us with such clear choices of who and how we want to be in 2023. American culture has so trivialized New Year’s resolutions that they are no longer substantive enough for the weight of the profound question of what constitutes the good life. Rather let us make a commitment in keeping with such morally serious matters. All of us live as mixed creatures, drawn to virtue and prone to vice. May we all strive this coming year to help each other meet the high bar another great man of virtue Abraham Lincoln set in his first inaugural address, to be the “better angels of our natures.”¹⁰

Regular readers of Federal Practitioner may recall that I have had a tradition of dedicating the last column of the year to an ethics rendition of the popular trope of the annual best and worst. This year we will examine the stories of 2 military physicians through the lens of virtue ethics. Aristotle (384-322 bce), arguably the most famous Western philosopher, is the acknowledged founder of virtue ethics.

Virtue ethics is among the oldest of ethical theories, and Aristotle articulates this school of thought in his work Nicomachean Ethics.² It is a good fit for Federal Practitioner as it has been constructively applied to the moral development of both military³ and medical professionals.⁴

Here is a Reader’s Digest version of virtue theory with apologizes to all the real philosophers out there. There are different ways to categorize ethical theories. One approach is to distinguish them based on the aspects of primary interest. Consequentialist ethics theories are concerned with the outcomes of actions. Deontologic theories emphasize the intention of the moral agent. In contrast, virtue ethics theories focus on the character of a person. The virtuous individual is one who has practiced the habits of moral excellence and embodies the good life. They are honored as heroes and revered as saints; they are the exemplars we imitate in our aspirations.³

The epigraph sums up one of Aristotle’s central philosophical doctrines: the close relationship of ethics and politics.¹ Personal virtue is intelligible only in the context of community and aim, and the goal of virtue is to contribute to human happiness.⁵ War, whether in ancient Greece or modern Europe, is among the forces most inimical to human flourishing. The current war in Ukraine that has united much of the Western world in opposition to tyranny has divided the 2 physicians in our story along the normative lines of virtue ethics.

The doctor of virtue: Michael Siclari, MD. A 71-year-old US Department of Veterans Affairs physician, Siclari had previously served in the military as a National Guard physician during Operation Enduring Freedom (2001-2014) in Afghanistan. He decided to serve again in Ukraine. Siclari expressed his reasons for going to Ukraine in the language of what Aristotle thought was among the highest virtues: justice. “In retrospect, as I think about why I wanted to go to Ukraine, I think it’s more of a sense that I thought an injustice was happening.”⁷

Echoing the great Rabbi Hillel, Siclari saw the Russian invasion of Ukraine as a personal call to use his experience and training as a trauma and emergency medicine physician to help the Ukrainian people. “If not me, then who?” Siclari demonstrated another virtue: generosity in taking 10 days of personal leave in August 2022 to make the trip to Ukraine, hoping to work in a combat zone tending to wounded soldiers as he had in Afghanistan. When due to logistics he instead was assigned to care for refugees and assist with evacuations from the battlefield, he humbly and compassionately cared for those in his charge. Even now, back home, he speaks to audiences of health care professionals encouraging them to consider similar acts of altruism.⁵

Virtue for Aristotle is technically defined as the mean between 2 extremes of disposition or temperament. The virtue of courage is found in the moral middle ground between the deficiency of bravery that is cowardice and the vice of excess of reckless abandon. The former person fears too much and the latter too little and both thus exhibit vicious behavior.

The doctor of vice: James Lee Henry. Henry is a major and internal medicine physician in the United States Army stationed at Fort Bragg, headquarters of the US Army Special Operations Command. Along with his wife Anna Gabrielian, a civilian anesthesiologist, he was charged in September with conspiring to divulge the protected health information of American military and government employees to the Russian government.⁸ According to the Grand Jury indictment, Henry delivered into the hands of an undercover Federal Bureau of Investigation (FBI) agent, the medical records of a US Army officer, Department of Defense employee, and the spouses of 3 Army veterans, 2 of whom were deceased.⁹ In a gross twisting of virtue language, Gabrielian explained her motivation for the couple’s espionage in terms of sacrifice and loyalty. In an antipode of Siclari’s service, Henry purportedly wanted to join the Russian army but did not have the requisite combat experience. For his part, Henry’s abysmal defense of his betrayal of his country and his oath speaks for itself, if the United States were to declare war on Russia, Henry told the FBI agent, “at that point, I’ll have some ethical issues I have to work through.”⁸

We become virtuous people through imitating the example of those who have perfected the habits of moral excellence. During 2022, 2 federal practitioners responded to the challenge of war: one displayed the zenith of virtue, the other exhibited the nadir of vice. Seldom does a single year present us with such clear choices of who and how we want to be in 2023. American culture has so trivialized New Year’s resolutions that they are no longer substantive enough for the weight of the profound question of what constitutes the good life. Rather let us make a commitment in keeping with such morally serious matters. All of us live as mixed creatures, drawn to virtue and prone to vice. May we all strive this coming year to help each other meet the high bar another great man of virtue Abraham Lincoln set in his first inaugural address, to be the “better angels of our natures.”¹⁰

We are all seeing more children on the autism spectrum than we ever expected. With a Centers for Disease Control–estimated prevalence of 1 in 44, the average pediatrician will be caring for 45 children with autism. It may feel like even more as parents bring in their children with related concerns or fears. Early entry into services has been shown to improve functioning, making early identification important. However, screening at the youngest ages has important limitations.

Sharing a concern about possible autism with parents is a painful aspect of primary care practice. We want to get it right, not frighten parents unnecessarily, nor miss children and delay intervention.

Autism screening is recommended by the American Academy of Pediatrics at 18- and 24-month pediatric well-child visits. There are several reasons for screening repeatedly: Autism symptoms emerge gradually in the toddler period; about 32% of children later found to have autism were developing in a typical pattern and appeared normal at 18 months only to regress by age 24 months; children may miss the 18 month screen; and all screens have false negatives as well as false positives. But even screening at these two ages is not enough.

One criticism of current screening tests pointed out by the U.S. Preventive Services Task Force has been a problem with the sample used to develop or validate the tool. Many test development studies included only children at risk by being in early intervention, siblings of children with diagnosed autism, or children only failing the screening tests rather than a community sample that the screen in actually used for.

Another obstacle to prediction of autism diagnoses made years later is that some children may not have had any clinical manifestations at the younger age even as judged by the best gold standard testing and, thus, negative screens were ambiguous. Additionally, data from prospective studies of high-risk infant siblings reveal that only 18% of children diagnosed with autism at 36 months were given that diagnosis at 18 months of age despite use of comprehensive diagnostic assessments.

Prevalence is also reported as 30% higher at age 8-12 years as at 3-7 years on gold-standard tests. Children identified later with autism tend to have milder symptoms and higher cognitive functioning. Therefore, we need some humility in thinking we can identify children as early as 18 months; rather, we need to use the best available methods at all ages and remain vigilant to symptoms as they evolve as well as to new screening and testing measures.

The most commonly used parent report screen is the 20-item Modified Checklist for Autism in Toddlers–Revised (M-CHAT-R), a modification of the original CHAT screen. To have reasonable positive predictive value, the M-CHAT-R authors recommend a clinician or trained staff member conduct a structured follow-up interview with the parent when the M-CHAT-R has a score of 3-7. Scores of 8 or more reflect enough symptoms to more strongly predict an autism diagnosis and thus the interview may be skipped in those cases. The recommended two-step process is called M-CHAT-R/F. At 18 months without the R/F, a positive M-CHAT-R only is associated with an autism diagnosis 27% of the time (PPV, 0.27); which is unacceptable for primary care use.

Unfortunately, the M-CHAT-R/F appears to be less accurate for 18-month-olds than 24-month-olds, in part because its yes/no response options are harder for a caregiver to answer, especially for behaviors just developing, or because of lack of experience with toddlers.

An alternative modification of the original CHAT called the Quantitative CHAT or Q-CHAT-10 has a range of response options for the caregiver; for example, always/usually/sometimes/rarely/never or many times a day/a few times a day/a few times a week/less than once a week/never. The authors of the Q-CHAT-10, however, recommend a summary pass/fail result for ease of use rather than using the range of response option values in the score. We recently published a study testing accuracy using add-up scoring that utilized the entire range of response option values, called Q-CHAT-10-O (O for ordinal), for children 16-20 months old as well as cartoon depictions of the behaviors. Our study also included diagnostic testing of screen-negative as well as screen-positive children to accurately calculate sensitivity and specificity for this method. In our study, Q-CHAT-10-O with a cutoff score greater than 11 showed higher sensitivity (0.63) than either M-CHAT-R/F (0.34) or Q-CHAT-10 (0.31) for this age range although the PPV (0.35) and negative predictive value (0.92) were comparable with M-CHAT R/F. Although Q-CHAT-10-O sensitivity (0.63) is less than M-CHAT-R (without follow-up; 0.73) and specificity (0.79) is less than the two-stage R/F procedure (0.90), on balance, it is more accurate and more practical for a primary care population. After 20 months of age, the M-CHAT-R/F has adequate accuracy to rescreen, if indicated, and for the subsequent 24 month screening. Language items are often of highest value in predicting outcomes in several tools including in the screen we are now validating for 18 month olds.

The Q-CHAT-10-O with ordinal scoring and pictures can also be recommended because it shows advantages over M-CHAT-R/F with half the number of items (10 vs. 20), no requirement for a follow-up interview, and improved sensitivity. Unlike M-CHAT-R, it also contributes to equity in screening because results did not differ depending on race or socioeconomic background.

Is there an even better way to detect autism in primary care? In 2022 an article was published regarding an exciting method of early autism detection called the Social Attention and Communication Surveillance–Revised (SACS-R), an eight-item observation checklist completed at public health nurse check-ups in Australia. The observers had 4 years of nursing degree education and a 3.5-hour training session.

The SACS-R and the preschool version (for older children) had significant associations with diagnostic testing at 12, 18, 24, and 42 months. The SACS-R had excellent PPV (82.6%), NPV (98.7%), and specificity (99.6%) and moderate sensitivity (61.5%) when used between 12 and 24 months of age. Pointing, eye contact, waving “bye, bye,” social communication by showing, and pretend play were the key indicators for observations at 18 months, with absence of three or more indicating risk for autism. Different key indicators were used at the other ages, reflecting the evolution of autism symptoms. This hybrid (observation and scoring) surveillance method by professionals shows hopeful data for the critical ability to identify children at risk for autism in primary care very early but requires more than parent report, that is, new levels of autism-specific clinician training and direct observations at multiple visits over time.

The takeaway is to remember that we should all watch closely for early signs of autism, informed by research on the key findings that a professional might observe, as well as by using the best screens available. We should remember that both false positives and false negatives are inherent in screening, especially at the youngest ages. We need to combine our concern with the parent’s concern as well as screen results and be sure to follow-up closely as symptoms can change in even a few months. Many factors may prevent a family from returning to see us or following our advice to go for testing or intervention, so tracking the child and their service use is an important part of the good care we strive to provide children with autism.

Other screening tools

You may have heard of other parent-report screens for autism. It is important to compare their accuracy specifically for 18-month-olds in a community setting.

• The Infant Toddler Checklist (https://psychology-tools.com/test/infant-toddler-checklist) has moderate overall psychometrics with sensitivity ranging from 0.55 to 0.77; specificity from 0.42 to 0.85; PPV from 0.20 to 0.55; and NPV from 0.83 to 0.94. However, the data were based on a sample including both community-dwelling toddlers and those with a family history of autism.
• The Brief Infant-Toddler Social and Emotional Assessment (https://eprovide.mapi-trust.org/instruments/brief-infant-toddler-social-emotional-assessment/) – the screen’s four autism-specific scales had high specificity (84%-90%) but low sensitivity (40%-52%).
• Canvas Dx (https://canvasdx.com/) from the Cognoa company is not a parent-report measure but rather a three-part evaluation including an app-based parent questionnaire, parent uploads of home videos analyzed by a specialist, and a 13- to 15-item primary care physician observational checklist. There were 56 diagnosed of the 426 children in the 18- to 24-month-old range from a sample of children presenting with parent or clinician concerns rather than from a community sample.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. Email her at [email protected].

References

Sturner R et al. Autism screening at 18 months of age: A comparison of the Q-CHAT-10 and M-CHAT screeners. Molecular Autism. Jan 3;13(1):2.

Barbaro J et al. Diagnostic accuracy of the Social Attention and Communication Surveillance–Revised with preschool tool for early autism detection in very young children. JAMA Netw Open. 2022;5(3):e2146415.

We are all seeing more children on the autism spectrum than we ever expected. With a Centers for Disease Control–estimated prevalence of 1 in 44, the average pediatrician will be caring for 45 children with autism. It may feel like even more as parents bring in their children with related concerns or fears. Early entry into services has been shown to improve functioning, making early identification important. However, screening at the youngest ages has important limitations.

Sharing a concern about possible autism with parents is a painful aspect of primary care practice. We want to get it right, not frighten parents unnecessarily, nor miss children and delay intervention.

Autism screening is recommended by the American Academy of Pediatrics at 18- and 24-month pediatric well-child visits. There are several reasons for screening repeatedly: Autism symptoms emerge gradually in the toddler period; about 32% of children later found to have autism were developing in a typical pattern and appeared normal at 18 months only to regress by age 24 months; children may miss the 18 month screen; and all screens have false negatives as well as false positives. But even screening at these two ages is not enough.

One criticism of current screening tests pointed out by the U.S. Preventive Services Task Force has been a problem with the sample used to develop or validate the tool. Many test development studies included only children at risk by being in early intervention, siblings of children with diagnosed autism, or children only failing the screening tests rather than a community sample that the screen in actually used for.

Another obstacle to prediction of autism diagnoses made years later is that some children may not have had any clinical manifestations at the younger age even as judged by the best gold standard testing and, thus, negative screens were ambiguous. Additionally, data from prospective studies of high-risk infant siblings reveal that only 18% of children diagnosed with autism at 36 months were given that diagnosis at 18 months of age despite use of comprehensive diagnostic assessments.

Prevalence is also reported as 30% higher at age 8-12 years as at 3-7 years on gold-standard tests. Children identified later with autism tend to have milder symptoms and higher cognitive functioning. Therefore, we need some humility in thinking we can identify children as early as 18 months; rather, we need to use the best available methods at all ages and remain vigilant to symptoms as they evolve as well as to new screening and testing measures.

The most commonly used parent report screen is the 20-item Modified Checklist for Autism in Toddlers–Revised (M-CHAT-R), a modification of the original CHAT screen. To have reasonable positive predictive value, the M-CHAT-R authors recommend a clinician or trained staff member conduct a structured follow-up interview with the parent when the M-CHAT-R has a score of 3-7. Scores of 8 or more reflect enough symptoms to more strongly predict an autism diagnosis and thus the interview may be skipped in those cases. The recommended two-step process is called M-CHAT-R/F. At 18 months without the R/F, a positive M-CHAT-R only is associated with an autism diagnosis 27% of the time (PPV, 0.27); which is unacceptable for primary care use.

Unfortunately, the M-CHAT-R/F appears to be less accurate for 18-month-olds than 24-month-olds, in part because its yes/no response options are harder for a caregiver to answer, especially for behaviors just developing, or because of lack of experience with toddlers.

An alternative modification of the original CHAT called the Quantitative CHAT or Q-CHAT-10 has a range of response options for the caregiver; for example, always/usually/sometimes/rarely/never or many times a day/a few times a day/a few times a week/less than once a week/never. The authors of the Q-CHAT-10, however, recommend a summary pass/fail result for ease of use rather than using the range of response option values in the score. We recently published a study testing accuracy using add-up scoring that utilized the entire range of response option values, called Q-CHAT-10-O (O for ordinal), for children 16-20 months old as well as cartoon depictions of the behaviors. Our study also included diagnostic testing of screen-negative as well as screen-positive children to accurately calculate sensitivity and specificity for this method. In our study, Q-CHAT-10-O with a cutoff score greater than 11 showed higher sensitivity (0.63) than either M-CHAT-R/F (0.34) or Q-CHAT-10 (0.31) for this age range although the PPV (0.35) and negative predictive value (0.92) were comparable with M-CHAT R/F. Although Q-CHAT-10-O sensitivity (0.63) is less than M-CHAT-R (without follow-up; 0.73) and specificity (0.79) is less than the two-stage R/F procedure (0.90), on balance, it is more accurate and more practical for a primary care population. After 20 months of age, the M-CHAT-R/F has adequate accuracy to rescreen, if indicated, and for the subsequent 24 month screening. Language items are often of highest value in predicting outcomes in several tools including in the screen we are now validating for 18 month olds.

The Q-CHAT-10-O with ordinal scoring and pictures can also be recommended because it shows advantages over M-CHAT-R/F with half the number of items (10 vs. 20), no requirement for a follow-up interview, and improved sensitivity. Unlike M-CHAT-R, it also contributes to equity in screening because results did not differ depending on race or socioeconomic background.

Is there an even better way to detect autism in primary care? In 2022 an article was published regarding an exciting method of early autism detection called the Social Attention and Communication Surveillance–Revised (SACS-R), an eight-item observation checklist completed at public health nurse check-ups in Australia. The observers had 4 years of nursing degree education and a 3.5-hour training session.

The SACS-R and the preschool version (for older children) had significant associations with diagnostic testing at 12, 18, 24, and 42 months. The SACS-R had excellent PPV (82.6%), NPV (98.7%), and specificity (99.6%) and moderate sensitivity (61.5%) when used between 12 and 24 months of age. Pointing, eye contact, waving “bye, bye,” social communication by showing, and pretend play were the key indicators for observations at 18 months, with absence of three or more indicating risk for autism. Different key indicators were used at the other ages, reflecting the evolution of autism symptoms. This hybrid (observation and scoring) surveillance method by professionals shows hopeful data for the critical ability to identify children at risk for autism in primary care very early but requires more than parent report, that is, new levels of autism-specific clinician training and direct observations at multiple visits over time.

The takeaway is to remember that we should all watch closely for early signs of autism, informed by research on the key findings that a professional might observe, as well as by using the best screens available. We should remember that both false positives and false negatives are inherent in screening, especially at the youngest ages. We need to combine our concern with the parent’s concern as well as screen results and be sure to follow-up closely as symptoms can change in even a few months. Many factors may prevent a family from returning to see us or following our advice to go for testing or intervention, so tracking the child and their service use is an important part of the good care we strive to provide children with autism.

Other screening tools

You may have heard of other parent-report screens for autism. It is important to compare their accuracy specifically for 18-month-olds in a community setting.

• The Infant Toddler Checklist (https://psychology-tools.com/test/infant-toddler-checklist) has moderate overall psychometrics with sensitivity ranging from 0.55 to 0.77; specificity from 0.42 to 0.85; PPV from 0.20 to 0.55; and NPV from 0.83 to 0.94. However, the data were based on a sample including both community-dwelling toddlers and those with a family history of autism.
• The Brief Infant-Toddler Social and Emotional Assessment (https://eprovide.mapi-trust.org/instruments/brief-infant-toddler-social-emotional-assessment/) – the screen’s four autism-specific scales had high specificity (84%-90%) but low sensitivity (40%-52%).
• Canvas Dx (https://canvasdx.com/) from the Cognoa company is not a parent-report measure but rather a three-part evaluation including an app-based parent questionnaire, parent uploads of home videos analyzed by a specialist, and a 13- to 15-item primary care physician observational checklist. There were 56 diagnosed of the 426 children in the 18- to 24-month-old range from a sample of children presenting with parent or clinician concerns rather than from a community sample.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. Email her at [email protected].

References

Sturner R et al. Autism screening at 18 months of age: A comparison of the Q-CHAT-10 and M-CHAT screeners. Molecular Autism. Jan 3;13(1):2.

Barbaro J et al. Diagnostic accuracy of the Social Attention and Communication Surveillance–Revised with preschool tool for early autism detection in very young children. JAMA Netw Open. 2022;5(3):e2146415.

We are all seeing more children on the autism spectrum than we ever expected. With a Centers for Disease Control–estimated prevalence of 1 in 44, the average pediatrician will be caring for 45 children with autism. It may feel like even more as parents bring in their children with related concerns or fears. Early entry into services has been shown to improve functioning, making early identification important. However, screening at the youngest ages has important limitations.

Sharing a concern about possible autism with parents is a painful aspect of primary care practice. We want to get it right, not frighten parents unnecessarily, nor miss children and delay intervention.

Autism screening is recommended by the American Academy of Pediatrics at 18- and 24-month pediatric well-child visits. There are several reasons for screening repeatedly: Autism symptoms emerge gradually in the toddler period; about 32% of children later found to have autism were developing in a typical pattern and appeared normal at 18 months only to regress by age 24 months; children may miss the 18 month screen; and all screens have false negatives as well as false positives. But even screening at these two ages is not enough.

One criticism of current screening tests pointed out by the U.S. Preventive Services Task Force has been a problem with the sample used to develop or validate the tool. Many test development studies included only children at risk by being in early intervention, siblings of children with diagnosed autism, or children only failing the screening tests rather than a community sample that the screen in actually used for.

Another obstacle to prediction of autism diagnoses made years later is that some children may not have had any clinical manifestations at the younger age even as judged by the best gold standard testing and, thus, negative screens were ambiguous. Additionally, data from prospective studies of high-risk infant siblings reveal that only 18% of children diagnosed with autism at 36 months were given that diagnosis at 18 months of age despite use of comprehensive diagnostic assessments.

Prevalence is also reported as 30% higher at age 8-12 years as at 3-7 years on gold-standard tests. Children identified later with autism tend to have milder symptoms and higher cognitive functioning. Therefore, we need some humility in thinking we can identify children as early as 18 months; rather, we need to use the best available methods at all ages and remain vigilant to symptoms as they evolve as well as to new screening and testing measures.

The most commonly used parent report screen is the 20-item Modified Checklist for Autism in Toddlers–Revised (M-CHAT-R), a modification of the original CHAT screen. To have reasonable positive predictive value, the M-CHAT-R authors recommend a clinician or trained staff member conduct a structured follow-up interview with the parent when the M-CHAT-R has a score of 3-7. Scores of 8 or more reflect enough symptoms to more strongly predict an autism diagnosis and thus the interview may be skipped in those cases. The recommended two-step process is called M-CHAT-R/F. At 18 months without the R/F, a positive M-CHAT-R only is associated with an autism diagnosis 27% of the time (PPV, 0.27); which is unacceptable for primary care use.

Unfortunately, the M-CHAT-R/F appears to be less accurate for 18-month-olds than 24-month-olds, in part because its yes/no response options are harder for a caregiver to answer, especially for behaviors just developing, or because of lack of experience with toddlers.

An alternative modification of the original CHAT called the Quantitative CHAT or Q-CHAT-10 has a range of response options for the caregiver; for example, always/usually/sometimes/rarely/never or many times a day/a few times a day/a few times a week/less than once a week/never. The authors of the Q-CHAT-10, however, recommend a summary pass/fail result for ease of use rather than using the range of response option values in the score. We recently published a study testing accuracy using add-up scoring that utilized the entire range of response option values, called Q-CHAT-10-O (O for ordinal), for children 16-20 months old as well as cartoon depictions of the behaviors. Our study also included diagnostic testing of screen-negative as well as screen-positive children to accurately calculate sensitivity and specificity for this method. In our study, Q-CHAT-10-O with a cutoff score greater than 11 showed higher sensitivity (0.63) than either M-CHAT-R/F (0.34) or Q-CHAT-10 (0.31) for this age range although the PPV (0.35) and negative predictive value (0.92) were comparable with M-CHAT R/F. Although Q-CHAT-10-O sensitivity (0.63) is less than M-CHAT-R (without follow-up; 0.73) and specificity (0.79) is less than the two-stage R/F procedure (0.90), on balance, it is more accurate and more practical for a primary care population. After 20 months of age, the M-CHAT-R/F has adequate accuracy to rescreen, if indicated, and for the subsequent 24 month screening. Language items are often of highest value in predicting outcomes in several tools including in the screen we are now validating for 18 month olds.

The Q-CHAT-10-O with ordinal scoring and pictures can also be recommended because it shows advantages over M-CHAT-R/F with half the number of items (10 vs. 20), no requirement for a follow-up interview, and improved sensitivity. Unlike M-CHAT-R, it also contributes to equity in screening because results did not differ depending on race or socioeconomic background.

Is there an even better way to detect autism in primary care? In 2022 an article was published regarding an exciting method of early autism detection called the Social Attention and Communication Surveillance–Revised (SACS-R), an eight-item observation checklist completed at public health nurse check-ups in Australia. The observers had 4 years of nursing degree education and a 3.5-hour training session.

The SACS-R and the preschool version (for older children) had significant associations with diagnostic testing at 12, 18, 24, and 42 months. The SACS-R had excellent PPV (82.6%), NPV (98.7%), and specificity (99.6%) and moderate sensitivity (61.5%) when used between 12 and 24 months of age. Pointing, eye contact, waving “bye, bye,” social communication by showing, and pretend play were the key indicators for observations at 18 months, with absence of three or more indicating risk for autism. Different key indicators were used at the other ages, reflecting the evolution of autism symptoms. This hybrid (observation and scoring) surveillance method by professionals shows hopeful data for the critical ability to identify children at risk for autism in primary care very early but requires more than parent report, that is, new levels of autism-specific clinician training and direct observations at multiple visits over time.

The takeaway is to remember that we should all watch closely for early signs of autism, informed by research on the key findings that a professional might observe, as well as by using the best screens available. We should remember that both false positives and false negatives are inherent in screening, especially at the youngest ages. We need to combine our concern with the parent’s concern as well as screen results and be sure to follow-up closely as symptoms can change in even a few months. Many factors may prevent a family from returning to see us or following our advice to go for testing or intervention, so tracking the child and their service use is an important part of the good care we strive to provide children with autism.

Other screening tools

You may have heard of other parent-report screens for autism. It is important to compare their accuracy specifically for 18-month-olds in a community setting.

• The Infant Toddler Checklist (https://psychology-tools.com/test/infant-toddler-checklist) has moderate overall psychometrics with sensitivity ranging from 0.55 to 0.77; specificity from 0.42 to 0.85; PPV from 0.20 to 0.55; and NPV from 0.83 to 0.94. However, the data were based on a sample including both community-dwelling toddlers and those with a family history of autism.
• The Brief Infant-Toddler Social and Emotional Assessment (https://eprovide.mapi-trust.org/instruments/brief-infant-toddler-social-emotional-assessment/) – the screen’s four autism-specific scales had high specificity (84%-90%) but low sensitivity (40%-52%).
• Canvas Dx (https://canvasdx.com/) from the Cognoa company is not a parent-report measure but rather a three-part evaluation including an app-based parent questionnaire, parent uploads of home videos analyzed by a specialist, and a 13- to 15-item primary care physician observational checklist. There were 56 diagnosed of the 426 children in the 18- to 24-month-old range from a sample of children presenting with parent or clinician concerns rather than from a community sample.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. Email her at [email protected].

References

Sturner R et al. Autism screening at 18 months of age: A comparison of the Q-CHAT-10 and M-CHAT screeners. Molecular Autism. Jan 3;13(1):2.

Barbaro J et al. Diagnostic accuracy of the Social Attention and Communication Surveillance–Revised with preschool tool for early autism detection in very young children. JAMA Netw Open. 2022;5(3):e2146415.

When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.

Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.

The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.

Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.

For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.

The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.

Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.

In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:

• During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
• A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
• The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
• Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).

In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.

Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”

In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.

Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.

Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.

Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.

Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.

The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.

Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.

For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.

The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.

Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.

In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:

• During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
• A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
• The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
• Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).

In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.

Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”

In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.

Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.

Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.

Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.

Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.

The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.

Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.

For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.

The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.

Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.

In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:

• During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
• A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
• The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
• Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).

In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.

Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”

In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.

Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.

Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.

Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

NASHVILLE, TENN. – Patients with dementia and active seizures experience faster cognitive and functional decline and have a greater risk of dying younger than people with dementia who don’t have seizures, according to a multicenter study presented at the 2022 annual meeting of the American Epilepsy Society.

“When we compared patients with seizures with those who did not have seizures, we found that patients with seizures were more likely to have more severe cognitive impairment; they were more likely to have physical dependence and so worse functional outcomes; and they also had higher mortality rates at a younger age,” lead study author Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, Charlottesville, said in an interview.

“The average age of mortality for seizure patients was around 72 years and the average age of mortality for nonseizure patients was around 79 years, so there was a 7- to 8-year difference in mortality,” she said.
 

Seizures make matters worse

The study analyzed data on 26,425 patients with dementia, 374 (1.4%) of whom had seizures, collected from 2005 to 2021 at 39 Alzheimer’s disease centers in the United States. Patients who had seizures were significantly younger when cognitive decline began (ages 62.9 vs. 68.4 years, P < .001) and died younger (72.99 vs. 79.72 years, P < .001).

The study also found a number of factors associated with active seizures, including a history of dominant Alzheimer’s disease mutation (odds ratio, 5.55; P < .001), stroke (OR, 3.17; P < .001), transient ischemic attack (OR, 1.72; P = .003), traumatic brain injury (OR, 1.92; P < .001), Parkinson’s disease (OR, 1.79; P = .025), active depression (OR, 1.61; P < .001) and lower education (OR, 0.97; P =.043).

After the study made adjustments for sex and other associated factors, it found that patients with seizures were still at a 76% higher risk of dying younger (hazard ratio, 1.76; P < .001).

The study also determined that patients with seizures had worse functional assessment scores and were more likely to be physically dependent on others (OR, 2.52; P < .001). Seizure patients also performed worse on Mini-Mental Status Examination (18.50 vs. 22.88; P < .001) and Clinical Dementia Rating-Sum of boxes (7.95 vs. 4.28; P < .001) after adjusting for age and duration of cognitive decline.
 

A tip for caregivers

Dr. Zawar acknowledged that differentiating seizures from transient bouts of confusion in people with dementia can be difficult for family members and caregivers, but she offered advice to help them do so. “If they notice any unusual confusion or any altered mentation which is episodic in nature,” she said, “they should bring it to the neurologist’s attention as early as possible, because there are studies that have shown the diagnosis of seizures is delayed, and if they are treated in time they can be well-controlled.” Electroencephalography can also confirm the presence of seizures, she added.

Double whammy

One limitation of this study is the lack of details on the types of seizures the participants had along with the inconsistency of EEGs performed on the study population. “In future studies, I would like to have more EEG data on the types of seizures and the frequency of seizures to assess these factors further,” Dr. Zawar said.

Having more detailed information on the seizures would make the findings more valuable, Andrew J. Cole, MD, director of the epilepsy service at Massachusetts General Hospital in Boston said in an interview. “We know a lot about clinically apparent seizures, as witnessed by this paper, but we still don’t know a whole lot about clinically silent or cryptic or nighttime-only seizures that maybe no one would really recognize as such unless they were specifically looking for them, and this paper doesn’t address that issue,” he said.

While the finding that patients with other neurologic diseases have more seizures even if they also have Alzheimer’s disease isn’t “a huge surprise,” Dr. Cole added. “On the other hand, the paper is important because it shows us that in the course of having Alzheimer’s disease, having seizures also makes your outcome worse, the speed of progression faster, and it complicates the management and living with this disease, and they make that point quite clear.”

Dr. Zawar and Dr. Cole have no relevant disclosures.
 

NASHVILLE, TENN. – Patients with dementia and active seizures experience faster cognitive and functional decline and have a greater risk of dying younger than people with dementia who don’t have seizures, according to a multicenter study presented at the 2022 annual meeting of the American Epilepsy Society.

“When we compared patients with seizures with those who did not have seizures, we found that patients with seizures were more likely to have more severe cognitive impairment; they were more likely to have physical dependence and so worse functional outcomes; and they also had higher mortality rates at a younger age,” lead study author Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, Charlottesville, said in an interview.

“The average age of mortality for seizure patients was around 72 years and the average age of mortality for nonseizure patients was around 79 years, so there was a 7- to 8-year difference in mortality,” she said.
 

Seizures make matters worse

The study analyzed data on 26,425 patients with dementia, 374 (1.4%) of whom had seizures, collected from 2005 to 2021 at 39 Alzheimer’s disease centers in the United States. Patients who had seizures were significantly younger when cognitive decline began (ages 62.9 vs. 68.4 years, P < .001) and died younger (72.99 vs. 79.72 years, P < .001).

The study also found a number of factors associated with active seizures, including a history of dominant Alzheimer’s disease mutation (odds ratio, 5.55; P < .001), stroke (OR, 3.17; P < .001), transient ischemic attack (OR, 1.72; P = .003), traumatic brain injury (OR, 1.92; P < .001), Parkinson’s disease (OR, 1.79; P = .025), active depression (OR, 1.61; P < .001) and lower education (OR, 0.97; P =.043).

After the study made adjustments for sex and other associated factors, it found that patients with seizures were still at a 76% higher risk of dying younger (hazard ratio, 1.76; P < .001).

The study also determined that patients with seizures had worse functional assessment scores and were more likely to be physically dependent on others (OR, 2.52; P < .001). Seizure patients also performed worse on Mini-Mental Status Examination (18.50 vs. 22.88; P < .001) and Clinical Dementia Rating-Sum of boxes (7.95 vs. 4.28; P < .001) after adjusting for age and duration of cognitive decline.
 

A tip for caregivers

Dr. Zawar acknowledged that differentiating seizures from transient bouts of confusion in people with dementia can be difficult for family members and caregivers, but she offered advice to help them do so. “If they notice any unusual confusion or any altered mentation which is episodic in nature,” she said, “they should bring it to the neurologist’s attention as early as possible, because there are studies that have shown the diagnosis of seizures is delayed, and if they are treated in time they can be well-controlled.” Electroencephalography can also confirm the presence of seizures, she added.

Double whammy

One limitation of this study is the lack of details on the types of seizures the participants had along with the inconsistency of EEGs performed on the study population. “In future studies, I would like to have more EEG data on the types of seizures and the frequency of seizures to assess these factors further,” Dr. Zawar said.

Having more detailed information on the seizures would make the findings more valuable, Andrew J. Cole, MD, director of the epilepsy service at Massachusetts General Hospital in Boston said in an interview. “We know a lot about clinically apparent seizures, as witnessed by this paper, but we still don’t know a whole lot about clinically silent or cryptic or nighttime-only seizures that maybe no one would really recognize as such unless they were specifically looking for them, and this paper doesn’t address that issue,” he said.

While the finding that patients with other neurologic diseases have more seizures even if they also have Alzheimer’s disease isn’t “a huge surprise,” Dr. Cole added. “On the other hand, the paper is important because it shows us that in the course of having Alzheimer’s disease, having seizures also makes your outcome worse, the speed of progression faster, and it complicates the management and living with this disease, and they make that point quite clear.”

Dr. Zawar and Dr. Cole have no relevant disclosures.
 

NASHVILLE, TENN. – Patients with dementia and active seizures experience faster cognitive and functional decline and have a greater risk of dying younger than people with dementia who don’t have seizures, according to a multicenter study presented at the 2022 annual meeting of the American Epilepsy Society.

“When we compared patients with seizures with those who did not have seizures, we found that patients with seizures were more likely to have more severe cognitive impairment; they were more likely to have physical dependence and so worse functional outcomes; and they also had higher mortality rates at a younger age,” lead study author Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, Charlottesville, said in an interview.

“The average age of mortality for seizure patients was around 72 years and the average age of mortality for nonseizure patients was around 79 years, so there was a 7- to 8-year difference in mortality,” she said.
 

Seizures make matters worse

The study analyzed data on 26,425 patients with dementia, 374 (1.4%) of whom had seizures, collected from 2005 to 2021 at 39 Alzheimer’s disease centers in the United States. Patients who had seizures were significantly younger when cognitive decline began (ages 62.9 vs. 68.4 years, P < .001) and died younger (72.99 vs. 79.72 years, P < .001).

The study also found a number of factors associated with active seizures, including a history of dominant Alzheimer’s disease mutation (odds ratio, 5.55; P < .001), stroke (OR, 3.17; P < .001), transient ischemic attack (OR, 1.72; P = .003), traumatic brain injury (OR, 1.92; P < .001), Parkinson’s disease (OR, 1.79; P = .025), active depression (OR, 1.61; P < .001) and lower education (OR, 0.97; P =.043).

After the study made adjustments for sex and other associated factors, it found that patients with seizures were still at a 76% higher risk of dying younger (hazard ratio, 1.76; P < .001).

The study also determined that patients with seizures had worse functional assessment scores and were more likely to be physically dependent on others (OR, 2.52; P < .001). Seizure patients also performed worse on Mini-Mental Status Examination (18.50 vs. 22.88; P < .001) and Clinical Dementia Rating-Sum of boxes (7.95 vs. 4.28; P < .001) after adjusting for age and duration of cognitive decline.
 

A tip for caregivers

Dr. Zawar acknowledged that differentiating seizures from transient bouts of confusion in people with dementia can be difficult for family members and caregivers, but she offered advice to help them do so. “If they notice any unusual confusion or any altered mentation which is episodic in nature,” she said, “they should bring it to the neurologist’s attention as early as possible, because there are studies that have shown the diagnosis of seizures is delayed, and if they are treated in time they can be well-controlled.” Electroencephalography can also confirm the presence of seizures, she added.

Double whammy

One limitation of this study is the lack of details on the types of seizures the participants had along with the inconsistency of EEGs performed on the study population. “In future studies, I would like to have more EEG data on the types of seizures and the frequency of seizures to assess these factors further,” Dr. Zawar said.

Having more detailed information on the seizures would make the findings more valuable, Andrew J. Cole, MD, director of the epilepsy service at Massachusetts General Hospital in Boston said in an interview. “We know a lot about clinically apparent seizures, as witnessed by this paper, but we still don’t know a whole lot about clinically silent or cryptic or nighttime-only seizures that maybe no one would really recognize as such unless they were specifically looking for them, and this paper doesn’t address that issue,” he said.

While the finding that patients with other neurologic diseases have more seizures even if they also have Alzheimer’s disease isn’t “a huge surprise,” Dr. Cole added. “On the other hand, the paper is important because it shows us that in the course of having Alzheimer’s disease, having seizures also makes your outcome worse, the speed of progression faster, and it complicates the management and living with this disease, and they make that point quite clear.”

Dr. Zawar and Dr. Cole have no relevant disclosures.
 

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

AT ASH 2022 NEW ORLEANS – Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of those who survive into adulthood then pay a high price in terms of accelerated aging and neurocognitive impairment.

The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.

The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.

In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”

Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.

“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.

“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.

“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”

Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.

Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”

She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
 

Long-term complications

Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.

In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.

The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.

The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.

All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.

Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.

As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).

More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.

HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).

In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.

HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.

The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.

Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”

The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.

The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.

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

AT ASH 2022 NEW ORLEANS – Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of those who survive into adulthood then pay a high price in terms of accelerated aging and neurocognitive impairment.

The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.

The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.

In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”

Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.

“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.

“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.

“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”

Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.

Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”

She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
 

Long-term complications

Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.

In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.

The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.

The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.

All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.

Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.

As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).

More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.

HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).

In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.

HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.

The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.

Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”

The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.

The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.

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

AT ASH 2022 NEW ORLEANS – Children with Hodgkin lymphoma can be cured with intensive chemotherapy, radiation, and other modalities, but a large majority of those who survive into adulthood then pay a high price in terms of accelerated aging and neurocognitive impairment.

The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.

The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.

In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.

“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”

Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.

“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.

“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.

“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”

Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.

Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”

She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
 

Long-term complications

Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.

In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.

The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.

The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.

All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.

Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.

As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).

More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.

HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).

In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.

HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.

The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.

Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”

The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.

The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.

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

NEW ORLEANS – Save lives; save money. What’s not to love? That’s the claim made for a proposed nationwide data bank on alloantibodies, which develop in response to foreign red blood cells in individuals who undergo repeated blood transfusions. They can occur after pregnancy or transplants, as well as in patients with sickle cell disease.

A central repository of data on alloantibodies would save lives by preventing serious immune reactions among patients with sickle cell disease and other maladies, and would save costs associated with hospitalization for serious and potentially fatal infusion reactions, say the creators of a mathematical model demonstrating the clear value of such a databank.

“The findings from our model are pretty definitive,” said George Goshua, MD, MSc, of Yale University, New Haven, Conn. “Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction (DHTR).”

Dr. Goshua presented the study at the American Society of Hematology annual meeting. The proposed registry would significantly reduce the risk that transfusion-dependent patients, and others who require occasional transfusions, would develop complications requiring hospitalization, he said.

A similar registry has been up and running in the Netherlands for 15 years, he said at a press briefing.

Briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children’s National Research Institute in Washington, asked Dr. Goshua why such an exchange hasn’t been started in the United States already.

“I will say first that our European colleagues are far ahead in terms of preventative care,” he replied.

“On top of that, there’s a unique environment in the United States – and this dates back about 15 years now – where we are almost allergic to putting costs on benefits, that is, attaching a cost value to a benefit that a population can gain,” Dr. Goshua said. “So in this context, there hasn’t been an analysis that shows that this [exchange] actually makes sense, but I think it’s one of those analyses kind of showing people that the sky is blue but proving it quantitatively.”

Dr. Bollard said that the potential beneficial impact of such an exchange “is huge,” but it would “require upfront expenditure to actually realize these massive gains you will get down the road for these patients.”
 

Would be cost-effective

Although hospitals and transfusion centers check donated blood against an individual patient’s alloantibody profile, that information is usually kept in localized records and is not typically shared across health systems nationwide.

It’s different in the Netherlands, where the Transfusion Register of Irregular Antibodies and Cross-match Problems (TRIX) was launched in 2007. Under this system, transfusion laboratories register the presence of irregular red blood cell alloantibodies for their patients and can consult the database for information that is relevant for pretransfusion testing.

To see whether such a system, if implemented in the United States, would satisfy even the most parsimonious administrator or insurer, Dr. Goshua and colleagues created a computer simulation.

They estimated age- and gender-adjusted quality-adjusted life years (QALYs) for patients living with sickle cell disease, who typically require frequent transfusions and are thus especially at risk for developing alloantibodies and immune reactions from repeat exposures to the blood of others.

The model included age- and gender-adjusted costs based on 10 years of claims data, with the assumption that equal numbers of male and females would be in the sample.

The model estimated that by reducing DHTR incidence and DHTR-specific mortality in 20% to 44% of alloimmunized patients (a very conservative estimate, according to Dr. Goshua), the existence of a U.S. exchange would result in a gain of between 7,140 and 15,710 QALYs.

Assuming a willingness to pay up to $100,000 per QALY, a commonly used threshold in economic analyses in the United States, the exchange (vs. no exchange) would be preferred in 100% of 10,000 different iterations of a cost-effectiveness acceptability curve, Dr. Goshua said.

Even if the lifetime operational costs of such an exchange exceeded $600 million, it would still be cost-effective, and the net monetary benefit to the U.S. economy would be $0.7 billion, the authors found.

And although the model was limited to patients with sickle cell anemia, many other alloimmunized patients would be likely to benefit from such an exchange, including women with a prior pregnancy, and patients with autoimmunity, myelodysplastic syndrome, or beta-thalassemia, Dr. Goshua said.

The study was supported by the American Society of Hematology, the Yale School of Medicine, and Yale Center. Dr. Goshua and Dr. Bollard reported no relevant financial relationships.

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

NEW ORLEANS – Save lives; save money. What’s not to love? That’s the claim made for a proposed nationwide data bank on alloantibodies, which develop in response to foreign red blood cells in individuals who undergo repeated blood transfusions. They can occur after pregnancy or transplants, as well as in patients with sickle cell disease.

A central repository of data on alloantibodies would save lives by preventing serious immune reactions among patients with sickle cell disease and other maladies, and would save costs associated with hospitalization for serious and potentially fatal infusion reactions, say the creators of a mathematical model demonstrating the clear value of such a databank.

“The findings from our model are pretty definitive,” said George Goshua, MD, MSc, of Yale University, New Haven, Conn. “Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction (DHTR).”

Dr. Goshua presented the study at the American Society of Hematology annual meeting. The proposed registry would significantly reduce the risk that transfusion-dependent patients, and others who require occasional transfusions, would develop complications requiring hospitalization, he said.

A similar registry has been up and running in the Netherlands for 15 years, he said at a press briefing.

Briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children’s National Research Institute in Washington, asked Dr. Goshua why such an exchange hasn’t been started in the United States already.

“I will say first that our European colleagues are far ahead in terms of preventative care,” he replied.

“On top of that, there’s a unique environment in the United States – and this dates back about 15 years now – where we are almost allergic to putting costs on benefits, that is, attaching a cost value to a benefit that a population can gain,” Dr. Goshua said. “So in this context, there hasn’t been an analysis that shows that this [exchange] actually makes sense, but I think it’s one of those analyses kind of showing people that the sky is blue but proving it quantitatively.”

Dr. Bollard said that the potential beneficial impact of such an exchange “is huge,” but it would “require upfront expenditure to actually realize these massive gains you will get down the road for these patients.”
 

Would be cost-effective

Although hospitals and transfusion centers check donated blood against an individual patient’s alloantibody profile, that information is usually kept in localized records and is not typically shared across health systems nationwide.

It’s different in the Netherlands, where the Transfusion Register of Irregular Antibodies and Cross-match Problems (TRIX) was launched in 2007. Under this system, transfusion laboratories register the presence of irregular red blood cell alloantibodies for their patients and can consult the database for information that is relevant for pretransfusion testing.

To see whether such a system, if implemented in the United States, would satisfy even the most parsimonious administrator or insurer, Dr. Goshua and colleagues created a computer simulation.

They estimated age- and gender-adjusted quality-adjusted life years (QALYs) for patients living with sickle cell disease, who typically require frequent transfusions and are thus especially at risk for developing alloantibodies and immune reactions from repeat exposures to the blood of others.

The model included age- and gender-adjusted costs based on 10 years of claims data, with the assumption that equal numbers of male and females would be in the sample.

The model estimated that by reducing DHTR incidence and DHTR-specific mortality in 20% to 44% of alloimmunized patients (a very conservative estimate, according to Dr. Goshua), the existence of a U.S. exchange would result in a gain of between 7,140 and 15,710 QALYs.

Assuming a willingness to pay up to $100,000 per QALY, a commonly used threshold in economic analyses in the United States, the exchange (vs. no exchange) would be preferred in 100% of 10,000 different iterations of a cost-effectiveness acceptability curve, Dr. Goshua said.

Even if the lifetime operational costs of such an exchange exceeded $600 million, it would still be cost-effective, and the net monetary benefit to the U.S. economy would be $0.7 billion, the authors found.

And although the model was limited to patients with sickle cell anemia, many other alloimmunized patients would be likely to benefit from such an exchange, including women with a prior pregnancy, and patients with autoimmunity, myelodysplastic syndrome, or beta-thalassemia, Dr. Goshua said.

The study was supported by the American Society of Hematology, the Yale School of Medicine, and Yale Center. Dr. Goshua and Dr. Bollard reported no relevant financial relationships.

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

NEW ORLEANS – Save lives; save money. What’s not to love? That’s the claim made for a proposed nationwide data bank on alloantibodies, which develop in response to foreign red blood cells in individuals who undergo repeated blood transfusions. They can occur after pregnancy or transplants, as well as in patients with sickle cell disease.

A central repository of data on alloantibodies would save lives by preventing serious immune reactions among patients with sickle cell disease and other maladies, and would save costs associated with hospitalization for serious and potentially fatal infusion reactions, say the creators of a mathematical model demonstrating the clear value of such a databank.

“The findings from our model are pretty definitive,” said George Goshua, MD, MSc, of Yale University, New Haven, Conn. “Despite very conservative assumptions, our results still show a huge financial benefit to having a system in place to serve as a preventive net that catches patients before they have to go through a delayed hemolytic transfusion reaction (DHTR).”

Dr. Goshua presented the study at the American Society of Hematology annual meeting. The proposed registry would significantly reduce the risk that transfusion-dependent patients, and others who require occasional transfusions, would develop complications requiring hospitalization, he said.

A similar registry has been up and running in the Netherlands for 15 years, he said at a press briefing.

Briefing moderator Catherine Bollard, MD, of the Center for Cancer and Immunology at Children’s National Research Institute in Washington, asked Dr. Goshua why such an exchange hasn’t been started in the United States already.

“I will say first that our European colleagues are far ahead in terms of preventative care,” he replied.

“On top of that, there’s a unique environment in the United States – and this dates back about 15 years now – where we are almost allergic to putting costs on benefits, that is, attaching a cost value to a benefit that a population can gain,” Dr. Goshua said. “So in this context, there hasn’t been an analysis that shows that this [exchange] actually makes sense, but I think it’s one of those analyses kind of showing people that the sky is blue but proving it quantitatively.”

Dr. Bollard said that the potential beneficial impact of such an exchange “is huge,” but it would “require upfront expenditure to actually realize these massive gains you will get down the road for these patients.”
 

Would be cost-effective

Although hospitals and transfusion centers check donated blood against an individual patient’s alloantibody profile, that information is usually kept in localized records and is not typically shared across health systems nationwide.

It’s different in the Netherlands, where the Transfusion Register of Irregular Antibodies and Cross-match Problems (TRIX) was launched in 2007. Under this system, transfusion laboratories register the presence of irregular red blood cell alloantibodies for their patients and can consult the database for information that is relevant for pretransfusion testing.

To see whether such a system, if implemented in the United States, would satisfy even the most parsimonious administrator or insurer, Dr. Goshua and colleagues created a computer simulation.

They estimated age- and gender-adjusted quality-adjusted life years (QALYs) for patients living with sickle cell disease, who typically require frequent transfusions and are thus especially at risk for developing alloantibodies and immune reactions from repeat exposures to the blood of others.

The model included age- and gender-adjusted costs based on 10 years of claims data, with the assumption that equal numbers of male and females would be in the sample.

The model estimated that by reducing DHTR incidence and DHTR-specific mortality in 20% to 44% of alloimmunized patients (a very conservative estimate, according to Dr. Goshua), the existence of a U.S. exchange would result in a gain of between 7,140 and 15,710 QALYs.

Assuming a willingness to pay up to $100,000 per QALY, a commonly used threshold in economic analyses in the United States, the exchange (vs. no exchange) would be preferred in 100% of 10,000 different iterations of a cost-effectiveness acceptability curve, Dr. Goshua said.

Even if the lifetime operational costs of such an exchange exceeded $600 million, it would still be cost-effective, and the net monetary benefit to the U.S. economy would be $0.7 billion, the authors found.

And although the model was limited to patients with sickle cell anemia, many other alloimmunized patients would be likely to benefit from such an exchange, including women with a prior pregnancy, and patients with autoimmunity, myelodysplastic syndrome, or beta-thalassemia, Dr. Goshua said.

The study was supported by the American Society of Hematology, the Yale School of Medicine, and Yale Center. Dr. Goshua and Dr. Bollard reported no relevant financial relationships.

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

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

Nearly 90% of beta-thalassemia patients were transfusion free for up to 8 years after treatment with the one-time gene therapy betibeglogene autotemcel (beti-cel), according to a report at the American Society of Hematology annual meeting.

Surveyed at 3 years, patients also reported ongoing benefits from treatment, including positive impacts on employment, school attendance, and physical activity, according to a second report.

The findings address a major question about betibeglogene autotemcel: Its durability. The therapy is priced at over $2 million per treatment, based on the premise that it will benefit patients in the long-term, in part by offsetting the cost of ongoing transfusions. Therefore, proof of long-standing benefit is important.

The Food and Drug Administration approved betibeglogene autotemcel in August 2022 for children and adults with transfusion dependent beta-thalassemia, a condition that causes patients to have absent or reduced levels of hemoglobin due to mutations in the beta-globin gene. Patients typically require transfusions every 2-5 weeks.

The treatment inserts functional copies of the mutated gene into the patients’ hematopoietic stem cells via a replication-defective lentivirus. The cells are then transfused back into the patient.

As of August 2021, 63 patients had undergone treatment and been followed for a median of 41.4 months. So far, durability looks solid.

“We now have up to 8 years efficacy and safety follow-up” with beti-cel. “Patients experience durable transfusion independence,” said Mark Walters, MD, a pediatric hematologist/oncologist at the University of California, San Francisco, who presented the long-term efficacy data at the meeting.

Overall, 89.5% of patients (34/38) in phase 3 testing achieved transfusion independence, meaning that they had hemoglobin levels of at least 9 g/dL without transfusions for a year or more.

The response rate was an improvement over phase 1/2 testing, in which 68% of subjects (15/22) became transfusion free. Improvements in the manufacturing process led to better outcomes in phase 3, Dr. Walters said.

As for quality of life (QoL), improvement “continues through 3 years following treatment,” said Franco Locatelli, MD, a pediatric hematologist/oncologist at Catholic University of the Sacred Heart, Rome, who led the QoL study.

When patients who achieved transfusion independence were surveyed 3 years after treatment, 93% of adults were employed or able to seek employment, up from 67% before treatment. School absences were down among children, almost half of subjects no longer needed symptom management, and 81% reported improvements in physical activity.

There were also improvements on various quality of life scales, including in physical functioning and mental health.

Patient age and underlying thalassemia genotype had no impact on the likelihood of transfusion independence. Those who achieved it also had reductions in markers of ineffective erythropoiesis and iron overload.

On multivariate analysis, the greatest predictor of transfusion independence was having at least 62% of cells transduced prior to reintroduction to the patient.

As for adverse events, seven subjects (11%) developed severe veno-occlusive liver disease that resolved with supportive care. Mucositis and febrile neutropenia are also a concern and related to the busulfan conditioning regimen.

No malignancies, insertional oncogenesis, or lentivirus replication have been observed.

The studies were funded by beti-cel maker Bluebird Bio, and many of the investigators are employees. Others reported ties to Bluebird and a range of other companies. Among his industry ties, Dr. Locatelli is a speaker for Bluebird. Dr. Walters also had industry relationships, but didn’t report any ties to Bluebird.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.