Hematology News

TOPLINE:

Age-standardized mortality rates for hepatocellular carcinoma (HCC) in the United States are expected to rise from 5.03 per 100,000 persons in 2022 to 6.39 per 100,000 persons by 2040. Alcohol-associated liver disease (ALD) will likely become the leading cause of HCC-related mortality by 2026, and metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to become the second leading cause by 2032, a new analysis found. 

METHODOLOGY:

• HCC accounts for 75%-85% of primary liver cancers and most liver cancer deaths. Researchers have observed an upward trend in the incidence of and mortality from HCC in the past 2 decades.
• This cross-sectional study analyzed 188,280 HCC-related deaths among adults aged 25 and older to determine trends in mortality rates and project age-standardized mortality rates through 2040. Data came from the National Vital Statistics System database from 2006 to 2022.
• Researchers stratified mortality data by etiology of liver disease (ALD, hepatitis B virus, hepatitis C virus, and MASLD), age groups (25-64 or 65 and older years), sex, and race/ethnicity.
• Demographic data showed that 77.4% of deaths occurred in men, 55.6% in individuals aged 65 years or older, and 62.3% in White individuals.

TAKEAWAY:

• Overall, the age-standardized mortality rate for HCC-related deaths increased from 3.65 per 100,000 persons in 2006 to 5.03 in 2022 and was projected to increase to 6.39 per 100,000 persons by 2040.
• Sex- and age-related disparities were substantial. Men had much higher rates of HCC-related mortality than women (8.15 vs 2.33 per 100,000 persons), with a projected rate among men of 9.78 per 100,000 persons by 2040. HCC-related mortality rates for people aged 65 years or older were 10 times higher than for those aged 25-64 years (18.37 vs 1.79 per 100,000 persons) in 2022 and was projected to reach 32.81 per 100,000 persons by 2040 in the older group.
• Although hepatitis C virus–related deaths were projected to decline from 0.69 to 0.03 per 100,000 persons by 2034, ALD- and MASLD-related deaths showed increasing trends, with both projected to become the two leading causes of HCC-related mortality in the next few years.
• Racial disparities were also evident. By 2040, the American Indian/Alaska Native population showed the highest increase in projected HCC-related mortality rates, which went from 5.46 per 100,000 persons in 2006 to a project increase to 14.71 per 100,000 persons.

IN PRACTICE:

“HCC mortality was projected to continue increasing in the US, primarily due to rising rates of deaths attributable to ALD and MASLD,” the authors wrote. 

This “study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future,” Emad Qayed, MD, MPH, Emory University School of Medicine, Atlanta, wrote in an accompanying editorial.

SOURCE:

The study was led by Sikai Qiu, MM, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, and was published online in JAMA Network Open.
 

LIMITATIONS:

The National Vital Statistics System database used in this study captured only mortality data without access to detailed clinical records or individual medical histories. Researchers could not analyze socioeconomic factors or individual-level risk factors owing to data anonymization requirements. Additionally, the inclusion of the COVID-19 pandemic period could have influenced observed trends and reliability of future projections.
 

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China. Several authors reported receiving consulting fees, speaking fees, or research support from various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Age-standardized mortality rates for hepatocellular carcinoma (HCC) in the United States are expected to rise from 5.03 per 100,000 persons in 2022 to 6.39 per 100,000 persons by 2040. Alcohol-associated liver disease (ALD) will likely become the leading cause of HCC-related mortality by 2026, and metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to become the second leading cause by 2032, a new analysis found. 

METHODOLOGY:

• HCC accounts for 75%-85% of primary liver cancers and most liver cancer deaths. Researchers have observed an upward trend in the incidence of and mortality from HCC in the past 2 decades.
• This cross-sectional study analyzed 188,280 HCC-related deaths among adults aged 25 and older to determine trends in mortality rates and project age-standardized mortality rates through 2040. Data came from the National Vital Statistics System database from 2006 to 2022.
• Researchers stratified mortality data by etiology of liver disease (ALD, hepatitis B virus, hepatitis C virus, and MASLD), age groups (25-64 or 65 and older years), sex, and race/ethnicity.
• Demographic data showed that 77.4% of deaths occurred in men, 55.6% in individuals aged 65 years or older, and 62.3% in White individuals.

TAKEAWAY:

• Overall, the age-standardized mortality rate for HCC-related deaths increased from 3.65 per 100,000 persons in 2006 to 5.03 in 2022 and was projected to increase to 6.39 per 100,000 persons by 2040.
• Sex- and age-related disparities were substantial. Men had much higher rates of HCC-related mortality than women (8.15 vs 2.33 per 100,000 persons), with a projected rate among men of 9.78 per 100,000 persons by 2040. HCC-related mortality rates for people aged 65 years or older were 10 times higher than for those aged 25-64 years (18.37 vs 1.79 per 100,000 persons) in 2022 and was projected to reach 32.81 per 100,000 persons by 2040 in the older group.
• Although hepatitis C virus–related deaths were projected to decline from 0.69 to 0.03 per 100,000 persons by 2034, ALD- and MASLD-related deaths showed increasing trends, with both projected to become the two leading causes of HCC-related mortality in the next few years.
• Racial disparities were also evident. By 2040, the American Indian/Alaska Native population showed the highest increase in projected HCC-related mortality rates, which went from 5.46 per 100,000 persons in 2006 to a project increase to 14.71 per 100,000 persons.

IN PRACTICE:

“HCC mortality was projected to continue increasing in the US, primarily due to rising rates of deaths attributable to ALD and MASLD,” the authors wrote. 

This “study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future,” Emad Qayed, MD, MPH, Emory University School of Medicine, Atlanta, wrote in an accompanying editorial.

SOURCE:

The study was led by Sikai Qiu, MM, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, and was published online in JAMA Network Open.
 

LIMITATIONS:

The National Vital Statistics System database used in this study captured only mortality data without access to detailed clinical records or individual medical histories. Researchers could not analyze socioeconomic factors or individual-level risk factors owing to data anonymization requirements. Additionally, the inclusion of the COVID-19 pandemic period could have influenced observed trends and reliability of future projections.
 

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China. Several authors reported receiving consulting fees, speaking fees, or research support from various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Age-standardized mortality rates for hepatocellular carcinoma (HCC) in the United States are expected to rise from 5.03 per 100,000 persons in 2022 to 6.39 per 100,000 persons by 2040. Alcohol-associated liver disease (ALD) will likely become the leading cause of HCC-related mortality by 2026, and metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to become the second leading cause by 2032, a new analysis found. 

METHODOLOGY:

• HCC accounts for 75%-85% of primary liver cancers and most liver cancer deaths. Researchers have observed an upward trend in the incidence of and mortality from HCC in the past 2 decades.
• This cross-sectional study analyzed 188,280 HCC-related deaths among adults aged 25 and older to determine trends in mortality rates and project age-standardized mortality rates through 2040. Data came from the National Vital Statistics System database from 2006 to 2022.
• Researchers stratified mortality data by etiology of liver disease (ALD, hepatitis B virus, hepatitis C virus, and MASLD), age groups (25-64 or 65 and older years), sex, and race/ethnicity.
• Demographic data showed that 77.4% of deaths occurred in men, 55.6% in individuals aged 65 years or older, and 62.3% in White individuals.

TAKEAWAY:

• Overall, the age-standardized mortality rate for HCC-related deaths increased from 3.65 per 100,000 persons in 2006 to 5.03 in 2022 and was projected to increase to 6.39 per 100,000 persons by 2040.
• Sex- and age-related disparities were substantial. Men had much higher rates of HCC-related mortality than women (8.15 vs 2.33 per 100,000 persons), with a projected rate among men of 9.78 per 100,000 persons by 2040. HCC-related mortality rates for people aged 65 years or older were 10 times higher than for those aged 25-64 years (18.37 vs 1.79 per 100,000 persons) in 2022 and was projected to reach 32.81 per 100,000 persons by 2040 in the older group.
• Although hepatitis C virus–related deaths were projected to decline from 0.69 to 0.03 per 100,000 persons by 2034, ALD- and MASLD-related deaths showed increasing trends, with both projected to become the two leading causes of HCC-related mortality in the next few years.
• Racial disparities were also evident. By 2040, the American Indian/Alaska Native population showed the highest increase in projected HCC-related mortality rates, which went from 5.46 per 100,000 persons in 2006 to a project increase to 14.71 per 100,000 persons.

IN PRACTICE:

“HCC mortality was projected to continue increasing in the US, primarily due to rising rates of deaths attributable to ALD and MASLD,” the authors wrote. 

This “study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future,” Emad Qayed, MD, MPH, Emory University School of Medicine, Atlanta, wrote in an accompanying editorial.

SOURCE:

The study was led by Sikai Qiu, MM, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, and was published online in JAMA Network Open.
 

LIMITATIONS:

The National Vital Statistics System database used in this study captured only mortality data without access to detailed clinical records or individual medical histories. Researchers could not analyze socioeconomic factors or individual-level risk factors owing to data anonymization requirements. Additionally, the inclusion of the COVID-19 pandemic period could have influenced observed trends and reliability of future projections.
 

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China. Several authors reported receiving consulting fees, speaking fees, or research support from various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Laura Vater remembers sneaking into her home after 12-hour night shifts during medical training while her husband distracted their toddler. The stealthy tag-teaming effort helped her get enough undisturbed sleep before returning to an Indiana University hospital the following night to repeat the pattern.

“He would pretend to take out the trash when I pulled in,” said Vater, MD, now a gastrointestinal oncologist and assistant professor of medicine at IU Health Simon Cancer Center in Indianapolis. “I would sneak in so she [their daughter] wouldn’t see me, and then he would go back in.”

For Vater, prioritizing sleep during the day to combat sleep deprivation common among doctors-in-training on night shifts required enlisting a supportive spouse. It’s just one of the tips she and a few chief residents shared with this news organization for staying sharp and healthy during overnight rotations.

While the pace of patient rounds may slow from the frenetic daytime rush, training as a doctor after the sun goes down can be quite challenging for residents, they told this news organization. From sleep deprivation working while the rest of us slumbers to the after-effects of late-night caffeine, learning to manage night rotations requires a balance of preparation and attention to personal health while caring for others, the residents and adviser said.

Compromised sleep is one of the biggest hurdles residents have to overcome. Sleep loss comes with risks to cardiovascular disease and type 2 diabetes, among other heath conditions, according to Medscape Medical News reports. And night shift workers  who sleep 6 or fewer hours a night have at least one sleep disorder.

Sleep deprivation associated with overnight call schedules also can worsen a resident’s mood and motivation while impairing their judgment, leading to medical errors, according to a new study published in JAMA Open Network. The study proposed shorter consecutive night shifts and naps as ways to offset the results of sleep loss, especially for interns or first-year residents. 

Residency programs recently have been experimenting with shorter call schedules.

 

Catching Zzs

Working the night shift demands a disciplined sleep schedule, said Nat deQuillfeldt, MD, a Denver Health chief resident in the University of Colorado’s internal medicine residency program.

“When I was on night admissions, I was very strict about going to sleep at 8 AM and waking at 3 PM every single day. It can be very tempting to try to stay up and spend time with loved ones, but my husband and I both prioritized my physical well-being for those weeks,” said deQuillfeldt, a PGY-4 resident. “It was especially challenging for me because I had to commute about 50 minutes each way and without such a rigid schedule I would have struggled to be on time.”

deQuillfeldt doesn’t have young children at home, a noisy community, or other distractions to interrupt sleep during the day. But it was still difficult for her to sleep while the sun was out. “I used an eye mask and ear plugs but definitely woke up more often than I would at night.”

Blackout curtains may have helped, she added.

“Without adequate sleep, your clinical thinking is not as sharp. When emergencies happen overnight, you’re often the first person to arrive and need to be able to make rapid, accurate assessments and decisions.”

As a chief resident, she chooses never to sleep during night shifts.

“I personally didn’t want to leave my interns alone or make them feel like they were waking me up or bothering me if they needed help, and I also didn’t want to be groggy in case of a rapid response or code blue.”

But napping on night shift is definitely possible, deQuillfeldt said. Between following up on overnight lab results, answering nurses’ questions, and responding to emergencies, she found downtime on night shift to eat and hydrate. She believes others can catch an hour or 2 of shut eye, even if they work in the intensive care unit, or 3-4 hours on rare quiet nights.

Vater suggests residents transitioning from daytime work to night shift prepare by trying to catch an afternoon nap, staying up later the night before the change, and banking sleep hours in advance.

When he knows he’s starting night shifts, Apurva Popat, MD, said he tries to go to sleep an hour or so later nights before to avoid becoming sleep deprived. The chief resident of internal medicine at Marshfield Clinic Health System in Marshfield, Wisconsin, doesn’t recommend sleeping during the night shift.

“I typically try not to sleep, even if I have time, so I can go home and sleep later in the morning,” said Popat, a PGY-3 resident.

To help him snooze, he uses blackout curtains and a fan to block out noise. His wife, a first-year internal medicine intern, often works a different shift, so she helps set up his sleeping environment and he reciprocates when it’s her turn for night shifts.

Some interns may need to catch a 20- to 30-minute nap on the first night shift, he said.

Popat also seeks out brighter areas of the hospital, such as the emergency department, where there are more people and colleagues to keep him alert.

 

Bypass Vending Machines

Lack of sleep makes it even more difficult to eat healthy on night shift, said Vater, who advises residents about wellness issues at IU and on social media.

“When you are sleep deprived, when you do not get enough sleep, you eat but you don’t feel full,” she said. “It’s hard to eat well on night shift. It’s harder if you go to the break room and there’s candy and junk food.”

Vater said that, as a resident, she brought a lunch bag to the hospital during night shifts. “I never had time to prep food, so I’d bring a whole apple, a whole orange, a whole avocado or nuts. It allowed me to eat more fruits and vegetables than I normally would.”

She advises caution when considering coffee to stay awake, especially after about 9 PM, which could interfere with sleep residents need later when they finish their shifts. Caffeine may help in the moment, but it prevents deep sleep, Vater said. So when residents finally get sleep after their shifts, they may wake up feeling tired, she said.

To avoid sleepiness, Popat brings protein shakes with him to night shifts. They stave off sugar spikes and keep his energy level high, he said. He might have a protein shake and fruit before he leaves home and carry his vegetarian dinner with him to eat in the early morning hours when the hospital is calm.

Eating small and frequent meals also helps ward off sleepiness, deQuillfeldt said.

 

Take the Stairs

Trying to stay healthy on night shifts, Vater also checked on patients by taking the stairs. “I’d set the timer on my phone for 30 minutes and if I got paged at 15, I’d pause the timer and reset it if I had a moment later. I’d get at least 30 minutes in, although not always continuous. I think some activity is better than none.”

Vater said her hospital had a gym, but it wasn’t practical for her because it was further away from where she worked. “Sometimes my coresidents would be more creative, and we would do squats.”

Popat tries to lift weights 2 hours before his night shift, but he also takes short walks between patients’ rooms in the early morning hours when it’s quietest. He also promotes deep breathing to stay alert.

 

Ask for a Ride

Vater urges those coming off night shifts, especially those transitioning for the first time from daytime rotations, not to drive if they’re exhausted. “Get an Uber. ... Make sure you get a ride home.”

The CU residency program covers the cost of a ridesharing service when doctors-in-training are too tired to drive home, deQuillfeldt said. “We really try to encourage people to use this to reduce the risk of car accidents.”

 

Promoting Mental Health

The residency program also links residents with primary care and mental health services. People who really struggle with shift work sleep disorder may qualify for medications to help them stay awake overnight, in addition to sleep hygiene apps and sleep aides.

“Night shifts can put a strain on mental health, especially when you’re only working, eating, and sleeping and not spending any time with family and friends,” deQuillfeldt said. “My husband works late afternoons, so we often would go weeks seeing each other for 15-20 minutes a day.”

“Sleeping when the sun is out often leads to a lack of light exposure which can compound the problem. Seeking mental health support early is really important to avoiding burnout,” she said.

She also recommended planning a fun weekend activity, trip, or celebration with friends or family after night shifts end “so you have something to look forward to…It’s so important to have a light at the end of the tunnel, which will allow you to enjoy the sense of accomplishment even more.”

For more advice on the subject, consider the American Medical Association guide to managing sleep deprivation in residency or Laura Vater’s tips for night shifts.

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

Laura Vater remembers sneaking into her home after 12-hour night shifts during medical training while her husband distracted their toddler. The stealthy tag-teaming effort helped her get enough undisturbed sleep before returning to an Indiana University hospital the following night to repeat the pattern.

“He would pretend to take out the trash when I pulled in,” said Vater, MD, now a gastrointestinal oncologist and assistant professor of medicine at IU Health Simon Cancer Center in Indianapolis. “I would sneak in so she [their daughter] wouldn’t see me, and then he would go back in.”

For Vater, prioritizing sleep during the day to combat sleep deprivation common among doctors-in-training on night shifts required enlisting a supportive spouse. It’s just one of the tips she and a few chief residents shared with this news organization for staying sharp and healthy during overnight rotations.

While the pace of patient rounds may slow from the frenetic daytime rush, training as a doctor after the sun goes down can be quite challenging for residents, they told this news organization. From sleep deprivation working while the rest of us slumbers to the after-effects of late-night caffeine, learning to manage night rotations requires a balance of preparation and attention to personal health while caring for others, the residents and adviser said.

Compromised sleep is one of the biggest hurdles residents have to overcome. Sleep loss comes with risks to cardiovascular disease and type 2 diabetes, among other heath conditions, according to Medscape Medical News reports. And night shift workers  who sleep 6 or fewer hours a night have at least one sleep disorder.

Sleep deprivation associated with overnight call schedules also can worsen a resident’s mood and motivation while impairing their judgment, leading to medical errors, according to a new study published in JAMA Open Network. The study proposed shorter consecutive night shifts and naps as ways to offset the results of sleep loss, especially for interns or first-year residents. 

Residency programs recently have been experimenting with shorter call schedules.

 

Catching Zzs

Working the night shift demands a disciplined sleep schedule, said Nat deQuillfeldt, MD, a Denver Health chief resident in the University of Colorado’s internal medicine residency program.

“When I was on night admissions, I was very strict about going to sleep at 8 AM and waking at 3 PM every single day. It can be very tempting to try to stay up and spend time with loved ones, but my husband and I both prioritized my physical well-being for those weeks,” said deQuillfeldt, a PGY-4 resident. “It was especially challenging for me because I had to commute about 50 minutes each way and without such a rigid schedule I would have struggled to be on time.”

deQuillfeldt doesn’t have young children at home, a noisy community, or other distractions to interrupt sleep during the day. But it was still difficult for her to sleep while the sun was out. “I used an eye mask and ear plugs but definitely woke up more often than I would at night.”

Blackout curtains may have helped, she added.

“Without adequate sleep, your clinical thinking is not as sharp. When emergencies happen overnight, you’re often the first person to arrive and need to be able to make rapid, accurate assessments and decisions.”

As a chief resident, she chooses never to sleep during night shifts.

“I personally didn’t want to leave my interns alone or make them feel like they were waking me up or bothering me if they needed help, and I also didn’t want to be groggy in case of a rapid response or code blue.”

But napping on night shift is definitely possible, deQuillfeldt said. Between following up on overnight lab results, answering nurses’ questions, and responding to emergencies, she found downtime on night shift to eat and hydrate. She believes others can catch an hour or 2 of shut eye, even if they work in the intensive care unit, or 3-4 hours on rare quiet nights.

Vater suggests residents transitioning from daytime work to night shift prepare by trying to catch an afternoon nap, staying up later the night before the change, and banking sleep hours in advance.

When he knows he’s starting night shifts, Apurva Popat, MD, said he tries to go to sleep an hour or so later nights before to avoid becoming sleep deprived. The chief resident of internal medicine at Marshfield Clinic Health System in Marshfield, Wisconsin, doesn’t recommend sleeping during the night shift.

“I typically try not to sleep, even if I have time, so I can go home and sleep later in the morning,” said Popat, a PGY-3 resident.

To help him snooze, he uses blackout curtains and a fan to block out noise. His wife, a first-year internal medicine intern, often works a different shift, so she helps set up his sleeping environment and he reciprocates when it’s her turn for night shifts.

Some interns may need to catch a 20- to 30-minute nap on the first night shift, he said.

Popat also seeks out brighter areas of the hospital, such as the emergency department, where there are more people and colleagues to keep him alert.

 

Bypass Vending Machines

Lack of sleep makes it even more difficult to eat healthy on night shift, said Vater, who advises residents about wellness issues at IU and on social media.

“When you are sleep deprived, when you do not get enough sleep, you eat but you don’t feel full,” she said. “It’s hard to eat well on night shift. It’s harder if you go to the break room and there’s candy and junk food.”

Vater said that, as a resident, she brought a lunch bag to the hospital during night shifts. “I never had time to prep food, so I’d bring a whole apple, a whole orange, a whole avocado or nuts. It allowed me to eat more fruits and vegetables than I normally would.”

She advises caution when considering coffee to stay awake, especially after about 9 PM, which could interfere with sleep residents need later when they finish their shifts. Caffeine may help in the moment, but it prevents deep sleep, Vater said. So when residents finally get sleep after their shifts, they may wake up feeling tired, she said.

To avoid sleepiness, Popat brings protein shakes with him to night shifts. They stave off sugar spikes and keep his energy level high, he said. He might have a protein shake and fruit before he leaves home and carry his vegetarian dinner with him to eat in the early morning hours when the hospital is calm.

Eating small and frequent meals also helps ward off sleepiness, deQuillfeldt said.

 

Take the Stairs

Trying to stay healthy on night shifts, Vater also checked on patients by taking the stairs. “I’d set the timer on my phone for 30 minutes and if I got paged at 15, I’d pause the timer and reset it if I had a moment later. I’d get at least 30 minutes in, although not always continuous. I think some activity is better than none.”

Vater said her hospital had a gym, but it wasn’t practical for her because it was further away from where she worked. “Sometimes my coresidents would be more creative, and we would do squats.”

Popat tries to lift weights 2 hours before his night shift, but he also takes short walks between patients’ rooms in the early morning hours when it’s quietest. He also promotes deep breathing to stay alert.

 

Ask for a Ride

Vater urges those coming off night shifts, especially those transitioning for the first time from daytime rotations, not to drive if they’re exhausted. “Get an Uber. ... Make sure you get a ride home.”

The CU residency program covers the cost of a ridesharing service when doctors-in-training are too tired to drive home, deQuillfeldt said. “We really try to encourage people to use this to reduce the risk of car accidents.”

 

Promoting Mental Health

The residency program also links residents with primary care and mental health services. People who really struggle with shift work sleep disorder may qualify for medications to help them stay awake overnight, in addition to sleep hygiene apps and sleep aides.

“Night shifts can put a strain on mental health, especially when you’re only working, eating, and sleeping and not spending any time with family and friends,” deQuillfeldt said. “My husband works late afternoons, so we often would go weeks seeing each other for 15-20 minutes a day.”

“Sleeping when the sun is out often leads to a lack of light exposure which can compound the problem. Seeking mental health support early is really important to avoiding burnout,” she said.

She also recommended planning a fun weekend activity, trip, or celebration with friends or family after night shifts end “so you have something to look forward to…It’s so important to have a light at the end of the tunnel, which will allow you to enjoy the sense of accomplishment even more.”

For more advice on the subject, consider the American Medical Association guide to managing sleep deprivation in residency or Laura Vater’s tips for night shifts.

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

Laura Vater remembers sneaking into her home after 12-hour night shifts during medical training while her husband distracted their toddler. The stealthy tag-teaming effort helped her get enough undisturbed sleep before returning to an Indiana University hospital the following night to repeat the pattern.

“He would pretend to take out the trash when I pulled in,” said Vater, MD, now a gastrointestinal oncologist and assistant professor of medicine at IU Health Simon Cancer Center in Indianapolis. “I would sneak in so she [their daughter] wouldn’t see me, and then he would go back in.”

For Vater, prioritizing sleep during the day to combat sleep deprivation common among doctors-in-training on night shifts required enlisting a supportive spouse. It’s just one of the tips she and a few chief residents shared with this news organization for staying sharp and healthy during overnight rotations.

While the pace of patient rounds may slow from the frenetic daytime rush, training as a doctor after the sun goes down can be quite challenging for residents, they told this news organization. From sleep deprivation working while the rest of us slumbers to the after-effects of late-night caffeine, learning to manage night rotations requires a balance of preparation and attention to personal health while caring for others, the residents and adviser said.

Compromised sleep is one of the biggest hurdles residents have to overcome. Sleep loss comes with risks to cardiovascular disease and type 2 diabetes, among other heath conditions, according to Medscape Medical News reports. And night shift workers  who sleep 6 or fewer hours a night have at least one sleep disorder.

Sleep deprivation associated with overnight call schedules also can worsen a resident’s mood and motivation while impairing their judgment, leading to medical errors, according to a new study published in JAMA Open Network. The study proposed shorter consecutive night shifts and naps as ways to offset the results of sleep loss, especially for interns or first-year residents. 

Residency programs recently have been experimenting with shorter call schedules.

 

Catching Zzs

Working the night shift demands a disciplined sleep schedule, said Nat deQuillfeldt, MD, a Denver Health chief resident in the University of Colorado’s internal medicine residency program.

“When I was on night admissions, I was very strict about going to sleep at 8 AM and waking at 3 PM every single day. It can be very tempting to try to stay up and spend time with loved ones, but my husband and I both prioritized my physical well-being for those weeks,” said deQuillfeldt, a PGY-4 resident. “It was especially challenging for me because I had to commute about 50 minutes each way and without such a rigid schedule I would have struggled to be on time.”

deQuillfeldt doesn’t have young children at home, a noisy community, or other distractions to interrupt sleep during the day. But it was still difficult for her to sleep while the sun was out. “I used an eye mask and ear plugs but definitely woke up more often than I would at night.”

Blackout curtains may have helped, she added.

“Without adequate sleep, your clinical thinking is not as sharp. When emergencies happen overnight, you’re often the first person to arrive and need to be able to make rapid, accurate assessments and decisions.”

As a chief resident, she chooses never to sleep during night shifts.

“I personally didn’t want to leave my interns alone or make them feel like they were waking me up or bothering me if they needed help, and I also didn’t want to be groggy in case of a rapid response or code blue.”

But napping on night shift is definitely possible, deQuillfeldt said. Between following up on overnight lab results, answering nurses’ questions, and responding to emergencies, she found downtime on night shift to eat and hydrate. She believes others can catch an hour or 2 of shut eye, even if they work in the intensive care unit, or 3-4 hours on rare quiet nights.

Vater suggests residents transitioning from daytime work to night shift prepare by trying to catch an afternoon nap, staying up later the night before the change, and banking sleep hours in advance.

When he knows he’s starting night shifts, Apurva Popat, MD, said he tries to go to sleep an hour or so later nights before to avoid becoming sleep deprived. The chief resident of internal medicine at Marshfield Clinic Health System in Marshfield, Wisconsin, doesn’t recommend sleeping during the night shift.

“I typically try not to sleep, even if I have time, so I can go home and sleep later in the morning,” said Popat, a PGY-3 resident.

To help him snooze, he uses blackout curtains and a fan to block out noise. His wife, a first-year internal medicine intern, often works a different shift, so she helps set up his sleeping environment and he reciprocates when it’s her turn for night shifts.

Some interns may need to catch a 20- to 30-minute nap on the first night shift, he said.

Popat also seeks out brighter areas of the hospital, such as the emergency department, where there are more people and colleagues to keep him alert.

 

Bypass Vending Machines

Lack of sleep makes it even more difficult to eat healthy on night shift, said Vater, who advises residents about wellness issues at IU and on social media.

“When you are sleep deprived, when you do not get enough sleep, you eat but you don’t feel full,” she said. “It’s hard to eat well on night shift. It’s harder if you go to the break room and there’s candy and junk food.”

Vater said that, as a resident, she brought a lunch bag to the hospital during night shifts. “I never had time to prep food, so I’d bring a whole apple, a whole orange, a whole avocado or nuts. It allowed me to eat more fruits and vegetables than I normally would.”

She advises caution when considering coffee to stay awake, especially after about 9 PM, which could interfere with sleep residents need later when they finish their shifts. Caffeine may help in the moment, but it prevents deep sleep, Vater said. So when residents finally get sleep after their shifts, they may wake up feeling tired, she said.

To avoid sleepiness, Popat brings protein shakes with him to night shifts. They stave off sugar spikes and keep his energy level high, he said. He might have a protein shake and fruit before he leaves home and carry his vegetarian dinner with him to eat in the early morning hours when the hospital is calm.

Eating small and frequent meals also helps ward off sleepiness, deQuillfeldt said.

 

Take the Stairs

Trying to stay healthy on night shifts, Vater also checked on patients by taking the stairs. “I’d set the timer on my phone for 30 minutes and if I got paged at 15, I’d pause the timer and reset it if I had a moment later. I’d get at least 30 minutes in, although not always continuous. I think some activity is better than none.”

Vater said her hospital had a gym, but it wasn’t practical for her because it was further away from where she worked. “Sometimes my coresidents would be more creative, and we would do squats.”

Popat tries to lift weights 2 hours before his night shift, but he also takes short walks between patients’ rooms in the early morning hours when it’s quietest. He also promotes deep breathing to stay alert.

 

Ask for a Ride

Vater urges those coming off night shifts, especially those transitioning for the first time from daytime rotations, not to drive if they’re exhausted. “Get an Uber. ... Make sure you get a ride home.”

The CU residency program covers the cost of a ridesharing service when doctors-in-training are too tired to drive home, deQuillfeldt said. “We really try to encourage people to use this to reduce the risk of car accidents.”

 

Promoting Mental Health

The residency program also links residents with primary care and mental health services. People who really struggle with shift work sleep disorder may qualify for medications to help them stay awake overnight, in addition to sleep hygiene apps and sleep aides.

“Night shifts can put a strain on mental health, especially when you’re only working, eating, and sleeping and not spending any time with family and friends,” deQuillfeldt said. “My husband works late afternoons, so we often would go weeks seeing each other for 15-20 minutes a day.”

“Sleeping when the sun is out often leads to a lack of light exposure which can compound the problem. Seeking mental health support early is really important to avoiding burnout,” she said.

She also recommended planning a fun weekend activity, trip, or celebration with friends or family after night shifts end “so you have something to look forward to…It’s so important to have a light at the end of the tunnel, which will allow you to enjoy the sense of accomplishment even more.”

For more advice on the subject, consider the American Medical Association guide to managing sleep deprivation in residency or Laura Vater’s tips for night shifts.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

While fewer than 10% of US physicians are unionized, the number of official union drives among private-sector doctors have skyrocketed in the last 2 years, compared with 2 decades prior, according to a new study. 

Researchers counted 21 union drives in 2023 and 12 in the first 5 months of 2024, compared with 0-6 drives each year between 2000 and 2022. 

If the 2023 and 2024 drives succeed, unions will represent 3523 new physicians — nearly equal to the 3541 doctors who sought unionization between 2000 and 2022.

“We were able to document a significant uptick in union petitions and success in certification drives,” said corresponding author Hayden Rooke-Ley, JD, of the Center for Advancing Health Policy Through Research, Brown University School of Public Health, Providence, Rhode Island. “We were surprised to see such a marked shift in 2023.”

About 72,000 physicians, an estimated 8% of all US doctors, are covered by unions, including some in the public sector. Physicians who are self-employed, now comprising less than a fifth of all doctors, are not eligible to join labor unions.

The study authors launched their research to better understand trends in physician unionization in light of high-profile union drives, especially among residents. Rooke-Ley said: “We suspected that declining morale and increased corporate employment for physicians were leading them to consider unionization.”

The researchers gathered data from the National Labor Relations Board about union drives by potential bargaining units that included physicians. From 2000 to 2022, 44 union petitions were filed. The number jumped to 33 from 2023-2024. 

 

“Tip of the Iceberg”

“This is the tip of the iceberg,” said ethicist Joseph F. Kras, MD, DDS, MA, an associate professor of anesthesiology at Washington University in St. Louis, Missouri, and corresponding author of a recent Anesthesia & Analgesia report about physician unionization.

“We are independent by nature,” Kras said. “But when you put us in an employed environment and start treating us as widgets, then we will act like employees of Amazon, Starbucks, and other companies and join together to push back against the increasing emphasis on profit over all at the expense of our independent judgment on what’s best for the patient.”

Of the 66 unionization efforts between 2000 and 2024 that were decided, 62% were certified, according to the JAMA study. The drives targeted hospitals (49%), community health centers (38%), and nonhospital corporate owners (13%).

The researchers only analyzed private-sector unionization and did not include physicians who are unionized at public institutions. 

 

What’s Behind Union Drives?

Alyssa Burgart, MD, MA, an ethicist and clinical associate professor of anesthesiology and pediatrics at Stanford University in California, told this news organization that physician unionization “is a big topic with a lot of really strong opinions.” 

Many doctors wrongly assume they can’t unionize because they’re physicians, said Burgart, a coauthor of the Anesthesia & Analgesia report.

Supporters of unionization believe it’s a strategy to be “recognized not as simply as a single physician with a concern,” she said. “When you’re among clinicians who can speak as a more unified group, organizations are more likely to take that seriously.”

A union may also be able to hold employers to account in areas such as the gender wage gap, sexual harassment, and bias in hiring and firing, Burgart said. And union supporters believe they’ll make more money if they collectively bargain. 

Other factors driving interest in unions include “increasing physician burnout, increasing physician exhaustion, and immense frustration with the ways that private equity is influencing how physicians need to work in order to practice,” she said. 

Earlier in 2024, physicians in Delaware’s ChristianaCare health system voted 288-130 to be represented by Doctors Council/Service Employees International, according to the union. 

“We have still not been able to staff up enough to where us physicians can get back to just focusing on taking care of patients,” a unionization leader told WHYY. 

The JAMA study examined news reports regarding most of the 2023-2024 union drives and found that supporters claimed they were motivated by working conditions (85%), lack of voice in management (81%), patient care concerns (54%), and pay (4%).

 

Critics Worry They’ll Lose Pay Because of Unions

Skeptics of unionization worry about whether “I’m going to be required to stand by some union stance that is actually out of alignment with my values as a physician,” Burgart said. And, she said, critics such as highly paid surgeons fear that adjustments to salaries because of union contracts could cause them to lose income.

In regard to compensation, a 2024 study surveyed unionized residents — along with faculty and staff — at general surgery programs and found evidence that unionization didn’t improve resident well-being or benefits, although it “provided a mechanism for resident voice and agency.”

“It is critical to study the outcomes of those who unionized to ensure that the reasons for unionizing were realized over time,” said that study’s coauthor Karl Bilimoria, MD, MS, chair of surgery at Indiana University School of Medicine, Indianapolis. “The unintended consequences of unionization must be examined along with the potential improvements.”

Rooke-Ley discloses consulting fees from the American Economic Liberties Project, National Academy of State Health Policy, and 32BJ Funds. Kras and Burgart disclose previous union membership. Bilimoria has no disclosures.

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

Cultural competency is one of the most important values in the practice of medicine. Defined as the “ability to collaborate effectively with individuals from different cultures,” this type of competence “improves healthcare experiences and outcomes.” But within the context of cultural familiarity, it’s equally important to “understand that each person is an individual and may or may not adhere to certain cultural beliefs or practices common in his or her culture,” according to the Agency for Healthcare Research and Quality’s (AHRQ’s) Health Literacy Universal Precautions Toolkit.

Sarah Candler, MD, MPH, an internal medicine physician specializing in primary care for older adults in Washington, DC, said that the medical code of ethics consists of several pillars, with patient autonomy as the “first and most primary of those pillars.” She calls the balance of patient autonomy and cultural respect a “complicated tightrope to walk,” but says that these ethical principles can inform medical decisions and the patient-physician relationship.

 

Cultural Familiarity

It’s important to be as familiar as possible with the patient’s culture, Santina Wheat, MD, program director, Northwestern McGaw Family Medicine Residency at Delnor Hospital, Geneva, told this news organization. “For example, we serve many Orthodox Jewish patients. We had a meeting with rabbis from the community to present to us what religious laws might affect our patients. Until recently, I was delivering babies, and there was always a 24-hour emergency rabbi on call if an Orthodox patient wanted the input of a rabbi into her decisions.”

Jay W. Lee, MD, MPH, a member of the board of directors of the American Academy of Family Physicians, also sets out to educate himself about the cultural norms of his patients if they come from populations he’s not familiar with. “For example, this comes up when a new refugee population comes to the United States — most recently, there was a population of Afghan refugees,” Lee told this news organization.

Lee spent “a lot of time trying to learn about their cultural norms,” which prepared him to “ask more targeted questions about the patient’s understanding of the tests we were ordering or treatment options we were bringing forward.”

Lee, also the medical director at Integrated Health Partners of Southern California and associate clinical professor of family medicine at the University of California, Irvine, said it might be best if the physician is “language congruent or culturally similar.” Lee is of Asian descent and also speaks Spanish fluently. “I enjoy cultural exchanges with my patients, and I encourage patients to find a physician who’s the best fit.” But being from the same culture isn’t absolutely necessary for building relationships with the patient. “The key is offering the patient autonomy” while understanding the cultural context.

 

Don’t Assume ... Always Ask

Cultural familiarity doesn’t equate with stereotyping, Wheat emphasized. “Proceeding without assumptions opens the opportunity to ask questions for clarification and understanding and to improve patient care,” said Lee.

Sara Glass, PhD, LCSW, agrees. She’s the clinical director of Soul Wellness NYC, New York City, a psychotherapy practice that specializes in treating trauma. Based on her own experiences, she knows that some physicians and other healthcare professionals confuse cultural sensitivity with cultural stereotyping.

Glass, formerly Hasidic and ultra-Orthodox, shared an example from her own life. During the delivery of her second child, she sustained a vaginal tear. At her 6-week postpartum visit, her ob/gyn said, “Just remind me when you’re in your ninth month next time, and I can sew it up right after you deliver.”

Much of this physician’s practice “consisted of Hasidic women who looked just like me, wearing the same garb — head coverings such as wigs and scarves and long skirts. Most women in that community have multiple pregnancies,” Glass told this news organization. “My sister has 10 children, and that’s not unusual. The doctor simply assumed I’d be going on to have more babies without asking if that’s what I wanted.”

Glass says she was also never given information by her physician about the range of available contraceptive options. The rabbis of the Hasidic sect to which Glass belonged allowed women to practice contraception for 6 months following childbirth, or for longer, in the setting of certain medical conditions, but only certain types of birth control were religiously permissible. Other options were not mentioned to her by her physician, and she didn’t know that they existed.

Making no assumptions applies not only to patients from other cultures but also to all patients — including members of “mainstream American culture.”

Candler recalls a young patient with a new baby, who shared “how exhausted she was and how much time, energy, and work it took to care for children,” Candler recounted. “To me, it sounded as though she didn’t want another child, and I was about to offer contraception when it occurred to me to first ask if she wanted to have more children.” Candler was surprised when the patient said that, although she wasn’t actively looking to become pregnant again, she didn’t want to take preventive measures. “I’m so glad I asked, rather than simply assuming.”

 

Culture Is Mutable

Important questions to ask patients include whether there are aspects of their culture or religion that might affect their care — which can include medications they may feel uncomfortable using — and what family members they want to have involved in clinical discussions and decisions, said Wheat.

Lee described treating a refugee from Afghanistan who was in her sixth month of pregnancy. “I quickly needed to learn about what her expectations were for her care and my presence as a male on her care team,” he recounted. Lee arranged for the patient to receive prenatal care from a different clinician and arranged for follow-up for her husband and children. “Everyone had good results.”

Candler noted that some patients choose their physician specifically because that practitioner is conversant with their culture and respectful of its mores — especially when physicians share the same culture as the patient. But that level of familiarity can make it easy to forget to ask questions about the experience of the individual patient within that culture.

Moreover, Glass suggested, some physicians who treat patients from a particular culture or religious group may be concerned about offending them or antagonizing religious leaders if they discuss medical options that aren’t accepted or practiced in that community or culture, such as vasectomy for male contraception. “But that deprives patients of knowing what choices are available and making truly informed decisions.”

This is especially important because “culture is mutable,” said Candler, and religious or cultural practices can “look one way on paper but be implemented, adopted, or executed in a completely different way by every human being who lives in that culture.” The best cultural competency “comes from continuing to build relationships with our patients. But even in a single visit, a single hospitalization, we should get to know patients as human beings, not just members of a given culture.”

There are cultures in which families want to be the liaison between the patient and the physician and to make decisions on the patient’s behalf. “I always ask patients what role they want their family members to play even if the cultural expectation is that the family will be heavily involved,” Candler said.

Sometimes, this can be awkward, and families might become upset. Candler described an elderly, frail patient who was diagnosed with end-stage cancer. She had always relied heavily on family to care for her. Concerned about overburdening them, she didn’t want them to know her diagnosis. The patient was mentally competent to make that decision.

“Usually, I would have had the family at the bedside so I could be sure everyone was appropriately informed and prepared for what lay ahead, but in this case, I couldn’t do so,” Candler said. “I had to inform her entire care team not to discuss the cancer diagnosis with any family members because this was the patient’s express wish. And when the family asked me if the diagnosis was cancer, I had to respond, ‘I’m so sorry, but your loved one doesn’t want us to discuss details of her diagnosis.’”

Other patients don’t want to know their own diagnosis and specifically ask Candler to inform a family member. “I’ve had patients request that I tell their children. They want their children to make decisions on their behalf.”

The main thing, Candler emphasized, is to “ask the patient, make sure the patient is competent to make that decision, thoroughly document the patient’s decision in the chart, and respect whatever that decision is.”

 

You Can Revisit the Questions

Having a longitudinal relationship means that the physician can revisit the same questions at different junctures because people’s perspectives sometimes change over time. “Discussing what a patient wants isn’t necessarily a one-time occurrence,” Wheat said. For example, “I’ve had situations where a patient has been a member of Jehovah’s Witnesses and won’t accept blood products — like transfusions — in treatment. I tell these patients that if an emergent situation arises, I would like to have the conversation again.”

Of course, sometimes patients are seen in the emergency department or in other situations where the physician has no prior relationship with them. “I always go into a room, especially with new patients, aiming to build rapport, communicate with a high level of respect, introduce myself, explain my approach, and understand the patient’s wishes,” Lee said. “As scenarios play out, I ask in multiple ways for the patient to confirm those wishes.”

He acknowledges that this can be time-consuming, “but it helps ensure the care that patient receives is complete, thorough, comprehensive, and respectful of the patient’s values and wishes.”

Candler disclosed paid part-time clinical work at CuraCapitol Primary Care Services, volunteer advocacy (reimbursed for travel) for the American College of Physicians, volunteer advocacy (reimbursed for travel) for the American Medical Association while serving on their Task Force to Preserve the Patient-Physician Relationship, and serving as a partner representative (reimbursed for time) for the AHRQ’s Person-Centered Care Planning Partnership, representing the American College of Physicians. Lee, Wheat, and Glass disclosed no relevant financial relationships.

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

Cultural competency is one of the most important values in the practice of medicine. Defined as the “ability to collaborate effectively with individuals from different cultures,” this type of competence “improves healthcare experiences and outcomes.” But within the context of cultural familiarity, it’s equally important to “understand that each person is an individual and may or may not adhere to certain cultural beliefs or practices common in his or her culture,” according to the Agency for Healthcare Research and Quality’s (AHRQ’s) Health Literacy Universal Precautions Toolkit.

Sarah Candler, MD, MPH, an internal medicine physician specializing in primary care for older adults in Washington, DC, said that the medical code of ethics consists of several pillars, with patient autonomy as the “first and most primary of those pillars.” She calls the balance of patient autonomy and cultural respect a “complicated tightrope to walk,” but says that these ethical principles can inform medical decisions and the patient-physician relationship.

 

Cultural Familiarity

It’s important to be as familiar as possible with the patient’s culture, Santina Wheat, MD, program director, Northwestern McGaw Family Medicine Residency at Delnor Hospital, Geneva, told this news organization. “For example, we serve many Orthodox Jewish patients. We had a meeting with rabbis from the community to present to us what religious laws might affect our patients. Until recently, I was delivering babies, and there was always a 24-hour emergency rabbi on call if an Orthodox patient wanted the input of a rabbi into her decisions.”

Jay W. Lee, MD, MPH, a member of the board of directors of the American Academy of Family Physicians, also sets out to educate himself about the cultural norms of his patients if they come from populations he’s not familiar with. “For example, this comes up when a new refugee population comes to the United States — most recently, there was a population of Afghan refugees,” Lee told this news organization.

Lee spent “a lot of time trying to learn about their cultural norms,” which prepared him to “ask more targeted questions about the patient’s understanding of the tests we were ordering or treatment options we were bringing forward.”

Lee, also the medical director at Integrated Health Partners of Southern California and associate clinical professor of family medicine at the University of California, Irvine, said it might be best if the physician is “language congruent or culturally similar.” Lee is of Asian descent and also speaks Spanish fluently. “I enjoy cultural exchanges with my patients, and I encourage patients to find a physician who’s the best fit.” But being from the same culture isn’t absolutely necessary for building relationships with the patient. “The key is offering the patient autonomy” while understanding the cultural context.

 

Don’t Assume ... Always Ask

Cultural familiarity doesn’t equate with stereotyping, Wheat emphasized. “Proceeding without assumptions opens the opportunity to ask questions for clarification and understanding and to improve patient care,” said Lee.

Sara Glass, PhD, LCSW, agrees. She’s the clinical director of Soul Wellness NYC, New York City, a psychotherapy practice that specializes in treating trauma. Based on her own experiences, she knows that some physicians and other healthcare professionals confuse cultural sensitivity with cultural stereotyping.

Glass, formerly Hasidic and ultra-Orthodox, shared an example from her own life. During the delivery of her second child, she sustained a vaginal tear. At her 6-week postpartum visit, her ob/gyn said, “Just remind me when you’re in your ninth month next time, and I can sew it up right after you deliver.”

Much of this physician’s practice “consisted of Hasidic women who looked just like me, wearing the same garb — head coverings such as wigs and scarves and long skirts. Most women in that community have multiple pregnancies,” Glass told this news organization. “My sister has 10 children, and that’s not unusual. The doctor simply assumed I’d be going on to have more babies without asking if that’s what I wanted.”

Glass says she was also never given information by her physician about the range of available contraceptive options. The rabbis of the Hasidic sect to which Glass belonged allowed women to practice contraception for 6 months following childbirth, or for longer, in the setting of certain medical conditions, but only certain types of birth control were religiously permissible. Other options were not mentioned to her by her physician, and she didn’t know that they existed.

Making no assumptions applies not only to patients from other cultures but also to all patients — including members of “mainstream American culture.”

Candler recalls a young patient with a new baby, who shared “how exhausted she was and how much time, energy, and work it took to care for children,” Candler recounted. “To me, it sounded as though she didn’t want another child, and I was about to offer contraception when it occurred to me to first ask if she wanted to have more children.” Candler was surprised when the patient said that, although she wasn’t actively looking to become pregnant again, she didn’t want to take preventive measures. “I’m so glad I asked, rather than simply assuming.”

 

Culture Is Mutable

Important questions to ask patients include whether there are aspects of their culture or religion that might affect their care — which can include medications they may feel uncomfortable using — and what family members they want to have involved in clinical discussions and decisions, said Wheat.

Lee described treating a refugee from Afghanistan who was in her sixth month of pregnancy. “I quickly needed to learn about what her expectations were for her care and my presence as a male on her care team,” he recounted. Lee arranged for the patient to receive prenatal care from a different clinician and arranged for follow-up for her husband and children. “Everyone had good results.”

Candler noted that some patients choose their physician specifically because that practitioner is conversant with their culture and respectful of its mores — especially when physicians share the same culture as the patient. But that level of familiarity can make it easy to forget to ask questions about the experience of the individual patient within that culture.

Moreover, Glass suggested, some physicians who treat patients from a particular culture or religious group may be concerned about offending them or antagonizing religious leaders if they discuss medical options that aren’t accepted or practiced in that community or culture, such as vasectomy for male contraception. “But that deprives patients of knowing what choices are available and making truly informed decisions.”

This is especially important because “culture is mutable,” said Candler, and religious or cultural practices can “look one way on paper but be implemented, adopted, or executed in a completely different way by every human being who lives in that culture.” The best cultural competency “comes from continuing to build relationships with our patients. But even in a single visit, a single hospitalization, we should get to know patients as human beings, not just members of a given culture.”

There are cultures in which families want to be the liaison between the patient and the physician and to make decisions on the patient’s behalf. “I always ask patients what role they want their family members to play even if the cultural expectation is that the family will be heavily involved,” Candler said.

Sometimes, this can be awkward, and families might become upset. Candler described an elderly, frail patient who was diagnosed with end-stage cancer. She had always relied heavily on family to care for her. Concerned about overburdening them, she didn’t want them to know her diagnosis. The patient was mentally competent to make that decision.

“Usually, I would have had the family at the bedside so I could be sure everyone was appropriately informed and prepared for what lay ahead, but in this case, I couldn’t do so,” Candler said. “I had to inform her entire care team not to discuss the cancer diagnosis with any family members because this was the patient’s express wish. And when the family asked me if the diagnosis was cancer, I had to respond, ‘I’m so sorry, but your loved one doesn’t want us to discuss details of her diagnosis.’”

Other patients don’t want to know their own diagnosis and specifically ask Candler to inform a family member. “I’ve had patients request that I tell their children. They want their children to make decisions on their behalf.”

The main thing, Candler emphasized, is to “ask the patient, make sure the patient is competent to make that decision, thoroughly document the patient’s decision in the chart, and respect whatever that decision is.”

 

You Can Revisit the Questions

Having a longitudinal relationship means that the physician can revisit the same questions at different junctures because people’s perspectives sometimes change over time. “Discussing what a patient wants isn’t necessarily a one-time occurrence,” Wheat said. For example, “I’ve had situations where a patient has been a member of Jehovah’s Witnesses and won’t accept blood products — like transfusions — in treatment. I tell these patients that if an emergent situation arises, I would like to have the conversation again.”

Of course, sometimes patients are seen in the emergency department or in other situations where the physician has no prior relationship with them. “I always go into a room, especially with new patients, aiming to build rapport, communicate with a high level of respect, introduce myself, explain my approach, and understand the patient’s wishes,” Lee said. “As scenarios play out, I ask in multiple ways for the patient to confirm those wishes.”

He acknowledges that this can be time-consuming, “but it helps ensure the care that patient receives is complete, thorough, comprehensive, and respectful of the patient’s values and wishes.”

Candler disclosed paid part-time clinical work at CuraCapitol Primary Care Services, volunteer advocacy (reimbursed for travel) for the American College of Physicians, volunteer advocacy (reimbursed for travel) for the American Medical Association while serving on their Task Force to Preserve the Patient-Physician Relationship, and serving as a partner representative (reimbursed for time) for the AHRQ’s Person-Centered Care Planning Partnership, representing the American College of Physicians. Lee, Wheat, and Glass disclosed no relevant financial relationships.

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

Cultural competency is one of the most important values in the practice of medicine. Defined as the “ability to collaborate effectively with individuals from different cultures,” this type of competence “improves healthcare experiences and outcomes.” But within the context of cultural familiarity, it’s equally important to “understand that each person is an individual and may or may not adhere to certain cultural beliefs or practices common in his or her culture,” according to the Agency for Healthcare Research and Quality’s (AHRQ’s) Health Literacy Universal Precautions Toolkit.

Sarah Candler, MD, MPH, an internal medicine physician specializing in primary care for older adults in Washington, DC, said that the medical code of ethics consists of several pillars, with patient autonomy as the “first and most primary of those pillars.” She calls the balance of patient autonomy and cultural respect a “complicated tightrope to walk,” but says that these ethical principles can inform medical decisions and the patient-physician relationship.

 

Cultural Familiarity

It’s important to be as familiar as possible with the patient’s culture, Santina Wheat, MD, program director, Northwestern McGaw Family Medicine Residency at Delnor Hospital, Geneva, told this news organization. “For example, we serve many Orthodox Jewish patients. We had a meeting with rabbis from the community to present to us what religious laws might affect our patients. Until recently, I was delivering babies, and there was always a 24-hour emergency rabbi on call if an Orthodox patient wanted the input of a rabbi into her decisions.”

Jay W. Lee, MD, MPH, a member of the board of directors of the American Academy of Family Physicians, also sets out to educate himself about the cultural norms of his patients if they come from populations he’s not familiar with. “For example, this comes up when a new refugee population comes to the United States — most recently, there was a population of Afghan refugees,” Lee told this news organization.

Lee spent “a lot of time trying to learn about their cultural norms,” which prepared him to “ask more targeted questions about the patient’s understanding of the tests we were ordering or treatment options we were bringing forward.”

Lee, also the medical director at Integrated Health Partners of Southern California and associate clinical professor of family medicine at the University of California, Irvine, said it might be best if the physician is “language congruent or culturally similar.” Lee is of Asian descent and also speaks Spanish fluently. “I enjoy cultural exchanges with my patients, and I encourage patients to find a physician who’s the best fit.” But being from the same culture isn’t absolutely necessary for building relationships with the patient. “The key is offering the patient autonomy” while understanding the cultural context.

 

Don’t Assume ... Always Ask

Cultural familiarity doesn’t equate with stereotyping, Wheat emphasized. “Proceeding without assumptions opens the opportunity to ask questions for clarification and understanding and to improve patient care,” said Lee.

Sara Glass, PhD, LCSW, agrees. She’s the clinical director of Soul Wellness NYC, New York City, a psychotherapy practice that specializes in treating trauma. Based on her own experiences, she knows that some physicians and other healthcare professionals confuse cultural sensitivity with cultural stereotyping.

Glass, formerly Hasidic and ultra-Orthodox, shared an example from her own life. During the delivery of her second child, she sustained a vaginal tear. At her 6-week postpartum visit, her ob/gyn said, “Just remind me when you’re in your ninth month next time, and I can sew it up right after you deliver.”

Much of this physician’s practice “consisted of Hasidic women who looked just like me, wearing the same garb — head coverings such as wigs and scarves and long skirts. Most women in that community have multiple pregnancies,” Glass told this news organization. “My sister has 10 children, and that’s not unusual. The doctor simply assumed I’d be going on to have more babies without asking if that’s what I wanted.”

Glass says she was also never given information by her physician about the range of available contraceptive options. The rabbis of the Hasidic sect to which Glass belonged allowed women to practice contraception for 6 months following childbirth, or for longer, in the setting of certain medical conditions, but only certain types of birth control were religiously permissible. Other options were not mentioned to her by her physician, and she didn’t know that they existed.

Making no assumptions applies not only to patients from other cultures but also to all patients — including members of “mainstream American culture.”

Candler recalls a young patient with a new baby, who shared “how exhausted she was and how much time, energy, and work it took to care for children,” Candler recounted. “To me, it sounded as though she didn’t want another child, and I was about to offer contraception when it occurred to me to first ask if she wanted to have more children.” Candler was surprised when the patient said that, although she wasn’t actively looking to become pregnant again, she didn’t want to take preventive measures. “I’m so glad I asked, rather than simply assuming.”

 

Culture Is Mutable

Important questions to ask patients include whether there are aspects of their culture or religion that might affect their care — which can include medications they may feel uncomfortable using — and what family members they want to have involved in clinical discussions and decisions, said Wheat.

Lee described treating a refugee from Afghanistan who was in her sixth month of pregnancy. “I quickly needed to learn about what her expectations were for her care and my presence as a male on her care team,” he recounted. Lee arranged for the patient to receive prenatal care from a different clinician and arranged for follow-up for her husband and children. “Everyone had good results.”

Candler noted that some patients choose their physician specifically because that practitioner is conversant with their culture and respectful of its mores — especially when physicians share the same culture as the patient. But that level of familiarity can make it easy to forget to ask questions about the experience of the individual patient within that culture.

Moreover, Glass suggested, some physicians who treat patients from a particular culture or religious group may be concerned about offending them or antagonizing religious leaders if they discuss medical options that aren’t accepted or practiced in that community or culture, such as vasectomy for male contraception. “But that deprives patients of knowing what choices are available and making truly informed decisions.”

This is especially important because “culture is mutable,” said Candler, and religious or cultural practices can “look one way on paper but be implemented, adopted, or executed in a completely different way by every human being who lives in that culture.” The best cultural competency “comes from continuing to build relationships with our patients. But even in a single visit, a single hospitalization, we should get to know patients as human beings, not just members of a given culture.”

There are cultures in which families want to be the liaison between the patient and the physician and to make decisions on the patient’s behalf. “I always ask patients what role they want their family members to play even if the cultural expectation is that the family will be heavily involved,” Candler said.

Sometimes, this can be awkward, and families might become upset. Candler described an elderly, frail patient who was diagnosed with end-stage cancer. She had always relied heavily on family to care for her. Concerned about overburdening them, she didn’t want them to know her diagnosis. The patient was mentally competent to make that decision.

“Usually, I would have had the family at the bedside so I could be sure everyone was appropriately informed and prepared for what lay ahead, but in this case, I couldn’t do so,” Candler said. “I had to inform her entire care team not to discuss the cancer diagnosis with any family members because this was the patient’s express wish. And when the family asked me if the diagnosis was cancer, I had to respond, ‘I’m so sorry, but your loved one doesn’t want us to discuss details of her diagnosis.’”

Other patients don’t want to know their own diagnosis and specifically ask Candler to inform a family member. “I’ve had patients request that I tell their children. They want their children to make decisions on their behalf.”

The main thing, Candler emphasized, is to “ask the patient, make sure the patient is competent to make that decision, thoroughly document the patient’s decision in the chart, and respect whatever that decision is.”

 

You Can Revisit the Questions

Having a longitudinal relationship means that the physician can revisit the same questions at different junctures because people’s perspectives sometimes change over time. “Discussing what a patient wants isn’t necessarily a one-time occurrence,” Wheat said. For example, “I’ve had situations where a patient has been a member of Jehovah’s Witnesses and won’t accept blood products — like transfusions — in treatment. I tell these patients that if an emergent situation arises, I would like to have the conversation again.”

Of course, sometimes patients are seen in the emergency department or in other situations where the physician has no prior relationship with them. “I always go into a room, especially with new patients, aiming to build rapport, communicate with a high level of respect, introduce myself, explain my approach, and understand the patient’s wishes,” Lee said. “As scenarios play out, I ask in multiple ways for the patient to confirm those wishes.”

He acknowledges that this can be time-consuming, “but it helps ensure the care that patient receives is complete, thorough, comprehensive, and respectful of the patient’s values and wishes.”

Candler disclosed paid part-time clinical work at CuraCapitol Primary Care Services, volunteer advocacy (reimbursed for travel) for the American College of Physicians, volunteer advocacy (reimbursed for travel) for the American Medical Association while serving on their Task Force to Preserve the Patient-Physician Relationship, and serving as a partner representative (reimbursed for time) for the AHRQ’s Person-Centered Care Planning Partnership, representing the American College of Physicians. Lee, Wheat, and Glass disclosed no relevant financial relationships.

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

TOPLINE:

Survivors of blood or marrow transplant (BMT) face a significant risk of developing cutaneous malignant neoplasms, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, with a cumulative incidence of 27.4% over 30 years, according to the results of a cohort study.

METHODOLOGY:

• The retrospective cohort study included 3880 BMT survivors (median age, 44 years; 55.8% men; 4.9% Black, 12.1 Hispanic, and 74.7% non-Hispanic White individuals) who underwent transplant between 1974 to 2014.
• Participants completed the BMT Survivor Study survey and were followed up for a median of 9.5 years.
• The primary outcomes were the development of subsequent cutaneous malignant neoplasms (BCC, SCC, or melanoma).

TAKEAWAY:

• The 30-year cumulative incidence of any cutaneous malignant neoplasm was 27.4% — 18% for BCC, 9.8% for SCC, and 3.7% for melanoma.
• A higher risk for skin cancer was reported for patients aged 50 years or more (subdistribution hazard ratio [SHR], 2.23; 95% CI, 1.83-2.71), and men (SHR, 1.40; 95% CI, 1.18-1.65).
• Allogeneic BMT with chronic graft-vs-host disease (cGVHD) increased the risk for skin cancer (SHR, 1.84; 95% CI, 1.37-2.47), compared with autologous BMT, while post-BMT immunosuppression increased risk for all types (overall SHR, 1.53; 95% CI, 1.26-1.86).
• The risk for any skin cancer was significantly lower in Black individuals (SHR, 0.14; 95% CI, 0.05-0.37), Hispanic individuals (SHR, 0.29; 95%CI, 0.20-0.62), and patients of other races or who were multiracial (SHR, 0.22; 95% CI, 0.13-0.37) than in non-Hispanic White patients.

IN PRACTICE:

In the study, “risk factors for post-BMT cutaneous malignant neoplasms included pretransplant treatment with a monoclonal antibody, cGVHD, and posttransplant immunosuppression,” the authors wrote, adding that the findings “could inform targeted surveillance of BMT survivors.” Most BMT survivors, “do not undergo routine dermatologic surveillance, highlighting the need to understand risk factors and incorporate risk-informed dermatologic surveillance into survivorship care plans.”

SOURCE:

The study was led by Kristy K. Broman, MD, MPH, University of Alabama at Birmingham, and was published online on December 18 in JAMA Dermatology.

LIMITATIONS:

Limitations included self-reported data and possible underreporting of melanoma cases in the SEER database. Additionally, the study did not capture other risk factors for cutaneous malignant neoplasms such as skin phototype, ultraviolet light exposure, or family history. The duration of posttransplant immunosuppression was not collected, and surveys were administered at variable intervals, though all were completed more than 2 years post BMT.

DISCLOSURES:

The study was supported by the National Cancer Institute (NCI) and the Leukemia and Lymphoma Society. Broman received grants from NCI, the National Center for Advancing Translational Sciences, the American Society of Clinical Oncology, and the American College of Surgeons. Another author reported receiving grants outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Survivors of blood or marrow transplant (BMT) face a significant risk of developing cutaneous malignant neoplasms, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, with a cumulative incidence of 27.4% over 30 years, according to the results of a cohort study.

METHODOLOGY:

• The retrospective cohort study included 3880 BMT survivors (median age, 44 years; 55.8% men; 4.9% Black, 12.1 Hispanic, and 74.7% non-Hispanic White individuals) who underwent transplant between 1974 to 2014.
• Participants completed the BMT Survivor Study survey and were followed up for a median of 9.5 years.
• The primary outcomes were the development of subsequent cutaneous malignant neoplasms (BCC, SCC, or melanoma).

TAKEAWAY:

• The 30-year cumulative incidence of any cutaneous malignant neoplasm was 27.4% — 18% for BCC, 9.8% for SCC, and 3.7% for melanoma.
• A higher risk for skin cancer was reported for patients aged 50 years or more (subdistribution hazard ratio [SHR], 2.23; 95% CI, 1.83-2.71), and men (SHR, 1.40; 95% CI, 1.18-1.65).
• Allogeneic BMT with chronic graft-vs-host disease (cGVHD) increased the risk for skin cancer (SHR, 1.84; 95% CI, 1.37-2.47), compared with autologous BMT, while post-BMT immunosuppression increased risk for all types (overall SHR, 1.53; 95% CI, 1.26-1.86).
• The risk for any skin cancer was significantly lower in Black individuals (SHR, 0.14; 95% CI, 0.05-0.37), Hispanic individuals (SHR, 0.29; 95%CI, 0.20-0.62), and patients of other races or who were multiracial (SHR, 0.22; 95% CI, 0.13-0.37) than in non-Hispanic White patients.

IN PRACTICE:

In the study, “risk factors for post-BMT cutaneous malignant neoplasms included pretransplant treatment with a monoclonal antibody, cGVHD, and posttransplant immunosuppression,” the authors wrote, adding that the findings “could inform targeted surveillance of BMT survivors.” Most BMT survivors, “do not undergo routine dermatologic surveillance, highlighting the need to understand risk factors and incorporate risk-informed dermatologic surveillance into survivorship care plans.”

SOURCE:

The study was led by Kristy K. Broman, MD, MPH, University of Alabama at Birmingham, and was published online on December 18 in JAMA Dermatology.

LIMITATIONS:

Limitations included self-reported data and possible underreporting of melanoma cases in the SEER database. Additionally, the study did not capture other risk factors for cutaneous malignant neoplasms such as skin phototype, ultraviolet light exposure, or family history. The duration of posttransplant immunosuppression was not collected, and surveys were administered at variable intervals, though all were completed more than 2 years post BMT.

DISCLOSURES:

The study was supported by the National Cancer Institute (NCI) and the Leukemia and Lymphoma Society. Broman received grants from NCI, the National Center for Advancing Translational Sciences, the American Society of Clinical Oncology, and the American College of Surgeons. Another author reported receiving grants outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Survivors of blood or marrow transplant (BMT) face a significant risk of developing cutaneous malignant neoplasms, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, with a cumulative incidence of 27.4% over 30 years, according to the results of a cohort study.

METHODOLOGY:

• The retrospective cohort study included 3880 BMT survivors (median age, 44 years; 55.8% men; 4.9% Black, 12.1 Hispanic, and 74.7% non-Hispanic White individuals) who underwent transplant between 1974 to 2014.
• Participants completed the BMT Survivor Study survey and were followed up for a median of 9.5 years.
• The primary outcomes were the development of subsequent cutaneous malignant neoplasms (BCC, SCC, or melanoma).

TAKEAWAY:

• The 30-year cumulative incidence of any cutaneous malignant neoplasm was 27.4% — 18% for BCC, 9.8% for SCC, and 3.7% for melanoma.
• A higher risk for skin cancer was reported for patients aged 50 years or more (subdistribution hazard ratio [SHR], 2.23; 95% CI, 1.83-2.71), and men (SHR, 1.40; 95% CI, 1.18-1.65).
• Allogeneic BMT with chronic graft-vs-host disease (cGVHD) increased the risk for skin cancer (SHR, 1.84; 95% CI, 1.37-2.47), compared with autologous BMT, while post-BMT immunosuppression increased risk for all types (overall SHR, 1.53; 95% CI, 1.26-1.86).
• The risk for any skin cancer was significantly lower in Black individuals (SHR, 0.14; 95% CI, 0.05-0.37), Hispanic individuals (SHR, 0.29; 95%CI, 0.20-0.62), and patients of other races or who were multiracial (SHR, 0.22; 95% CI, 0.13-0.37) than in non-Hispanic White patients.

IN PRACTICE:

In the study, “risk factors for post-BMT cutaneous malignant neoplasms included pretransplant treatment with a monoclonal antibody, cGVHD, and posttransplant immunosuppression,” the authors wrote, adding that the findings “could inform targeted surveillance of BMT survivors.” Most BMT survivors, “do not undergo routine dermatologic surveillance, highlighting the need to understand risk factors and incorporate risk-informed dermatologic surveillance into survivorship care plans.”

SOURCE:

The study was led by Kristy K. Broman, MD, MPH, University of Alabama at Birmingham, and was published online on December 18 in JAMA Dermatology.

LIMITATIONS:

Limitations included self-reported data and possible underreporting of melanoma cases in the SEER database. Additionally, the study did not capture other risk factors for cutaneous malignant neoplasms such as skin phototype, ultraviolet light exposure, or family history. The duration of posttransplant immunosuppression was not collected, and surveys were administered at variable intervals, though all were completed more than 2 years post BMT.

DISCLOSURES:

The study was supported by the National Cancer Institute (NCI) and the Leukemia and Lymphoma Society. Broman received grants from NCI, the National Center for Advancing Translational Sciences, the American Society of Clinical Oncology, and the American College of Surgeons. Another author reported receiving grants outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

The question has been lingering for years in medical science circles. Since 2020, when the artificial intelligence (AI) model AlphaFold made it possible to predict protein structures, would the technology open the drug discovery floodgates?

Short answer: No. At least not yet.

The longer answer goes something like this:

A drug target (such as a mutation) is like a lock. The right drug (a protein designed to bind to the mutation, stopping its activity) is the key. But proteins are fidgety and flexible.

“They’re basically molecular springs,” said Gabriel Monteiro da Silva, PhD, a computational chemistry research scientist at Genesis Therapeutics. “Your key can bend and alter the shape of the lock, and if you don’t account for that, your key might fail.”

This is the protein problem in drug development. Another issue making this challenge so vexing is that proteins don’t act in isolation. Their interactions with other proteins, ribonucleic acid, and DNA can affect how they bind to molecules and the shapes they adopt.

Newer versions of AlphaFold, such as AlphaFold Multimer and AlphaFold 3 (the code for which was recently revealed for academic use), can predict many interactions among proteins and between proteins and other molecules. But these tools still have weak points scientists are trying to overcome or work around.

“Those kinds of dynamics and multiple conformations are still quite challenging for the AI models to predict,” said James Zou, PhD, associate professor of biomedical data science at Stanford University in California.

“We’re finding more and more that the only way we can make these structures useful for drug discovery is if we incorporate dynamics, if we incorporate more physics into the model,” said Monteiro da Silva.

Monteiro da Silva spent 3 years during his PhD at Brown University, Providence, Rhode Island, running physics-based simulations in the lab, trying to understand why proteins carrying certain mutations are drug resistant. His results showed how “the changing landscape of shapes that a protein can take” prevented the drug from binding.

It took him 3 years to model just four mutations.

AI can do better — and the struggle is fascinating. By developing models that build on the predictive power of AlphaFold, scientists are uncovering new details about protein activity — insights that can lead to new therapeutics and reveal why existing ones stop working — much faster than they could with traditional methods or AlphaFold alone.

 

New Windows into Protein Dynamics

By predicting protein structural details, AlphaFold models also made it possible to predict pockets where drugs could bind.

A notable step, “but that’s just the starting point,” said Pedro Beltrao, PhD, an associate professor at Institute of Molecular Systems Biology, ETH Zurich in Switzerland. “It’s still very difficult, given a pocket, to actually design the drug or figure out what the pocket binds.”

Going back to the lock-and-key analogy: While he was at Brown, with a team of researchers in the Rubenstein Group, Monteiro da Silva helped create a model to better understand how mutations affect “the shape and dynamics of the lock.” They manipulated the amino acid sequences of proteins, guiding their evolution. This enabled them to use AlphaFold to predict “protein ensembles” and how frequently those ensembles appear. Each ensemble represents the many different shapes a protein can take under given conditions.

“Essentially, it tries to find the most common shapes that a protein will take over an arbitrary amount of time,” Monteiro da Silva said. “If we can predict these ensembles at scale and fast, then we can screen many mutations that cause resistance and develop drugs that will not be affected by that resistance.”

To evaluate their method, the researchers focused on ABL1, a well-studied kinase that causes leukemia. ABL1 can be drugged – unless it carries or develops a mutation that causes drug resistance. Currently there are no drugs that work against proteins carrying those mutations, according to Monteiro da Silva. The researchers used their hybrid AI-meets-physics method to investigate how drugs bind to different ABL1 mutations, screening 100 mutations in just 1 month.

“It’s not going to be perfect for every one of them. But if we have 100 and we get 20 with good accuracy, that’s better than doing four over 3 years,” Monteiro da Silva said.

A forthcoming paper will make their model publicly available in “an easy-to-use graphical interface” that they hope clinicians and medicinal chemists will try out. It can also complement other AI-based tools that dig into protein dynamics, according to Monteiro da Silva.

 

Complementary Tools to Speed Up Discovery 

Another aspect of the protein problem is scale. One protein can interact with hundreds of other proteins, which in turn may interact with hundreds more, all of which comprise the human interactome.

Feixiong Cheng, PhD, helped build PIONEER, a deep learning model that predicts the three-dimensional (3D) structure of interactions between proteins across the interactome.

Most disease mutations disrupt specific interactions between proteins, making their affinity stronger or weaker, explained Cheng. To treat a disease without causing major side effects, scientists need a precise understanding of those interactions.

“From the drug discovery perspective, we cannot just focus on single proteins. We have to understand the protein environment, in particular how the protein interacts with other proteins,” said Cheng, director of Cleveland Clinic Genome Center, Cleveland.

PIONEER helps by blending AlphaFold’s protein structure predictions with next-generation sequencing, a type of genomic research that identifies mutations in the human genome. The model predicts the 3D structure of the places where proteins interact — the binding sites, or interfaces — across the interactome.

“We tell you not only that a binds b, but where on a and where on b the two proteins interact,” said Haiyuan Yu, PhD, director of the Center for Innovative Proteomics, Cornell University, and co-creator of PIONEER.

This can help scientists understand “why a mutation, protein, or even network is a good target for therapeutic discovery,” Cheng said.

The researchers validated PIONEER’s predictions in the lab, testing the impacts of roughly 3000 mutations on 7000 pairs of interacting proteins. Based on their findings, they plan to develop and test treatments for lung and endometrial cancer.

PIONEER can also help scientists home in on how a mutation causes a disease, such as by showing recurrent mutations.

“If you find cancer mutations hitting an interface again and again and again, it means that this is likely to be driving cancer progression,” said Beltrao.

Beltrao’s lab and others have looked for recurrent mutations by using AlphaFold Multimer and AlphaFold 3 to directly model protein interactions. It’s a much slower approach (Pioneer is more than 5000 faster than AlphaFold Multimer, according to Cheng). But it could allow scientists to model interfaces that are not shown by PIONEER.

“You will need many different things to try to come up with a structural modeling of the interactome, and all these will have limitations,” said Beltrao. “Their method is a very good step forward, and there’ll be other approaches that are complementary, to continue to add details.”

 

And It Wouldn’t be an AI Mission Without ChatGPT

Large language models, such as ChatGPT, are another way that scientists are adding details to protein structure predictions. Zou used GPT-4 to “fine tune” a protein language model, called evolutionary scale modeling (ESM-2), which predicts protein structures directly from a protein sequence.

First, they trained ChatGPT on thousands of papers and studies containing information about the functions, biophysical properties, and disease relevance of different mutations. Next, they used the trained model to “teach” ESM-2, boosting its ability “to predict which mutations are likely to have larger effects or smaller effects,” Zou said. The same could be done for a model like AlphaFold, according to Zou.

“They are quite complementary in that the large language model contains a lot more information about the functions and the biophysics of different mutations and proteins as captured in text,” he said, whereas “you can’t give AlphaFold a piece of paper.”

Exactly how AlphaFold makes its predictions is another mystery. “It will somehow learn protein dynamics phenomenologically,” said Monteiro da Silva. He and others are trying to understand how that happens, in hopes of creating even more accurate predictive models. But for the time being, AI-based methods still need assistance from physics.

“The dream is that we achieve a state where we rely on just the fast methods, and they’re accurate enough,” he said. “But we’re so far from that.”

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

The question has been lingering for years in medical science circles. Since 2020, when the artificial intelligence (AI) model AlphaFold made it possible to predict protein structures, would the technology open the drug discovery floodgates?

Short answer: No. At least not yet.

The longer answer goes something like this:

A drug target (such as a mutation) is like a lock. The right drug (a protein designed to bind to the mutation, stopping its activity) is the key. But proteins are fidgety and flexible.

“They’re basically molecular springs,” said Gabriel Monteiro da Silva, PhD, a computational chemistry research scientist at Genesis Therapeutics. “Your key can bend and alter the shape of the lock, and if you don’t account for that, your key might fail.”

This is the protein problem in drug development. Another issue making this challenge so vexing is that proteins don’t act in isolation. Their interactions with other proteins, ribonucleic acid, and DNA can affect how they bind to molecules and the shapes they adopt.

Newer versions of AlphaFold, such as AlphaFold Multimer and AlphaFold 3 (the code for which was recently revealed for academic use), can predict many interactions among proteins and between proteins and other molecules. But these tools still have weak points scientists are trying to overcome or work around.

“Those kinds of dynamics and multiple conformations are still quite challenging for the AI models to predict,” said James Zou, PhD, associate professor of biomedical data science at Stanford University in California.

“We’re finding more and more that the only way we can make these structures useful for drug discovery is if we incorporate dynamics, if we incorporate more physics into the model,” said Monteiro da Silva.

Monteiro da Silva spent 3 years during his PhD at Brown University, Providence, Rhode Island, running physics-based simulations in the lab, trying to understand why proteins carrying certain mutations are drug resistant. His results showed how “the changing landscape of shapes that a protein can take” prevented the drug from binding.

It took him 3 years to model just four mutations.

AI can do better — and the struggle is fascinating. By developing models that build on the predictive power of AlphaFold, scientists are uncovering new details about protein activity — insights that can lead to new therapeutics and reveal why existing ones stop working — much faster than they could with traditional methods or AlphaFold alone.

 

New Windows into Protein Dynamics

By predicting protein structural details, AlphaFold models also made it possible to predict pockets where drugs could bind.

A notable step, “but that’s just the starting point,” said Pedro Beltrao, PhD, an associate professor at Institute of Molecular Systems Biology, ETH Zurich in Switzerland. “It’s still very difficult, given a pocket, to actually design the drug or figure out what the pocket binds.”

Going back to the lock-and-key analogy: While he was at Brown, with a team of researchers in the Rubenstein Group, Monteiro da Silva helped create a model to better understand how mutations affect “the shape and dynamics of the lock.” They manipulated the amino acid sequences of proteins, guiding their evolution. This enabled them to use AlphaFold to predict “protein ensembles” and how frequently those ensembles appear. Each ensemble represents the many different shapes a protein can take under given conditions.

“Essentially, it tries to find the most common shapes that a protein will take over an arbitrary amount of time,” Monteiro da Silva said. “If we can predict these ensembles at scale and fast, then we can screen many mutations that cause resistance and develop drugs that will not be affected by that resistance.”

To evaluate their method, the researchers focused on ABL1, a well-studied kinase that causes leukemia. ABL1 can be drugged – unless it carries or develops a mutation that causes drug resistance. Currently there are no drugs that work against proteins carrying those mutations, according to Monteiro da Silva. The researchers used their hybrid AI-meets-physics method to investigate how drugs bind to different ABL1 mutations, screening 100 mutations in just 1 month.

“It’s not going to be perfect for every one of them. But if we have 100 and we get 20 with good accuracy, that’s better than doing four over 3 years,” Monteiro da Silva said.

A forthcoming paper will make their model publicly available in “an easy-to-use graphical interface” that they hope clinicians and medicinal chemists will try out. It can also complement other AI-based tools that dig into protein dynamics, according to Monteiro da Silva.

 

Complementary Tools to Speed Up Discovery 

Another aspect of the protein problem is scale. One protein can interact with hundreds of other proteins, which in turn may interact with hundreds more, all of which comprise the human interactome.

Feixiong Cheng, PhD, helped build PIONEER, a deep learning model that predicts the three-dimensional (3D) structure of interactions between proteins across the interactome.

Most disease mutations disrupt specific interactions between proteins, making their affinity stronger or weaker, explained Cheng. To treat a disease without causing major side effects, scientists need a precise understanding of those interactions.

“From the drug discovery perspective, we cannot just focus on single proteins. We have to understand the protein environment, in particular how the protein interacts with other proteins,” said Cheng, director of Cleveland Clinic Genome Center, Cleveland.

PIONEER helps by blending AlphaFold’s protein structure predictions with next-generation sequencing, a type of genomic research that identifies mutations in the human genome. The model predicts the 3D structure of the places where proteins interact — the binding sites, or interfaces — across the interactome.

“We tell you not only that a binds b, but where on a and where on b the two proteins interact,” said Haiyuan Yu, PhD, director of the Center for Innovative Proteomics, Cornell University, and co-creator of PIONEER.

This can help scientists understand “why a mutation, protein, or even network is a good target for therapeutic discovery,” Cheng said.

The researchers validated PIONEER’s predictions in the lab, testing the impacts of roughly 3000 mutations on 7000 pairs of interacting proteins. Based on their findings, they plan to develop and test treatments for lung and endometrial cancer.

PIONEER can also help scientists home in on how a mutation causes a disease, such as by showing recurrent mutations.

“If you find cancer mutations hitting an interface again and again and again, it means that this is likely to be driving cancer progression,” said Beltrao.

Beltrao’s lab and others have looked for recurrent mutations by using AlphaFold Multimer and AlphaFold 3 to directly model protein interactions. It’s a much slower approach (Pioneer is more than 5000 faster than AlphaFold Multimer, according to Cheng). But it could allow scientists to model interfaces that are not shown by PIONEER.

“You will need many different things to try to come up with a structural modeling of the interactome, and all these will have limitations,” said Beltrao. “Their method is a very good step forward, and there’ll be other approaches that are complementary, to continue to add details.”

 

And It Wouldn’t be an AI Mission Without ChatGPT

Large language models, such as ChatGPT, are another way that scientists are adding details to protein structure predictions. Zou used GPT-4 to “fine tune” a protein language model, called evolutionary scale modeling (ESM-2), which predicts protein structures directly from a protein sequence.

First, they trained ChatGPT on thousands of papers and studies containing information about the functions, biophysical properties, and disease relevance of different mutations. Next, they used the trained model to “teach” ESM-2, boosting its ability “to predict which mutations are likely to have larger effects or smaller effects,” Zou said. The same could be done for a model like AlphaFold, according to Zou.

“They are quite complementary in that the large language model contains a lot more information about the functions and the biophysics of different mutations and proteins as captured in text,” he said, whereas “you can’t give AlphaFold a piece of paper.”

Exactly how AlphaFold makes its predictions is another mystery. “It will somehow learn protein dynamics phenomenologically,” said Monteiro da Silva. He and others are trying to understand how that happens, in hopes of creating even more accurate predictive models. But for the time being, AI-based methods still need assistance from physics.

“The dream is that we achieve a state where we rely on just the fast methods, and they’re accurate enough,” he said. “But we’re so far from that.”

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

The question has been lingering for years in medical science circles. Since 2020, when the artificial intelligence (AI) model AlphaFold made it possible to predict protein structures, would the technology open the drug discovery floodgates?

Short answer: No. At least not yet.

The longer answer goes something like this:

A drug target (such as a mutation) is like a lock. The right drug (a protein designed to bind to the mutation, stopping its activity) is the key. But proteins are fidgety and flexible.

“They’re basically molecular springs,” said Gabriel Monteiro da Silva, PhD, a computational chemistry research scientist at Genesis Therapeutics. “Your key can bend and alter the shape of the lock, and if you don’t account for that, your key might fail.”

This is the protein problem in drug development. Another issue making this challenge so vexing is that proteins don’t act in isolation. Their interactions with other proteins, ribonucleic acid, and DNA can affect how they bind to molecules and the shapes they adopt.

Newer versions of AlphaFold, such as AlphaFold Multimer and AlphaFold 3 (the code for which was recently revealed for academic use), can predict many interactions among proteins and between proteins and other molecules. But these tools still have weak points scientists are trying to overcome or work around.

“Those kinds of dynamics and multiple conformations are still quite challenging for the AI models to predict,” said James Zou, PhD, associate professor of biomedical data science at Stanford University in California.

“We’re finding more and more that the only way we can make these structures useful for drug discovery is if we incorporate dynamics, if we incorporate more physics into the model,” said Monteiro da Silva.

Monteiro da Silva spent 3 years during his PhD at Brown University, Providence, Rhode Island, running physics-based simulations in the lab, trying to understand why proteins carrying certain mutations are drug resistant. His results showed how “the changing landscape of shapes that a protein can take” prevented the drug from binding.

It took him 3 years to model just four mutations.

AI can do better — and the struggle is fascinating. By developing models that build on the predictive power of AlphaFold, scientists are uncovering new details about protein activity — insights that can lead to new therapeutics and reveal why existing ones stop working — much faster than they could with traditional methods or AlphaFold alone.

 

New Windows into Protein Dynamics

By predicting protein structural details, AlphaFold models also made it possible to predict pockets where drugs could bind.

A notable step, “but that’s just the starting point,” said Pedro Beltrao, PhD, an associate professor at Institute of Molecular Systems Biology, ETH Zurich in Switzerland. “It’s still very difficult, given a pocket, to actually design the drug or figure out what the pocket binds.”

Going back to the lock-and-key analogy: While he was at Brown, with a team of researchers in the Rubenstein Group, Monteiro da Silva helped create a model to better understand how mutations affect “the shape and dynamics of the lock.” They manipulated the amino acid sequences of proteins, guiding their evolution. This enabled them to use AlphaFold to predict “protein ensembles” and how frequently those ensembles appear. Each ensemble represents the many different shapes a protein can take under given conditions.

“Essentially, it tries to find the most common shapes that a protein will take over an arbitrary amount of time,” Monteiro da Silva said. “If we can predict these ensembles at scale and fast, then we can screen many mutations that cause resistance and develop drugs that will not be affected by that resistance.”

To evaluate their method, the researchers focused on ABL1, a well-studied kinase that causes leukemia. ABL1 can be drugged – unless it carries or develops a mutation that causes drug resistance. Currently there are no drugs that work against proteins carrying those mutations, according to Monteiro da Silva. The researchers used their hybrid AI-meets-physics method to investigate how drugs bind to different ABL1 mutations, screening 100 mutations in just 1 month.

“It’s not going to be perfect for every one of them. But if we have 100 and we get 20 with good accuracy, that’s better than doing four over 3 years,” Monteiro da Silva said.

A forthcoming paper will make their model publicly available in “an easy-to-use graphical interface” that they hope clinicians and medicinal chemists will try out. It can also complement other AI-based tools that dig into protein dynamics, according to Monteiro da Silva.

 

Complementary Tools to Speed Up Discovery 

Another aspect of the protein problem is scale. One protein can interact with hundreds of other proteins, which in turn may interact with hundreds more, all of which comprise the human interactome.

Feixiong Cheng, PhD, helped build PIONEER, a deep learning model that predicts the three-dimensional (3D) structure of interactions between proteins across the interactome.

Most disease mutations disrupt specific interactions between proteins, making their affinity stronger or weaker, explained Cheng. To treat a disease without causing major side effects, scientists need a precise understanding of those interactions.

“From the drug discovery perspective, we cannot just focus on single proteins. We have to understand the protein environment, in particular how the protein interacts with other proteins,” said Cheng, director of Cleveland Clinic Genome Center, Cleveland.

PIONEER helps by blending AlphaFold’s protein structure predictions with next-generation sequencing, a type of genomic research that identifies mutations in the human genome. The model predicts the 3D structure of the places where proteins interact — the binding sites, or interfaces — across the interactome.

“We tell you not only that a binds b, but where on a and where on b the two proteins interact,” said Haiyuan Yu, PhD, director of the Center for Innovative Proteomics, Cornell University, and co-creator of PIONEER.

This can help scientists understand “why a mutation, protein, or even network is a good target for therapeutic discovery,” Cheng said.

The researchers validated PIONEER’s predictions in the lab, testing the impacts of roughly 3000 mutations on 7000 pairs of interacting proteins. Based on their findings, they plan to develop and test treatments for lung and endometrial cancer.

PIONEER can also help scientists home in on how a mutation causes a disease, such as by showing recurrent mutations.

“If you find cancer mutations hitting an interface again and again and again, it means that this is likely to be driving cancer progression,” said Beltrao.

Beltrao’s lab and others have looked for recurrent mutations by using AlphaFold Multimer and AlphaFold 3 to directly model protein interactions. It’s a much slower approach (Pioneer is more than 5000 faster than AlphaFold Multimer, according to Cheng). But it could allow scientists to model interfaces that are not shown by PIONEER.

“You will need many different things to try to come up with a structural modeling of the interactome, and all these will have limitations,” said Beltrao. “Their method is a very good step forward, and there’ll be other approaches that are complementary, to continue to add details.”

 

And It Wouldn’t be an AI Mission Without ChatGPT

Large language models, such as ChatGPT, are another way that scientists are adding details to protein structure predictions. Zou used GPT-4 to “fine tune” a protein language model, called evolutionary scale modeling (ESM-2), which predicts protein structures directly from a protein sequence.

First, they trained ChatGPT on thousands of papers and studies containing information about the functions, biophysical properties, and disease relevance of different mutations. Next, they used the trained model to “teach” ESM-2, boosting its ability “to predict which mutations are likely to have larger effects or smaller effects,” Zou said. The same could be done for a model like AlphaFold, according to Zou.

“They are quite complementary in that the large language model contains a lot more information about the functions and the biophysics of different mutations and proteins as captured in text,” he said, whereas “you can’t give AlphaFold a piece of paper.”

Exactly how AlphaFold makes its predictions is another mystery. “It will somehow learn protein dynamics phenomenologically,” said Monteiro da Silva. He and others are trying to understand how that happens, in hopes of creating even more accurate predictive models. But for the time being, AI-based methods still need assistance from physics.

“The dream is that we achieve a state where we rely on just the fast methods, and they’re accurate enough,” he said. “But we’re so far from that.”

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

This transcript has been edited for clarity. 

Oh, insurance claim denials. When patient care or treatment is warranted by a specific diagnosis, I wish insurers would just reimburse it without any hassle. That’s not reality. Let’s talk about insurance claim denials, how they’re rising and harming patient care, and what we can do about it. That’s kind of complicated.

Rising Trend in Claim Denials and Financial Impact

First, denials are increasing. Experian Health surveyed provider revenue cycle leaders— that’s a fancy term for people who manage billing and insurance claims — and 75% said that denials are increasing. This is up from 42% a few years ago. Those surveyed also said that reimbursement times and errors in claims are also increasing, and changes in policy are happening more frequently. This all adds to the problem. 

Aside from being time-consuming and annoying, claim denials take a toll on hospitals and patients. One analysis, which made headlines everywhere, showed that hospitals and health systems spent nearly $20 billion in 2022 trying to repeal overturned claims. This analysis was done by Premier, a health insurance performance company.

 

Breakdown of Denial Rates and Costs

Let’s do some quick whiteboard math. Health insurance companies get about 3 billion claims per year. According to surveys, about 15% of those claims are denied, so that leaves us with 450 million denied claims. Hospitals spend, on average, $43.84 per denied claim in administrative fees trying to get them overturned.

That’s about $19.7 billion spent on claim denials. Here’s the gut punch: Around 54% of those claims are ultimately paid, so that leaves us with $10.7 billion that we definitely should have saved. 

 

Common Reasons for Denials

Let’s take a look at major causes and what’s going on. 

Insurance denial rates are all over the place. It depends on state and plan. According to one analysis, the average for in-network claim denials across some states was 4% to 5%. It was 40% in Mississippi. According to HealthCare.gov, in 2021, around 17% of in-network claims were denied. 

The most common reasons were excluded services, a lack of referral or preauthorization, or a medical treatment not being deemed necessary. Then there’s the black box of “other,” just some arbitrary reason to make a claim denial. 

Many times, these denials are done by an algorithm, not by individual people. 

What’s more, a Kaiser Family Foundation analysis found that private insurers, including Medicare Advantage plans, were more likely to deny claims than public options. 

When broken down, the problem was higher among employer-sponsored and marketplace insurance, and less so with Medicare and Medicaid. 

 

Impact on Patient Care

Many consumers don’t truly understand what their health insurance covers and what’s going to be out of pocket, and many people don’t know that they have appeal rights. They don’t know who to call for help either. 

The ACA set up Consumer Assistance Programs (CAPs), which are designed to help people navigate health insurance problems. By law, private insurers have to share data with CAPs. Yet, only 3% of people who had trouble with health insurance claims called a CAP for help.

We all know some of the downstream effects of this problem. Patients may skip or delay treatments if they can’t get insurance to cover it or it’s too expensive. When post-acute care, such as transfer to a skilled nursing facility or rehab center, isn’t covered and we’re trying to discharge patients from the hospital, hospital stays become lengthened, which means they’re more expensive, and this comes with its own set of complications.

 

How Can We Address This?

I’m genuinely curious about what you all have done to efficiently address this problem. I’m looking at this publication from the American Health Information Management Association about major reasons for denial. We’ve already talked about a lack of preauthorization or procedures not being covered, but there are also reasons such as missing or incorrect information, duplicate claims, and not filing within the appropriate time.

Also, if treatments or procedures are bundled, they can’t be filed separately. 

Preventing all of this would take a large effort. Healthcare systems would have to have a dedicated team, who would understand all the major reasons for denials, identify common patterns, and then fill everything out with accurate information, with referrals, with preauthorizations, high-specificity codes, and the correct modifiers — and do all of this within the filing deadline every time. 

You would need physicians on board, but also people from IT, finance, compliance, case management, registration, and probably a bunch of other people who are already stretched too thin. 

Perhaps our government can do more to hold insurers accountable and make sure plans, such as Medicare Advantage, are holding up their end of the public health bargain.

It’s an uphill $20 billion battle, but I’m optimistic. What about you? What’s your unfiltered take on claim denials? What more can we be doing?

Dr. Patel is a clinical instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; pediatric hospitalist, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York City, and Benioff Children’s Hospital, University of California, San Francisco. He reported a conflict of interest with Medumo.

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

This transcript has been edited for clarity. 

Oh, insurance claim denials. When patient care or treatment is warranted by a specific diagnosis, I wish insurers would just reimburse it without any hassle. That’s not reality. Let’s talk about insurance claim denials, how they’re rising and harming patient care, and what we can do about it. That’s kind of complicated.

Rising Trend in Claim Denials and Financial Impact

First, denials are increasing. Experian Health surveyed provider revenue cycle leaders— that’s a fancy term for people who manage billing and insurance claims — and 75% said that denials are increasing. This is up from 42% a few years ago. Those surveyed also said that reimbursement times and errors in claims are also increasing, and changes in policy are happening more frequently. This all adds to the problem. 

Aside from being time-consuming and annoying, claim denials take a toll on hospitals and patients. One analysis, which made headlines everywhere, showed that hospitals and health systems spent nearly $20 billion in 2022 trying to repeal overturned claims. This analysis was done by Premier, a health insurance performance company.

 

Breakdown of Denial Rates and Costs

Let’s do some quick whiteboard math. Health insurance companies get about 3 billion claims per year. According to surveys, about 15% of those claims are denied, so that leaves us with 450 million denied claims. Hospitals spend, on average, $43.84 per denied claim in administrative fees trying to get them overturned.

That’s about $19.7 billion spent on claim denials. Here’s the gut punch: Around 54% of those claims are ultimately paid, so that leaves us with $10.7 billion that we definitely should have saved. 

 

Common Reasons for Denials

Let’s take a look at major causes and what’s going on. 

Insurance denial rates are all over the place. It depends on state and plan. According to one analysis, the average for in-network claim denials across some states was 4% to 5%. It was 40% in Mississippi. According to HealthCare.gov, in 2021, around 17% of in-network claims were denied. 

The most common reasons were excluded services, a lack of referral or preauthorization, or a medical treatment not being deemed necessary. Then there’s the black box of “other,” just some arbitrary reason to make a claim denial. 

Many times, these denials are done by an algorithm, not by individual people. 

What’s more, a Kaiser Family Foundation analysis found that private insurers, including Medicare Advantage plans, were more likely to deny claims than public options. 

When broken down, the problem was higher among employer-sponsored and marketplace insurance, and less so with Medicare and Medicaid. 

 

Impact on Patient Care

Many consumers don’t truly understand what their health insurance covers and what’s going to be out of pocket, and many people don’t know that they have appeal rights. They don’t know who to call for help either. 

The ACA set up Consumer Assistance Programs (CAPs), which are designed to help people navigate health insurance problems. By law, private insurers have to share data with CAPs. Yet, only 3% of people who had trouble with health insurance claims called a CAP for help.

We all know some of the downstream effects of this problem. Patients may skip or delay treatments if they can’t get insurance to cover it or it’s too expensive. When post-acute care, such as transfer to a skilled nursing facility or rehab center, isn’t covered and we’re trying to discharge patients from the hospital, hospital stays become lengthened, which means they’re more expensive, and this comes with its own set of complications.

 

How Can We Address This?

I’m genuinely curious about what you all have done to efficiently address this problem. I’m looking at this publication from the American Health Information Management Association about major reasons for denial. We’ve already talked about a lack of preauthorization or procedures not being covered, but there are also reasons such as missing or incorrect information, duplicate claims, and not filing within the appropriate time.

Also, if treatments or procedures are bundled, they can’t be filed separately. 

Preventing all of this would take a large effort. Healthcare systems would have to have a dedicated team, who would understand all the major reasons for denials, identify common patterns, and then fill everything out with accurate information, with referrals, with preauthorizations, high-specificity codes, and the correct modifiers — and do all of this within the filing deadline every time. 

You would need physicians on board, but also people from IT, finance, compliance, case management, registration, and probably a bunch of other people who are already stretched too thin. 

Perhaps our government can do more to hold insurers accountable and make sure plans, such as Medicare Advantage, are holding up their end of the public health bargain.

It’s an uphill $20 billion battle, but I’m optimistic. What about you? What’s your unfiltered take on claim denials? What more can we be doing?

Dr. Patel is a clinical instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; pediatric hospitalist, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York City, and Benioff Children’s Hospital, University of California, San Francisco. He reported a conflict of interest with Medumo.

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

This transcript has been edited for clarity. 

Oh, insurance claim denials. When patient care or treatment is warranted by a specific diagnosis, I wish insurers would just reimburse it without any hassle. That’s not reality. Let’s talk about insurance claim denials, how they’re rising and harming patient care, and what we can do about it. That’s kind of complicated.

Rising Trend in Claim Denials and Financial Impact

First, denials are increasing. Experian Health surveyed provider revenue cycle leaders— that’s a fancy term for people who manage billing and insurance claims — and 75% said that denials are increasing. This is up from 42% a few years ago. Those surveyed also said that reimbursement times and errors in claims are also increasing, and changes in policy are happening more frequently. This all adds to the problem. 

Aside from being time-consuming and annoying, claim denials take a toll on hospitals and patients. One analysis, which made headlines everywhere, showed that hospitals and health systems spent nearly $20 billion in 2022 trying to repeal overturned claims. This analysis was done by Premier, a health insurance performance company.

 

Breakdown of Denial Rates and Costs

Let’s do some quick whiteboard math. Health insurance companies get about 3 billion claims per year. According to surveys, about 15% of those claims are denied, so that leaves us with 450 million denied claims. Hospitals spend, on average, $43.84 per denied claim in administrative fees trying to get them overturned.

That’s about $19.7 billion spent on claim denials. Here’s the gut punch: Around 54% of those claims are ultimately paid, so that leaves us with $10.7 billion that we definitely should have saved. 

 

Common Reasons for Denials

Let’s take a look at major causes and what’s going on. 

Insurance denial rates are all over the place. It depends on state and plan. According to one analysis, the average for in-network claim denials across some states was 4% to 5%. It was 40% in Mississippi. According to HealthCare.gov, in 2021, around 17% of in-network claims were denied. 

The most common reasons were excluded services, a lack of referral or preauthorization, or a medical treatment not being deemed necessary. Then there’s the black box of “other,” just some arbitrary reason to make a claim denial. 

Many times, these denials are done by an algorithm, not by individual people. 

What’s more, a Kaiser Family Foundation analysis found that private insurers, including Medicare Advantage plans, were more likely to deny claims than public options. 

When broken down, the problem was higher among employer-sponsored and marketplace insurance, and less so with Medicare and Medicaid. 

 

Impact on Patient Care

Many consumers don’t truly understand what their health insurance covers and what’s going to be out of pocket, and many people don’t know that they have appeal rights. They don’t know who to call for help either. 

The ACA set up Consumer Assistance Programs (CAPs), which are designed to help people navigate health insurance problems. By law, private insurers have to share data with CAPs. Yet, only 3% of people who had trouble with health insurance claims called a CAP for help.

We all know some of the downstream effects of this problem. Patients may skip or delay treatments if they can’t get insurance to cover it or it’s too expensive. When post-acute care, such as transfer to a skilled nursing facility or rehab center, isn’t covered and we’re trying to discharge patients from the hospital, hospital stays become lengthened, which means they’re more expensive, and this comes with its own set of complications.

 

How Can We Address This?

I’m genuinely curious about what you all have done to efficiently address this problem. I’m looking at this publication from the American Health Information Management Association about major reasons for denial. We’ve already talked about a lack of preauthorization or procedures not being covered, but there are also reasons such as missing or incorrect information, duplicate claims, and not filing within the appropriate time.

Also, if treatments or procedures are bundled, they can’t be filed separately. 

Preventing all of this would take a large effort. Healthcare systems would have to have a dedicated team, who would understand all the major reasons for denials, identify common patterns, and then fill everything out with accurate information, with referrals, with preauthorizations, high-specificity codes, and the correct modifiers — and do all of this within the filing deadline every time. 

You would need physicians on board, but also people from IT, finance, compliance, case management, registration, and probably a bunch of other people who are already stretched too thin. 

Perhaps our government can do more to hold insurers accountable and make sure plans, such as Medicare Advantage, are holding up their end of the public health bargain.

It’s an uphill $20 billion battle, but I’m optimistic. What about you? What’s your unfiltered take on claim denials? What more can we be doing?

Dr. Patel is a clinical instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; pediatric hospitalist, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York City, and Benioff Children’s Hospital, University of California, San Francisco. He reported a conflict of interest with Medumo.

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

Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

 

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

 

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

 

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

 

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

 

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

 

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

 

A version of this article appeared on Medscape.com.

Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

 

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

 

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

 

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

 

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

 

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

 

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

 

A version of this article appeared on Medscape.com.

Despite being a targeted therapy, antibody-drug conjugates (ADCs) can cause significant off-target toxicity to the eyes of patients being treated for advanced multiple myeloma or cervical cancer, yet the risks remain relatively unknown, according to oncologists and ophthalmologists.

Such experts called for greater collaboration between oncologists and ophthalmologists, in interviews with Medscape Medical News.

ADCs combine a monoclonal antibody targeted at an antigen overexpressed on cancer cells with a toxic chemotherapy payload — the aim being to maximize the effectiveness of the drug against the tumor while minimizing the damage to healthy tissues and reducing systemic toxicity.

Yet trastuzumab duocarmazine (T-Duo), a third-generation human epidermal growth factor receptor 2 (HER2)–targeted ADC designed to treat HER2-positive breast cancer, was recently found to have a notable adverse effect in the TULIP trial of 437 patients.

As reported by Medscape Medical News, the drug was associated with a significant increase in progression-free survival over physician’s choice of therapy. However, 78% of patients in the ADC group experienced at least one treatment-emergent ocular toxicity adverse event vs 29.2% of those in the control group.

Moreover, grade 3 or high ocular toxicity events were reported by 21% of patients in the experimental group compared with none of those who received physician’s choice.

 

Ocular Toxicities Seen on Ocular Surface

Ocular toxicities with these drugs are “not necessarily a new thing,” said Joann J. Kang, MD, director, Cornea and Refractive Surgery, and associate professor of ophthalmology at Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

“But what we’re seeing with certain ADCs is a lot of ocular toxicity, especially on the ocular surface,” with the degree toxicity varying depending on the ADC in question. “It’s definitely a real concern.”

Kang noted that separate from T-Duo, certain ADCs already come with black box warnings for ocular toxicity, including:

• Belantamab mafodotin (Blenrep) — approved for relapsed or refractory multiple myeloma and carries a warning specifically for keratopathy.
• Tisotumab vedotin (Tivdak) — indicated for recurrent or metastatic cervical cancer and can cause changes in the corneal epithelium and conjunctiva.
• Mirvetuximab soravtansine (Elahere) — used to treat folate receptor (FR) alpha–positive ovarian, fallopian tube, and peritoneal cancers and can lead to keratopathy, blurred vision, and dry eyes.

Indeed, the American Academy of Ophthalmology 2024 annual meeting saw research presented indicating that mirvetuximab was associated with moderate or severe corneal toxicity in 47% of patients treated for primary gynecologic malignancies.

As reported by Medscape Medical News, the study, by researchers at Byers Eye Institute of Stanford University in Stanford, California, was a retrospective analysis of 36 eyes of 18 women who received mirvetuximab for FR alpha–positive, platinum-resistant primary ovarian cancer.

 

What Are the Causes?

But why would a drug that is targeted specifically to a cancer tumor, thanks to the presence of a monoclonal antibody, cause off-target effects such as ocular toxicity?

Kathy D. Miller, MD, professor of oncology and medicine at Indiana University School of Medicine in Indianapolis, pointed out that they are targeted in a relative and not absolute sense, meaning that the antigen target may not be truly limited to the tumor cells.

There can also be “a lot of ways that you could get systemic toxicities,” she said.

For example, if the linker connecting the antibody and the chemotherapy payload breaks prematurely or is not stable, or if the drug leaches out into the tumor microenvironment and then is “picked up into the circulation, that can give you systemic toxicity,” she said.

In addition, the drug may, once it is in the tumor cells, be metabolized to an active metabolite that could, again, result in systemic exposure.

 

Side Effects Are Underappreciated and Distressing

Ocular toxicity remains underappreciated among oncologists prescribing these drugs. One reason is that it “did not get enough attention” in the initial clinical trial reports, Miller said she suspects.

Another potential reason for this is that “we’re not used to thinking about it because it’s not particularly common among the drugs that oncologists use frequently,” she added. Additionally, it tends to come up later during treatment, “so people have to be on therapy for some time before you start to see it.”

Nevertheless, Miller underlined that ocular toxicity “can be particularly distressing for patients, as it’s uncomfortable [and] can lead to scarring, so some of the vision issues can be permanent.”

“We often see in these situations that there are different types of ocular toxicities that present in different patients,” said Jane L. Meisel, MD, co-director, Breast Medical Oncology, Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Corneal damage is pretty common, and patients can present with blurry vision, or dry eyes, or light sensitivity. And unlike some side effects, these are things that really impact people at every waking moment of their day.”

“So they’re pretty clinically significant side effects, even if they’re not life-threatening,” Meisel emphasized.

Miller suspects that more heavily pretreated patients may be more likely to experience ocular toxicity, as “there’s a much higher incidence of dry eyes in our patients than we recognize.”

She added: “We don’t usually ask about it, and we certainly don’t routinely do Schirmer’s tests,” which determine whether the eye produces enough tears to keep it moist.

 

Preventive Measures

For patients receiving tisotumab or mirvetuximab who experience ocular toxicity, Kang said the recommendation is to use steroid eye drops before, during, and after treatment with the ADC.

However, she noted that steroids have not been found to be useful in patients given belantamab, so clinicians have tried vasoconstrictor eye drops immediately prior to the infusion, as well as ocular cooling masks, which “are thought to help by reducing blood supply to the ocular areas.”

Other approaches to minimize ocular toxicity have included longer infusion times, so it’s “not so much of a hefty dose at one time,” Kang added.

She underlined that grade 2 and 3 ocular toxicities can lead to dose delays or dose modifications, and “usually by the time you get a grade 4 event, then you may need to discontinue the medication.”

This can have consequences for the patients because they are often “very sick, and this may be their third agent that they’re trying,” or it may be that their tumor is responding to a new treatment, but it has to be withheld because of an ocular toxicity.

“It can be incredibly frustrating for patients, and also for oncologists, and then for ophthalmologists,” Kang said.

 

Closer Collaboration Between Specialists Needed

What’s known about ocular side effects in patients taking ADCs underlines that there is a need for closer collaboration between oncologists and ophthalmologists.

“In oncology, especially as immunotherapies came to the forefront, our relationships with our endocrinology colleagues have become stronger because we’ve needed them to help us manage things like thyroid toxicity and pituitary issues related to immunotherapy,” Meisel said.

With toxicities that may be “very impactful for patient quality of life, like ocular toxicity, we will need to learn more about them and develop protocols for management, along with our ophthalmology colleagues, so that we can keep patients as comfortable as possible, while maximizing the efficacy of these drugs.”

Miller agreed, saying oncologists need to have “a conversation with a local ophthalmologist,” although she conceded that, in many areas, such specialists “are in short supply.”

The oncologist “not only needs to be aware” of and looking for ocular toxicity when using these ADCs but also needs to be thinking: “If I run into trouble here, who’s my ophthalmology backup? Are they familiar with this drug? And do we have a plan for the multispecialty management of patients who run into this toxicity?”

 

Setting Counts When Assessing Toxicities

But do all these considerations mean that ADCs’ potential ocular toxicity should give clinicians pause when considering whether to use these drugs?

“What my patients most want are drugs that work; that are effective in controlling their tumors,” Miller said.

“Every drug we use has potential toxicities, and which toxicities are most physically troublesome [or] are the greatest concern may vary from patient to patient, and it may vary a lot from patients with metastatic disease to those in the curative setting.”

She explained that “toxicities that might not be prohibitive at all in the metastatic setting [may] have to be a much bigger part of our considerations” when moving drugs into the adjuvant or neoadjuvant setting.

This, Miller underlined, is where the ocular toxicity with these ADCs “may be much more prohibitive.”

TULIP was funded by Byondis BV.

Turner declared relationships with Novartis, AstraZeneca, Pfizer, Merck Sharp & Dohme, Lilly, Repare Therapeutics, Roche, GlaxoSmithKline, Gilead Sciences, Inivata, Guardant Health, Exact Sciences, and Relay Therapeutics.

Meisel declared relationships with Novartis, AstraZeneca, Genentech, Seagen, Olema Oncology, GE Healthcare, Pfizer, Stemline, and Sermonix Pharmaceuticals.

 

A version of this article appeared on Medscape.com.

In the treatment of relapsed or refractory follicular lymphoma (R/R FL), the addition of tafasitamab to a standard 2-drug combination of lenalidomide and rituximab (len+R) significantly improves progression-free survival, with no increases in safety events.

“This study is the first to validate combining two monoclonal antibodies (anti-CD19 with anti-CD20) in the treatment of lymphoma,” said first author Laurie H. Sehn, MD, MPH, a clinical professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada. She presented the findings at the American Society of Hematology 2024 Annual Meeting.

“Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard-of-care option for patients with R/R follicular lymphoma,” she noted.

The results are from the international, phase 3 inMIND multicenter trial involving 548 patients with R/R FL, with a median age of 64. Of the patients, 45% had been treated with two or more prior lines of therapy.

At a median follow up of 14.1 months, those randomized to treatment with tafasitamab and len+R (n = 273) had a significantly lower risk for progression, relapse, or death than those receiving the double therapy with placebo (n = 275), with a median progression-free survival of 22.4 months vs 13.9 months, respectively (hazard ratio [HR], 0.43; P < .0001).

Improved progression-free survival was observed across all prespecified subgroups, including patients with disease progression within 24 months, those who were refractory to prior anti-CD20 monoclonal antibodies, and who received multiple prior lines of therapy.

“Although this study was not powered for individual subgroups, it is clear that there’s a significant benefit of tafasitamab in all subgroups regardless of status of [disease progression within 24 months] and regardless of refractoriness to prior anti-CD20 monoclonal antibodies,” Sehn noted.

FL, the most common, indolent form of B-cell non-Hodgkin lymphoma (NHL), is commonly treated with frontline therapy of chemoimmunotherapy; however, response durations begin to dwindle after successive lines of treatment.

Lenalidomide and rituximab are approved and commonly used in the treatment of FL after more than one prior line of treatment.

With tafasitamab, which is administered intravenously, already having been approved for use in combination with lenalidomide in the treatment of R/R diffuse large B-cell lymphoma, based on results of the previous L-MIND study, Sehn and colleagues investigated its benefits in FL or marginal zone NHL.

Of the patients included in the trial, 55% were men and 79% had intermediate or high-risk FLIPI scores, referring to the FL International Prognostic Index, a scoring system used for predicting prognoses of patients with FL.

Treatment in the study consisted of 12 mg/kg intravenous tafasitamab or placebo on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12, with standard dosing of len+R for up to 12 cycles of 28 days each. 

In terms of the data cutoff, patients in the tafasitamab arm received a median of 12 cycles of treatment vs 11 cycles for placebo, and 19% and 15% were still on treatment, respectively, at the cut-off. 

Of the patients, 81% and 84%, respectively, had discontinued treatment primarily because of treatment completion (54% and 43%) or disease progression (11% and 31%). 

In addition to the progression-free survival primary endpoint, the tafasitamab arm also had a higher rate of complete response (CR) on PET (49.4% vs 39.8%; P = .029) and higher overall response rate (83.5% vs 72.4%; P = .0014) than the placebo arm. 

The duration of response was also higher with tafasitamab (median, 21.2 months vs 13.6 months; HR, 0.47; P < .0001).

Overall survival data, though immature, also favored tafasitamab (HR, 0.59). 

The two arms had similar rates of treatment-emergent adverse events, with similar toxicity profiles and no new significant safety signals related to tafasitamab. The rates of discontinuations and dose reductions were similar, with a median dose intensity of 86% with tafasitamab vs 87%.

The most common grade 3 or 4 adverse events were similar between the tafasitamab and placebo groups, including neutropenia (40% vs 38%, respectively), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). 

“Importantly, the addition of tafasitamab did not impede the delivery of lenalidomide and rituximab, with similar observed dose discontinuations or interruptions in both cohorts,” Sehn said.

“The inMIND phase 3 study met its primary endpoint of improved progression-free survival with the addition of tafasitamab to lenalidomide and rituximab in patients with R/R follicular lymphoma, representing a 57% reduction in the risk of progression, relapse, or death,” Sehn said.

Commenting on the study, Juan Pablo Alderuccio, MD, an associate professor of medicine, Division of Hematology in the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine in Florida, said the findings are notable in that “this is the first time two monoclonal antibodies have been tested in follicular lymphoma.”

“The study demonstrates that simultaneously targeting CD19 and CD20 improves outcomes,” he said in an interview.

Alderuccio noted the key caveats include that “PET/CT complete response correlates well with survival in follicular lymphoma. In this study, the PET/CT CR rate was 49.4%, underscoring the need for longer follow-ups to better assess those responses’ durability.”

“Another caveat of this regimen is the treatment schedule, which requires weekly tafasitamab infusions during cycles 1-3 and every 2 weeks during cycles 4-12. This is associated with rituximab and lenalidomide administration,” he said.

Ultimately, “the results underscore the potential of tafasitamab in combination with lenalidomide and rituximab to become a new treatment option in the second-line or later follicular lymphoma.”

“However, I would like to see more follow-up data before considering it a new standard of care,” he cautioned.

The study was funded by Incyte. Sehn reported ties with AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Alderuccio disclosed relationships with Genmab, ADC Therapeutics, BeiGene, AbbVie, Genentech, Novartis, Regeneron, and Lilly.

A version of this article appeared on Medscape.com.

In the treatment of relapsed or refractory follicular lymphoma (R/R FL), the addition of tafasitamab to a standard 2-drug combination of lenalidomide and rituximab (len+R) significantly improves progression-free survival, with no increases in safety events.

“This study is the first to validate combining two monoclonal antibodies (anti-CD19 with anti-CD20) in the treatment of lymphoma,” said first author Laurie H. Sehn, MD, MPH, a clinical professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada. She presented the findings at the American Society of Hematology 2024 Annual Meeting.

“Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard-of-care option for patients with R/R follicular lymphoma,” she noted.

The results are from the international, phase 3 inMIND multicenter trial involving 548 patients with R/R FL, with a median age of 64. Of the patients, 45% had been treated with two or more prior lines of therapy.

At a median follow up of 14.1 months, those randomized to treatment with tafasitamab and len+R (n = 273) had a significantly lower risk for progression, relapse, or death than those receiving the double therapy with placebo (n = 275), with a median progression-free survival of 22.4 months vs 13.9 months, respectively (hazard ratio [HR], 0.43; P < .0001).

Improved progression-free survival was observed across all prespecified subgroups, including patients with disease progression within 24 months, those who were refractory to prior anti-CD20 monoclonal antibodies, and who received multiple prior lines of therapy.

“Although this study was not powered for individual subgroups, it is clear that there’s a significant benefit of tafasitamab in all subgroups regardless of status of [disease progression within 24 months] and regardless of refractoriness to prior anti-CD20 monoclonal antibodies,” Sehn noted.

FL, the most common, indolent form of B-cell non-Hodgkin lymphoma (NHL), is commonly treated with frontline therapy of chemoimmunotherapy; however, response durations begin to dwindle after successive lines of treatment.

Lenalidomide and rituximab are approved and commonly used in the treatment of FL after more than one prior line of treatment.

With tafasitamab, which is administered intravenously, already having been approved for use in combination with lenalidomide in the treatment of R/R diffuse large B-cell lymphoma, based on results of the previous L-MIND study, Sehn and colleagues investigated its benefits in FL or marginal zone NHL.

Of the patients included in the trial, 55% were men and 79% had intermediate or high-risk FLIPI scores, referring to the FL International Prognostic Index, a scoring system used for predicting prognoses of patients with FL.

Treatment in the study consisted of 12 mg/kg intravenous tafasitamab or placebo on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12, with standard dosing of len+R for up to 12 cycles of 28 days each. 

In terms of the data cutoff, patients in the tafasitamab arm received a median of 12 cycles of treatment vs 11 cycles for placebo, and 19% and 15% were still on treatment, respectively, at the cut-off. 

Of the patients, 81% and 84%, respectively, had discontinued treatment primarily because of treatment completion (54% and 43%) or disease progression (11% and 31%). 

In addition to the progression-free survival primary endpoint, the tafasitamab arm also had a higher rate of complete response (CR) on PET (49.4% vs 39.8%; P = .029) and higher overall response rate (83.5% vs 72.4%; P = .0014) than the placebo arm. 

The duration of response was also higher with tafasitamab (median, 21.2 months vs 13.6 months; HR, 0.47; P < .0001).

Overall survival data, though immature, also favored tafasitamab (HR, 0.59). 

The two arms had similar rates of treatment-emergent adverse events, with similar toxicity profiles and no new significant safety signals related to tafasitamab. The rates of discontinuations and dose reductions were similar, with a median dose intensity of 86% with tafasitamab vs 87%.

The most common grade 3 or 4 adverse events were similar between the tafasitamab and placebo groups, including neutropenia (40% vs 38%, respectively), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). 

“Importantly, the addition of tafasitamab did not impede the delivery of lenalidomide and rituximab, with similar observed dose discontinuations or interruptions in both cohorts,” Sehn said.

“The inMIND phase 3 study met its primary endpoint of improved progression-free survival with the addition of tafasitamab to lenalidomide and rituximab in patients with R/R follicular lymphoma, representing a 57% reduction in the risk of progression, relapse, or death,” Sehn said.

Commenting on the study, Juan Pablo Alderuccio, MD, an associate professor of medicine, Division of Hematology in the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine in Florida, said the findings are notable in that “this is the first time two monoclonal antibodies have been tested in follicular lymphoma.”

“The study demonstrates that simultaneously targeting CD19 and CD20 improves outcomes,” he said in an interview.

Alderuccio noted the key caveats include that “PET/CT complete response correlates well with survival in follicular lymphoma. In this study, the PET/CT CR rate was 49.4%, underscoring the need for longer follow-ups to better assess those responses’ durability.”

“Another caveat of this regimen is the treatment schedule, which requires weekly tafasitamab infusions during cycles 1-3 and every 2 weeks during cycles 4-12. This is associated with rituximab and lenalidomide administration,” he said.

Ultimately, “the results underscore the potential of tafasitamab in combination with lenalidomide and rituximab to become a new treatment option in the second-line or later follicular lymphoma.”

“However, I would like to see more follow-up data before considering it a new standard of care,” he cautioned.

The study was funded by Incyte. Sehn reported ties with AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Alderuccio disclosed relationships with Genmab, ADC Therapeutics, BeiGene, AbbVie, Genentech, Novartis, Regeneron, and Lilly.

A version of this article appeared on Medscape.com.

In the treatment of relapsed or refractory follicular lymphoma (R/R FL), the addition of tafasitamab to a standard 2-drug combination of lenalidomide and rituximab (len+R) significantly improves progression-free survival, with no increases in safety events.

“This study is the first to validate combining two monoclonal antibodies (anti-CD19 with anti-CD20) in the treatment of lymphoma,” said first author Laurie H. Sehn, MD, MPH, a clinical professor with the BC Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada. She presented the findings at the American Society of Hematology 2024 Annual Meeting.

“Tafasitamab plus lenalidomide and rituximab can be administered in community as well as academic settings and represents a potential new standard-of-care option for patients with R/R follicular lymphoma,” she noted.

The results are from the international, phase 3 inMIND multicenter trial involving 548 patients with R/R FL, with a median age of 64. Of the patients, 45% had been treated with two or more prior lines of therapy.

At a median follow up of 14.1 months, those randomized to treatment with tafasitamab and len+R (n = 273) had a significantly lower risk for progression, relapse, or death than those receiving the double therapy with placebo (n = 275), with a median progression-free survival of 22.4 months vs 13.9 months, respectively (hazard ratio [HR], 0.43; P < .0001).

Improved progression-free survival was observed across all prespecified subgroups, including patients with disease progression within 24 months, those who were refractory to prior anti-CD20 monoclonal antibodies, and who received multiple prior lines of therapy.

“Although this study was not powered for individual subgroups, it is clear that there’s a significant benefit of tafasitamab in all subgroups regardless of status of [disease progression within 24 months] and regardless of refractoriness to prior anti-CD20 monoclonal antibodies,” Sehn noted.

FL, the most common, indolent form of B-cell non-Hodgkin lymphoma (NHL), is commonly treated with frontline therapy of chemoimmunotherapy; however, response durations begin to dwindle after successive lines of treatment.

Lenalidomide and rituximab are approved and commonly used in the treatment of FL after more than one prior line of treatment.

With tafasitamab, which is administered intravenously, already having been approved for use in combination with lenalidomide in the treatment of R/R diffuse large B-cell lymphoma, based on results of the previous L-MIND study, Sehn and colleagues investigated its benefits in FL or marginal zone NHL.

Of the patients included in the trial, 55% were men and 79% had intermediate or high-risk FLIPI scores, referring to the FL International Prognostic Index, a scoring system used for predicting prognoses of patients with FL.

Treatment in the study consisted of 12 mg/kg intravenous tafasitamab or placebo on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12, with standard dosing of len+R for up to 12 cycles of 28 days each. 

In terms of the data cutoff, patients in the tafasitamab arm received a median of 12 cycles of treatment vs 11 cycles for placebo, and 19% and 15% were still on treatment, respectively, at the cut-off. 

Of the patients, 81% and 84%, respectively, had discontinued treatment primarily because of treatment completion (54% and 43%) or disease progression (11% and 31%). 

In addition to the progression-free survival primary endpoint, the tafasitamab arm also had a higher rate of complete response (CR) on PET (49.4% vs 39.8%; P = .029) and higher overall response rate (83.5% vs 72.4%; P = .0014) than the placebo arm. 

The duration of response was also higher with tafasitamab (median, 21.2 months vs 13.6 months; HR, 0.47; P < .0001).

Overall survival data, though immature, also favored tafasitamab (HR, 0.59). 

The two arms had similar rates of treatment-emergent adverse events, with similar toxicity profiles and no new significant safety signals related to tafasitamab. The rates of discontinuations and dose reductions were similar, with a median dose intensity of 86% with tafasitamab vs 87%.

The most common grade 3 or 4 adverse events were similar between the tafasitamab and placebo groups, including neutropenia (40% vs 38%, respectively), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). 

“Importantly, the addition of tafasitamab did not impede the delivery of lenalidomide and rituximab, with similar observed dose discontinuations or interruptions in both cohorts,” Sehn said.

“The inMIND phase 3 study met its primary endpoint of improved progression-free survival with the addition of tafasitamab to lenalidomide and rituximab in patients with R/R follicular lymphoma, representing a 57% reduction in the risk of progression, relapse, or death,” Sehn said.

Commenting on the study, Juan Pablo Alderuccio, MD, an associate professor of medicine, Division of Hematology in the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine in Florida, said the findings are notable in that “this is the first time two monoclonal antibodies have been tested in follicular lymphoma.”

“The study demonstrates that simultaneously targeting CD19 and CD20 improves outcomes,” he said in an interview.

Alderuccio noted the key caveats include that “PET/CT complete response correlates well with survival in follicular lymphoma. In this study, the PET/CT CR rate was 49.4%, underscoring the need for longer follow-ups to better assess those responses’ durability.”

“Another caveat of this regimen is the treatment schedule, which requires weekly tafasitamab infusions during cycles 1-3 and every 2 weeks during cycles 4-12. This is associated with rituximab and lenalidomide administration,” he said.

Ultimately, “the results underscore the potential of tafasitamab in combination with lenalidomide and rituximab to become a new treatment option in the second-line or later follicular lymphoma.”

“However, I would like to see more follow-up data before considering it a new standard of care,” he cautioned.

The study was funded by Incyte. Sehn reported ties with AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Alderuccio disclosed relationships with Genmab, ADC Therapeutics, BeiGene, AbbVie, Genentech, Novartis, Regeneron, and Lilly.

A version of this article appeared on Medscape.com.

SAN DIEGO — Final results of the phase 3 Andromeda study confirmed that adding daratumumab (DARA) — a human CD38-targeting monoclonal antibody — to bortezomib, cyclophosphamide, and dexamethasone (VCd) improves outcomes in patients with newly diagnosed amyloid light chain (AL) amyloidosis.

Adding DARA to VCd (D-VCd; Darzalex Faspro; Janssen Biotech) provided deeper and more rapid hematologic response and clinically meaningful and statistically significant improvement in overall survival (OS) and major organ deterioration progression-free survival (MOD-PFS), combined with 40.7% cardiac complete response (CR), first author Efstathios Kastritis, MD, said during presentation of an oral abstract at the American Society of Hematology (ASH) 2024 Annual Meeting.

“The Andromeda study is the first comparing two contemporary regimens that shows a significant survival improvement for patients with AL amyloidosis,” said Kastritis, an associate professor at the National and Kapodistrian University of Athens in Greece. “These findings reaffirm frontline D-VCd as the standard of care in this difficult-to-treat disease.”

The regimen was approved for this indication in 2021 based on prior earlier findings from the Andromeda trial. The current results are from a preplanned analysis for MOD-PFS and OS.

At a median follow-up of 61.4 months, the overall hematologic CR rates were 59.5% and 19.2% among 388 patients randomized to receive D-VCd or VCd, respectively (odds ratio, 6.03), which showed continued improvement with additional DARA vs the 53.3% and 18.1% rates observed at the primary analysis, Kastritis reported.

Time to hematologic CR was 67.5 days and 85.0 days in the treatment groups, respectively, and median duration of hematologic CR was not reached in either group.

A significant 56% improvement was also observed in MOD-PFS (hazard ratio [HR], 0.44). Median MOD-PFS was not reached in the D-VCd group and was 30.3 months in the VCd group.

A significant 38% improvement was observed in OS (HR, 0.62), 5-year OS was 76.1% vs 64.7% in the D-VCd and VCd groups, respectively, he said.

“[The OS] benefit occurred even though more than 70% of the patients in the VCd arm who received a subsequent therapy were treated with a DARA-based regimen,” he stressed. “This further emphasizes the importance of using DSTS in the frontline setting.”

Trial participants had newly diagnosed AL amyloidosis with measurable hematologic disease, one or more involved organs, cardiac stage I-IIIA, estimated glomerular filtration rate of at least 20 mL/min, and absence of symptomatic multiple myeloma. They were randomized 1:1 to the two treatment groups. All patients received 1.3 mg/m2 of bortezomib by weekly injection, 300 mg/m2 of cyclophosphamide either by weekly oral or intravenous administration, and 20-40 mg of dexamethasone by weekly oral or intravenous administration for six 28-day cycles.

Those in the D-VCd group also received 1800 mg of DARA coformulated with rHuPH20 as a weekly injection in cycles 1-2, as a biweekly injection in cycles 3-6, and by injection every 4 weeks thereafter for up to 24 28-day cycles.

The median duration of treatment was 21.3 months for D-VCd and 5.3 months for VCd, and of 122 patients who received subsequent therapy, 82 (67%) received subsequent DARA.

Patients who achieved hematologic CR had better MOD-PFS and OS (HR, 0.30 and 0.41, respectively), regardless of the treatment received, he noted, adding that “this further supports that complete hematologic response is a valid early endpoint for the evaluation of anti-monoclonal therapies in AL amyloidosis.”

“I think this is very important for the further development of new treatments in this disease,” he said.

Of note, cardiac and renal response rates in the D-VCd group were about two to three times greater than those in the VCd group at 6, 12, 24, 36, and 48 months, Kastritis said.

Among 235 patients with an evaluable cardiac response, 113 achieved a very good partial response or better, including 76 of 118 (64.4%) in the D-VCd group and 37 of 117 (31.6%) in the VCd group. Of these, 48 (40.7%) and 16 (13.7%) achieved a cardiac CR.

Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients in the D-VCd and VCd groups, respectively, were lymphopenia (13% and 10%), pneumonia (8% and 4%), hypokalemia (2% and 5%), and peripheral edema (3% and 6%), he noted, adding that systemic administration-related reactions occurred in 14 (7%) of patients receiving D-VCd; all were grade 1 or 2 and most (86%) occurred after the first injection. TEAEs led to treatment discontinuation in 5% and 4% of patients in the groups, respectively.

No new safety signals were observed during the extended follow-up, he said.

Kastritis reported relationships with Pfizer, Genesis Pharma, Sanofi, AbbVie, GSK, Prothena, Janssen, and Amgen.

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

SAN DIEGO — Final results of the phase 3 Andromeda study confirmed that adding daratumumab (DARA) — a human CD38-targeting monoclonal antibody — to bortezomib, cyclophosphamide, and dexamethasone (VCd) improves outcomes in patients with newly diagnosed amyloid light chain (AL) amyloidosis.

Adding DARA to VCd (D-VCd; Darzalex Faspro; Janssen Biotech) provided deeper and more rapid hematologic response and clinically meaningful and statistically significant improvement in overall survival (OS) and major organ deterioration progression-free survival (MOD-PFS), combined with 40.7% cardiac complete response (CR), first author Efstathios Kastritis, MD, said during presentation of an oral abstract at the American Society of Hematology (ASH) 2024 Annual Meeting.

“The Andromeda study is the first comparing two contemporary regimens that shows a significant survival improvement for patients with AL amyloidosis,” said Kastritis, an associate professor at the National and Kapodistrian University of Athens in Greece. “These findings reaffirm frontline D-VCd as the standard of care in this difficult-to-treat disease.”

The regimen was approved for this indication in 2021 based on prior earlier findings from the Andromeda trial. The current results are from a preplanned analysis for MOD-PFS and OS.

At a median follow-up of 61.4 months, the overall hematologic CR rates were 59.5% and 19.2% among 388 patients randomized to receive D-VCd or VCd, respectively (odds ratio, 6.03), which showed continued improvement with additional DARA vs the 53.3% and 18.1% rates observed at the primary analysis, Kastritis reported.

Time to hematologic CR was 67.5 days and 85.0 days in the treatment groups, respectively, and median duration of hematologic CR was not reached in either group.

A significant 56% improvement was also observed in MOD-PFS (hazard ratio [HR], 0.44). Median MOD-PFS was not reached in the D-VCd group and was 30.3 months in the VCd group.

A significant 38% improvement was observed in OS (HR, 0.62), 5-year OS was 76.1% vs 64.7% in the D-VCd and VCd groups, respectively, he said.

“[The OS] benefit occurred even though more than 70% of the patients in the VCd arm who received a subsequent therapy were treated with a DARA-based regimen,” he stressed. “This further emphasizes the importance of using DSTS in the frontline setting.”

Trial participants had newly diagnosed AL amyloidosis with measurable hematologic disease, one or more involved organs, cardiac stage I-IIIA, estimated glomerular filtration rate of at least 20 mL/min, and absence of symptomatic multiple myeloma. They were randomized 1:1 to the two treatment groups. All patients received 1.3 mg/m2 of bortezomib by weekly injection, 300 mg/m2 of cyclophosphamide either by weekly oral or intravenous administration, and 20-40 mg of dexamethasone by weekly oral or intravenous administration for six 28-day cycles.

Those in the D-VCd group also received 1800 mg of DARA coformulated with rHuPH20 as a weekly injection in cycles 1-2, as a biweekly injection in cycles 3-6, and by injection every 4 weeks thereafter for up to 24 28-day cycles.

The median duration of treatment was 21.3 months for D-VCd and 5.3 months for VCd, and of 122 patients who received subsequent therapy, 82 (67%) received subsequent DARA.

Patients who achieved hematologic CR had better MOD-PFS and OS (HR, 0.30 and 0.41, respectively), regardless of the treatment received, he noted, adding that “this further supports that complete hematologic response is a valid early endpoint for the evaluation of anti-monoclonal therapies in AL amyloidosis.”

“I think this is very important for the further development of new treatments in this disease,” he said.

Of note, cardiac and renal response rates in the D-VCd group were about two to three times greater than those in the VCd group at 6, 12, 24, 36, and 48 months, Kastritis said.

Among 235 patients with an evaluable cardiac response, 113 achieved a very good partial response or better, including 76 of 118 (64.4%) in the D-VCd group and 37 of 117 (31.6%) in the VCd group. Of these, 48 (40.7%) and 16 (13.7%) achieved a cardiac CR.

Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients in the D-VCd and VCd groups, respectively, were lymphopenia (13% and 10%), pneumonia (8% and 4%), hypokalemia (2% and 5%), and peripheral edema (3% and 6%), he noted, adding that systemic administration-related reactions occurred in 14 (7%) of patients receiving D-VCd; all were grade 1 or 2 and most (86%) occurred after the first injection. TEAEs led to treatment discontinuation in 5% and 4% of patients in the groups, respectively.

No new safety signals were observed during the extended follow-up, he said.

Kastritis reported relationships with Pfizer, Genesis Pharma, Sanofi, AbbVie, GSK, Prothena, Janssen, and Amgen.

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

SAN DIEGO — Final results of the phase 3 Andromeda study confirmed that adding daratumumab (DARA) — a human CD38-targeting monoclonal antibody — to bortezomib, cyclophosphamide, and dexamethasone (VCd) improves outcomes in patients with newly diagnosed amyloid light chain (AL) amyloidosis.

Adding DARA to VCd (D-VCd; Darzalex Faspro; Janssen Biotech) provided deeper and more rapid hematologic response and clinically meaningful and statistically significant improvement in overall survival (OS) and major organ deterioration progression-free survival (MOD-PFS), combined with 40.7% cardiac complete response (CR), first author Efstathios Kastritis, MD, said during presentation of an oral abstract at the American Society of Hematology (ASH) 2024 Annual Meeting.

“The Andromeda study is the first comparing two contemporary regimens that shows a significant survival improvement for patients with AL amyloidosis,” said Kastritis, an associate professor at the National and Kapodistrian University of Athens in Greece. “These findings reaffirm frontline D-VCd as the standard of care in this difficult-to-treat disease.”

The regimen was approved for this indication in 2021 based on prior earlier findings from the Andromeda trial. The current results are from a preplanned analysis for MOD-PFS and OS.

At a median follow-up of 61.4 months, the overall hematologic CR rates were 59.5% and 19.2% among 388 patients randomized to receive D-VCd or VCd, respectively (odds ratio, 6.03), which showed continued improvement with additional DARA vs the 53.3% and 18.1% rates observed at the primary analysis, Kastritis reported.

Time to hematologic CR was 67.5 days and 85.0 days in the treatment groups, respectively, and median duration of hematologic CR was not reached in either group.

A significant 56% improvement was also observed in MOD-PFS (hazard ratio [HR], 0.44). Median MOD-PFS was not reached in the D-VCd group and was 30.3 months in the VCd group.

A significant 38% improvement was observed in OS (HR, 0.62), 5-year OS was 76.1% vs 64.7% in the D-VCd and VCd groups, respectively, he said.

“[The OS] benefit occurred even though more than 70% of the patients in the VCd arm who received a subsequent therapy were treated with a DARA-based regimen,” he stressed. “This further emphasizes the importance of using DSTS in the frontline setting.”

Trial participants had newly diagnosed AL amyloidosis with measurable hematologic disease, one or more involved organs, cardiac stage I-IIIA, estimated glomerular filtration rate of at least 20 mL/min, and absence of symptomatic multiple myeloma. They were randomized 1:1 to the two treatment groups. All patients received 1.3 mg/m2 of bortezomib by weekly injection, 300 mg/m2 of cyclophosphamide either by weekly oral or intravenous administration, and 20-40 mg of dexamethasone by weekly oral or intravenous administration for six 28-day cycles.

Those in the D-VCd group also received 1800 mg of DARA coformulated with rHuPH20 as a weekly injection in cycles 1-2, as a biweekly injection in cycles 3-6, and by injection every 4 weeks thereafter for up to 24 28-day cycles.

The median duration of treatment was 21.3 months for D-VCd and 5.3 months for VCd, and of 122 patients who received subsequent therapy, 82 (67%) received subsequent DARA.

Patients who achieved hematologic CR had better MOD-PFS and OS (HR, 0.30 and 0.41, respectively), regardless of the treatment received, he noted, adding that “this further supports that complete hematologic response is a valid early endpoint for the evaluation of anti-monoclonal therapies in AL amyloidosis.”

“I think this is very important for the further development of new treatments in this disease,” he said.

Of note, cardiac and renal response rates in the D-VCd group were about two to three times greater than those in the VCd group at 6, 12, 24, 36, and 48 months, Kastritis said.

Among 235 patients with an evaluable cardiac response, 113 achieved a very good partial response or better, including 76 of 118 (64.4%) in the D-VCd group and 37 of 117 (31.6%) in the VCd group. Of these, 48 (40.7%) and 16 (13.7%) achieved a cardiac CR.

Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients in the D-VCd and VCd groups, respectively, were lymphopenia (13% and 10%), pneumonia (8% and 4%), hypokalemia (2% and 5%), and peripheral edema (3% and 6%), he noted, adding that systemic administration-related reactions occurred in 14 (7%) of patients receiving D-VCd; all were grade 1 or 2 and most (86%) occurred after the first injection. TEAEs led to treatment discontinuation in 5% and 4% of patients in the groups, respectively.

No new safety signals were observed during the extended follow-up, he said.

Kastritis reported relationships with Pfizer, Genesis Pharma, Sanofi, AbbVie, GSK, Prothena, Janssen, and Amgen.

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