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New Clues on How Blast Exposure May Lead to Alzheimer’s Disease
In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.
A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”
Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.
A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.
In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”
In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.
Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
What Is the Underlying Biology?
Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.
The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.
“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
Common Biomarker Signatures
A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.
“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.
The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.
The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.
For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).
High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.
The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).
In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
Is Impaired Clearance the Culprit?
Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.
“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”
Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”
A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.
The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.
In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”
It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.
The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”
Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.
In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.
And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.
The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
Veterans Especially Vulnerable
Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.
“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”
The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.
Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”
Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.
Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”
Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”
He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
Clinical Implications
For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.
But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”
The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.
Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.
Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”
Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”
Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”
Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.
The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
A version of this article appeared on Medscape.com.
In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.
A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”
Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.
A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.
In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”
In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.
Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
What Is the Underlying Biology?
Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.
The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.
“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
Common Biomarker Signatures
A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.
“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.
The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.
The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.
For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).
High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.
The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).
In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
Is Impaired Clearance the Culprit?
Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.
“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”
Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”
A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.
The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.
In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”
It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.
The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”
Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.
In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.
And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.
The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
Veterans Especially Vulnerable
Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.
“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”
The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.
Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”
Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.
Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”
Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”
He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
Clinical Implications
For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.
But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”
The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.
Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.
Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”
Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”
Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”
Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.
The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
A version of this article appeared on Medscape.com.
In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As reported by The New York Times, his family said that he had become increasingly erratic and violent during the months before the rampage.
A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a press release. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”
Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.
A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.
In 2022, the US Department of Defense (DOD) launched its Warfighter Brain Health Initiative with the aim of “optimizing service member brain health and countering traumatic brain injuries.”
In April 2024, the Blast Overpressure Safety Act was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD initiated 26 blast overpressure studies.
Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”
What Is the Underlying Biology?
Dr. Snyder was the lead author of a white paper produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.
The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.
“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.
Common Biomarker Signatures
A recent study in Neurology comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.
“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.
The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.
The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.
For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).
High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.
The mTBI group also showed worse cognitive performance at older ages (P < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (P ≤ .05).
In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.
Is Impaired Clearance the Culprit?
Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.
“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”
Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”
A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.
The evidence base corroborating that hypothesis is in its infancy; however, new research conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.
In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”
It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.
The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”
Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.
In their new study, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.
And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.
The earlier Neurology study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.
Veterans Especially Vulnerable
Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.
“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”
The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to The New York Times.
Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”
Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.
Dr. Snyder hopes that the researchers will follow the participants in the Neurology study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”
Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”
He coauthored an editorial on the earlier Neurology study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”
Clinical Implications
For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.
But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”
The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.
Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.
Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”
Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic data suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”
Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”
Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.
The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.
A version of this article appeared on Medscape.com.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>168515</fileName> <TBEID>0C050B44.SIG</TBEID> <TBUniqueIdentifier>MD_0C050B44</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname>Blast Exposure Alzheimer's</storyname> <articleType>2</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20240624T131312</QCDate> <firstPublished>20240624T131548</firstPublished> <LastPublished>20240624T131548</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240624T131548</CMSDate> <articleSource/> <facebookInfo/> <meetingNumber/> <byline>Batya Swift Yasgur</byline> <bylineText>BATYA SWIFT YASGUR</bylineText> <bylineFull>BATYA SWIFT YASGUR</bylineFull> <bylineTitleText/> <USOrGlobal/> <wireDocType/> <newsDocType>News</newsDocType> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s </metaDescription> <articlePDF/> <teaserImage/> <teaser>A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues.</teaser> <title>New Clues on How Blast Exposure May Lead to Alzheimer’s Disease</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2024</pubPubdateYear> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>CPN</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName>January 2021</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> </publications_g> <publications> <term>9</term> <term canonical="true">22</term> </publications> <sections> <term>39313</term> <term>86</term> <term canonical="true">27970</term> </sections> <topics> <term>309</term> <term canonical="true">180</term> <term>258</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>New Clues on How Blast Exposure May Lead to Alzheimer’s Disease</title> <deck/> </itemMeta> <itemContent> <p><br/><br/>In October 2023, Robert Card — a grenade instructor in the Army Reserve — shot and killed 18 people in Maine, before turning the gun on himself. As <span class="Hyperlink"><a href="https://www.nytimes.com/2024/03/06/us/maine-shooting-brain-injury.html">reported</a></span> by <em>The New York Times</em>, his family said that he had become increasingly erratic and violent during the months before the rampage.<br/><br/>A postmortem conducted by the Chronic Traumatic Encephalopathy (CTE) Center at Boston University found “significant evidence of traumatic brain injuries” [TBIs] and “significant degeneration, axonal and myelin loss, inflammation, and small blood vessel injury” in the white matter, the center’s director, Ann McKee, MD, said in a <span class="Hyperlink"><a href="https://concussionfoundation.org/news/press-release/family-of-Robert-Card-II-releases-findings-of-his-brain-tissue-analysis-in-effort-to-prevent-future-tragedies">press release</a></span>. “These findings align with our previous studies on the effects of blast injury in humans and experimental models.”<br/><br/>Members of the military, such as Mr. Card, are exposed to blasts from repeated firing of heavy weapons not only during combat but also during training.<br/><br/><span class="tag metaDescription">New data suggest that repeated blast exposure may impair the brain’s waste clearance system, leading to biomarker changes indicative of preclinical Alzheimer’s disease 20 years earlier than typical.</span> A higher index of suspicion for dementia or Alzheimer’s disease may be warranted in patients with a history of blast exposure or subconcussive brain injury who present with cognitive issues, according to experts interviewed.<br/><br/>In 2022, the US Department of Defense (DOD) launched its <span class="Hyperlink"><a href="https://health.mil/Military-Health-Topics/Warfighter-Brain-Health">Warfighter Brain Health Initiative</a></span> with the aim of “optimizing service member brain health and countering traumatic brain injuries.”<br/><br/>In April 2024, <span class="Hyperlink"><a href="https://www.warren.senate.gov/newsroom/press-releases/warren-ernst-khanna-senators-announce-bipartisan-bill-to-mitigate-blast-overpressure-and-protect-service-members">the Blast Overpressure Safety Act </a></span>was introduced in the Senate to require the DOD to enact better blast screening, tracking, prevention, and treatment. The DOD <span class="Hyperlink"><a href="https://www.defense.gov/News/News-Stories/Article/Article/3622388/defense-department-taking-action-with-warfighter-brain-health-initiative/">initiated 26 blast overpressure </a></span>studies.<br/><br/>Heather Snyder, PhD, Alzheimer’s Association vice president of Medical and Scientific Relations, said that an important component of that research involves “the need to study the difference between TBI-caused dementia and dementia caused independently” and “the need to study biomarkers to better understand the long-term consequences of TBI.”<br/><br/></p> <h2>What Is the Underlying Biology?</h2> <p>Dr. Snyder was the lead author of a <span class="Hyperlink"><a href="https://www.sciencedirect.com/science/article/pii/S1552526018335209?via%3Dihub">white paper</a></span> produced by the Alzheimer’s Association in 2018 on military-related risk factors for Alzheimer’s disease and related dementias. “There is a lot of work trying to understand the effect of pure blast waves on the brain, as opposed to the actual impact of the injury,” she said.<br/><br/>The white paper speculated that blast exposure may be analogous to subconcussive brain injury in athletes where there are no obvious immediate clinical symptoms or neurological dysfunction but which can cause cumulative injury and functional impairment over time.<br/><br/>“We are also trying to understand the underlying biology around brain changes, such as accumulation of tau and amyloid and other specific markers related to brain changes in Alzheimer’s disease,” said Dr. Snyder, chair of the Peer Reviewed Alzheimer’s Research Program Programmatic Panel for Alzheimer’s Disease/Alzheimer’s Disease and Related Dementias and TBI.<br/><br/></p> <h2>Common Biomarker Signatures</h2> <p>A recent <span class="Hyperlink"><a href="https://www.neurology.org/doi/10.1212/WNL.0000000000209197">study</a></span> in <em>Neurology</em> comparing 51 veterans with mild TBI (mTBI) with 85 veterans and civilians with no lifetime history of TBI is among the first to explore these biomarker changes in human beings.<br/><br/>“Our findings suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes that are precursors to Alzheimer’s disease onset,” said coauthor Elaine R. Peskind, MD, professor of psychiatry and behavioral sciences, University of Washington, Seattle.<br/><br/>The largely male participants were a mean age of 34 years and underwent standardized clinical and neuropsychological testing as well as lumbar puncture to collect cerebrospinal fluid (CSF). The mTBI group had experienced at least one war zone blast or combined blast/impact that met criteria for mTBI, but 91% had more than one blast mTBI, and the study took place over 13 years.<br/><br/>The researchers found that the mTBI group “had biomarker signatures in common with the earliest stages of Alzheimer’s disease,” said Dr. Peskind.<br/><br/>For example, at age 50, they had lower mean levels of CSF amyloid beta 42 (Abeta42), the earliest marker of brain parenchymal Abeta deposition, compared with the control group (154 pg/mL and 1864 pg/mL lower, respectively).<br/><br/>High CSF phosphorylated tau181 (p-tau181) and total tau are established biomarkers for Alzheimer’s disease. However, levels of these biomarkers remained “relatively constant with age” in participants with mTBI but were higher in older ages for the non-TBI group.<br/><br/>The mTBI group also showed worse cognitive performance at older ages (<em>P</em> < .08). Poorer verbal memory and verbal fluency performance were associated with lower CSF Abeta42 in older participants (<em>P</em> ≤ .05).<br/><br/>In Alzheimer’s disease, a reduction in CSF Abeta42 may occur up to 20 years before the onset of clinical symptoms, according to Dr. Peskind. “But what we don’t know from this study is what this means, as total tau protein and p-tau181 in the CSF were also low, which isn’t entirely typical in the picture of preclinical Alzheimer’s disease,” she said. However, changes in total tau and p-tau181 lag behind changes in Abeta42.<br/><br/></p> <h2>Is Impaired Clearance the Culprit?</h2> <p>Coauthor Jeffrey Iliff, PhD, professor, University of Washington Department of Psychiatry and Behavioral Sciences and University of Washington Department of Neurology, Seattle, elaborated.<br/><br/>“In the setting of Alzheimer’s disease, a signature of the disease is reduced CSF Abeta42, which is thought to reflect that much of the amyloid gets ‘stuck’ in the brain in the form of amyloid plaques,” he said. “There are usually higher levels of phosphorylated tau and total tau, which are thought to reflect the presence of tau tangles and degeneration of neurons in the brain. But in this study, all of those were lowered, which is not exactly an Alzheimer’s disease profile.”<br/><br/>Dr. Iliff, associate director for research, VA Northwest Mental Illness Research, Education, and Clinical Center at VA Puget Sound Health Care System, Seattle, suggested that the culprit may be impairment in the brain’s glymphatic system. “Recently described biological research supports [the concept of] clearance of waste out of the brain during sleep via the glymphatic system, with amyloid and tau being cleared from the brain interstitium during sleep.”<br/><br/>A recent hypothesis is that blast TBI impairs that process. “This is why we see less of those proteins in the CSF. They’re not being cleared, which might contribute downstream to the clumping up of protein in the brain,” he suggested.<br/><br/>The evidence base corroborating that hypothesis is in its infancy; however, <span class="Hyperlink"><a href="https://doi.org/10.1093/brain/awae065">new research</a></span> conducted by Dr. Iliff and his colleagues sheds light on this potential mechanism.<br/><br/>In blast TBI, energy from the explosion and resulting overpressure wave are “transmitted through the brain, which causes tissues of different densities — such as gray and white matter — to accelerate at different rates,” according to Dr. Iliff. This results in the shearing and stretching of brain tissue, leading to a “diffuse pattern of tissue damage.”<br/><br/>It is known that blast TBI has clinical overlap and associations with posttraumatic stress disorder (PTSD), depression, and persistent neurobehavioral symptoms; that veterans with a history of TBI are more than twice as likely to die by suicide than veterans with no TBI history; and that TBI may increase the risk for Alzheimer’s disease and related dementing disorders, as well as CTE.<br/><br/>The missing link may be the glymphatic system — a “brain-wide network of perivascular pathways, along which CSF and interstitial fluid (ISF) exchange, supporting the clearance of interstitial solutes, including amyloid-beta.”<br/><br/>Dr. Iliff and his group previously found that glymphatic function is “markedly and chronically impaired” following impact TBI in mice and that this impairment is associated with the mislocalization of astroglial aquaporin 4 (AQP4), a water channel that lines perivascular spaces and plays a role in healthy glymphatic exchange.<br/><br/>In their new <span class="Hyperlink"><a href="https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae065/7680673?searchresult=1&login=true">study</a></span>, the researchers examined both the expression and the localization of AQP4 in the human postmortem frontal cortex and found “distinct laminar differences” in AQP4 expression following blast exposure. They observed similar changes as well as impairment of glymphatic function, which emerged 28 days following blast injury in a mouse model of repetitive blast mTBI.<br/><br/>And in a cohort of veterans with blast mTBI, blast exposure was found to be associated with an increased burden of frontal cortical MRI-visible perivascular spaces — a “putative neuroimaging marker” of glymphatic perivascular dysfunction.<br/><br/>The earlier <em>Neurology</em> study “showed impairment of biomarkers in the CSF, but the new study showed ‘why’ or ‘how’ these biomarkers are impaired, which is via impairment of the glymphatic clearance process,” Dr. Iliff explained.<br/><br/></p> <h2>Veterans Especially Vulnerable</h2> <p>Dr. Peskind, co-director of the VA Northwest Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, noted that while the veterans in the earlier study had at least one TBI, the average number was 20, and it was more common to have more than 50 mTBIs than to have a single one.<br/><br/>“These were highly exposed combat vets,” she said. “And that number doesn’t even account for subconcussive exposure to blasts, which now appear to cause detectable brain damage, even in the absence of a diagnosable TBI.”<br/><br/>The Maine shooter, Mr. Card, had not seen combat and was not assessed for TBI during a psychiatric hospitalization, according to <em>The New York Times</em>.<br/><br/>Dr. Peskind added that this type of blast damage is likely specific to individuals in the military. “It isn’t the sound that causes the damage,” she explained. “It’s the blast wave, the pressure wave, and there aren’t a lot of other occupations that have those types of occupational exposures.”<br/><br/>Dr. Snyder added that the majority of blast TBIs have been studied in military personnel, and she is not aware of studies that have looked at blast injuries in other industries, such as demolition or mining, to see if they have the same type of biologic consequences.<br/><br/>Dr. Snyder hopes that the researchers will follow the participants in the <em>Neurology</em> study and continue looking at specific markers related to Alzheimer’s disease brain changes. What the research so far shows “is that, at an earlier age, we’re starting to see those markers changing, suggesting that the underlying biology in people with mild blast TBI is similar to the underlying biology in Alzheimer’s disease as well.”<br/><br/>Michael Alosco, PhD, associate professor and vice chair of research, department of neurology, Boston University Chobanian & Avedisian School of Medicine, called the issue of blast exposure and TBI “a very complex and nuanced topic,” especially because TBI is “considered a risk factor of Alzheimer’s disease” and “different types of TBIs could trigger distinct pathophysiologic processes; however, the long-term impact of repetitive blast TBIs on neurodegenerative disease changes remains unknown.”<br/><br/>He coauthored an <span class="Hyperlink"><a href="https://www.neurology.org/doi/10.1212/WNL.0000000000209294?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed">editorial</a></span> on the earlier <em>Neurology</em> study that noted its limitations, such as a small sample size and lack of consideration of lifestyle and health factors but acknowledged that the “findings provide preliminary evidence that repetitive blast exposures might influence beta-amyloid accumulation.”<br/><br/></p> <h2>Clinical Implications</h2> <p>For Dr. Peskind, the “inflection point” was seeing lower CSF Abeta42, about 20 years earlier than ages 60 and 70, which is more typical in cognitively normal community volunteers.</p> <p>But she described herself as “loath to say that veterans or service members have a 20-year acceleration of risk of Alzheimer’s disease,” adding, “I don’t want to scare the heck out of our service members of veterans.” Although “this is what we fear, we’re not ready to say it for sure yet because we need to do more work. Nevertheless, it does increase the index of suspicion.”<br/><br/>The clinical take-home messages are not unique to service members or veterans or people with a history of head injuries or a genetic predisposition to Alzheimer’s disease, she emphasized. “If anyone of any age or occupation comes in with cognitive issues, such as [impaired] memory or executive function, they deserve a workup for dementing disorders.” Frontotemporal dementia, for example, can present earlier than Alzheimer’s disease typically does.<br/><br/>Common comorbidities with TBI are PTSD and obstructive sleep apnea (OSA), which can also cause cognitive issues and are also risk factors for dementia.<br/><br/>Dr. Iliff agreed. “If you see a veteran with a history of PTSD, a history of blast TBI, and a history of OSA or some combination of those three, I recommend having a higher index of suspicion [for potential dementia] than for an average person without any of these, even at a younger age than one would ordinarily expect.”<br/><br/>Of all of these factors, the only truly directly modifiable one is sleep disruption, including that caused by OSA or sleep disorders related to PTSD, he added. “Epidemiologic <span class="Hyperlink"><a href="https://www.neurology.org/doi/10.1212/WNL.0000000000209294?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed">data</a></span> suggest a connection particularly between midlife sleep disruption and the risk of dementia and Alzheimer’s disease, and so it’s worth thinking about sleep as a modifiable risk factor even as early as the 40s and 50s, whether the patient is or isn’t a veteran.”<br/><br/>Dr. Peskind recommended asking patients, “Do they snore? Do they thrash about during sleep? Do they have trauma nightmares? This will inform the type of intervention required.”<br/><br/>Dr. Alosco added that there is no known “safe” threshold of exposure to blasts, and that thresholds are “unclear, particularly at the individual level.” In American football, there is a dose-response relationship between years of play and risk for later-life neurological disorder. “The best way to mitigate risk is to limit cumulative exposure,” he said.<br/><br/>The study by Li and colleagues was funded by grant funding from the Department of Veterans Affairs Rehabilitation Research and Development Service and the University of Washington Friends of Alzheimer’s Research. Other sources of funding to individual researchers are listed in the original paper. The study by Braun and colleagues was supported by the National Heart, Lung and Blood Institute; the Department of Veterans Affairs Rehabilitation Research and Development Service; and the National Institute on Aging. The white paper included studies that received funding from numerous sources, including the National Institutes of Health and the DOD. Dr. Iliff serves as the chair of the Scientific Advisory Board for Applied Cognition Inc., from which he receives compensation and in which he holds an equity stake. In the last year, he served as a paid consultant to Gryphon Biosciences. Dr. Peskind has served as a paid consultant to the companies Genentech, Roche, and Alpha Cognition. Dr. Alosco was supported by grant funding from the NIH; he received research support from Rainwater Charitable Foundation Inc., and Life Molecular Imaging Inc.; he has received a single honorarium from the Michael J. Fox Foundation for services unrelated to this editorial; and he received royalties from Oxford University Press Inc. The other authors’ disclosures are listed in the original papers.<br/><br/></p> <p> <em>A version of this article appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/new-clues-how-blast-exposure-may-lead-alzheimers-disease-2024a1000bne">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
Migraine Linked to Cardiovascular Risk in Veterans Study
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
SAN DIEGO — , according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.
Gender Matters
The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.
The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.
Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.
The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.
Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).
While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
Another Piece of the Puzzle
The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.
The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.
Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Migraine may be associated with a greater risk of cardiovascular disease, ischemic stroke, and transient ischemic attack (TIA), but also a reduction in risk of </metaDescription> <articlePDF/> <teaserImage/> <teaser>A Veterans Administration study of migraine found a greater risk of stroke and TIA and a reduced risk of hemorrhagic stroke in men. </teaser> <title>Migraine Linked to Cardiovascular Risk in Veterans Study</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2024</pubPubdateYear> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName>January 2021</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>mrc</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> </publications_g> <publications> <term canonical="true">22</term> <term>46994</term> </publications> <sections> <term>39313</term> <term canonical="true">53</term> </sections> <topics> <term canonical="true">222</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Migraine Linked to Cardiovascular Risk in Veterans Study</title> <deck/> </itemMeta> <itemContent> <p><span class="dateline">SAN DIEGO </span>— <span class="tag metaDescription">Migraine may be associated with a greater risk of cardiovascular disease, ischemic stroke, and transient ischemic attack (TIA), but also a reduction in risk of hemorrhagic stroke in men</span>, according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men. </p> <h2>Gender Matters</h2> <p>The research complements other studies, such as an <span class="Hyperlink"><a href="https://www.bmj.com/content/353/bmj.i2610">analysis</a></span> drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study <span class="Hyperlink"><a href="https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/412278">found an increased risk of major cardiovascular events</a></span> of 1.24 (<em>P</em> = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview. </p> <p>The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.<br/><br/>Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine. <br/><br/>The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care. <br/><br/>Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).<br/><br/>While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.<br/><br/></p> <h2>Another Piece of the Puzzle</h2> <p>The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.</p> <p>The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.<br/><br/>Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures. </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM AHS 2024
OTC Supplement Linked to Hyperpigmentation
CHICAGO —The .
“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the Skin of Color Division at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.
Used Like an Opioid, But It’s Not Regulated
Kratom is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a case report published in February in the Journal of Integrative Dermatology. It is used worldwide and is not regulated in the United States.
“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on social media platforms.
In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.
Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.
Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”
Case Reports Show Patterns of Presentation
A 2022 report from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in JAAD Case Reports, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.
An estimated 1.7 million Americans aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.
In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous four to five years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice three to four times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”
Dark Gray-Blue Skin
In the more recent case report, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.
The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.
“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”
Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.
According to an information page on kratom on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s MedWatch program.
A version of this article appeared on Medscape.com.
CHICAGO —The .
“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the Skin of Color Division at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.
Used Like an Opioid, But It’s Not Regulated
Kratom is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a case report published in February in the Journal of Integrative Dermatology. It is used worldwide and is not regulated in the United States.
“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on social media platforms.
In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.
Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.
Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”
Case Reports Show Patterns of Presentation
A 2022 report from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in JAAD Case Reports, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.
An estimated 1.7 million Americans aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.
In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous four to five years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice three to four times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”
Dark Gray-Blue Skin
In the more recent case report, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.
The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.
“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”
Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.
According to an information page on kratom on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s MedWatch program.
A version of this article appeared on Medscape.com.
CHICAGO —The .
“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the Skin of Color Division at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.
Used Like an Opioid, But It’s Not Regulated
Kratom is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a case report published in February in the Journal of Integrative Dermatology. It is used worldwide and is not regulated in the United States.
“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on social media platforms.
In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.
Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.
Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”
Case Reports Show Patterns of Presentation
A 2022 report from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in JAAD Case Reports, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.
An estimated 1.7 million Americans aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.
In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous four to five years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice three to four times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”
Dark Gray-Blue Skin
In the more recent case report, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.
The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.
“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”
Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.
According to an information page on kratom on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s MedWatch program.
A version of this article appeared on Medscape.com.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>use of kratom, an opioid-like supplement widely available over the counter at convenience stores, smoke shops, and online, is resulting in emerging cases of hyp</metaDescription> <articlePDF/> <teaserImage/> <title>OTC Supplement Linked to Hyperpigmentation</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>skin</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>cpn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">13</term> <term>15</term> <term>21</term> <term>9</term> </publications> <sections> <term>53</term> <term canonical="true">39313</term> </sections> <topics> <term canonical="true">276</term> <term>174</term> <term>203</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>OTC Supplement Linked to Hyperpigmentation</title> <deck/> </itemMeta> <itemContent> <p><br/><br/><span class="dateline">CHICAGO</span> —The <span class="tag metaDescription">use of kratom, an opioid-like supplement widely available over the counter at convenience stores, smoke shops, and online, is resulting in emerging cases of hyperpigmentation, most often on the face and hands</span>.<br/><br/>“This is something we will see more and more,” Heather Woolery-Lloyd, MD, director of the <span class="Hyperlink"><a href="https://med.miami.edu/departments/dermatology/divisions-and-programs/skin-of-color-division">Skin of Color Division</a></span> at the University of Miami Department of Dermatology, said at the Pigmentary Disorders Exchange Symposium. The key marker of this hyperpigmentation, she said, is that “it’s strongly photoaccentuated,” affecting areas exposed to the sun — but it also tends to spare the knuckles on patients’ hands.<br/><br/></p> <h2>Used Like an Opioid, But It’s Not Regulated</h2> <p><span class="Hyperlink"><a href="https://nida.nih.gov/research-topics/kratom">Kratom</a></span> is a plant common in southeast Asia and is used as an analgesic. It’s marketed as a “legal opioid” or “legal high” and is sold in 2- or 3-ounce containers of extract or sold as a powder, Dr. Woolery-Lloyd said. The leaves may be boiled into a tea, smoked, chewed, or put into capsules, according to a <span class="Hyperlink"><a href="https://www.jintegrativederm.org/article/92542-photo-distributed-gray-blue-hyperpigmentation-due-to-kratom-use">case report</a></span> published in February in the <em>Journal of Integrative Dermatology</em>. It is used worldwide and is not regulated in the United States.<br/><br/>“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, Dr. Woolery-Lloyd said. Its popularity is increasing as reflected by the number of posts related to kratom on <span class="Hyperlink"><a href="https://www.tiktok.com/tag/kratomtiktok">social media platforms</a></span>.<br/><br/>In the February case report, Shaina Patel, BA, and Nathaniel Phelan, MD, from Kansas City University, Kansas City, Missouri, wrote that side effects of kratom include drowsiness, tachycardia, vomiting, respiratory depression, and cardiac arrest, in addition to confusion and hallucinations.<br/><br/>Kratom also has many different effects on the psyche, Dr. Woolery-Lloyd said at the meeting. At low doses, it blocks the reuptake of norepinephrine, serotonin, and dopamine, producing a motivational effect, and at high doses, it creates an analgesic, calming effect. And people who chronically consume high doses of kratom may be susceptible to hyperpigmentation.<br/><br/>Kratom-associated hyperpigmentation should be considered as a diagnosis when evaluating patients for other drug-associated pigmentary disorders, “especially if pigment is photodistributed,” she said. “If you see new-onset hyperpigmentation or onset over several months and it’s very photoaccentuated, definitely ask about use of kratom.”<br/><br/></p> <h2>Case Reports Show Patterns of Presentation</h2> <p>A <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523091/">2022 report</a></span> from Landon R. Powell, BS, with the department of biology, Whitworth University in Spokane, Washington, and coauthors, published in <em>JAAD Case Reports</em>, noted that kratom use in the United States has increased dramatically. “As measured by call reports to the United States National Poison Data System, in 2011, there were 11 reported kratom exposures, and in the first 7 months of 2018, there were 357 reported exposures,” they wrote.<br/><br/>An estimated <span class="Hyperlink"><a href="https://www.samhsa.gov/data/sites/default/files/reports/rpt39443/2021NSDUHFFRRev010323.pdf">1.7 million Americans</a></span> aged ≥ 12 years said they had used kratom in the previous year, according to the Substance Abuse and Mental Health Services Administration 2021 National Survey on Drug Use and Health.<br/><br/>In the case report, Mr. Powell and coauthors described a 54-year-old White male patient who had been using kratom for the previous 4-5 years to reduce opioid use. During this period, he consumed kratom powder mixed with orange juice times a day. He presented with “diffuse hyperpigmented patches on his arms and face in a photodistributed manner, with notable sparing of the knuckles on both hands.”<br/><br/></p> <h2>Dark Gray-Blue Skin</h2> <p>In the more recent <span class="Hyperlink"><a href="https://www.jintegrativederm.org/article/92542-photo-distributed-gray-blue-hyperpigmentation-due-to-kratom-use">case report</a></span>, Ms. Patel and Dr. Phelan described a 30-year-old White male patient who presented with dark gray-blue skin coloring on his cheeks, back of his neck, and the backs of his hands and forearms. He had no other medical conditions and did not take any medications or supplements that cause hyperpigmentation while using kratom.<br/><br/>The patient had been taking kratom for years in the wake of an opioid addiction following medications for a high school injury. He developed an opioid use disorder and tried to replace his pain medications with kratom.<br/><br/>“The patient stopped using kratom in May 2022, but the discoloration remains. It has not regressed in the following 16 months after discontinuing kratom use,” the authors wrote, noting that “whether or not the hyperpigmentation is able to regress is unknown.”<br/><br/>Dr. Woolery-Lloyd is a consultant for AbbVie, Incyte, Johnson & Johnson Consumer, LivDerm, and L’Oreal; a speaker for Eli Lilly, Incyte, L’Oreal, and Ortho Dermatologics; and a researcher/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer, Sanofi, and Vyne Therapeutics.<br/><br/></p> <p> <em>According to an <a href="https://www.fda.gov/news-events/public-health-focus/fda-and-kratom">information page on kratom</a> on the Food and Drug Administration website, health care professionals and consumers can report adverse reactions associated with kratom to the FDA’s <a href="https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program">MedWatch</a> program.</em> </p> <p> <em>A version of this article appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/cases-kratom-induced-hyperpigmentation-emerging-2024a1000awc">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p>“Many of our patients think kratom is a safe, herbal supplement” but often don’t know it can have several side effects and can be addictive, said Heather Woolery-Lloyd, MD. </p> </itemContent> </newsItem> </itemSet></root>
Lung Cancer Expert at ASCO: From Fatal to ‘Chronic Disease’
After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.
That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.
Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?
Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.
Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?
Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.
I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.
Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.
That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.
Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.
Question: And you went from being a community oncologist to academic research?
Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.
Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.
In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.
Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.
Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.
Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.
And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.
But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.
And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.
And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.
Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.
This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.
After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.
That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.
Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?
Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.
Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?
Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.
I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.
Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.
That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.
Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.
Question: And you went from being a community oncologist to academic research?
Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.
Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.
In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.
Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.
Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.
Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.
And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.
But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.
And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.
And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.
Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.
This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.
After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997.
That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease.
Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.
Question: At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?
Dr. Mok: KRYSTAL-12 is a randomized phase 3 study comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant.
Question: Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like to make — anything you’d like to add?
Dr. Mok: You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.
I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C?
Question: Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? Dr. Mok: In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.
Question: What clinical trials should oncologist be watching to come into this space?Dr. Mok: There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the KRYSTAL-7 trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%.
That’s one example. And then there is the CodeBreaK 202 trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.
Question: I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.
Dr. Mok: Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life.
Question: And you went from being a community oncologist to academic research?
Dr. Mok: Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.
Question: Why do you say that was the best decision you ever made?Dr. Mok: At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.
In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.
Question: At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.Dr. Mok: Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the IPASS study [2009]. That’s how I started my academic career.
Question: I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.
Dr. Mok: The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene.
And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.
Question: So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? Dr. Mok: Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant.
But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do.
Question: You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? Dr. Mok: I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China.
And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time.
And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.
Question: There’s also a population with these mutations.Dr. Mok: That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds.
Question: Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?Dr. Mok: I think the most important one I was engaged in is the CROWN study. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer.
This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>168485</fileName> <TBEID>0C050A6E.SIG</TBEID> <TBUniqueIdentifier>MD_0C050A6E</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname/> <articleType>2</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20240620T154219</QCDate> <firstPublished>20240620T161702</firstPublished> <LastPublished>20240620T161702</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240620T161702</CMSDate> <articleSource>FROM ASCO 2024</articleSource> <facebookInfo/> <meetingNumber>3035-24</meetingNumber> <byline>Susan Ruel</byline> <bylineText>SUSAN RUEL, PHD</bylineText> <bylineFull>SUSAN RUEL, PHD</bylineFull> <bylineTitleText>MDedge News</bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType/> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>CHICAGO — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dr</metaDescription> <articlePDF/> <teaserImage>301947</teaserImage> <teaser>Tony Shu-Kam Mok, MD, discusses latest KRAS G12C findings and more.</teaser> <title>Lung Cancer Expert at ASCO: From Fatal to ‘Chronic Disease’</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> </publications> <sections> <term canonical="true">53</term> <term>39313</term> </sections> <topics> <term canonical="true">65133</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012a46.jpg</altRep> <description role="drol:caption">Dr. Tony Shu-Kam Mok</description> <description role="drol:credit">courtesy of Dr. Tony Mok</description> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Lung Cancer Expert at ASCO: From Fatal to ‘Chronic Disease’</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription"><span class="dateline">CHICAGO</span> — Prominent Chinese oncologist Tony Shu-Kam Mok, MD, who presented as first author of a phase 3 non–small cell lung cancer study at ASCO 2024, made a dramatic swerve in his career path at age 36.</span> </p> <p>After 20 years in Canada — 7 spent practicing community oncology near Toronto — Dr. Mok was visiting family in his native Hong Kong back in 1996 when a job offer there enabled him to revive his early dream of doing academic research. Dr. Mok and his family moved back home just before the former British colony was returned to China in 1997. <br/><br/>[[{"fid":"301947","view_mode":"medstat_image_flush_right","fields":{"format":"medstat_image_flush_right","field_file_image_alt_text[und][0][value]":"Dr. Tony Shu-Kam Mok, MD, Li Shu Fan Medical Foundation Professor, Department of Clinical Oncology, The Chinese University of Hong Kong","field_file_image_credit[und][0][value]":"courtesy of Dr. Tony Mok","field_file_image_caption[und][0][value]":"Dr. Tony Shu-Kam Mok"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_right"}}]]That leap of faith helped Dr. Mok play a role in the global paradigm shift on treating lung cancer. He chairs the department of clinical oncology at the Chinese University of Hong Kong. A leader in ushering in targeted therapies and personalized medicine in China and globally, he has helped advance the goal of transforming lung cancer from a death sentence to a chronic disease. <br/><br/>Among Dr. Mok’s other accomplishments, he has published eight books and more than 200 journal articles. Since 2006, he has been writing a twice-weekly column in the Hong Kong Economic Times. At the annual meeting of the American Society of Clinical Oncology (ASCO), Dr. Mok sat down with this news organization to discuss his latest findings, his career path, and China’s ever-growing presence in multinational clinical trials, pharmaceuticals, and cancer research in general.<br/><br/></p> <p><strong>Question:</strong> <strong>At ASCO 2024 in Chicago, you presented as first author of the KRYSTAL-12 study. Can you give a short “elevator speech” summarizing those findings?</strong> <br/><br/><strong>Dr. Mok:</strong> KRYSTAL-12 is a randomized <span class="Hyperlink"><a href="https://meetings.asco.org/abstracts-presentations/232538">phase 3 study</a></span> comparing adagrasib with docetaxel in patients with previously treated advanced/metastatic non–small cell lung cancer harboring a KRAS G12C-mutation. And the findings are positive, with a median progression free survival of 5.5 months vs 3.8 months, with a significant hazard ratio [of 0.58]. And then there are also differences in their response rates of 32% versus 9%, and that gives you an [odds] ratio of 4.86. So yes, it’s significant. </p> <p><strong>Question:</strong> <strong>Now that you’ve given this presentation and perhaps taken some good, meaningful questions about it, are there any further points you’d like make </strong>— <strong>anything you’d like to add?</strong> <br/><br/><strong>Dr. Mok:</strong> You have to understand that whatever I said has been scrutinized by the pharmaceutical company, but now I can say whatever I like. I think the key point is that we actually have made the first so-called achievement in the KRAS G12C space. But this is only the beginning.</p> <p>I want to note that the median progression-free survival is different, but not the best. The median 5.5 months result is good, but not good enough. So, we still have to work hard to answer the question: How can we best deliver care to patients with KRAS G12C? <br/><br/></p> <p><strong>Question:</strong> <strong>Speaking more generally about the challenges of targeting KRAS, what issues arise in terms of biomarker testing for KRAS mutations in the clinic? </strong><strong>Dr. Mok:</strong> In colorectal cancer, there has been testing for KRAS [mutations] for a long, long time. So, most of the laboratories, as long as they are well equipped, will be able to test for KRAS. Usually, the cheaper way is to buy PCR [polymerase chain reaction]. However, these days it’s getting trendier to use NGS [next-generation sequencing]. So, one way or another, specificity is very high. I don’t think we have too much of a problem. The only difference between colorectal cancer and lung cancer is that the tissue sample may not be as good for lung cancer with a small biopsy, but otherwise testing is not an issue.</p> <p><strong>Question:</strong> <strong>What clinical trials should oncologist be watching to come into this space?</strong><strong>Dr. Mok:</strong> There are a lot. Right now, there is the so-called first-line study that’s coming up. So, I can cite you some examples for the <span class="Hyperlink"><a href="https://classic.clinicaltrials.gov/ct2/show/NCT04613596">KRYSTAL-7</a></span> trial, which is the combination of pembrolizumab together with adagrasib in the PD-L1 Tumor Proportion Score ≥ 50%. <br/><br/>That’s one example. And then there is the <span class="Hyperlink"><a href="https://classic.clinicaltrials.gov/ct2/show/NCT05920356">CodeBreaK 202</a></span> trial, which is actually the combination of chemotherapy with sotorasib versus chemotherapy and I-O [immune-oncology]. That is also an ongoing study.<br/><br/></p> <p><strong>Question:</strong> <strong>I also want to ask you some background questions about yourself. Back in the day, you lived in Canada and were a community oncologist. Then you made a very big change in your life and moved back home to Hong Kong in 1996, on the eve of its return to China the following year.</strong> <br/><br/><strong>Dr. Mok:</strong> Well, I was born and raised in Hong Kong, but I left for Canada for education when I was 16 and kind of stayed there and got medical school oncology training and then started my practice. At that time, I never imagined myself going back. But 1996 was a big year. Incidentally, I went back to Hong Kong then to visit my friends and was offered a job at the Chinese University of Hong Kong. Then 1997 was coming. I found it very exciting that we could work with China. So that’s why I decided to return. And this was probably one of my best decisions I ever made in my life. </p> <p><strong>Question:</strong> <strong>And you went from being a community oncologist to academic research?</strong> <br/><br/><strong>Dr. Mok:</strong> Here’s a personal thing that I can share with you: When I finished my oncology training at Princess Margaret Hospital in Toronto, I thought of going into research and becoming an academic. However, my son was born. Household costs went up, and I didn’t want to be a low-income, poor PhD student, so I decided that I may as well go into private practice. Returning to Hong Kong [in 1996] gave me a second chance. I went from being a community oncologist for seven years in Canada to a totally new environment in Hong Kong, where I started my academic work at age 36. It has been a good journey.</p> <p><strong>Question:</strong> <strong>Why do you say that was the best decision you ever made?</strong><strong>Dr. Mok:</strong> At that time, it took me about 2 weeks to make this important decision. Basically: I had to give up my big house and my big car in Canada and move back to a small apartment in Hong Kong. That was a tough decision to make. However, it was a matter of certainty versus uncertainty.</p> <p>In Canada, I actually had a very stable situation. I had a big practice in the Scarborough area [of Toronto], with a lot of Chinese patients, so I had a better, more comfortable life. It was predictable. But then I asked myself what I would be like in 10 years if I stayed in Canada versus Hong Kong. My answer is that I had no idea what would happen to me 10 years later in Hong Kong. In certain parts of life, you have to decide between certainty and uncertainty. And this time, uncertainty brought me great adventure. I definitely would not have done the things I’ve done if I’d stayed in Canada.<br/><br/><br/><br/><strong>Question:</strong> <strong>At this ASCO, you’ve spoken primarily about your latest research on non–small cell lung cancer with KRAS G12C mutation.</strong><strong>Dr. Mok:</strong> Actually, my research has been mostly on targeted therapy. My first break was on the EGFR [epidermal growth factor receptor] mutation. I was one of the first to help define personalized medicine according to the EGFR mutation in the <span class="Hyperlink"><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa0810699">IPASS study</a></span> [2009]. That’s how I started my academic career. <br/><br/><br/><br/><strong>Question:</strong> <strong>I read some quotes from your writing some years back about “living with imperfection,” and where you wrote about the whole continuum of cancer research. Years ago, you noted that lung cancer was moving from being a death sentence to becoming a chronic condition.</strong> <br/><br/><strong>Dr. Mok:</strong> The objective is this: A lot of cancer patients, especially lung cancer patients, had a very short survival, but now we are able to identify a subgroup of patients with a driver oncogene. <br/><br/>And with that, we can use a tyrosine kinase inhibitor — which although it has toxicity, it’s manageable toxicity — such that you can take one pill a day and continue to live a normal life. So that would be not so different from diabetes or hypertension: You live with the disease. So that’s what we like to see: the conversion of a fatal disease into a chronic disease.<br/><br/></p> <p><strong>Question:</strong> <strong>So many countries now, including the United States and many others, are facing the challenges of cancer care in rural versus urban areas. Is this a topic you’d be willing to address? </strong><strong>Dr. Mok:</strong> Well, in Hong Kong we don’t have rural areas! But in China, this is a major problem. There most of the cancer care is focused on the so-called three major cities [Shanghai, Beijing, Guangzhou]. And after that, there are second-tier cities that also have reasonably good care. But when you filter down to the third and fourth layer, the oncology care actually deteriorates. So that’s why we end up with a lot of people from the more rural areas moving and going to the city looking for care and consultation. So yes, the disparity is significant. </p> <p>But China is a growing country. It takes time to change. Right now, we can see at ASCO this year, there are a lot of investigators from China sharing their new findings, which is a major development, compared to 10 years ago. Therefore, I think that when you have this type of proliferative development, eventually the good care, the high-quality care will filter down to more rural areas. So, at this moment, I think there is still a lot of work to do. <br/><br/></p> <p><strong>Question:</strong> <strong>You’ve talked about how oncologists from China are coming up in the field, and this year they have an even greater presence at ASCO, as well as oncologists from elsewhere in Asia, including South Korea, Japan, and Vietnam. You’ve been coming to ASCO for many years. Can you talk about the factors behind China’s increasing presence? </strong><strong>Dr. Mok:</strong> I think it’s a combination of factors. First of all, I had the honor of working with lung cancer researchers from China from way back, 25 years ago. At that time, we all had nothing. Then with the development of multitargeted therapies, they managed to build up a very good infrastructure for clinical trials. And then, based on that good infrastructure, they were able to do international collaborative studies and provide a supply of patient resources and high-quality data. So, they’ve learned the trick, done a good job, but they cannot have so-called independence until there is a development of pharmaceuticals in China. </p> <p>And then over the past 10 years, there’s been a proliferation — actually an explosion I would even say — of high-quality pharmaceutical companies in China. First, they’ve got the resources to build the companies. Second, they’ve got the talent resources returning from the United States. So, putting all that together, these were able to go from start-ups to full-fledged functional companies in a very short time. <br/><br/>And with that, they actually sponsored a lot of trials within China. And you can see that putting all the components together: you’ve got high-quality researchers, you’ve got the infrastructure, and now you’ve got your drugs and the money to do the trials. As a result, you’ve got a lot of good data coming from China.<br/><br/> </p> <p><strong>Question:</strong> <strong>There’s also a population with these mutations.</strong><strong>Dr. Mok:</strong> That for one, but most have multitargeted therapies, but they also have immunotherapies that have nothing to do with the high incidence. But I think in a sense, in the beginning, they were doing `me-too’ compounds, but now I think they are starting to do ‘me-better’ compounds. </p> <p><strong>Question:</strong> <strong>Is there anything you want to say about some of the other presentations that have your name on them at ASCO this year?</strong><strong>Dr. Mok:</strong> I think the most important one I was engaged in is the <span class="Hyperlink"><a href="https://ascopubs.org/doi/10.1200/JCO.24.00581">CROWN study</a></span>. The CROWN study is actually a phase 3 study that compares lorlatinib versus crizotinib in patients with advanced, ALK-positive non–small cell lung cancer. </p> <p>This is a 5-year follow-up, and we were actually able to report an outrageously encouraging 5-year progression-free rate at 60%, meaning that the patient is walking in the door 5 years later when they are on the drug, and 60% of them actually do not have progression, not death, just not progression, just staying on the same pill—which is quite outrageously good for lung cancer.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM ASCO 2024
One Patient Changed This Oncologist’s View of Hope. Here’s How.
CHICAGO — Carlos, a 21-year-old, lay in a hospital bed, barely clinging to life. Following a stem cell transplant for leukemia, Carlos had developed a life-threatening case of graft-vs-host disease.
But Carlos’ mother had faith.
“I have hope things will get better,” she said, via interpreter, to Richard Leiter, MD, a palliative care doctor in training at that time.
“I hope they will,” Dr. Leiter told her.
“I should have stopped there,” said Dr. Leiter, recounting an early-career lesson on hope during the ASCO Voices session at the American Society of Clinical Oncology annual meeting. “But in my eagerness to show my attending and myself that I could handle this conversation, I kept going, mistakenly.”
“But none of us think they will,” Dr. Leiter continued.
Carlos’ mother looked Dr. Leiter in the eye. “You want him to die,” she said.
“I knew, even then, that she was right,” recalled Dr. Leiter, now a palliative care physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School, Boston.
Although there was nothing he could do to save Carlos, Dr. Leiter also couldn’t sit with the extreme suffering. “The pain was too great,” Dr. Leiter said. “I needed her to adopt our narrative that we had done everything we could to help him live, and now, we would do everything we could to help his death be a comfortable one.”
But looking back, Dr. Leiter realized, “How could we have asked her to accept what was fundamentally unacceptable, to comprehend the incomprehensible?”
The Importance of Hope
Alan B. Astrow, MD, said during an ASCO symposium on “The Art and Science of Hope.”
“How we think about hope directly influences patient care,” said Dr. Astrow, chief of hematology and medical oncology at NewYork-Presbyterian Brooklyn Methodist Hospital and a professor of clinical medicine at Weill Cornell Medicine in New York City.
Hope, whatever it turns out to be neurobiologically, is “very much a gift” that underlies human existence, he said.
Physicians have the capacity to restore or shatter a patient’s hopes, and those who come to understand the importance of hope will wish to extend the gift to others, Dr. Astrow said.
Asking patients about their hopes is the “golden question,” Steven Z. Pantilat, MD, said at the symposium. “When you think about the future, what do you hope for?”
Often, the answers reveal not only “things beyond a cure that matter tremendously to the patient but things that we can help with,” said Dr. Pantilat, professor and chief of the Division of Palliative Medicine at the University of California San Francisco.
Dr. Pantilat recalled a patient with advanced pancreatic cancer who wished to see her daughter’s wedding in 10 months. He knew that was unlikely, but the discussion led to another solution.
Her daughter moved the wedding to the ICU.
Hope can persist and uplift even in the darkest of times, and “as clinicians, we need to be in the true hope business,” he said.
While some patients may wish for a cure, others may want more time with family or comfort in the face of suffering. People can “hope for all the things that can still be, despite the fact that there’s a lot of things that can’t,” he said.
However, fear that a patient will hope for a cure, and that the difficult discussions to follow might destroy hope or lead to false hope, sometimes means physicians won’t begin the conversation.
“We want to be honest with our patients — compassionate and kind, but honest — when we talk about their hopes,” Dr. Pantilat explained. Sometimes that means he needs to tell patients, “I wish that could happen. I wish I had a treatment that could make your cancer go away, but unfortunately, I don’t. So let’s think about what else we can do to help you.”
Having these difficult discussions matters. The evidence, although limited, indicates that feeling hopeful can improve patients’ well-being and may even boost their cancer outcomes.
One recent study found, for instance, that patients who reported feeling more hopeful also had lower levels of depression and anxiety. Early research also suggests that greater levels of hope may have a hand in reducing inflammation in patients with ovarian cancer and could even improve survival in some patients with advanced cancer.
For Dr. Leiter, while these lessons came early in his career as a palliative care physician, they persist and influence his practice today.
“I know that I could not have prevented Carlos’ death. None of us could have, and none of us could have protected his mother from the unimaginable grief that will stay with her for the rest of her life,” he said. “But I could have made things just a little bit less difficult for her.
“I could have acted as her guide rather than her cross-examiner,” he continued, explaining that he now sees hope as “a generous collaborator” that can coexist with rising creatinine levels, failing livers, and fears about intubation.
“As clinicians, we can always find space to hope with our patients and their families,” he said. “So now, years later when I sit with a terrified and grieving family and they tell me they hope their loved one gets better, I remember Carlos’ mother’s eyes piercing mine ... and I know how to respond: ‘I hope so, too.’ And I do.”
A version of this article appeared on Medscape.com.
CHICAGO — Carlos, a 21-year-old, lay in a hospital bed, barely clinging to life. Following a stem cell transplant for leukemia, Carlos had developed a life-threatening case of graft-vs-host disease.
But Carlos’ mother had faith.
“I have hope things will get better,” she said, via interpreter, to Richard Leiter, MD, a palliative care doctor in training at that time.
“I hope they will,” Dr. Leiter told her.
“I should have stopped there,” said Dr. Leiter, recounting an early-career lesson on hope during the ASCO Voices session at the American Society of Clinical Oncology annual meeting. “But in my eagerness to show my attending and myself that I could handle this conversation, I kept going, mistakenly.”
“But none of us think they will,” Dr. Leiter continued.
Carlos’ mother looked Dr. Leiter in the eye. “You want him to die,” she said.
“I knew, even then, that she was right,” recalled Dr. Leiter, now a palliative care physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School, Boston.
Although there was nothing he could do to save Carlos, Dr. Leiter also couldn’t sit with the extreme suffering. “The pain was too great,” Dr. Leiter said. “I needed her to adopt our narrative that we had done everything we could to help him live, and now, we would do everything we could to help his death be a comfortable one.”
But looking back, Dr. Leiter realized, “How could we have asked her to accept what was fundamentally unacceptable, to comprehend the incomprehensible?”
The Importance of Hope
Alan B. Astrow, MD, said during an ASCO symposium on “The Art and Science of Hope.”
“How we think about hope directly influences patient care,” said Dr. Astrow, chief of hematology and medical oncology at NewYork-Presbyterian Brooklyn Methodist Hospital and a professor of clinical medicine at Weill Cornell Medicine in New York City.
Hope, whatever it turns out to be neurobiologically, is “very much a gift” that underlies human existence, he said.
Physicians have the capacity to restore or shatter a patient’s hopes, and those who come to understand the importance of hope will wish to extend the gift to others, Dr. Astrow said.
Asking patients about their hopes is the “golden question,” Steven Z. Pantilat, MD, said at the symposium. “When you think about the future, what do you hope for?”
Often, the answers reveal not only “things beyond a cure that matter tremendously to the patient but things that we can help with,” said Dr. Pantilat, professor and chief of the Division of Palliative Medicine at the University of California San Francisco.
Dr. Pantilat recalled a patient with advanced pancreatic cancer who wished to see her daughter’s wedding in 10 months. He knew that was unlikely, but the discussion led to another solution.
Her daughter moved the wedding to the ICU.
Hope can persist and uplift even in the darkest of times, and “as clinicians, we need to be in the true hope business,” he said.
While some patients may wish for a cure, others may want more time with family or comfort in the face of suffering. People can “hope for all the things that can still be, despite the fact that there’s a lot of things that can’t,” he said.
However, fear that a patient will hope for a cure, and that the difficult discussions to follow might destroy hope or lead to false hope, sometimes means physicians won’t begin the conversation.
“We want to be honest with our patients — compassionate and kind, but honest — when we talk about their hopes,” Dr. Pantilat explained. Sometimes that means he needs to tell patients, “I wish that could happen. I wish I had a treatment that could make your cancer go away, but unfortunately, I don’t. So let’s think about what else we can do to help you.”
Having these difficult discussions matters. The evidence, although limited, indicates that feeling hopeful can improve patients’ well-being and may even boost their cancer outcomes.
One recent study found, for instance, that patients who reported feeling more hopeful also had lower levels of depression and anxiety. Early research also suggests that greater levels of hope may have a hand in reducing inflammation in patients with ovarian cancer and could even improve survival in some patients with advanced cancer.
For Dr. Leiter, while these lessons came early in his career as a palliative care physician, they persist and influence his practice today.
“I know that I could not have prevented Carlos’ death. None of us could have, and none of us could have protected his mother from the unimaginable grief that will stay with her for the rest of her life,” he said. “But I could have made things just a little bit less difficult for her.
“I could have acted as her guide rather than her cross-examiner,” he continued, explaining that he now sees hope as “a generous collaborator” that can coexist with rising creatinine levels, failing livers, and fears about intubation.
“As clinicians, we can always find space to hope with our patients and their families,” he said. “So now, years later when I sit with a terrified and grieving family and they tell me they hope their loved one gets better, I remember Carlos’ mother’s eyes piercing mine ... and I know how to respond: ‘I hope so, too.’ And I do.”
A version of this article appeared on Medscape.com.
CHICAGO — Carlos, a 21-year-old, lay in a hospital bed, barely clinging to life. Following a stem cell transplant for leukemia, Carlos had developed a life-threatening case of graft-vs-host disease.
But Carlos’ mother had faith.
“I have hope things will get better,” she said, via interpreter, to Richard Leiter, MD, a palliative care doctor in training at that time.
“I hope they will,” Dr. Leiter told her.
“I should have stopped there,” said Dr. Leiter, recounting an early-career lesson on hope during the ASCO Voices session at the American Society of Clinical Oncology annual meeting. “But in my eagerness to show my attending and myself that I could handle this conversation, I kept going, mistakenly.”
“But none of us think they will,” Dr. Leiter continued.
Carlos’ mother looked Dr. Leiter in the eye. “You want him to die,” she said.
“I knew, even then, that she was right,” recalled Dr. Leiter, now a palliative care physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School, Boston.
Although there was nothing he could do to save Carlos, Dr. Leiter also couldn’t sit with the extreme suffering. “The pain was too great,” Dr. Leiter said. “I needed her to adopt our narrative that we had done everything we could to help him live, and now, we would do everything we could to help his death be a comfortable one.”
But looking back, Dr. Leiter realized, “How could we have asked her to accept what was fundamentally unacceptable, to comprehend the incomprehensible?”
The Importance of Hope
Alan B. Astrow, MD, said during an ASCO symposium on “The Art and Science of Hope.”
“How we think about hope directly influences patient care,” said Dr. Astrow, chief of hematology and medical oncology at NewYork-Presbyterian Brooklyn Methodist Hospital and a professor of clinical medicine at Weill Cornell Medicine in New York City.
Hope, whatever it turns out to be neurobiologically, is “very much a gift” that underlies human existence, he said.
Physicians have the capacity to restore or shatter a patient’s hopes, and those who come to understand the importance of hope will wish to extend the gift to others, Dr. Astrow said.
Asking patients about their hopes is the “golden question,” Steven Z. Pantilat, MD, said at the symposium. “When you think about the future, what do you hope for?”
Often, the answers reveal not only “things beyond a cure that matter tremendously to the patient but things that we can help with,” said Dr. Pantilat, professor and chief of the Division of Palliative Medicine at the University of California San Francisco.
Dr. Pantilat recalled a patient with advanced pancreatic cancer who wished to see her daughter’s wedding in 10 months. He knew that was unlikely, but the discussion led to another solution.
Her daughter moved the wedding to the ICU.
Hope can persist and uplift even in the darkest of times, and “as clinicians, we need to be in the true hope business,” he said.
While some patients may wish for a cure, others may want more time with family or comfort in the face of suffering. People can “hope for all the things that can still be, despite the fact that there’s a lot of things that can’t,” he said.
However, fear that a patient will hope for a cure, and that the difficult discussions to follow might destroy hope or lead to false hope, sometimes means physicians won’t begin the conversation.
“We want to be honest with our patients — compassionate and kind, but honest — when we talk about their hopes,” Dr. Pantilat explained. Sometimes that means he needs to tell patients, “I wish that could happen. I wish I had a treatment that could make your cancer go away, but unfortunately, I don’t. So let’s think about what else we can do to help you.”
Having these difficult discussions matters. The evidence, although limited, indicates that feeling hopeful can improve patients’ well-being and may even boost their cancer outcomes.
One recent study found, for instance, that patients who reported feeling more hopeful also had lower levels of depression and anxiety. Early research also suggests that greater levels of hope may have a hand in reducing inflammation in patients with ovarian cancer and could even improve survival in some patients with advanced cancer.
For Dr. Leiter, while these lessons came early in his career as a palliative care physician, they persist and influence his practice today.
“I know that I could not have prevented Carlos’ death. None of us could have, and none of us could have protected his mother from the unimaginable grief that will stay with her for the rest of her life,” he said. “But I could have made things just a little bit less difficult for her.
“I could have acted as her guide rather than her cross-examiner,” he continued, explaining that he now sees hope as “a generous collaborator” that can coexist with rising creatinine levels, failing livers, and fears about intubation.
“As clinicians, we can always find space to hope with our patients and their families,” he said. “So now, years later when I sit with a terrified and grieving family and they tell me they hope their loved one gets better, I remember Carlos’ mother’s eyes piercing mine ... and I know how to respond: ‘I hope so, too.’ And I do.”
A version of this article appeared on Medscape.com.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Hope is not only a feature of human cognition but also a measurable and malleable construct that can affect life outcomes,</metaDescription> <articlePDF/> <teaserImage/> <teaser>“How we think about hope directly influences patient care,” according to a professor of clinical medicine at Weill Cornell Medicine in New York City.</teaser> <title>One Patient Changed This Oncologist’s View of Hope. Here’s How.</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>hemn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>skin</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>ob</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>nr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle>Neurology Reviews</journalTitle> <journalFullTitle>Neurology Reviews</journalFullTitle> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>GIHOLD</publicationCode> <pubIssueName>January 2014</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> <publicationData> <publicationCode>endo</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> <term>18</term> <term>21</term> <term>15</term> <term>13</term> <term>23</term> <term>22</term> <term>34</term> </publications> <sections> <term>39313</term> <term canonical="true">53</term> <term>27980</term> </sections> <topics> <term>192</term> <term>198</term> <term>61821</term> <term>59244</term> <term>67020</term> <term>214</term> <term>217</term> <term>221</term> <term>238</term> <term>240</term> <term>242</term> <term>244</term> <term>39570</term> <term>27442</term> <term>256</term> <term>245</term> <term canonical="true">270</term> <term>271</term> <term>278</term> <term>280</term> <term>31848</term> <term>178</term> <term>179</term> <term>181</term> <term>59374</term> <term>37637</term> <term>233</term> <term>243</term> <term>49434</term> <term>250</term> <term>263</term> <term>268</term> <term>228</term> <term>210</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>One Patient Changed This Oncologist’s View of Hope. Here’s How.</title> <deck/> </itemMeta> <itemContent> <p><span class="dateline">CHICAGO</span> — Carlos, a 21-year-old, lay in a hospital bed, barely clinging to life. Following a stem cell transplant for leukemia, Carlos had developed a life-threatening case of graft-vs-host disease.<br/><br/>But Carlos’ mother had faith.<br/><br/>“I have hope things will get better,” she said, via interpreter, to Richard Leiter, MD, a palliative care doctor in training at that time.<br/><br/>“I hope they will,” Dr. Leiter told her.<br/><br/>“I should have stopped there,” said Dr. Leiter, recounting an early-career lesson on hope during the ASCO Voices session at the <span class="Hyperlink"><a href="https://www.medscape.com/viewcollection/37458">American Society of Clinical Oncology</a></span> annual meeting. “But in my eagerness to show my attending and myself that I could handle this conversation, I kept going, mistakenly.”<br/><br/>“But none of us think they will,” Dr. Leiter continued.<br/><br/>Carlos’ mother looked Dr. Leiter in the eye. “You want him to die,” she said.<br/><br/>“I knew, even then, that she was right,” recalled Dr. Leiter, now a palliative care physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital and an assistant professor of medicine at Harvard Medical School, Boston.<br/><br/>Although there was nothing he could do to save Carlos, Dr. Leiter also couldn’t sit with the extreme suffering. “The pain was too great,” Dr. Leiter said. “I needed her to adopt our narrative that we had done everything we could to help him live, and now, we would do everything we could to help his death be a comfortable one.”<br/><br/>But looking back, Dr. Leiter realized, “How could we have asked her to accept what was fundamentally unacceptable, to comprehend the incomprehensible?”<br/><br/></p> <h2>The Importance of Hope</h2> <p><span class="tag metaDescription">Hope is not only a feature of human cognition but also a measurable and malleable construct that can affect life outcomes,</span> Alan B. Astrow, MD, said during an ASCO symposium on “The Art and Science of Hope.”<br/><br/>“How we think about hope directly influences patient care,” said Dr. Astrow, chief of hematology and medical oncology at NewYork-Presbyterian Brooklyn Methodist Hospital and a professor of clinical medicine at Weill Cornell Medicine in New York City.<br/><br/>Hope, whatever it turns out to be neurobiologically, is “very much a gift” that underlies human existence, he said.<br/><br/>Physicians have the capacity to restore or shatter a patient’s hopes, and those who come to understand the importance of hope will wish to extend the gift to others, Dr. Astrow said.<br/><br/>Asking patients about their hopes is the “golden question,” Steven Z. Pantilat, MD, said at the symposium. “When you think about the future, what do you hope for?”<br/><br/>Often, the answers reveal not only “things beyond a cure that matter tremendously to the patient but things that we can help with,” said Dr. Pantilat, professor and chief of the Division of Palliative Medicine at the University of California San Francisco.<br/><br/>Dr. Pantilat recalled a patient with advanced <span class="Hyperlink">pancreatic cancer</span> who wished to see her daughter’s wedding in 10 months. He knew that was unlikely, but the discussion led to another solution.<br/><br/>Her daughter moved the wedding to the ICU.<br/><br/>Hope can persist and uplift even in the darkest of times, and “as clinicians, we need to be in the true hope business,” he said.<br/><br/>While some patients may wish for a cure, others may want more time with family or comfort in the face of suffering. People can “hope for all the things that can still be, despite the fact that there’s a lot of things that can’t,” he said.<br/><br/>However, fear that a patient will hope for a cure, and that the difficult discussions to follow might destroy hope or lead to false hope, sometimes means physicians won’t begin the conversation.<br/><br/>“We want to be honest with our patients — compassionate and kind, but honest — when we talk about their hopes,” Dr. Pantilat explained. Sometimes that means he needs to tell patients, “I wish that could happen. I wish I had a treatment that could make your cancer go away, but unfortunately, I don’t. So let’s think about what else we can do to help you.”<br/><br/>Having these difficult discussions matters. The evidence, although limited, indicates that feeling hopeful can improve patients’ well-being and may even boost their cancer outcomes.<br/><br/>One <span class="Hyperlink"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206604/">recent study</a></span> found, for instance, that patients who reported feeling more hopeful also had lower levels of <span class="Hyperlink">depression</span> and anxiety. Early research also suggests that greater levels of hope may have a hand in <span class="Hyperlink"><a href="https://pubmed.ncbi.nlm.nih.gov/38081436/">reducing inflammation</a></span> in patients with <span class="Hyperlink">ovarian cancer</span> and could even <span class="Hyperlink"><a href="https://pubmed.ncbi.nlm.nih.gov/34613617/">improve survival</a></span> in some patients with advanced cancer.<br/><br/>For Dr. Leiter, while these lessons came early in his career as a palliative care physician, they persist and influence his practice today.<br/><br/>“I know that I could not have prevented Carlos’ death. None of us could have, and none of us could have protected his mother from the unimaginable grief that will stay with her for the rest of her life,” he said. “But I could have made things just a little bit less difficult for her.<br/><br/>“I could have acted as her guide rather than her cross-examiner,” he continued, explaining that he now sees hope as “a generous collaborator” that can coexist with rising <span class="Hyperlink">creatinine</span> levels, failing livers, and fears about intubation.<br/><br/>“As clinicians, we can always find space to hope with our patients and their families,” he said. “So now, years later when I sit with a terrified and grieving family and they tell me they hope their loved one gets better, I remember Carlos’ mother’s eyes piercing mine ... and I know how to respond: ‘I hope so, too.’ And I do.”<br/><br/></p> <p> <em>A version of this article appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/hope-oncology-where-art-and-science-collide-2024a1000ayy">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM ASCO 2024
Is Location a Risk Factor for Early-Onset Cancer?
Early-onset cancer—diagnosed in adults aged ≤ 50 years—is on the rise. Researchers have studied a variety of factors driving the trend, such as type of cancer. However, geographic locality might have as much, if not more, to do with it, according to a study by researchers at Fox Chase Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center research facility.
Using the US Cancer Statistics Public Use Research Database, the researchers collected data from adults aged 20 to 49 years with invasive cancer (excluding in situ cases) diagnosed from 2015 through 2020. They calculated the incidence for each state using the national rate as the reference. Then, they calculated a second set of rates, comparing each state to the US in terms of overall incidence and advanced-stage incidence for all early-onset cancers.
The resulting maps indicated that early-onset cancer cases are not evenly distributed. States with worse-than-national rates are frequently near each other geographically. For instance, the rate of early-onset female breast cancer was worse than the national rate in 17 states, 16 of which were located in the eastern half of the US (Hawaii was the 17th state). Similarly, most states with worse-than-national rates of digestive cancers were located in the eastern half of the US, with a concentration in the South. Rates of male genital cancers were worse than national rates in 18 states, primarily in the eastern half of the country (plus Montana, Nebraska, and Puerto Rico).
Three states in the Southeast, 7 in the Northeast, and Puerto Rico had the highest incidence of lymphohematopoietic cancers. Incidence rates of endocrine cancers were worse than national rates in 25 states, which the researchers found formed “a horizontal core of the country running from east to west,” plus Puerto Rico. Rates of urinary system cancers were worse than national rates in 17 contiguous states, from New Mexico to Pennsylvania.
Rates of female genital cancers were worse than national rates in 16 states, largely in the Midwest and South, plus California and Puerto Rico. Skin cancer, on the other hand, was a great leveler, with worse-than-national rates in 32 states, mostly in the northern portion of the country.
Kentucky and West Virginia had the highest overall and advanced-stage incidence rates of early-onset cancer for all cancer sites combined. They were followed by Arkansas, Connecticut, Florida, Georgia, Iowa, Louisiana, Maine, Missouri, New Jersey, New York, North Carolina, Ohio, and Pennsylvania.
According to the researchers, this study provides the first analysis of age-adjusted rates of early-onset cancer based on state-level population and case numbers. Geographic patterns in early-onset cancer, they suggest, indicate possible similarities that could relate to demographic, socioeconomic, behavioral, or environmental risks. “Focusing prevention efforts on the highest-incidence states for the most prevalent sites may reduce the rate of early-onset cancer nationally.”
Early-onset cancer—diagnosed in adults aged ≤ 50 years—is on the rise. Researchers have studied a variety of factors driving the trend, such as type of cancer. However, geographic locality might have as much, if not more, to do with it, according to a study by researchers at Fox Chase Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center research facility.
Using the US Cancer Statistics Public Use Research Database, the researchers collected data from adults aged 20 to 49 years with invasive cancer (excluding in situ cases) diagnosed from 2015 through 2020. They calculated the incidence for each state using the national rate as the reference. Then, they calculated a second set of rates, comparing each state to the US in terms of overall incidence and advanced-stage incidence for all early-onset cancers.
The resulting maps indicated that early-onset cancer cases are not evenly distributed. States with worse-than-national rates are frequently near each other geographically. For instance, the rate of early-onset female breast cancer was worse than the national rate in 17 states, 16 of which were located in the eastern half of the US (Hawaii was the 17th state). Similarly, most states with worse-than-national rates of digestive cancers were located in the eastern half of the US, with a concentration in the South. Rates of male genital cancers were worse than national rates in 18 states, primarily in the eastern half of the country (plus Montana, Nebraska, and Puerto Rico).
Three states in the Southeast, 7 in the Northeast, and Puerto Rico had the highest incidence of lymphohematopoietic cancers. Incidence rates of endocrine cancers were worse than national rates in 25 states, which the researchers found formed “a horizontal core of the country running from east to west,” plus Puerto Rico. Rates of urinary system cancers were worse than national rates in 17 contiguous states, from New Mexico to Pennsylvania.
Rates of female genital cancers were worse than national rates in 16 states, largely in the Midwest and South, plus California and Puerto Rico. Skin cancer, on the other hand, was a great leveler, with worse-than-national rates in 32 states, mostly in the northern portion of the country.
Kentucky and West Virginia had the highest overall and advanced-stage incidence rates of early-onset cancer for all cancer sites combined. They were followed by Arkansas, Connecticut, Florida, Georgia, Iowa, Louisiana, Maine, Missouri, New Jersey, New York, North Carolina, Ohio, and Pennsylvania.
According to the researchers, this study provides the first analysis of age-adjusted rates of early-onset cancer based on state-level population and case numbers. Geographic patterns in early-onset cancer, they suggest, indicate possible similarities that could relate to demographic, socioeconomic, behavioral, or environmental risks. “Focusing prevention efforts on the highest-incidence states for the most prevalent sites may reduce the rate of early-onset cancer nationally.”
Early-onset cancer—diagnosed in adults aged ≤ 50 years—is on the rise. Researchers have studied a variety of factors driving the trend, such as type of cancer. However, geographic locality might have as much, if not more, to do with it, according to a study by researchers at Fox Chase Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center research facility.
Using the US Cancer Statistics Public Use Research Database, the researchers collected data from adults aged 20 to 49 years with invasive cancer (excluding in situ cases) diagnosed from 2015 through 2020. They calculated the incidence for each state using the national rate as the reference. Then, they calculated a second set of rates, comparing each state to the US in terms of overall incidence and advanced-stage incidence for all early-onset cancers.
The resulting maps indicated that early-onset cancer cases are not evenly distributed. States with worse-than-national rates are frequently near each other geographically. For instance, the rate of early-onset female breast cancer was worse than the national rate in 17 states, 16 of which were located in the eastern half of the US (Hawaii was the 17th state). Similarly, most states with worse-than-national rates of digestive cancers were located in the eastern half of the US, with a concentration in the South. Rates of male genital cancers were worse than national rates in 18 states, primarily in the eastern half of the country (plus Montana, Nebraska, and Puerto Rico).
Three states in the Southeast, 7 in the Northeast, and Puerto Rico had the highest incidence of lymphohematopoietic cancers. Incidence rates of endocrine cancers were worse than national rates in 25 states, which the researchers found formed “a horizontal core of the country running from east to west,” plus Puerto Rico. Rates of urinary system cancers were worse than national rates in 17 contiguous states, from New Mexico to Pennsylvania.
Rates of female genital cancers were worse than national rates in 16 states, largely in the Midwest and South, plus California and Puerto Rico. Skin cancer, on the other hand, was a great leveler, with worse-than-national rates in 32 states, mostly in the northern portion of the country.
Kentucky and West Virginia had the highest overall and advanced-stage incidence rates of early-onset cancer for all cancer sites combined. They were followed by Arkansas, Connecticut, Florida, Georgia, Iowa, Louisiana, Maine, Missouri, New Jersey, New York, North Carolina, Ohio, and Pennsylvania.
According to the researchers, this study provides the first analysis of age-adjusted rates of early-onset cancer based on state-level population and case numbers. Geographic patterns in early-onset cancer, they suggest, indicate possible similarities that could relate to demographic, socioeconomic, behavioral, or environmental risks. “Focusing prevention efforts on the highest-incidence states for the most prevalent sites may reduce the rate of early-onset cancer nationally.”
Surgeons Most Likely to Behave Unprofessionally: Study
Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent study of more than 35,000 physicians.
The research, published on June 6 in JAMA Network Open, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.
Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) Coworker Observation Reporting System (CORS) program, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.
The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.
Why Surgeons?
The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.
Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.
“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”
Types of Unprofessional Behaviors
The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.
In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”
The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.
Impact of Unprofessional Behavior
Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.
Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.
However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.
“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.
The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.
Study Limitations
The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.
A version of this article appeared on Medscape.com.
Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent study of more than 35,000 physicians.
The research, published on June 6 in JAMA Network Open, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.
Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) Coworker Observation Reporting System (CORS) program, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.
The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.
Why Surgeons?
The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.
Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.
“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”
Types of Unprofessional Behaviors
The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.
In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”
The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.
Impact of Unprofessional Behavior
Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.
Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.
However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.
“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.
The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.
Study Limitations
The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.
A version of this article appeared on Medscape.com.
Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent study of more than 35,000 physicians.
The research, published on June 6 in JAMA Network Open, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.
Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) Coworker Observation Reporting System (CORS) program, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.
The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.
Why Surgeons?
The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.
Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.
“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”
Types of Unprofessional Behaviors
The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.
In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”
The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.
Impact of Unprofessional Behavior
Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.
Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.
However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.
“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.
The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.
Study Limitations
The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.
A version of this article appeared on Medscape.com.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings </metaDescription> <articlePDF/> <teaserImage/> <teaser>“When things that are outside the control of the surgeon don’t go well that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”</teaser> <title>Surgeons Most Likely to Behave Unprofessionally: Study</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>card</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>chph</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>mdsurg</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement>2018 Frontline Medical Communications Inc.,</copyrightStatement> </publicationData> <publicationData> <publicationCode>ob</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">5</term> <term>6</term> <term>15</term> <term>21</term> <term>52226</term> <term>23</term> <term>31</term> </publications> <sections> <term canonical="true">39313</term> <term>27970</term> </sections> <topics> <term canonical="true">38029</term> <term>278</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Surgeons Most Likely to Behave Unprofessionally: Study</title> <deck/> </itemMeta> <itemContent> <p><br/><br/>Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent <span class="Hyperlink"><a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2819632">study</a></span> of more than 35,000 physicians.<br/><br/>The research, published on June 6 in <em>JAMA Network Open</em>, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.<br/><br/>Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) <span class="Hyperlink"><a href="https://www.vumc.org/patient-professional-advocacy/cors-program">Coworker Observation Reporting System (CORS) program</a></span>, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.<br/><br/>The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.<br/><br/></p> <h2>Why Surgeons?</h2> <p>The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.<br/><br/>Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.<br/><br/>“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”<br/><br/></p> <h2>Types of Unprofessional Behaviors</h2> <p>The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.<br/><br/>In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”<br/><br/>The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.<br/><br/></p> <h2>Impact of Unprofessional Behavior</h2> <p>Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.<br/><br/>Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.<br/><br/>However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.<br/><br/>“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.<br/><br/>The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.<br/><br/></p> <h2>Study Limitations</h2> <p>The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.<br/><br/></p> <p> <em>A version of this article appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/surgeons-most-likely-behave-unprofessionally-study-2024a1000b7h">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
Surviving to Thriving: Enhancing Quality of Life in Breast Cancer
Advances in breast cancer detection and treatment over the past decades have led to an increase in the number of women diagnosed at earlier stages and successfully treated, ushering in a new era of survivorship.
According to the American Cancer Society, there are currently roughly four million breast cancer survivors in the United States, including those still receiving treatment. The mortality rates for women with breast cancer have been decreasing since 1989, with an overall decline of 42% through 2021.
As the population of breast cancer survivors continues to grow, developing and delivering comprehensive survivorship care is crucial, Thelma Brown told attendees at the American Society of Clinical Oncology (ASCO) 2024 annual meeting. Ms. Brown’s talk was part of an educational session focused on addressing issues among early breast cancer survivors, evolving practices in breast cancer surveillance, and mitigating recurrence risk.
The challenges following breast cancer diagnosis and treatment can be both visible and invisible, said Ms. Brown, a patient advocate and member of the Breast Cancer Working Group at the University of Alabama at Birmingham.
Up to 90% of early breast cancer survivors experience long-term effects from treatment, which often include fatigue, loss of mobility, chronic pain, peripheral neuropathy, lymphedema, and infertility.
Survivors face an elevated risk for depression, anxiety, and fear of recurrence. “Fear of recurrence is a big issue, and it’s almost universal,” she noted.
Cancer treatment is also costly, leading to financial toxicity for many patients, which also “affects adherence to treatment and overall family well-being,” Ms. Brown explained. Survivors may struggle to access financial assistance due to complex eligibility requirements and a lack of awareness about available resources.
There is a need for holistic and coordinated survivorship care that includes management of long-term effects and surveillance for recurrence to help breast cancer survivors to transition from merely surviving to thriving, said Ms. Brown.
Surveilling and Mitigating Recurrence
Surveillance in patients with breast cancer post treatment remains a debated area, particularly when it comes to detecting distant recurrences, David Cescon, MD, PhD, with Princess Margaret Cancer Center, University Health Network, Toronto, said in his talk.
While breast imaging standards are well established, systemic surveillance through imaging and laboratory tests for asymptomatic patients lacks consensus and uniform guidelines, he explained.
Several clinical trials conducted from the late 1980s to the early 2000s showed no survival benefit from intensive surveillance strategies, including imaging and laboratory tests, compared to routine clinical follow-up. Some studies even demonstrated a trend toward harm, given the number of false positives.
These studies formed the basis for guidelines that discourage surveillance among asymptomatic survivors. Currently, no major guideline organization — the National Comprehensive Cancer Network, ASCO, and the European Society for Medical Oncology — recommends routine (nonbreast) radiologic surveillance or laboratory tests for detecting asymptomatic distant breast cancer recurrence, Dr. Cescon said.
Yet, that may change in the coming years, he told attendees.
Ongoing prospective studies will hopefully generate high-quality evidence on the effectiveness of modern surveillance techniques, particularly detection of circulating tumor DNA (ctDNA) and its effect on survival and quality of life, said Dr. Cescon.
These liquid biopsy assays have shown promise in identifying minimal residual disease before radiographic recurrence, he explained. Retrospective studies suggest high prognostic value, with nearly all patients with detectable ctDNA post therapy experiencing recurrence.
He cautioned, however, that while sensitive ctDNA tests exist and have clinical validity in identifying minimal residual disease, “their clinical utility has not yet been demonstrated,” Dr. Cescon said, adding that any surveillance strategy must consider the psychological effect of frequent testing and the potential for false positives or negatives.
The ultimate goal is preventing disease recurrence, said Neil M. Iyengar, MD, with Memorial Sloan Kettering Cancer Center in New York, in his talk on mitigating recurrence risk.
Lifestyle modifications are an important targeted intervention for patients entering the survivorship phase, with a “robust level of evidence” supporting their use to mitigate adverse effects associated with cancer therapy and improve quality of life, he told attendees. Most notably, smoking cessation, healthy dietary patterns, physical activity, and reduced alcohol have been associated with improvements in breast cancer outcomes.
Going forward, it will be important to “understand the antitumor potential of lifestyle modification and how we can wield this type of intervention as a precision tool to potentially enhance the effects of cancer therapy and potentially cancer biology,” said Dr. Iyengar.
Ms. Brown disclosed relationships with AstraZeneca. Dr. Cescon disclosed relationships with AstraZeneca, Gilead Sciences, Daiichi Sankyo Europe GmbH, Eisai, GlaxoSmithKline, and other companies. Dr. Iyengar disclosed relationships with Curio Science, DAVA Oncology, Novartis, Pfizer, and others.
A version of this article first appeared on Medscape.com.
Advances in breast cancer detection and treatment over the past decades have led to an increase in the number of women diagnosed at earlier stages and successfully treated, ushering in a new era of survivorship.
According to the American Cancer Society, there are currently roughly four million breast cancer survivors in the United States, including those still receiving treatment. The mortality rates for women with breast cancer have been decreasing since 1989, with an overall decline of 42% through 2021.
As the population of breast cancer survivors continues to grow, developing and delivering comprehensive survivorship care is crucial, Thelma Brown told attendees at the American Society of Clinical Oncology (ASCO) 2024 annual meeting. Ms. Brown’s talk was part of an educational session focused on addressing issues among early breast cancer survivors, evolving practices in breast cancer surveillance, and mitigating recurrence risk.
The challenges following breast cancer diagnosis and treatment can be both visible and invisible, said Ms. Brown, a patient advocate and member of the Breast Cancer Working Group at the University of Alabama at Birmingham.
Up to 90% of early breast cancer survivors experience long-term effects from treatment, which often include fatigue, loss of mobility, chronic pain, peripheral neuropathy, lymphedema, and infertility.
Survivors face an elevated risk for depression, anxiety, and fear of recurrence. “Fear of recurrence is a big issue, and it’s almost universal,” she noted.
Cancer treatment is also costly, leading to financial toxicity for many patients, which also “affects adherence to treatment and overall family well-being,” Ms. Brown explained. Survivors may struggle to access financial assistance due to complex eligibility requirements and a lack of awareness about available resources.
There is a need for holistic and coordinated survivorship care that includes management of long-term effects and surveillance for recurrence to help breast cancer survivors to transition from merely surviving to thriving, said Ms. Brown.
Surveilling and Mitigating Recurrence
Surveillance in patients with breast cancer post treatment remains a debated area, particularly when it comes to detecting distant recurrences, David Cescon, MD, PhD, with Princess Margaret Cancer Center, University Health Network, Toronto, said in his talk.
While breast imaging standards are well established, systemic surveillance through imaging and laboratory tests for asymptomatic patients lacks consensus and uniform guidelines, he explained.
Several clinical trials conducted from the late 1980s to the early 2000s showed no survival benefit from intensive surveillance strategies, including imaging and laboratory tests, compared to routine clinical follow-up. Some studies even demonstrated a trend toward harm, given the number of false positives.
These studies formed the basis for guidelines that discourage surveillance among asymptomatic survivors. Currently, no major guideline organization — the National Comprehensive Cancer Network, ASCO, and the European Society for Medical Oncology — recommends routine (nonbreast) radiologic surveillance or laboratory tests for detecting asymptomatic distant breast cancer recurrence, Dr. Cescon said.
Yet, that may change in the coming years, he told attendees.
Ongoing prospective studies will hopefully generate high-quality evidence on the effectiveness of modern surveillance techniques, particularly detection of circulating tumor DNA (ctDNA) and its effect on survival and quality of life, said Dr. Cescon.
These liquid biopsy assays have shown promise in identifying minimal residual disease before radiographic recurrence, he explained. Retrospective studies suggest high prognostic value, with nearly all patients with detectable ctDNA post therapy experiencing recurrence.
He cautioned, however, that while sensitive ctDNA tests exist and have clinical validity in identifying minimal residual disease, “their clinical utility has not yet been demonstrated,” Dr. Cescon said, adding that any surveillance strategy must consider the psychological effect of frequent testing and the potential for false positives or negatives.
The ultimate goal is preventing disease recurrence, said Neil M. Iyengar, MD, with Memorial Sloan Kettering Cancer Center in New York, in his talk on mitigating recurrence risk.
Lifestyle modifications are an important targeted intervention for patients entering the survivorship phase, with a “robust level of evidence” supporting their use to mitigate adverse effects associated with cancer therapy and improve quality of life, he told attendees. Most notably, smoking cessation, healthy dietary patterns, physical activity, and reduced alcohol have been associated with improvements in breast cancer outcomes.
Going forward, it will be important to “understand the antitumor potential of lifestyle modification and how we can wield this type of intervention as a precision tool to potentially enhance the effects of cancer therapy and potentially cancer biology,” said Dr. Iyengar.
Ms. Brown disclosed relationships with AstraZeneca. Dr. Cescon disclosed relationships with AstraZeneca, Gilead Sciences, Daiichi Sankyo Europe GmbH, Eisai, GlaxoSmithKline, and other companies. Dr. Iyengar disclosed relationships with Curio Science, DAVA Oncology, Novartis, Pfizer, and others.
A version of this article first appeared on Medscape.com.
Advances in breast cancer detection and treatment over the past decades have led to an increase in the number of women diagnosed at earlier stages and successfully treated, ushering in a new era of survivorship.
According to the American Cancer Society, there are currently roughly four million breast cancer survivors in the United States, including those still receiving treatment. The mortality rates for women with breast cancer have been decreasing since 1989, with an overall decline of 42% through 2021.
As the population of breast cancer survivors continues to grow, developing and delivering comprehensive survivorship care is crucial, Thelma Brown told attendees at the American Society of Clinical Oncology (ASCO) 2024 annual meeting. Ms. Brown’s talk was part of an educational session focused on addressing issues among early breast cancer survivors, evolving practices in breast cancer surveillance, and mitigating recurrence risk.
The challenges following breast cancer diagnosis and treatment can be both visible and invisible, said Ms. Brown, a patient advocate and member of the Breast Cancer Working Group at the University of Alabama at Birmingham.
Up to 90% of early breast cancer survivors experience long-term effects from treatment, which often include fatigue, loss of mobility, chronic pain, peripheral neuropathy, lymphedema, and infertility.
Survivors face an elevated risk for depression, anxiety, and fear of recurrence. “Fear of recurrence is a big issue, and it’s almost universal,” she noted.
Cancer treatment is also costly, leading to financial toxicity for many patients, which also “affects adherence to treatment and overall family well-being,” Ms. Brown explained. Survivors may struggle to access financial assistance due to complex eligibility requirements and a lack of awareness about available resources.
There is a need for holistic and coordinated survivorship care that includes management of long-term effects and surveillance for recurrence to help breast cancer survivors to transition from merely surviving to thriving, said Ms. Brown.
Surveilling and Mitigating Recurrence
Surveillance in patients with breast cancer post treatment remains a debated area, particularly when it comes to detecting distant recurrences, David Cescon, MD, PhD, with Princess Margaret Cancer Center, University Health Network, Toronto, said in his talk.
While breast imaging standards are well established, systemic surveillance through imaging and laboratory tests for asymptomatic patients lacks consensus and uniform guidelines, he explained.
Several clinical trials conducted from the late 1980s to the early 2000s showed no survival benefit from intensive surveillance strategies, including imaging and laboratory tests, compared to routine clinical follow-up. Some studies even demonstrated a trend toward harm, given the number of false positives.
These studies formed the basis for guidelines that discourage surveillance among asymptomatic survivors. Currently, no major guideline organization — the National Comprehensive Cancer Network, ASCO, and the European Society for Medical Oncology — recommends routine (nonbreast) radiologic surveillance or laboratory tests for detecting asymptomatic distant breast cancer recurrence, Dr. Cescon said.
Yet, that may change in the coming years, he told attendees.
Ongoing prospective studies will hopefully generate high-quality evidence on the effectiveness of modern surveillance techniques, particularly detection of circulating tumor DNA (ctDNA) and its effect on survival and quality of life, said Dr. Cescon.
These liquid biopsy assays have shown promise in identifying minimal residual disease before radiographic recurrence, he explained. Retrospective studies suggest high prognostic value, with nearly all patients with detectable ctDNA post therapy experiencing recurrence.
He cautioned, however, that while sensitive ctDNA tests exist and have clinical validity in identifying minimal residual disease, “their clinical utility has not yet been demonstrated,” Dr. Cescon said, adding that any surveillance strategy must consider the psychological effect of frequent testing and the potential for false positives or negatives.
The ultimate goal is preventing disease recurrence, said Neil M. Iyengar, MD, with Memorial Sloan Kettering Cancer Center in New York, in his talk on mitigating recurrence risk.
Lifestyle modifications are an important targeted intervention for patients entering the survivorship phase, with a “robust level of evidence” supporting their use to mitigate adverse effects associated with cancer therapy and improve quality of life, he told attendees. Most notably, smoking cessation, healthy dietary patterns, physical activity, and reduced alcohol have been associated with improvements in breast cancer outcomes.
Going forward, it will be important to “understand the antitumor potential of lifestyle modification and how we can wield this type of intervention as a precision tool to potentially enhance the effects of cancer therapy and potentially cancer biology,” said Dr. Iyengar.
Ms. Brown disclosed relationships with AstraZeneca. Dr. Cescon disclosed relationships with AstraZeneca, Gilead Sciences, Daiichi Sankyo Europe GmbH, Eisai, GlaxoSmithKline, and other companies. Dr. Iyengar disclosed relationships with Curio Science, DAVA Oncology, Novartis, Pfizer, and others.
A version of this article first appeared on Medscape.com.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Advances in breast cancer detection and treatment over the past decades have led to an increase in the number of women diagnosed at earlier stages and successfu</metaDescription> <articlePDF/> <teaserImage/> <teaser>Up to 90% of early breast cancer survivors experience long-term effects from treatment, which often include fatigue, loss of mobility, chronic pain, peripheral neuropathy, lymphedema, infertility, and depression.</teaser> <title>Surviving to Thriving: Enhancing Quality of Life in Breast Cancer</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>ob</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term>15</term> <term>21</term> <term>23</term> <term canonical="true">31</term> </publications> <sections> <term>53</term> <term canonical="true">39313</term> </sections> <topics> <term>270</term> <term canonical="true">192</term> <term>322</term> <term>263</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Surviving to Thriving: Enhancing Quality of Life in Breast Cancer</title> <deck/> </itemMeta> <itemContent> <p>Advances in breast cancer detection and treatment over the past decades have led to an increase in the number of women diagnosed at earlier stages and successfully treated, ushering in a new era of survivorship.</p> <p>According to the American Cancer Society, there are currently roughly four million breast cancer survivors in the United States, including those still receiving treatment. The mortality rates for women with breast cancer have been decreasing since 1989, with an overall decline of 42% through 2021.<br/><br/>As the population of breast cancer survivors continues to grow, developing and delivering comprehensive survivorship care is crucial, Thelma Brown told attendees at the <a href="https://www.medscape.com/viewcollection/37458">American Society of Clinical Oncology (ASCO) 2024 annual meeting</a>. Ms. Brown’s talk was part of an educational session focused on addressing issues among early breast cancer survivors, evolving practices in breast cancer surveillance, and mitigating recurrence risk.<br/><br/>The challenges following breast cancer diagnosis and treatment can be both visible and invisible, said Ms. Brown, a patient advocate and member of the Breast Cancer Working Group at the University of Alabama at Birmingham.<br/><br/>Up to 90% of early breast cancer survivors experience long-term effects from treatment, which often include fatigue, loss of mobility, chronic pain, peripheral neuropathy, lymphedema, and infertility.<br/><br/>Survivors face an elevated risk for depression, anxiety, and fear of recurrence. “Fear of recurrence is a big issue, and it’s almost universal,” she noted.<br/><br/>Cancer treatment is also costly, leading to financial toxicity for many patients, which also “affects adherence to treatment and overall family well-being,” Ms. Brown explained. Survivors may struggle to access financial assistance due to complex eligibility requirements and a lack of awareness about available resources. <br/><br/>There is a need for holistic and coordinated survivorship care that includes management of long-term effects and surveillance for recurrence to help breast cancer survivors to transition from merely surviving to thriving, said Ms. Brown.<br/><br/></p> <h2>Surveilling and Mitigating Recurrence</h2> <p>Surveillance in patients with breast cancer post treatment remains a debated area, particularly when it comes to detecting distant recurrences, David Cescon, MD, PhD, with Princess Margaret Cancer Center, University Health Network, Toronto, said in his talk.</p> <p>While breast imaging standards are well established, systemic surveillance through imaging and laboratory tests for asymptomatic patients lacks consensus and uniform guidelines, he explained.<br/><br/>Several clinical trials conducted from the late 1980s to the early 2000s showed no survival benefit from intensive surveillance strategies, including imaging and laboratory tests, compared to routine clinical follow-up. Some studies even demonstrated a trend toward harm, given the number of false positives.<br/><br/>These studies formed the basis for guidelines that discourage surveillance among asymptomatic survivors. Currently, no major guideline organization — the National Comprehensive Cancer Network, ASCO, and the European Society for Medical Oncology — recommends routine (nonbreast) radiologic surveillance or laboratory tests for detecting asymptomatic distant breast cancer recurrence, Dr. Cescon said.<br/><br/>Yet, that may change in the coming years, he told attendees.<br/><br/>Ongoing prospective studies will hopefully generate high-quality evidence on the effectiveness of modern surveillance techniques, particularly detection of circulating tumor DNA (ctDNA) and its effect on survival and quality of life, said Dr. Cescon.<br/><br/>These liquid biopsy assays have shown promise in identifying minimal residual disease before radiographic recurrence, he explained. Retrospective studies suggest high prognostic value, with nearly all patients with detectable ctDNA post therapy experiencing recurrence. <br/><br/>He cautioned, however, that while sensitive ctDNA tests exist and have clinical validity in identifying minimal residual disease, “their clinical utility has not yet been demonstrated,” Dr. Cescon said, adding that any surveillance strategy must consider the psychological effect of frequent testing and the potential for false positives or negatives.<br/><br/>The ultimate goal is preventing disease recurrence, said Neil M. Iyengar, MD, with Memorial Sloan Kettering Cancer Center in New York, in his talk on mitigating recurrence risk. <br/><br/>Lifestyle modifications are an important targeted intervention for patients entering the survivorship phase, with a “robust level of evidence” supporting their use to mitigate adverse effects associated with cancer therapy and improve quality of life, he told attendees. Most notably, smoking cessation, healthy dietary patterns, physical activity, and reduced alcohol have been associated with improvements in breast cancer outcomes.<br/><br/>Going forward, it will be important to “understand the antitumor potential of lifestyle modification and how we can wield this type of intervention as a precision tool to potentially enhance the effects of cancer therapy and potentially cancer biology,” said Dr. Iyengar.<br/><br/>Ms. Brown disclosed relationships with AstraZeneca. Dr. Cescon disclosed relationships with AstraZeneca, Gilead Sciences, Daiichi Sankyo Europe GmbH, Eisai, GlaxoSmithKline, and other companies. Dr. Iyengar disclosed relationships with Curio Science, DAVA Oncology, Novartis, Pfizer, and others.<span class="end"/></p> <p> <em>A version of this article first appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/surviving-thriving-enhancing-quality-life-breast-cancer-2024a1000b5b">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM ASCO 2024
Beta Thalassemia: Pricey Gene Therapy Hits The Mark
With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations.
Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried.
Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia.
A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.
There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life.
“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”
Anemia Becomes a Lifetime Threat
Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.
Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.)
The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent.
In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”
In addition, the bones become thinner and more brittle, he said, leading to fractures.
Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview.
Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother.
But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor.
Stem Cells Out, Stem Cells In
Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow.
In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians met the media at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated 100,000-plus people in the world who are diagnosed with transfusion-dependent beta thalassemia each year.
Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a 2022 open-label phase 3 study published in the New England Journal of Medicine. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported.
Costly Treatment Seems to Be Cost-Effective
As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as $2.8 million per treatment making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”
The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”
In addition, the independent Institute for Clinical and Economic Review reported in 2022 that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”
Moving Forward, Clinicians Want to Reduce Complications
What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA approved a second gene therapy treatment called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.
In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy.
“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said.
One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”
Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”
Back on Long Island, a Sense of Relief
Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)
As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief.
Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.
With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations.
Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried.
Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia.
A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.
There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life.
“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”
Anemia Becomes a Lifetime Threat
Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.
Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.)
The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent.
In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”
In addition, the bones become thinner and more brittle, he said, leading to fractures.
Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview.
Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother.
But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor.
Stem Cells Out, Stem Cells In
Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow.
In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians met the media at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated 100,000-plus people in the world who are diagnosed with transfusion-dependent beta thalassemia each year.
Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a 2022 open-label phase 3 study published in the New England Journal of Medicine. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported.
Costly Treatment Seems to Be Cost-Effective
As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as $2.8 million per treatment making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”
The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”
In addition, the independent Institute for Clinical and Economic Review reported in 2022 that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”
Moving Forward, Clinicians Want to Reduce Complications
What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA approved a second gene therapy treatment called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.
In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy.
“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said.
One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”
Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”
Back on Long Island, a Sense of Relief
Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)
As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief.
Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.
With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations.
Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried.
Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia.
A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.
There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life.
“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”
Anemia Becomes a Lifetime Threat
Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.
Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.)
The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent.
In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”
In addition, the bones become thinner and more brittle, he said, leading to fractures.
Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview.
Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother.
But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor.
Stem Cells Out, Stem Cells In
Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow.
In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians met the media at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated 100,000-plus people in the world who are diagnosed with transfusion-dependent beta thalassemia each year.
Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a 2022 open-label phase 3 study published in the New England Journal of Medicine. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported.
Costly Treatment Seems to Be Cost-Effective
As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as $2.8 million per treatment making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”
The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”
In addition, the independent Institute for Clinical and Economic Review reported in 2022 that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”
Moving Forward, Clinicians Want to Reduce Complications
What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA approved a second gene therapy treatment called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.
In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy.
“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said.
One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”
Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”
Back on Long Island, a Sense of Relief
Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)
As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief.
Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>When she got the news that her young son had been diagnosed with the rare blood disorder known as transfusion-dependent beta thalassemia, Yusara Ahmed knew the </metaDescription> <articlePDF/> <teaserImage/> <teaser>A landmark new treatment for bleeding disorder banishes the need for transfusions, but it’s exorbitantly expensive.</teaser> <title>Beta Thalassemia: Pricey Gene Therapy Hits The Mark</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>hemn</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">18</term> </publications> <sections> <term canonical="true">27980</term> <term>39313</term> </sections> <topics> <term canonical="true">191</term> <term>195</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Beta Thalassemia: Pricey Gene Therapy Hits The Mark</title> <deck/> </itemMeta> <itemContent> <p> <span class="tag metaDescription">When she got the news that her young son had been diagnosed with the rare blood disorder known as transfusion-dependent beta thalassemia, Yusara Ahmed knew the drill. Her sister had also experienced the inherited condition and needed to undergo regular blood transfusions simply to survive.</span> </p> <p>With luck, maybe Ms. Ahmed’s son could follow in his aunt’s footsteps and get a stem cell transplant from a compatible family donor. But while little Yusuf Saeed has a twin sister of his own, she wasn’t a match. Without another treatment option, he’d face the prospect of a lifetime not only cut short but burdened by multiple monthly transfusions and severe limitations. <br/><br/>Then came glimpses of hope. One of Yusuf’s physicians at Cohen Children’s Medical Center in Long Island, New York, told Yusuf’s mother about a new kind of gene therapy on the horizon. But it took time to get FDA approval. Yusuf grew older, heading toward his teenage years, when regular transfusions would be a huge burden. “He’s turning 5 and 6, and there’s nothing,” Ms. Ahmed recalled, and the family worried. <br/><br/>Finally, the FDA approved the one-time treatment — betibeglogene autotemcel (beti-cel, Zynteglo) in 2022. By January 2024, the hospital was ready to treat Yusuf. At age 8, he became the first patient in the state of New York to undergo gene therapy for beta thalassemia. <br/><br/>A medical team infused Yusuf with his own stem cells, which had been genetically engineered to boost production of hemoglobin and prevent thalassemia’s devastating effects.<br/><br/>There are caveats about the treatment. It’s an extraordinarily expensive therapy that can be performed at only a few institutions. And it’s so brand new that caveats may not even have appeared yet. Yet, for kids like Yusuf, the gene therapy could transform a life. <br/><br/>“We feel like a weight has been lifted,” Ms. Ahmed said in an interview. “It’s something we’ve been waiting for.”<br/><br/></p> <h2>Anemia Becomes a Lifetime Threat </h2> <p>Among all genetic diseases, thalassemia stands alone. It’s the most common condition caused by a single gene, according to Hanny Al-Samkari, MD, a hematologist/clinical investigator at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.</p> <p>Millions of people have the thalassemia trait, especially in southern Europe, the Middle East, southeast Asia, and Africa, Dr. Al-Samkari said. (Yusuf’s parents are from Pakistan.) <br/><br/>The trait, which appears to provide protection against malaria, may cause mild anemia in some cases but is otherwise harmless. However, a child born to parents with the same kind of trait has a high risk of developing alpha thalassemia or beta thalassemia. Like his aunt, Yusuf developed beta thalassemia, which is generally more severe. Yusuf’s bleeding disorder requires him to be transfusion-dependent. <br/><br/>In these patients, the disease disrupts the production of red blood cells in the bone marrow, Dr. Al-Samkari said. Hemoglobin levels can fall to 7 or 8 g/dL, compared with the normal levels of 12-16 g/dL in adults. “They’re chronically anemic, and that low hemoglobin that leads to things you associate with anemia: fatigue, reduced exercise tolerance, mind fog, challenges with work or school, and hypersomnolence.”<br/><br/>In addition, the bones become thinner and more brittle, he said, leading to fractures. <br/><br/>Transfusions are one treatment option, but they’re needed for a lifetime and cause their own problems, such as iron overload. Care of thalassemia patients “becomes quite complex and quite challenging for both families and medical institutions,” Alexis A. Thompson MD, MPH, chief of hematology at Children’s Hospital of Philadelphia, Pennsylvania, said in an interview. <br/><br/>Yusara Ahmed remembers her sister’s endless visits to the hospital after she was diagnosed at age 4. “We were all very traumatized by the hospital environment,” she said. But good news came in 2008, a few years later, when her sister was able to get a stem cell transplant from their brother. <br/><br/>But while stem cell transplants can be curative, most children don’t have a relative who can be a suitable match as a donor, Dr. Thompson said. Now, gene therapy offers another option, by turning a patient into his or her own matched donor. <br/><br/></p> <h2>Stem Cells Out, Stem Cells In</h2> <p>Last year, Yusuf went to Cohen Children’s Medical Center to donate stem cells, which were sent to a laboratory where they were genetically engineered to add copies of the beta-globin gene. Then, in January 2024, the modified stem cells were infused back into Yusuf after he underwent chemotherapy to make room for them in his bone marrow. </p> <p>In April, a bald-headed Yusuf played with toy dinosaurs while his mother and clinicians <span class="Hyperlink"><a href="https://www.northwell.edu/news/the-latest/zynteglo-for-beta-thalassemia-cohen-first-in-ny">met the media</a> </span>at a hospital press conference about his so-far-successful treatment. Early reports about the efficacy of the treatment suggest it may be the proverbial “game changer” for many of the estimated <span class="Hyperlink"><a href="https://www.childrenshospital.org/conditions/thalassemia">100,000-plus people</a> </span>in the world who are diagnosed with transfusion-dependent beta thalassemia each year.<br/><br/>Over a median follow-up of 29.5 months, 20 of 22 patients treated with beti-cel no longer needed transfusions, according to a <span class="Hyperlink"><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2113206">2022 open-label phase 3 study</a> </span>published in the <em>New England Journal of Medicine</em>. Only one adverse event — thrombocytopenia in one patient — was considered both serious and related to the treatment, the industry-funded trial reported. <br/><br/></p> <h2>Costly Treatment Seems to Be Cost-Effective</h2> <p>As of 2022, gene therapy for transfusion-dependent beta thalassemia was listed as <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/982026#:~:text=How much can a company,drugmaker Bluebird Bio%3A %242.8 million.">$2.8 million per treatment</a></span> making it the most expensive single-treatment therapy ever approved in the United States. The price is “extraordinary,” said Dr. Thompson. “For some families, it gives them pause when they first hear about it.”</p> <p>The hospital makes the case to insurers that covering the treatment is cost-effective in the long run, considering the high cost of traditional treatment, she said. “We’ve been very successful in getting coverage.”<br/><br/>In addition, the independent Institute for Clinical and Economic Review <span class="Hyperlink"><a href="https://icer.org/wp-content/uploads/2021/11/ICER_Beta-Thalassemia_Final-Report_071922.pdf">reported in 2022</a> </span>that the treatment will be cost-effective at the “anticipated price of $2.1 million with an 80% payback option for patients who do not achieve and maintain transfusion independence over a 5-year period.”<br/><br/></p> <h2>Moving Forward, Clinicians Want to Reduce Complications</h2> <p>What’s next for transfusion-dependent beta thalassemia treatment? Earlier this year, the FDA <span class="Hyperlink"><a href="https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene">approved a second gene therapy treatment</a> </span>called exagamglogene autotemcel (exa-cel, Casgevy). “We’re just beginning to evaluate individuals for the product, and we intend to make it available for families as well,” Dr. Thompson said.</p> <p>In the bigger picture, she said gene therapy still has room for improvement. The need for chemotherapy is one target. According to her, it causes most of the complications related to gene therapy. <br/><br/>“Chemotherapy is a part of all gene therapies today because one has to make space in the bone marrow in order to have modified stem cells to come back to settle in and grow,” she said. <br/><br/>One strategy is to reduce the number of stem cells that are required for the therapy to work. “That would essentially eliminate the need for chemotherapy,” she said. “We’re not there yet.”<br/><br/>Another goal is to reduce the small risk of complications from gene therapy itself, she said. “Overall, though, this doesn’t detract us at all from being very excited about how well children are doing with the current approach. We’re very enthusiastic and very confident in recommending it to families.”<br/><br/></p> <h2>Back on Long Island, a Sense of Relief </h2> <p>Several months after his treatment, Yusuf is doing well. His hemoglobin levels are increasing, and his bone marrow has grown back, his mother said. He’s being home-schooled for the time being because he still faces a risk of infection. (Ms. Ahmed, a stay-at-home mom, has worked a teacher and mosque volunteer. Her husband runs a consumer electronics business.)</p> <p>As Yusuf gets better, his parents hope they’ll soon be able to take a long trip back home to Pakistan to see relatives. They’ll be able to share their son with family along with something else: a sense of relief. <br/><br/>Dr. Al-Samkari discloses consulting for Agios. Dr. Thompson discloses research for Beam, Bluebird Bio, Editas, Novartis, and Novo Nordisk and consulting for Beam, Bluebird Bio, Editas, Roche, and Vertex.<span class="end"/> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
Engineering Mind Helps Investigator Develop New Cancer Therapies
Dr. Kopetz received the AACR-Waun Ki Hong Award in April. The American Association for Cancer Research (AACR) granted Dr. Kopetz this award to recognize his leadership in the development of novel therapies for patients with BRAF-mutated metastatic colon cancer with poor prognoses, according to a statement from the AACR.
Using molecular profiling and patient-derived xenografts, Dr. Kopetz discovered resistance mechanisms and helped develop approaches to overcome such resistant pathways. His clinical studies analyzing vemurafenib, cetuximab, and irinotecan resulted in new additions to National Comprehensive Cancer Network guidelines and led to the FDA approval of encorafenib plus cetuximab for adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation after prior therapy.
In an interview, Dr. Kopetz shared his unique road to research, how his engineering background influences his work, and why his recent award’s namesake holds special significance to him.
What led to your medical career? Growing up, did you always want to be a doctor?
Dr. Kopetz: My interest initially was in engineering. I grew up in Tennessee from a family of engineers and doctors. In college, I completed a degree in biomedical engineering and electrical engineering.
I had the opportunity to spend one summer at the National Institutes of Health, where I did some research on the structure of the HIV integrase enzyme. It was fundamental basic research with some engineering overlay and required spending 4 days a week working in the dark in a laser lab to analyze the structure of this protein.
One day a week, I was at Georgetown in the HIV/AIDS Clinic, where I collected blood samples and saw HIV/AIDS patients. At the end of the summer, I reflected and realized that I really enjoyed that 1 day out of the week, much more than the other 4. I enjoyed working with patients and interacting with people and thought I’d enjoy the more direct way to help patients, so made a pivot into medicine.
Was the rest of your medical training more traditional?
Dr. Kopetz: My path was a little atypical for a physician scientist. I pursued a medical degree at Johns Hopkins, did internal medicine training at Duke, and then came down to MD Anderson Cancer Center [in Houston, Texas] to do a fellowship in medical oncology, and also obtained a PhD in cancer biology, where I explored mechanisms of resistance to colorectal cancer treatment.
While a traditional physician scientist typically obtains a PhD training in the middle of their medical school, I completed my medical training and then went back to get a PhD. It was a different, nontraditional route.
What is your current role, and what is most inspiring about your work?
Dr. Kopetz: I’ve been at MD Anderson now for 20 years in GI medical oncology. I recently stepped into a new role of helping facilitate translational research at the institution and am now Associate VP for translational research.
I’m excited about where we are in cancer research. I think we’re moving into an era where the amount of information that we can get out of patients and the rapidity in which we can move discoveries is much greater than it has ever been.
Our ability to extract information out of patient biopsies, surgical samples, or even minimally invasive techniques to sample the tumors, such as liquid biopsy, has provided tremendous insights into how tumors are evolving and adapting to therapies and [provides us] opportunities for novel interventions. This opens up ways where I think as a field, we can more readily accelerate our understanding of cancer.
The second component is seeing the rapidity in which we’re now able to execute ideas in the drug development space compared to years before. The pace of new drug development has increased and the innovations in the chemistries have opened up new opportunities and new targets that in the past were considered undruggable. For example, the mutated oncogene, KRAS, was once an extremely challenging therapeutic target and considered undruggable. Mutations in the p53 gene, a tumor suppressor gene, were similarly challenging. I think the convergence of these two trends are going to more rapidly accelerate the advances for our patients. I’m optimistic about the future.
Tell us more about the novel therapies for patients with BRAF-mutated metastatic colon cancer for which you were a lead researcher.
Dr. Kopetz: A lot of [my] work goes back over 10 years, where my [research colleagues and I] were targeting the BRAF V600E oncogene in colorectal cancer melanoma and identified that this worked well in melanoma but was relatively inactive in colorectal cancer despite the same drugs and the same mutations. This led to a recognition of optimal combination drugs that really blocked some of the adaptive feedback that we saw in colorectal cancer. This was a key recognition that these tumors, after you block one node of signaling, rapidly adapt and reactivate the signaling through alternate nodes. This finding really resonated with me with my engineering background, thinking about the networks, signaling networks, and the concepts of feedback regulation of complex systems.
The strategy of blocking the primary oncogene and then blocking the feedback mechanisms that the tumors were utilizing was adopted in colorectal cancer through this work. It took us 10 years to get to an FDA approval with this strategy, but it’s really encouraging that we’re now using this strategy and applying it to the new wave of KRAS inhibitors, where the exact same feedback pathway appears to be at play.
Does your engineering background impact your work today?
Dr. Kopetz: Yes, I’ve found that my engineering training has provided me with complementary skills that can significantly contribute to the development of innovative technologies, computational approaches, and interdisciplinary strategies for advancing cancer research.
Today, I do a lot of work understanding and recognizing complex networks of signaling, and it’s the same network theories that we learned and developed in engineering.
These same theories are now being applied to biology. For example, we are very interested in how tumors adapt over the longer term, over multiple lines of therapy, where there is both clonal selection and clonal evolution occurring with our various standard-of-care therapies. Our hope is that application of engineering principles can help uncover new vulnerabilities in cancer that weren’t evident when we were thinking about CRC as a static tumor.
I understand your recently awarded AACR-Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research has special significance to you. Can you explain why that is?
Dr. Kopetz: This holds a special meaning for me, because Dr. Hong provided a lot of guidance [to me] over the years. He was the division head for cancer medicine at MD Anderson for many years and was instrumental in helping advocate [for me] and advance my career as well as the careers of so many others in and outside of the institution. I considered him a key mentor and sponsor. He helped provide me with guidance early in my oncology career, helping me identify high-value projects and critically evaluate research directions to pursue. He also helped me think about how to balance my research portfolio and provided guidance about how to work well within a team.
It’s really humbling to have a reward bearing his name as somebody who I so deeply respected, and I’m so grateful for the impact he had on my life.
Dr. Kopetz received the AACR-Waun Ki Hong Award in April. The American Association for Cancer Research (AACR) granted Dr. Kopetz this award to recognize his leadership in the development of novel therapies for patients with BRAF-mutated metastatic colon cancer with poor prognoses, according to a statement from the AACR.
Using molecular profiling and patient-derived xenografts, Dr. Kopetz discovered resistance mechanisms and helped develop approaches to overcome such resistant pathways. His clinical studies analyzing vemurafenib, cetuximab, and irinotecan resulted in new additions to National Comprehensive Cancer Network guidelines and led to the FDA approval of encorafenib plus cetuximab for adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation after prior therapy.
In an interview, Dr. Kopetz shared his unique road to research, how his engineering background influences his work, and why his recent award’s namesake holds special significance to him.
What led to your medical career? Growing up, did you always want to be a doctor?
Dr. Kopetz: My interest initially was in engineering. I grew up in Tennessee from a family of engineers and doctors. In college, I completed a degree in biomedical engineering and electrical engineering.
I had the opportunity to spend one summer at the National Institutes of Health, where I did some research on the structure of the HIV integrase enzyme. It was fundamental basic research with some engineering overlay and required spending 4 days a week working in the dark in a laser lab to analyze the structure of this protein.
One day a week, I was at Georgetown in the HIV/AIDS Clinic, where I collected blood samples and saw HIV/AIDS patients. At the end of the summer, I reflected and realized that I really enjoyed that 1 day out of the week, much more than the other 4. I enjoyed working with patients and interacting with people and thought I’d enjoy the more direct way to help patients, so made a pivot into medicine.
Was the rest of your medical training more traditional?
Dr. Kopetz: My path was a little atypical for a physician scientist. I pursued a medical degree at Johns Hopkins, did internal medicine training at Duke, and then came down to MD Anderson Cancer Center [in Houston, Texas] to do a fellowship in medical oncology, and also obtained a PhD in cancer biology, where I explored mechanisms of resistance to colorectal cancer treatment.
While a traditional physician scientist typically obtains a PhD training in the middle of their medical school, I completed my medical training and then went back to get a PhD. It was a different, nontraditional route.
What is your current role, and what is most inspiring about your work?
Dr. Kopetz: I’ve been at MD Anderson now for 20 years in GI medical oncology. I recently stepped into a new role of helping facilitate translational research at the institution and am now Associate VP for translational research.
I’m excited about where we are in cancer research. I think we’re moving into an era where the amount of information that we can get out of patients and the rapidity in which we can move discoveries is much greater than it has ever been.
Our ability to extract information out of patient biopsies, surgical samples, or even minimally invasive techniques to sample the tumors, such as liquid biopsy, has provided tremendous insights into how tumors are evolving and adapting to therapies and [provides us] opportunities for novel interventions. This opens up ways where I think as a field, we can more readily accelerate our understanding of cancer.
The second component is seeing the rapidity in which we’re now able to execute ideas in the drug development space compared to years before. The pace of new drug development has increased and the innovations in the chemistries have opened up new opportunities and new targets that in the past were considered undruggable. For example, the mutated oncogene, KRAS, was once an extremely challenging therapeutic target and considered undruggable. Mutations in the p53 gene, a tumor suppressor gene, were similarly challenging. I think the convergence of these two trends are going to more rapidly accelerate the advances for our patients. I’m optimistic about the future.
Tell us more about the novel therapies for patients with BRAF-mutated metastatic colon cancer for which you were a lead researcher.
Dr. Kopetz: A lot of [my] work goes back over 10 years, where my [research colleagues and I] were targeting the BRAF V600E oncogene in colorectal cancer melanoma and identified that this worked well in melanoma but was relatively inactive in colorectal cancer despite the same drugs and the same mutations. This led to a recognition of optimal combination drugs that really blocked some of the adaptive feedback that we saw in colorectal cancer. This was a key recognition that these tumors, after you block one node of signaling, rapidly adapt and reactivate the signaling through alternate nodes. This finding really resonated with me with my engineering background, thinking about the networks, signaling networks, and the concepts of feedback regulation of complex systems.
The strategy of blocking the primary oncogene and then blocking the feedback mechanisms that the tumors were utilizing was adopted in colorectal cancer through this work. It took us 10 years to get to an FDA approval with this strategy, but it’s really encouraging that we’re now using this strategy and applying it to the new wave of KRAS inhibitors, where the exact same feedback pathway appears to be at play.
Does your engineering background impact your work today?
Dr. Kopetz: Yes, I’ve found that my engineering training has provided me with complementary skills that can significantly contribute to the development of innovative technologies, computational approaches, and interdisciplinary strategies for advancing cancer research.
Today, I do a lot of work understanding and recognizing complex networks of signaling, and it’s the same network theories that we learned and developed in engineering.
These same theories are now being applied to biology. For example, we are very interested in how tumors adapt over the longer term, over multiple lines of therapy, where there is both clonal selection and clonal evolution occurring with our various standard-of-care therapies. Our hope is that application of engineering principles can help uncover new vulnerabilities in cancer that weren’t evident when we were thinking about CRC as a static tumor.
I understand your recently awarded AACR-Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research has special significance to you. Can you explain why that is?
Dr. Kopetz: This holds a special meaning for me, because Dr. Hong provided a lot of guidance [to me] over the years. He was the division head for cancer medicine at MD Anderson for many years and was instrumental in helping advocate [for me] and advance my career as well as the careers of so many others in and outside of the institution. I considered him a key mentor and sponsor. He helped provide me with guidance early in my oncology career, helping me identify high-value projects and critically evaluate research directions to pursue. He also helped me think about how to balance my research portfolio and provided guidance about how to work well within a team.
It’s really humbling to have a reward bearing his name as somebody who I so deeply respected, and I’m so grateful for the impact he had on my life.
Dr. Kopetz received the AACR-Waun Ki Hong Award in April. The American Association for Cancer Research (AACR) granted Dr. Kopetz this award to recognize his leadership in the development of novel therapies for patients with BRAF-mutated metastatic colon cancer with poor prognoses, according to a statement from the AACR.
Using molecular profiling and patient-derived xenografts, Dr. Kopetz discovered resistance mechanisms and helped develop approaches to overcome such resistant pathways. His clinical studies analyzing vemurafenib, cetuximab, and irinotecan resulted in new additions to National Comprehensive Cancer Network guidelines and led to the FDA approval of encorafenib plus cetuximab for adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation after prior therapy.
In an interview, Dr. Kopetz shared his unique road to research, how his engineering background influences his work, and why his recent award’s namesake holds special significance to him.
What led to your medical career? Growing up, did you always want to be a doctor?
Dr. Kopetz: My interest initially was in engineering. I grew up in Tennessee from a family of engineers and doctors. In college, I completed a degree in biomedical engineering and electrical engineering.
I had the opportunity to spend one summer at the National Institutes of Health, where I did some research on the structure of the HIV integrase enzyme. It was fundamental basic research with some engineering overlay and required spending 4 days a week working in the dark in a laser lab to analyze the structure of this protein.
One day a week, I was at Georgetown in the HIV/AIDS Clinic, where I collected blood samples and saw HIV/AIDS patients. At the end of the summer, I reflected and realized that I really enjoyed that 1 day out of the week, much more than the other 4. I enjoyed working with patients and interacting with people and thought I’d enjoy the more direct way to help patients, so made a pivot into medicine.
Was the rest of your medical training more traditional?
Dr. Kopetz: My path was a little atypical for a physician scientist. I pursued a medical degree at Johns Hopkins, did internal medicine training at Duke, and then came down to MD Anderson Cancer Center [in Houston, Texas] to do a fellowship in medical oncology, and also obtained a PhD in cancer biology, where I explored mechanisms of resistance to colorectal cancer treatment.
While a traditional physician scientist typically obtains a PhD training in the middle of their medical school, I completed my medical training and then went back to get a PhD. It was a different, nontraditional route.
What is your current role, and what is most inspiring about your work?
Dr. Kopetz: I’ve been at MD Anderson now for 20 years in GI medical oncology. I recently stepped into a new role of helping facilitate translational research at the institution and am now Associate VP for translational research.
I’m excited about where we are in cancer research. I think we’re moving into an era where the amount of information that we can get out of patients and the rapidity in which we can move discoveries is much greater than it has ever been.
Our ability to extract information out of patient biopsies, surgical samples, or even minimally invasive techniques to sample the tumors, such as liquid biopsy, has provided tremendous insights into how tumors are evolving and adapting to therapies and [provides us] opportunities for novel interventions. This opens up ways where I think as a field, we can more readily accelerate our understanding of cancer.
The second component is seeing the rapidity in which we’re now able to execute ideas in the drug development space compared to years before. The pace of new drug development has increased and the innovations in the chemistries have opened up new opportunities and new targets that in the past were considered undruggable. For example, the mutated oncogene, KRAS, was once an extremely challenging therapeutic target and considered undruggable. Mutations in the p53 gene, a tumor suppressor gene, were similarly challenging. I think the convergence of these two trends are going to more rapidly accelerate the advances for our patients. I’m optimistic about the future.
Tell us more about the novel therapies for patients with BRAF-mutated metastatic colon cancer for which you were a lead researcher.
Dr. Kopetz: A lot of [my] work goes back over 10 years, where my [research colleagues and I] were targeting the BRAF V600E oncogene in colorectal cancer melanoma and identified that this worked well in melanoma but was relatively inactive in colorectal cancer despite the same drugs and the same mutations. This led to a recognition of optimal combination drugs that really blocked some of the adaptive feedback that we saw in colorectal cancer. This was a key recognition that these tumors, after you block one node of signaling, rapidly adapt and reactivate the signaling through alternate nodes. This finding really resonated with me with my engineering background, thinking about the networks, signaling networks, and the concepts of feedback regulation of complex systems.
The strategy of blocking the primary oncogene and then blocking the feedback mechanisms that the tumors were utilizing was adopted in colorectal cancer through this work. It took us 10 years to get to an FDA approval with this strategy, but it’s really encouraging that we’re now using this strategy and applying it to the new wave of KRAS inhibitors, where the exact same feedback pathway appears to be at play.
Does your engineering background impact your work today?
Dr. Kopetz: Yes, I’ve found that my engineering training has provided me with complementary skills that can significantly contribute to the development of innovative technologies, computational approaches, and interdisciplinary strategies for advancing cancer research.
Today, I do a lot of work understanding and recognizing complex networks of signaling, and it’s the same network theories that we learned and developed in engineering.
These same theories are now being applied to biology. For example, we are very interested in how tumors adapt over the longer term, over multiple lines of therapy, where there is both clonal selection and clonal evolution occurring with our various standard-of-care therapies. Our hope is that application of engineering principles can help uncover new vulnerabilities in cancer that weren’t evident when we were thinking about CRC as a static tumor.
I understand your recently awarded AACR-Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research has special significance to you. Can you explain why that is?
Dr. Kopetz: This holds a special meaning for me, because Dr. Hong provided a lot of guidance [to me] over the years. He was the division head for cancer medicine at MD Anderson for many years and was instrumental in helping advocate [for me] and advance my career as well as the careers of so many others in and outside of the institution. I considered him a key mentor and sponsor. He helped provide me with guidance early in my oncology career, helping me identify high-value projects and critically evaluate research directions to pursue. He also helped me think about how to balance my research portfolio and provided guidance about how to work well within a team.
It’s really humbling to have a reward bearing his name as somebody who I so deeply respected, and I’m so grateful for the impact he had on my life.
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>A renowned leader in colorectal cancer research, Scott Kopetz, MD, PhD, was recently honored for helping establish new standards of care for BRAF-mutated metast</metaDescription> <articlePDF/> <teaserImage>301912</teaserImage> <teaser>Leading colorectal cancer investigator Dr. Scott Kopetz discusses his unusual start to medicine and how his engineering background helped him make advances in his research.</teaser> <title>Engineering Mind Helps Investigator Develop New Cancer Therapies</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>GIHOLD</publicationCode> <pubIssueName>January 2014</pubIssueName> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> <journalTitle/> <journalFullTitle/> <copyrightStatement/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> </publications> <sections> <term canonical="true">27980</term> <term>39313</term> </sections> <topics> <term canonical="true">67020</term> <term>213</term> <term>270</term> </topics> <links> <link> <itemClass qcode="ninat:picture"/> <altRep contenttype="image/jpeg">images/24012a13.jpg</altRep> <description role="drol:caption">Dr. Scott Kopetz</description> <description role="drol:credit"/> </link> </links> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Engineering Mind Helps Investigator Develop New Cancer Therapies</title> <deck/> </itemMeta> <itemContent> <p> <span class="tag metaDescription">A renowned leader in colorectal cancer research, Scott Kopetz, MD, PhD, was recently honored for helping establish new standards of care for BRAF-mutated metastatic colorectal cancer.</span> </p> <p>Dr. Kopetz received the <span class="Hyperlink"><a href="https://www.mdanderson.org/newsroom/aacr-md-andersons-scott-kopetz-elizabeth-travis-honored-2024-scientific-achievement-awards.h00-159696756.html">AACR-Waun Ki Hong Award</a></span> in April. The American Association for Cancer Research (AACR) granted Dr. Kopetz this award to recognize his leadership in the development of novel therapies for patients with BRAF-mutated metastatic colon cancer with poor prognoses, according to a statement from the AACR.[[{"fid":"301912","view_mode":"medstat_image_flush_left","fields":{"format":"medstat_image_flush_left","field_file_image_alt_text[und][0][value]":"Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston","field_file_image_credit[und][0][value]":"","field_file_image_caption[und][0][value]":"Dr. Scott Kopetz"},"type":"media","attributes":{"class":"media-element file-medstat_image_flush_left"}}]]<br/><br/>Using molecular profiling and patient-derived xenografts, Dr. Kopetz discovered resistance mechanisms and helped develop approaches to overcome such resistant pathways. His clinical studies analyzing vemurafenib, cetuximab, and irinotecan resulted in new additions to National Comprehensive Cancer Network guidelines and led to the FDA <span class="Hyperlink"><a href="https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-combination-cetuximab-metastatic-colorectal-cancer-braf-v600e-mutation">approval of encorafenib plus cetuximab</a></span> for adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation after prior therapy.<br/><br/>In an interview, Dr. Kopetz shared his unique road to research, how his engineering background influences his work, and why his recent award’s namesake holds special significance to him.<br/><br/></p> <h2>What led to your medical career? Growing up, did you always want to be a doctor?</h2> <p><strong>Dr. Kopetz: </strong>My interest initially was in engineering. I grew up in Tennessee from a family of engineers and doctors. In college, I completed a degree in biomedical engineering and electrical engineering. </p> <p>I had the opportunity to spend one summer at the National Institutes of Health, where I did some research on the structure of the HIV integrase enzyme. It was fundamental basic research with some engineering overlay and required spending 4 days a week working in the dark in a laser lab to analyze the structure of this protein. <br/><br/>One day a week, I was at Georgetown in the HIV/AIDS Clinic, where I collected blood samples and saw HIV/AIDS patients. At the end of the summer, I reflected and realized that I really enjoyed that 1 day out of the week, much more than the other 4. I enjoyed working with patients and interacting with people and thought I’d enjoy the more direct way to help patients, so made a pivot into medicine. <br/><br/></p> <h2>Was the rest of your medical training more traditional?</h2> <p><strong>Dr. Kopetz:</strong> My path was a little atypical for a physician scientist. I pursued a medical degree at Johns Hopkins, did internal medicine training at Duke, and then came down to MD Anderson Cancer Center [in Houston, Texas] to do a fellowship in medical oncology, and also obtained a PhD in cancer biology, where I explored mechanisms of resistance to colorectal cancer treatment.</p> <p>While a traditional physician scientist typically obtains a PhD training in the middle of their medical school, I completed my medical training and then went back to get a PhD. It was a different, nontraditional route. <br/><br/></p> <h2>What is your current role, and what is most inspiring about your work?</h2> <p><strong>Dr. Kopetz: </strong>I’ve been at MD Anderson now for 20 years in GI medical oncology. I recently stepped into a new role of helping facilitate translational research at the institution and am now Associate VP for translational research. </p> <p>I’m excited about where we are in cancer research. I think we’re moving into an era where the amount of information that we can get out of patients and the rapidity in which we can move discoveries is much greater than it has ever been. <br/><br/>Our ability to extract information out of patient biopsies, surgical samples, or even minimally invasive techniques to sample the tumors, such as liquid biopsy, has provided tremendous insights into how tumors are evolving and adapting to therapies and [provides us] opportunities for novel interventions. This opens up ways where I think as a field, we can more readily accelerate our understanding of cancer. <br/><br/>The second component is seeing the rapidity in which we’re now able to execute ideas in the drug development space compared to years before. The pace of new drug development has increased and the innovations in the chemistries have opened up new opportunities and new targets that in the past were considered undruggable. For example, the mutated oncogene, KRAS, was once an extremely challenging therapeutic target and considered undruggable. Mutations in the p53 gene, a tumor suppressor gene, were similarly challenging. I think the convergence of these two trends are going to more rapidly accelerate the advances for our patients. I’m optimistic about the future. <br/><br/></p> <h2>Tell us more about the novel therapies for patients with BRAF-mutated metastatic colon cancer for which you were a lead researcher.</h2> <p><strong>Dr. Kopetz: </strong>A lot of [my] work goes back over 10 years, where my [research colleagues and I] were targeting the BRAF V600E oncogene in colorectal cancer melanoma and identified that this worked well in melanoma but was relatively inactive in colorectal cancer despite the same drugs and the same mutations. This led to a recognition of optimal combination drugs that really blocked some of the adaptive feedback that we saw in colorectal cancer. This was a key recognition that these tumors, after you block one node of signaling, rapidly adapt and reactivate the signaling through alternate nodes. This finding really resonated with me with my engineering background, thinking about the networks, signaling networks, and the concepts of feedback regulation of complex systems. </p> <p>The strategy of blocking the primary oncogene and then blocking the feedback mechanisms that the tumors were utilizing was adopted in colorectal cancer through this work. It took us 10 years to get to an FDA approval with this strategy, but it’s really encouraging that we’re now using this strategy and applying it to the new wave of KRAS inhibitors, where the exact same feedback pathway appears to be at play. <br/><br/></p> <h2>Does your engineering background impact your work today?</h2> <p><strong>Dr. Kopetz: </strong>Yes, I’ve found that my engineering training has provided me with complementary skills that can significantly contribute to the development of innovative technologies, computational approaches, and interdisciplinary strategies for advancing cancer research. </p> <p>Today, I do a lot of work understanding and recognizing complex networks of signaling, and it’s the same network theories that we learned and developed in engineering. <br/><br/>These same theories are now being applied to biology. For example, we are very interested in how tumors adapt over the longer term, over multiple lines of therapy, where there is both clonal selection and clonal evolution occurring with our various standard-of-care therapies. Our hope is that application of engineering principles can help uncover new vulnerabilities in cancer that weren’t evident when we were thinking about CRC as a static tumor.<br/><br/></p> <h2>I understand your recently awarded AACR-Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research has special significance to you. Can you explain why that is?</h2> <p><strong>Dr. Kopetz:</strong> This holds a special meaning for me, because Dr. Hong provided a lot of guidance [to me] over the years. He was the division head for cancer medicine at MD Anderson for many years and was instrumental in helping advocate [for me] and advance my career as well as the careers of so many others in and outside of the institution. I considered him a key mentor and sponsor. He helped provide me with guidance early in my oncology career, helping me identify high-value projects and critically evaluate research directions to pursue. He also helped me think about how to balance my research portfolio and provided guidance about how to work well within a team. </p> <p>It’s really humbling to have a reward bearing his name as somebody who I so deeply respected, and I’m so grateful for the impact he had on my life.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
