Dementia is a devastating condition resulting in major functional, emotional, and financial impact on patients, their caregivers, and families. Approximately 6.5 million Americans are living with Alzheimer disease (AD), the most common of many causes of dementia.¹ The prevalence of AD could increase to 12.7 million Americans by 2050 as the population ages.¹ Studies suggest that dementia, also known as major neurocognitive disorder, is common and underdiagnosed among US veterans, a population with a mean age of 65 years.² During cognitive screening, memory impairment is present in approximately 20% of veterans aged ≥ 75 years who have not been diagnosed with a neurocognitive disorder.³ In addition, veterans might be particularly vulnerable to dementia at an earlier age than the general population because of vascular risk factors and traumatic brain injuries.⁴ These concerns highlight the need for effective dementia care programs at US Department of Veterans Affairs (VA) facilities.

The US health care system often does not adequately address the needs of patients with dementia and their caregivers.⁵ Dementia care requires specialized medical care among collaborating professionals and caregiver and psychosocial interventions and services. However, the US health care system is fragmented with different clinicians and services siloed into separate practices and most dementia care occurring in primary care settings.⁶ Primary care professionals (PCPs) often are uncomfortable diagnosing and managing dementia because of time constraints, lack of expertise and training, and inability to deal with the range of care needs.⁷ PCPs do not identify approximately 42% of their patients with dementia and, when recognized, do not adhere to dementia care guidelines and address caregiver needs.^8-10 Research indicates that caregiver support improves dementia care by teaching behavioral management skills and caregiver coping strategies, allowing patients to stay at home and delay institutionalization.^6,11,12 Clinicians underuse available resources and do not incorporate them in their patient care.¹⁰ These community services benefit patients and caregivers and significantly improve the overall quality of care.⁶

Memory clinics have emerged to address these deficiencies when managing dementia.¹³ The most effective memory clinics maximize the use of specialists with different expertise in dementia care, particularly integrated programs where disciplines function together rather than independently.^1,5,14 Systematic reviews and meta-analyses have documented the effectiveness of collaborative care management programs.^11,12,15 Integration of dementia care management is associated with earlier diagnosis and interventions, decreased functional and cognitive symptom severity, decreased or delayed institutionalization, improved quality of life for patients and caregivers, enhanced overall quality of care and cost-effectiveness, and better integration of community services.^11,12,14-19 In these programs, designating a dementia care manager (DCM) as the patient’s advocate facilitates the integrated structure, increases the quality of care, helps caregivers, facilitates adherence to dementia practice guidelines, and prevents behavioral and psychological symptoms of dementia (BPSD).^{1,6,11,12,20,21}

The best interprofessional model for dementia care might be the transdisciplinary model that includes a DCM. To meet the specific demands of dementia care, there must be a high level of interprofessional collaboration rather than multiple health care professionals (HCPs) delivering care in isolation—an approach that is time consuming and often difficult to implement.²² Whereas multidisciplinary care refers to delivery of parallel services and interdisciplinary care implies a joint formulation, transdisciplinary care aims to maximize integration of HCPs and their specific expertise and contributions through interactions and discussions that deliver focused input to the lead physician. The transdisciplinary model addresses needs that often are missed and can minimize disparities in the quality of dementia care.²³ A DCM is an integral part of our program, facilitating understanding and implementation of the final care plan and providing long-term follow-up and care. We outline a conference-centered transdisciplinary dementia care model with a social worker as DCM (SW-DCM) at our VA medical center.

Program Description

In 2020, the VA Greater Los Angeles Healthcare System (VAGLAHS) in California established a multispecialty clinic dedicated to evaluation and treatment of veterans with memory and neurocognitive disorders and to provide support for their caregivers and families. With the agreement of leadership in mental health, neurology, and geriatrics services on the importance of collaboration for dementia care, the psychiatry and neurology services created a joint Memory and Neurobehavior Clinic, which completed its first 2 years of operation as a full-day program. In recent months, the clinic has scheduled 24 veterans per day, approximately 50% new evaluations and 50% follow-up patients, with wait times of < 2 months. There is a mean of 12 intake or lead physicians who could attend sessions in the morning, afternoon, or both. The general clinic flow consists of a 2-hour intake evaluation of new referrals by the lead physician followed by a clinic conference with transdisciplinary discussion. The DCM then follows up with the veteran/caregiver presenting a final care plan individualized to the veterans, caregivers, and families.

The Memory and Neurobehavior team includes behavioral neurologists, geriatric psychiatrists, neuropsychologists, geriatric fellows, advanced clinical nurses, and social workers who function as the DCM (Table 1).

Procedures

Before the office visit, the coordinating geriatric psychiatrist triages veterans to neurology, psychiatry, or geriatric physicians based on the clinical presentation, history of neurologic signs or symptoms, BPSD or psychiatric history, functional decline, or comorbid medical illnesses. Although veterans often have overlapping concerns, the triage process aims to coordinate the intake evaluations with the most indicated and available specialist with the intention to notify the other specialists during the transdisciplinary conference.

Referrals to the program occur from many sources, notably from primary care (70.8%), mental health (16.7%), and specialty clinics (12.5%). The clinic also receives referrals from the affiliated Veterans Cognitive Assessment and Management Program, which provides dementia evaluation and support via telehealth screening. This VAGLAHS program services a diverse population of veterans: 87% male; 43% aged > 65 years (75% in our clinic); 51% non-Hispanic White; 19% non-Hispanic African American; 16% Hispanic; 4% Asian; and 1% Native American. This population receives care at regional VA medical centers and community-based outpatient clinics over a wide geographic service area.

The initial standardized assessments by intake or lead physicians includes mental status screening with the Montreal Cognitive Assessment (with certified clinicians), the Neurobehavioral Status Examination for a more detailed assessment of cognitive domains, the Columbia-Suicide Severity Rating Scale, the Patient Health Questionnaire for depression screening, and assessment for impairments in instrumental or basic activities of daily living. This initial evaluation aims to apply clinical guidelines and diagnostic criteria for the differential diagnosis of neurocognitive disorders, determine eligibility for cognitive-enhancing medications and techniques, assess for BPSD and the need for nonpharmacologic or pharmacologic interventions, determine functional status, and evaluate the need for supervision, safety concerns, and evidence of neglect or abuse.

As part of its mission, the clinic is charged with implementing the VA Dementia System of Care (DSOC). The stated goals of the DSOC are to provide individualized person-centered dementia care to help veterans experiencing dementia and their caregivers maintain a positive and optimal quality of life and create an environment where VA medical center staff understand the health care needs of veterans with dementia and their caregivers’ role. As part of this initiative, the clinic includes (1) coordination of care through a SW-DCM; (2)

Transdisciplinary Conference

Clinic conferences are held after the veterans are seen. Staff gather to discuss the patient and review management. All team members are present, as well as the head of the clinical clerical staff who can facilitate appointments, make lobby and wait times more bearable for our patients and caregivers, and help manage emergencies. Although this is an in-person conference, the COVID-19 pandemic has allowed us to include staff who screen at remote sites via videoconferencing, similar to other VA programs.²⁴ The Memory and Neurobehavior Clinic has two ≤ 90-minute conferences daily. The lead physicians and their senior attendings present the new intake evaluations (4-6 at each conference session) with a preliminary formulation and questions for discussion. The moderator solicits contributions from the different disciplines, going from one to the next and recording their responses for each veteran. Further specialists are available for consultation through the conference mechanism if necessary. The final assessment is reviewed, a diagnosis is established, and a tailored, individualized care plan for adjusting or optimizing the veteran’s care is presented to the lead physician who makes the final determination. At the close of the conference, the team’s discussion is recorded along with the lead physician’s original detailed intake evaluation. Currently, the records go into the Computerized Patient Record System, but we are making plans to transition to Cerner as it is implemented.

During the discussion, team members review several areas of consideration. If there is neuroimaging, neurologists review the images projected on a large computer screen. Team members also will assess for the need to obtain biomarker studies, such as blood, cerebrospinal fluid, or positron emission tomography. Psychiatrists could review management of BPSD and use of psychotropic agents, and neuropsychologists might consider the need for more precise cognitive testing and whether a capacity assessment is indicated. Social work might bring up the need for a durable power of attorney as well as applicable caregiver and community resources. Geriatric medicine and nursing could provide input into medical management and care and the ability of veterans and caregivers to follow the prescribed regimen. Further areas of discussion include driving safety and restrictions on driving (as required in California) and the presence of guns in the home. Finally, brief education is provided in short 10-to-15-minute lectures covering pertinent topics so staff remain up-to-date in this changing field.

Postconference Continuity

After the conference, the SW-DCM continues to provide support throughout the disease course, helping veterans and their caregivers understand and follow through on the team’s recommendations. The SW-DCM, who is experienced and trained in case management, forms an ongoing relationship with the veterans and their caregivers and remains an advocate for their care. The SW-DCM communicates the final plan by phone and, when necessary, requests the lead physician to call to clarify any poorly understood or technical aspects of the care plan. About 50% of our veterans—primarily those who do not have a neurocognitive disorder or have mild cognitive impairment—return to their PCPs with our care plan consultation; about 25% are already enrolled in geriatric and other programs with long-term follow-up. The assigned SW-DCM follows up with the remaining veterans and caregivers regularly by phone, facilitates communication with other team members, and endeavors to assure postvisit continuity of care and support during advancing stages of the disease. In addition, the SW-DCM can provide supportive counseling and psychotherapy for stressed caregivers, refer to support groups and cognitive rehabilitation programs, and help develop long-term goals and consideration for supervised living environments. The nurse specialist participates with follow-up calls regarding medications and scheduled tests and appointments, clearing up confusion about instructions, avoiding medication errors, and providing education in dementia care. Both social worker and nurse are present throughout the week, reachable by phone, and, in turn, able to contact the clinic physicians for veterans’ needs.

Discussion

Because of the heterogenous medical and psychosocial needs of veterans with dementia and their caregivers, a transdisciplinary team with a dedicated DCM might offer the most effective and efficient model for dementia care. We present a transdisciplinary program that incorporates dementia specialists in a single evaluation by maximizing their time through a conference-centered program. Our program involves neurologists, psychiatrists, geriatricians, psychologists, nurses, and social workers collaborating and communicating to enact effective dementia care. It further meets the goals of the VA-DSOC in implementing individualized patient and caregiver care.

This transdisciplinary model addresses a number of issues, starting with the differential diagnosis of underlying neurologic conditions. Within the transdisciplinary team, the neurologist can provide specific insights into any neurologic findings and illnesses, such as Alzheimer disease and other neurodegenerative dementias, vascular dementia syndromes, normal pressure hydrocephalus, Creutzfeldt-Jakob disease, neurosyphilis, and others. Most veterans with dementia experience BPSD at some point during of their illness. The psychiatrists on the transdisciplinary team can maximize management of BPSD with nonpharmacologic interventions and the fewest and least aversive psychoactive medications. Our program also addresses the need for more precise cognitive evaluation. Neuropsychologists are present and available for administrating neuropsychologic tests and interpreting cognitive performance and any earlier neuropsychologic testing. This model also cares for the caregivers and assesses their needs. The social worker—as well as other members of the team—can provide caregivers with strategies for coping with disruptive and other behaviors related to dementia, counsel them on how to manage the veteran’s functional decline, and aid in establishing a safe living space. Because the social worker serves as a DCM, these coping and adjustment questions occupy significant clinical attention between appointments. This transdisciplinary model places the patient’s illness in the context of their functional status, diagnoses, and medications. The team geriatrician and the nurse specialist are indispensable resources. The clinic conference provides a teaching venue for staff and trainees and a mechanism to discuss new developments in dementia care, such as the increasing need to assess individuals with mild cognitive impairment.²⁵ This model depends on the DCM’s invaluable role in ensuring implementation of the dementia care plan and continuity of care.

Conclusions

We describe effective dementia care with a transdisciplinary team in a conference setting and with the participation of a dedicated DCM.⁵ To date, this program appears to be an efficient, sustainable application of the limited resources allocated to dementia care. Nevertheless, we are collecting data to compare with performance measures, track use, and assess the programs effects on continuity of care. We look forward to presenting metrics from our program that show improvement in the health care for veterans experiencing a devastating and increasingly common disorder.

Dementia is a devastating condition resulting in major functional, emotional, and financial impact on patients, their caregivers, and families. Approximately 6.5 million Americans are living with Alzheimer disease (AD), the most common of many causes of dementia.¹ The prevalence of AD could increase to 12.7 million Americans by 2050 as the population ages.¹ Studies suggest that dementia, also known as major neurocognitive disorder, is common and underdiagnosed among US veterans, a population with a mean age of 65 years.² During cognitive screening, memory impairment is present in approximately 20% of veterans aged ≥ 75 years who have not been diagnosed with a neurocognitive disorder.³ In addition, veterans might be particularly vulnerable to dementia at an earlier age than the general population because of vascular risk factors and traumatic brain injuries.⁴ These concerns highlight the need for effective dementia care programs at US Department of Veterans Affairs (VA) facilities.

The US health care system often does not adequately address the needs of patients with dementia and their caregivers.⁵ Dementia care requires specialized medical care among collaborating professionals and caregiver and psychosocial interventions and services. However, the US health care system is fragmented with different clinicians and services siloed into separate practices and most dementia care occurring in primary care settings.⁶ Primary care professionals (PCPs) often are uncomfortable diagnosing and managing dementia because of time constraints, lack of expertise and training, and inability to deal with the range of care needs.⁷ PCPs do not identify approximately 42% of their patients with dementia and, when recognized, do not adhere to dementia care guidelines and address caregiver needs.^8-10 Research indicates that caregiver support improves dementia care by teaching behavioral management skills and caregiver coping strategies, allowing patients to stay at home and delay institutionalization.^6,11,12 Clinicians underuse available resources and do not incorporate them in their patient care.¹⁰ These community services benefit patients and caregivers and significantly improve the overall quality of care.⁶

Memory clinics have emerged to address these deficiencies when managing dementia.¹³ The most effective memory clinics maximize the use of specialists with different expertise in dementia care, particularly integrated programs where disciplines function together rather than independently.^1,5,14 Systematic reviews and meta-analyses have documented the effectiveness of collaborative care management programs.^11,12,15 Integration of dementia care management is associated with earlier diagnosis and interventions, decreased functional and cognitive symptom severity, decreased or delayed institutionalization, improved quality of life for patients and caregivers, enhanced overall quality of care and cost-effectiveness, and better integration of community services.^11,12,14-19 In these programs, designating a dementia care manager (DCM) as the patient’s advocate facilitates the integrated structure, increases the quality of care, helps caregivers, facilitates adherence to dementia practice guidelines, and prevents behavioral and psychological symptoms of dementia (BPSD).^{1,6,11,12,20,21}

The best interprofessional model for dementia care might be the transdisciplinary model that includes a DCM. To meet the specific demands of dementia care, there must be a high level of interprofessional collaboration rather than multiple health care professionals (HCPs) delivering care in isolation—an approach that is time consuming and often difficult to implement.²² Whereas multidisciplinary care refers to delivery of parallel services and interdisciplinary care implies a joint formulation, transdisciplinary care aims to maximize integration of HCPs and their specific expertise and contributions through interactions and discussions that deliver focused input to the lead physician. The transdisciplinary model addresses needs that often are missed and can minimize disparities in the quality of dementia care.²³ A DCM is an integral part of our program, facilitating understanding and implementation of the final care plan and providing long-term follow-up and care. We outline a conference-centered transdisciplinary dementia care model with a social worker as DCM (SW-DCM) at our VA medical center.

Program Description

In 2020, the VA Greater Los Angeles Healthcare System (VAGLAHS) in California established a multispecialty clinic dedicated to evaluation and treatment of veterans with memory and neurocognitive disorders and to provide support for their caregivers and families. With the agreement of leadership in mental health, neurology, and geriatrics services on the importance of collaboration for dementia care, the psychiatry and neurology services created a joint Memory and Neurobehavior Clinic, which completed its first 2 years of operation as a full-day program. In recent months, the clinic has scheduled 24 veterans per day, approximately 50% new evaluations and 50% follow-up patients, with wait times of < 2 months. There is a mean of 12 intake or lead physicians who could attend sessions in the morning, afternoon, or both. The general clinic flow consists of a 2-hour intake evaluation of new referrals by the lead physician followed by a clinic conference with transdisciplinary discussion. The DCM then follows up with the veteran/caregiver presenting a final care plan individualized to the veterans, caregivers, and families.

The Memory and Neurobehavior team includes behavioral neurologists, geriatric psychiatrists, neuropsychologists, geriatric fellows, advanced clinical nurses, and social workers who function as the DCM (Table 1).

Procedures

Before the office visit, the coordinating geriatric psychiatrist triages veterans to neurology, psychiatry, or geriatric physicians based on the clinical presentation, history of neurologic signs or symptoms, BPSD or psychiatric history, functional decline, or comorbid medical illnesses. Although veterans often have overlapping concerns, the triage process aims to coordinate the intake evaluations with the most indicated and available specialist with the intention to notify the other specialists during the transdisciplinary conference.

Referrals to the program occur from many sources, notably from primary care (70.8%), mental health (16.7%), and specialty clinics (12.5%). The clinic also receives referrals from the affiliated Veterans Cognitive Assessment and Management Program, which provides dementia evaluation and support via telehealth screening. This VAGLAHS program services a diverse population of veterans: 87% male; 43% aged > 65 years (75% in our clinic); 51% non-Hispanic White; 19% non-Hispanic African American; 16% Hispanic; 4% Asian; and 1% Native American. This population receives care at regional VA medical centers and community-based outpatient clinics over a wide geographic service area.

The initial standardized assessments by intake or lead physicians includes mental status screening with the Montreal Cognitive Assessment (with certified clinicians), the Neurobehavioral Status Examination for a more detailed assessment of cognitive domains, the Columbia-Suicide Severity Rating Scale, the Patient Health Questionnaire for depression screening, and assessment for impairments in instrumental or basic activities of daily living. This initial evaluation aims to apply clinical guidelines and diagnostic criteria for the differential diagnosis of neurocognitive disorders, determine eligibility for cognitive-enhancing medications and techniques, assess for BPSD and the need for nonpharmacologic or pharmacologic interventions, determine functional status, and evaluate the need for supervision, safety concerns, and evidence of neglect or abuse.

As part of its mission, the clinic is charged with implementing the VA Dementia System of Care (DSOC). The stated goals of the DSOC are to provide individualized person-centered dementia care to help veterans experiencing dementia and their caregivers maintain a positive and optimal quality of life and create an environment where VA medical center staff understand the health care needs of veterans with dementia and their caregivers’ role. As part of this initiative, the clinic includes (1) coordination of care through a SW-DCM; (2)

Transdisciplinary Conference

Clinic conferences are held after the veterans are seen. Staff gather to discuss the patient and review management. All team members are present, as well as the head of the clinical clerical staff who can facilitate appointments, make lobby and wait times more bearable for our patients and caregivers, and help manage emergencies. Although this is an in-person conference, the COVID-19 pandemic has allowed us to include staff who screen at remote sites via videoconferencing, similar to other VA programs.²⁴ The Memory and Neurobehavior Clinic has two ≤ 90-minute conferences daily. The lead physicians and their senior attendings present the new intake evaluations (4-6 at each conference session) with a preliminary formulation and questions for discussion. The moderator solicits contributions from the different disciplines, going from one to the next and recording their responses for each veteran. Further specialists are available for consultation through the conference mechanism if necessary. The final assessment is reviewed, a diagnosis is established, and a tailored, individualized care plan for adjusting or optimizing the veteran’s care is presented to the lead physician who makes the final determination. At the close of the conference, the team’s discussion is recorded along with the lead physician’s original detailed intake evaluation. Currently, the records go into the Computerized Patient Record System, but we are making plans to transition to Cerner as it is implemented.

During the discussion, team members review several areas of consideration. If there is neuroimaging, neurologists review the images projected on a large computer screen. Team members also will assess for the need to obtain biomarker studies, such as blood, cerebrospinal fluid, or positron emission tomography. Psychiatrists could review management of BPSD and use of psychotropic agents, and neuropsychologists might consider the need for more precise cognitive testing and whether a capacity assessment is indicated. Social work might bring up the need for a durable power of attorney as well as applicable caregiver and community resources. Geriatric medicine and nursing could provide input into medical management and care and the ability of veterans and caregivers to follow the prescribed regimen. Further areas of discussion include driving safety and restrictions on driving (as required in California) and the presence of guns in the home. Finally, brief education is provided in short 10-to-15-minute lectures covering pertinent topics so staff remain up-to-date in this changing field.

Postconference Continuity

After the conference, the SW-DCM continues to provide support throughout the disease course, helping veterans and their caregivers understand and follow through on the team’s recommendations. The SW-DCM, who is experienced and trained in case management, forms an ongoing relationship with the veterans and their caregivers and remains an advocate for their care. The SW-DCM communicates the final plan by phone and, when necessary, requests the lead physician to call to clarify any poorly understood or technical aspects of the care plan. About 50% of our veterans—primarily those who do not have a neurocognitive disorder or have mild cognitive impairment—return to their PCPs with our care plan consultation; about 25% are already enrolled in geriatric and other programs with long-term follow-up. The assigned SW-DCM follows up with the remaining veterans and caregivers regularly by phone, facilitates communication with other team members, and endeavors to assure postvisit continuity of care and support during advancing stages of the disease. In addition, the SW-DCM can provide supportive counseling and psychotherapy for stressed caregivers, refer to support groups and cognitive rehabilitation programs, and help develop long-term goals and consideration for supervised living environments. The nurse specialist participates with follow-up calls regarding medications and scheduled tests and appointments, clearing up confusion about instructions, avoiding medication errors, and providing education in dementia care. Both social worker and nurse are present throughout the week, reachable by phone, and, in turn, able to contact the clinic physicians for veterans’ needs.

Discussion

Because of the heterogenous medical and psychosocial needs of veterans with dementia and their caregivers, a transdisciplinary team with a dedicated DCM might offer the most effective and efficient model for dementia care. We present a transdisciplinary program that incorporates dementia specialists in a single evaluation by maximizing their time through a conference-centered program. Our program involves neurologists, psychiatrists, geriatricians, psychologists, nurses, and social workers collaborating and communicating to enact effective dementia care. It further meets the goals of the VA-DSOC in implementing individualized patient and caregiver care.

This transdisciplinary model addresses a number of issues, starting with the differential diagnosis of underlying neurologic conditions. Within the transdisciplinary team, the neurologist can provide specific insights into any neurologic findings and illnesses, such as Alzheimer disease and other neurodegenerative dementias, vascular dementia syndromes, normal pressure hydrocephalus, Creutzfeldt-Jakob disease, neurosyphilis, and others. Most veterans with dementia experience BPSD at some point during of their illness. The psychiatrists on the transdisciplinary team can maximize management of BPSD with nonpharmacologic interventions and the fewest and least aversive psychoactive medications. Our program also addresses the need for more precise cognitive evaluation. Neuropsychologists are present and available for administrating neuropsychologic tests and interpreting cognitive performance and any earlier neuropsychologic testing. This model also cares for the caregivers and assesses their needs. The social worker—as well as other members of the team—can provide caregivers with strategies for coping with disruptive and other behaviors related to dementia, counsel them on how to manage the veteran’s functional decline, and aid in establishing a safe living space. Because the social worker serves as a DCM, these coping and adjustment questions occupy significant clinical attention between appointments. This transdisciplinary model places the patient’s illness in the context of their functional status, diagnoses, and medications. The team geriatrician and the nurse specialist are indispensable resources. The clinic conference provides a teaching venue for staff and trainees and a mechanism to discuss new developments in dementia care, such as the increasing need to assess individuals with mild cognitive impairment.²⁵ This model depends on the DCM’s invaluable role in ensuring implementation of the dementia care plan and continuity of care.

Conclusions

We describe effective dementia care with a transdisciplinary team in a conference setting and with the participation of a dedicated DCM.⁵ To date, this program appears to be an efficient, sustainable application of the limited resources allocated to dementia care. Nevertheless, we are collecting data to compare with performance measures, track use, and assess the programs effects on continuity of care. We look forward to presenting metrics from our program that show improvement in the health care for veterans experiencing a devastating and increasingly common disorder.

Dementia is a devastating condition resulting in major functional, emotional, and financial impact on patients, their caregivers, and families. Approximately 6.5 million Americans are living with Alzheimer disease (AD), the most common of many causes of dementia.¹ The prevalence of AD could increase to 12.7 million Americans by 2050 as the population ages.¹ Studies suggest that dementia, also known as major neurocognitive disorder, is common and underdiagnosed among US veterans, a population with a mean age of 65 years.² During cognitive screening, memory impairment is present in approximately 20% of veterans aged ≥ 75 years who have not been diagnosed with a neurocognitive disorder.³ In addition, veterans might be particularly vulnerable to dementia at an earlier age than the general population because of vascular risk factors and traumatic brain injuries.⁴ These concerns highlight the need for effective dementia care programs at US Department of Veterans Affairs (VA) facilities.

The US health care system often does not adequately address the needs of patients with dementia and their caregivers.⁵ Dementia care requires specialized medical care among collaborating professionals and caregiver and psychosocial interventions and services. However, the US health care system is fragmented with different clinicians and services siloed into separate practices and most dementia care occurring in primary care settings.⁶ Primary care professionals (PCPs) often are uncomfortable diagnosing and managing dementia because of time constraints, lack of expertise and training, and inability to deal with the range of care needs.⁷ PCPs do not identify approximately 42% of their patients with dementia and, when recognized, do not adhere to dementia care guidelines and address caregiver needs.^8-10 Research indicates that caregiver support improves dementia care by teaching behavioral management skills and caregiver coping strategies, allowing patients to stay at home and delay institutionalization.^6,11,12 Clinicians underuse available resources and do not incorporate them in their patient care.¹⁰ These community services benefit patients and caregivers and significantly improve the overall quality of care.⁶

Memory clinics have emerged to address these deficiencies when managing dementia.¹³ The most effective memory clinics maximize the use of specialists with different expertise in dementia care, particularly integrated programs where disciplines function together rather than independently.^1,5,14 Systematic reviews and meta-analyses have documented the effectiveness of collaborative care management programs.^11,12,15 Integration of dementia care management is associated with earlier diagnosis and interventions, decreased functional and cognitive symptom severity, decreased or delayed institutionalization, improved quality of life for patients and caregivers, enhanced overall quality of care and cost-effectiveness, and better integration of community services.^11,12,14-19 In these programs, designating a dementia care manager (DCM) as the patient’s advocate facilitates the integrated structure, increases the quality of care, helps caregivers, facilitates adherence to dementia practice guidelines, and prevents behavioral and psychological symptoms of dementia (BPSD).^{1,6,11,12,20,21}

The best interprofessional model for dementia care might be the transdisciplinary model that includes a DCM. To meet the specific demands of dementia care, there must be a high level of interprofessional collaboration rather than multiple health care professionals (HCPs) delivering care in isolation—an approach that is time consuming and often difficult to implement.²² Whereas multidisciplinary care refers to delivery of parallel services and interdisciplinary care implies a joint formulation, transdisciplinary care aims to maximize integration of HCPs and their specific expertise and contributions through interactions and discussions that deliver focused input to the lead physician. The transdisciplinary model addresses needs that often are missed and can minimize disparities in the quality of dementia care.²³ A DCM is an integral part of our program, facilitating understanding and implementation of the final care plan and providing long-term follow-up and care. We outline a conference-centered transdisciplinary dementia care model with a social worker as DCM (SW-DCM) at our VA medical center.

Program Description

In 2020, the VA Greater Los Angeles Healthcare System (VAGLAHS) in California established a multispecialty clinic dedicated to evaluation and treatment of veterans with memory and neurocognitive disorders and to provide support for their caregivers and families. With the agreement of leadership in mental health, neurology, and geriatrics services on the importance of collaboration for dementia care, the psychiatry and neurology services created a joint Memory and Neurobehavior Clinic, which completed its first 2 years of operation as a full-day program. In recent months, the clinic has scheduled 24 veterans per day, approximately 50% new evaluations and 50% follow-up patients, with wait times of < 2 months. There is a mean of 12 intake or lead physicians who could attend sessions in the morning, afternoon, or both. The general clinic flow consists of a 2-hour intake evaluation of new referrals by the lead physician followed by a clinic conference with transdisciplinary discussion. The DCM then follows up with the veteran/caregiver presenting a final care plan individualized to the veterans, caregivers, and families.

The Memory and Neurobehavior team includes behavioral neurologists, geriatric psychiatrists, neuropsychologists, geriatric fellows, advanced clinical nurses, and social workers who function as the DCM (Table 1).

Procedures

Before the office visit, the coordinating geriatric psychiatrist triages veterans to neurology, psychiatry, or geriatric physicians based on the clinical presentation, history of neurologic signs or symptoms, BPSD or psychiatric history, functional decline, or comorbid medical illnesses. Although veterans often have overlapping concerns, the triage process aims to coordinate the intake evaluations with the most indicated and available specialist with the intention to notify the other specialists during the transdisciplinary conference.

Referrals to the program occur from many sources, notably from primary care (70.8%), mental health (16.7%), and specialty clinics (12.5%). The clinic also receives referrals from the affiliated Veterans Cognitive Assessment and Management Program, which provides dementia evaluation and support via telehealth screening. This VAGLAHS program services a diverse population of veterans: 87% male; 43% aged > 65 years (75% in our clinic); 51% non-Hispanic White; 19% non-Hispanic African American; 16% Hispanic; 4% Asian; and 1% Native American. This population receives care at regional VA medical centers and community-based outpatient clinics over a wide geographic service area.

The initial standardized assessments by intake or lead physicians includes mental status screening with the Montreal Cognitive Assessment (with certified clinicians), the Neurobehavioral Status Examination for a more detailed assessment of cognitive domains, the Columbia-Suicide Severity Rating Scale, the Patient Health Questionnaire for depression screening, and assessment for impairments in instrumental or basic activities of daily living. This initial evaluation aims to apply clinical guidelines and diagnostic criteria for the differential diagnosis of neurocognitive disorders, determine eligibility for cognitive-enhancing medications and techniques, assess for BPSD and the need for nonpharmacologic or pharmacologic interventions, determine functional status, and evaluate the need for supervision, safety concerns, and evidence of neglect or abuse.

As part of its mission, the clinic is charged with implementing the VA Dementia System of Care (DSOC). The stated goals of the DSOC are to provide individualized person-centered dementia care to help veterans experiencing dementia and their caregivers maintain a positive and optimal quality of life and create an environment where VA medical center staff understand the health care needs of veterans with dementia and their caregivers’ role. As part of this initiative, the clinic includes (1) coordination of care through a SW-DCM; (2)

Transdisciplinary Conference

Clinic conferences are held after the veterans are seen. Staff gather to discuss the patient and review management. All team members are present, as well as the head of the clinical clerical staff who can facilitate appointments, make lobby and wait times more bearable for our patients and caregivers, and help manage emergencies. Although this is an in-person conference, the COVID-19 pandemic has allowed us to include staff who screen at remote sites via videoconferencing, similar to other VA programs.²⁴ The Memory and Neurobehavior Clinic has two ≤ 90-minute conferences daily. The lead physicians and their senior attendings present the new intake evaluations (4-6 at each conference session) with a preliminary formulation and questions for discussion. The moderator solicits contributions from the different disciplines, going from one to the next and recording their responses for each veteran. Further specialists are available for consultation through the conference mechanism if necessary. The final assessment is reviewed, a diagnosis is established, and a tailored, individualized care plan for adjusting or optimizing the veteran’s care is presented to the lead physician who makes the final determination. At the close of the conference, the team’s discussion is recorded along with the lead physician’s original detailed intake evaluation. Currently, the records go into the Computerized Patient Record System, but we are making plans to transition to Cerner as it is implemented.

During the discussion, team members review several areas of consideration. If there is neuroimaging, neurologists review the images projected on a large computer screen. Team members also will assess for the need to obtain biomarker studies, such as blood, cerebrospinal fluid, or positron emission tomography. Psychiatrists could review management of BPSD and use of psychotropic agents, and neuropsychologists might consider the need for more precise cognitive testing and whether a capacity assessment is indicated. Social work might bring up the need for a durable power of attorney as well as applicable caregiver and community resources. Geriatric medicine and nursing could provide input into medical management and care and the ability of veterans and caregivers to follow the prescribed regimen. Further areas of discussion include driving safety and restrictions on driving (as required in California) and the presence of guns in the home. Finally, brief education is provided in short 10-to-15-minute lectures covering pertinent topics so staff remain up-to-date in this changing field.

Postconference Continuity

After the conference, the SW-DCM continues to provide support throughout the disease course, helping veterans and their caregivers understand and follow through on the team’s recommendations. The SW-DCM, who is experienced and trained in case management, forms an ongoing relationship with the veterans and their caregivers and remains an advocate for their care. The SW-DCM communicates the final plan by phone and, when necessary, requests the lead physician to call to clarify any poorly understood or technical aspects of the care plan. About 50% of our veterans—primarily those who do not have a neurocognitive disorder or have mild cognitive impairment—return to their PCPs with our care plan consultation; about 25% are already enrolled in geriatric and other programs with long-term follow-up. The assigned SW-DCM follows up with the remaining veterans and caregivers regularly by phone, facilitates communication with other team members, and endeavors to assure postvisit continuity of care and support during advancing stages of the disease. In addition, the SW-DCM can provide supportive counseling and psychotherapy for stressed caregivers, refer to support groups and cognitive rehabilitation programs, and help develop long-term goals and consideration for supervised living environments. The nurse specialist participates with follow-up calls regarding medications and scheduled tests and appointments, clearing up confusion about instructions, avoiding medication errors, and providing education in dementia care. Both social worker and nurse are present throughout the week, reachable by phone, and, in turn, able to contact the clinic physicians for veterans’ needs.

Discussion

Because of the heterogenous medical and psychosocial needs of veterans with dementia and their caregivers, a transdisciplinary team with a dedicated DCM might offer the most effective and efficient model for dementia care. We present a transdisciplinary program that incorporates dementia specialists in a single evaluation by maximizing their time through a conference-centered program. Our program involves neurologists, psychiatrists, geriatricians, psychologists, nurses, and social workers collaborating and communicating to enact effective dementia care. It further meets the goals of the VA-DSOC in implementing individualized patient and caregiver care.

This transdisciplinary model addresses a number of issues, starting with the differential diagnosis of underlying neurologic conditions. Within the transdisciplinary team, the neurologist can provide specific insights into any neurologic findings and illnesses, such as Alzheimer disease and other neurodegenerative dementias, vascular dementia syndromes, normal pressure hydrocephalus, Creutzfeldt-Jakob disease, neurosyphilis, and others. Most veterans with dementia experience BPSD at some point during of their illness. The psychiatrists on the transdisciplinary team can maximize management of BPSD with nonpharmacologic interventions and the fewest and least aversive psychoactive medications. Our program also addresses the need for more precise cognitive evaluation. Neuropsychologists are present and available for administrating neuropsychologic tests and interpreting cognitive performance and any earlier neuropsychologic testing. This model also cares for the caregivers and assesses their needs. The social worker—as well as other members of the team—can provide caregivers with strategies for coping with disruptive and other behaviors related to dementia, counsel them on how to manage the veteran’s functional decline, and aid in establishing a safe living space. Because the social worker serves as a DCM, these coping and adjustment questions occupy significant clinical attention between appointments. This transdisciplinary model places the patient’s illness in the context of their functional status, diagnoses, and medications. The team geriatrician and the nurse specialist are indispensable resources. The clinic conference provides a teaching venue for staff and trainees and a mechanism to discuss new developments in dementia care, such as the increasing need to assess individuals with mild cognitive impairment.²⁵ This model depends on the DCM’s invaluable role in ensuring implementation of the dementia care plan and continuity of care.

Conclusions

We describe effective dementia care with a transdisciplinary team in a conference setting and with the participation of a dedicated DCM.⁵ To date, this program appears to be an efficient, sustainable application of the limited resources allocated to dementia care. Nevertheless, we are collecting data to compare with performance measures, track use, and assess the programs effects on continuity of care. We look forward to presenting metrics from our program that show improvement in the health care for veterans experiencing a devastating and increasingly common disorder.

Colorectal cancer is the third leading cause of cancer-related death in both men and women.¹ Colonoscopy is the current gold standard for screening due to the ability to remove precancerous lesions but remains highly dependent on the quality of bowel preparation.² Poor bowel preparation has been associated with impaired adenoma detection as well as increased health care utilization due to the need for a repeat colonoscopy.³

Multiple patient factors are associated with increased risk of poor bowel preparation, including age > 60 years, male sex, diabetes mellitus, and presence of a mental health diagnosis, factors that are prevalent among the veteran population.^3-5 Text messages have been shown to improve the quality of bowel preparation by increasing patients' understanding and adherence with the preparation process. Improved adherence with bowel preparation directions is associated with a cleaner colon prior to colonoscopy, leading to a thorough examination. Studies using text messaging instructions prior to colonoscopies have also shown measurable improvement in adenoma detection rate, patient preparation-associated discomfort, and completion of colonoscopy.^6-10

In 2016, the Veterans Health Administration (VHA) introduced Annie, one of the first automated text messaging services, named after Army Lieutenant Annie Fox, the first woman to receive the Purple Heart for combat. The Annie platform allows for notifications, instructions, and simple data collection. The development of this platform allows VHA practitioners to engage and educate veterans in a similar way to other health care systems using text messaging protocols. Annie text messages have been piloted for the use of hepatitis C treatment, demonstrating promise of improved medication adherence and patient satisfaction.¹¹ We aimed to develop and pilot the Annie bowel preparation protocol to improve the quality of colonoscopy bowel preparation for outpatients at the Minneapolis Veterans Affairs Medical Center (MVAMC) in Minnesota. A secondary goal included measuring patient satisfaction with the text messaging instructions for outpatient colonoscopy preparation.

Methods

We conducted a single center, prospective, endoscopist-blinded, study with two 3-month long Plan-Do-Study-Act (PDSA) cycles to improve the text messaging bowel preparation protocol at MVAMC between January 2019 and April 2020. The MVAMC Institutional Review Board determined the quality improvement project was exempt. Veterans who had outpatient colonoscopies scheduled were included. Veterans undergoing inpatient colonoscopies or outpatients who could not be reached to obtain informed consent, lacked text message capability, declined participation, or required extended colonoscopy preparation were excluded. Per MVAMC procedures, extended colonoscopy preparation was provided to patients receiving general or monitored anesthesia care, with a history of poor bowel preparation, or with risk factors for poor preparation as determined by the ordering health care professional (HCP). Standard bowel preparation involves ingestion of 4 L of polyethylene glycol 3350 with electrolytes; extended bowel preparation requires ingestion of an additional 2 L to total 6 L and uses a different set of instructions. Additionally, the patient population requiring extended bowel preparation also includes patients with spinal cord injuries, who often are admitted for assistance with extended preparation. Patients who consented to receiving text messages were placed in the Annie intervention group, and all others were placed in the control group.

The control group received standardized patient education, including a mailed copy of bowel preparation instructions and a phone call from a gastroenterology service nurse about 1 to 2 weeks before the procedure. Current MVAMC standard of care involves a phone call from a nurse to confirm that patients have received the polyethylene glycol preparation solution, the mailed instructions, have an escort and transportation, and to answer any questions. Both the usual care and intervention group received the phone call. During this call, the Annie text messaging bowel preparation protocol was introduced; if the veteran chose to participate, consent and enrollment were completed.

On the day of the colonoscopy, veterans in the intervention group were surveyed in the waiting room about their experience receiving the text messages and soliciting feedback for improvement or surveyed via telephone call within 3 days of their procedure. Patient satisfaction was quantified with a scale from 1 (low) to 10 (high), including questions about how helpful the texts were in relation to total number, timing, and content of messages as well as whether veterans would like to receive the text messages again for future procedures.

We reviewed individual charts and collected Boston Bowel Preparation Scale (BBPS) scores to determine adequate preparation. BBPS assigns a score of 0 to 3 for the right, transverse, and left colon applied upon withdrawal after flushing and suctioning have been completed.¹² Adequate preparation is considered a total score of ≥ 6 with no segment scoring < 2. This method of preparation assessment is preferred due to its ability to account for difference in preparation quality among colonic segments, well-defined scoring characteristics, and several studies validating its use showing inter- and intraobserver reliability.¹² Follow-up studies have shown validity of the BBPS when compared with relevant outcomes such as polyp detection rate and recommended timing for repeat procedure.¹³ Variables associated with poor bowel preparation (ie, gender, prior abdominal surgery, impaired mobility, high body mass index, diabetes mellitus, stroke, dementia, any neurologic diagnosis, cirrhosis, smoking, polypharmacy [> 8 active medications], and narcotic or tricyclic antidepressant medication use) were also collected through chart review.^3-5 We note that immobility was defined by International Classification of Diseases (ICD)-9 and ICD-10 codes and prescriptions for assistive devices (ie, canes, wheelchairs, 4-wheeled walkers).

Veterans assent to be enrolled in Annie. After enrollment, veterans must text back a specific word response to an initial text message to receive the protocolized messages from the Annie program. A contact phone number to the gastrointestinal nurse line was provided for questions during business hours. The start date for the text message protocol is 6 days prior to the procedure date. If a patient rescheduled their colonoscopy, the Annie database was updated manually.

Statistical Analysis

We used both Pearson χ² test and 2-sample t test analyses to compare demographic information and patient satisfaction scores between the control and intervention groups. We compared continuous BBPS scores between Annie intervention vs control group using parametric and nonparametric independent t tests using the Mann-Whitney U test. We repeated this analysis controlling for both mental health diagnoses and age using linear regression. We were unable to survey 61 of the 187 veterans who received Annie text messages. 

RESULTS

During PDSA cycles 1 and 2, 640 veterans were scheduled for outpatient colonoscopy: 453 veterans were in the control group; 187 veterans were in the intervention group, of which 126 were surveyed. A significant percentage of veterans declined participation because they felt like they did not need reinforced education; others were not eligible for Annie due to requirement for extended bowel preparation, cancelled colonoscopy, inability to physically read text messages, or lack of cell phone.

The mean (SD) age was 65 (8) years; 184 (28.8%) had a diabetes mellitus diagnosis, and the mean (SD) body mass index was 31.6 (6.4). The Annie group was slightly more likely to have mental health diagnoses and lower age compared with the control group (Table 1).

Patient Feedback

We collected feedback from veterans after each PDSA cycle to identify areas for improvement by both in-person and telephone surveys. Based on feedback from PDSA cycle 1, we decreased the total number of text messages to create a more succinct set of instructions. The most frequently requested change involved timing the text messages to align with the exact morning a specific instruction should take place.

Patient satisfaction with the Annie text messaging service was high.

DISCUSSION

To our knowledge, this is the first report of using Annie at a VAMC for colonoscopy bowel preparation improvement. We found a statistically significant improvement in the average BBPS in those receiving Annie text messages compared with the routine care control group. We also found high levels of patient satisfaction with most patients requesting to receive them again for future procedures.

The clinical significance of a BBPS of 7.8 vs 8.2 is unclear, although any score > 6 is considered to be adequate. However, subjectively speaking, the higher the BBPS the cleaner the colon, and theoretically the easier it is to see small or flat polyps. Future steps could include calculating adenoma detection rates for those enrolled in the Annie program vs the control group.

We have received inquiries regarding potential program implementation at other facilities. Success and sustainability of the program will require long-term commitment and ideally protected time for staff. It is helpful to remember that for each person who chooses to enroll in the intervention, the program currently requires that a brief consent note is placed in the patient’s chart. Thus, depending on the facilities’ resources, it is ideal for one staff member to be the designated lead to help oversee, troubleshoot, and train additional personnel. Surveys can be intermittently used to obtain feedback for improvement but are not required for sustainability. Automated text messaging is a promising addition to medicine for clinical education and communication. Future studies should examine the clinical significance (ie, adenoma detection rates) of text messaging bowel preparation protocols.

Limitations

Our study has several limitations. First, this was a single center study, thus generalizability is limited. MVAMC represents a predominantly White, male, and rural population. Second, data are likely an underestimation of the true impact of intervention, because results do not account for patients who were turned away on day of procedure (typically still reporting brown stools at time of check-in for procedure) due to poor preparation or aborted procedures secondary to poor preparation. Only about one-third of the 640 veterans opted to receive Annie text messages.

Studies have shown veterans are willing to use technology for health care; however, access to technology and lack of training remain barriers to use.¹⁴ This has been most robustly studied at the VA in veterans experiencing mental illness and homelessness. Targeted strategies to improve veteran adoption of technology within their health care include supplying veterans with cell phones and paid data plans and providing training on specific technology-based resources.^15-17 Future improvement for the Annie platform should include improved integration with CPRS. Integration will facilitate automatic import of key information such as mobile phone number or colonoscopy procedure date. Unfortunately, this is not currently an automated process, and the manual workload of staff limits sustainability. Since our study ended, the Annie database now allows an “event date” to be programmed in to center the text message series around. This will be entered at the time of Annie enrollment and eliminate manual activation of the protocol. The issue of updating information for rescheduled procedures remains.

Conclusions

There is increasing evidence that automated text messaging is a promising addition to medicine for clinical education and communication. It continues to gain traction as a readily available and acceptable option, and many patients are willing to incorporate the technology platform into their care plan. We found high patient satisfaction with our protocol, and Annie patients had cleaner bowel preparations compared with control patients. Our study supports the use of text message reminders as an effective intervention for improving patient adherence with bowel preparation instructions. We suspect that creation of a text messaging protocol designed for patients requiring outpatient extended bowel preparation will yield great benefit. As technology continues to improve, future implementation of Annie text messaging will become increasingly seamless within the field of gastroenterology and beyond.

Colorectal cancer is the third leading cause of cancer-related death in both men and women.¹ Colonoscopy is the current gold standard for screening due to the ability to remove precancerous lesions but remains highly dependent on the quality of bowel preparation.² Poor bowel preparation has been associated with impaired adenoma detection as well as increased health care utilization due to the need for a repeat colonoscopy.³

Multiple patient factors are associated with increased risk of poor bowel preparation, including age > 60 years, male sex, diabetes mellitus, and presence of a mental health diagnosis, factors that are prevalent among the veteran population.^3-5 Text messages have been shown to improve the quality of bowel preparation by increasing patients' understanding and adherence with the preparation process. Improved adherence with bowel preparation directions is associated with a cleaner colon prior to colonoscopy, leading to a thorough examination. Studies using text messaging instructions prior to colonoscopies have also shown measurable improvement in adenoma detection rate, patient preparation-associated discomfort, and completion of colonoscopy.^6-10

In 2016, the Veterans Health Administration (VHA) introduced Annie, one of the first automated text messaging services, named after Army Lieutenant Annie Fox, the first woman to receive the Purple Heart for combat. The Annie platform allows for notifications, instructions, and simple data collection. The development of this platform allows VHA practitioners to engage and educate veterans in a similar way to other health care systems using text messaging protocols. Annie text messages have been piloted for the use of hepatitis C treatment, demonstrating promise of improved medication adherence and patient satisfaction.¹¹ We aimed to develop and pilot the Annie bowel preparation protocol to improve the quality of colonoscopy bowel preparation for outpatients at the Minneapolis Veterans Affairs Medical Center (MVAMC) in Minnesota. A secondary goal included measuring patient satisfaction with the text messaging instructions for outpatient colonoscopy preparation.

Methods

We conducted a single center, prospective, endoscopist-blinded, study with two 3-month long Plan-Do-Study-Act (PDSA) cycles to improve the text messaging bowel preparation protocol at MVAMC between January 2019 and April 2020. The MVAMC Institutional Review Board determined the quality improvement project was exempt. Veterans who had outpatient colonoscopies scheduled were included. Veterans undergoing inpatient colonoscopies or outpatients who could not be reached to obtain informed consent, lacked text message capability, declined participation, or required extended colonoscopy preparation were excluded. Per MVAMC procedures, extended colonoscopy preparation was provided to patients receiving general or monitored anesthesia care, with a history of poor bowel preparation, or with risk factors for poor preparation as determined by the ordering health care professional (HCP). Standard bowel preparation involves ingestion of 4 L of polyethylene glycol 3350 with electrolytes; extended bowel preparation requires ingestion of an additional 2 L to total 6 L and uses a different set of instructions. Additionally, the patient population requiring extended bowel preparation also includes patients with spinal cord injuries, who often are admitted for assistance with extended preparation. Patients who consented to receiving text messages were placed in the Annie intervention group, and all others were placed in the control group.

The control group received standardized patient education, including a mailed copy of bowel preparation instructions and a phone call from a gastroenterology service nurse about 1 to 2 weeks before the procedure. Current MVAMC standard of care involves a phone call from a nurse to confirm that patients have received the polyethylene glycol preparation solution, the mailed instructions, have an escort and transportation, and to answer any questions. Both the usual care and intervention group received the phone call. During this call, the Annie text messaging bowel preparation protocol was introduced; if the veteran chose to participate, consent and enrollment were completed.

On the day of the colonoscopy, veterans in the intervention group were surveyed in the waiting room about their experience receiving the text messages and soliciting feedback for improvement or surveyed via telephone call within 3 days of their procedure. Patient satisfaction was quantified with a scale from 1 (low) to 10 (high), including questions about how helpful the texts were in relation to total number, timing, and content of messages as well as whether veterans would like to receive the text messages again for future procedures.

We reviewed individual charts and collected Boston Bowel Preparation Scale (BBPS) scores to determine adequate preparation. BBPS assigns a score of 0 to 3 for the right, transverse, and left colon applied upon withdrawal after flushing and suctioning have been completed.¹² Adequate preparation is considered a total score of ≥ 6 with no segment scoring < 2. This method of preparation assessment is preferred due to its ability to account for difference in preparation quality among colonic segments, well-defined scoring characteristics, and several studies validating its use showing inter- and intraobserver reliability.¹² Follow-up studies have shown validity of the BBPS when compared with relevant outcomes such as polyp detection rate and recommended timing for repeat procedure.¹³ Variables associated with poor bowel preparation (ie, gender, prior abdominal surgery, impaired mobility, high body mass index, diabetes mellitus, stroke, dementia, any neurologic diagnosis, cirrhosis, smoking, polypharmacy [> 8 active medications], and narcotic or tricyclic antidepressant medication use) were also collected through chart review.^3-5 We note that immobility was defined by International Classification of Diseases (ICD)-9 and ICD-10 codes and prescriptions for assistive devices (ie, canes, wheelchairs, 4-wheeled walkers).

Veterans assent to be enrolled in Annie. After enrollment, veterans must text back a specific word response to an initial text message to receive the protocolized messages from the Annie program. A contact phone number to the gastrointestinal nurse line was provided for questions during business hours. The start date for the text message protocol is 6 days prior to the procedure date. If a patient rescheduled their colonoscopy, the Annie database was updated manually.

Statistical Analysis

We used both Pearson χ² test and 2-sample t test analyses to compare demographic information and patient satisfaction scores between the control and intervention groups. We compared continuous BBPS scores between Annie intervention vs control group using parametric and nonparametric independent t tests using the Mann-Whitney U test. We repeated this analysis controlling for both mental health diagnoses and age using linear regression. We were unable to survey 61 of the 187 veterans who received Annie text messages. 

RESULTS

During PDSA cycles 1 and 2, 640 veterans were scheduled for outpatient colonoscopy: 453 veterans were in the control group; 187 veterans were in the intervention group, of which 126 were surveyed. A significant percentage of veterans declined participation because they felt like they did not need reinforced education; others were not eligible for Annie due to requirement for extended bowel preparation, cancelled colonoscopy, inability to physically read text messages, or lack of cell phone.

The mean (SD) age was 65 (8) years; 184 (28.8%) had a diabetes mellitus diagnosis, and the mean (SD) body mass index was 31.6 (6.4). The Annie group was slightly more likely to have mental health diagnoses and lower age compared with the control group (Table 1).

Patient Feedback

We collected feedback from veterans after each PDSA cycle to identify areas for improvement by both in-person and telephone surveys. Based on feedback from PDSA cycle 1, we decreased the total number of text messages to create a more succinct set of instructions. The most frequently requested change involved timing the text messages to align with the exact morning a specific instruction should take place.

Patient satisfaction with the Annie text messaging service was high.

DISCUSSION

To our knowledge, this is the first report of using Annie at a VAMC for colonoscopy bowel preparation improvement. We found a statistically significant improvement in the average BBPS in those receiving Annie text messages compared with the routine care control group. We also found high levels of patient satisfaction with most patients requesting to receive them again for future procedures.

The clinical significance of a BBPS of 7.8 vs 8.2 is unclear, although any score > 6 is considered to be adequate. However, subjectively speaking, the higher the BBPS the cleaner the colon, and theoretically the easier it is to see small or flat polyps. Future steps could include calculating adenoma detection rates for those enrolled in the Annie program vs the control group.

We have received inquiries regarding potential program implementation at other facilities. Success and sustainability of the program will require long-term commitment and ideally protected time for staff. It is helpful to remember that for each person who chooses to enroll in the intervention, the program currently requires that a brief consent note is placed in the patient’s chart. Thus, depending on the facilities’ resources, it is ideal for one staff member to be the designated lead to help oversee, troubleshoot, and train additional personnel. Surveys can be intermittently used to obtain feedback for improvement but are not required for sustainability. Automated text messaging is a promising addition to medicine for clinical education and communication. Future studies should examine the clinical significance (ie, adenoma detection rates) of text messaging bowel preparation protocols.

Limitations

Our study has several limitations. First, this was a single center study, thus generalizability is limited. MVAMC represents a predominantly White, male, and rural population. Second, data are likely an underestimation of the true impact of intervention, because results do not account for patients who were turned away on day of procedure (typically still reporting brown stools at time of check-in for procedure) due to poor preparation or aborted procedures secondary to poor preparation. Only about one-third of the 640 veterans opted to receive Annie text messages.

Studies have shown veterans are willing to use technology for health care; however, access to technology and lack of training remain barriers to use.¹⁴ This has been most robustly studied at the VA in veterans experiencing mental illness and homelessness. Targeted strategies to improve veteran adoption of technology within their health care include supplying veterans with cell phones and paid data plans and providing training on specific technology-based resources.^15-17 Future improvement for the Annie platform should include improved integration with CPRS. Integration will facilitate automatic import of key information such as mobile phone number or colonoscopy procedure date. Unfortunately, this is not currently an automated process, and the manual workload of staff limits sustainability. Since our study ended, the Annie database now allows an “event date” to be programmed in to center the text message series around. This will be entered at the time of Annie enrollment and eliminate manual activation of the protocol. The issue of updating information for rescheduled procedures remains.

Conclusions

There is increasing evidence that automated text messaging is a promising addition to medicine for clinical education and communication. It continues to gain traction as a readily available and acceptable option, and many patients are willing to incorporate the technology platform into their care plan. We found high patient satisfaction with our protocol, and Annie patients had cleaner bowel preparations compared with control patients. Our study supports the use of text message reminders as an effective intervention for improving patient adherence with bowel preparation instructions. We suspect that creation of a text messaging protocol designed for patients requiring outpatient extended bowel preparation will yield great benefit. As technology continues to improve, future implementation of Annie text messaging will become increasingly seamless within the field of gastroenterology and beyond.

Colorectal cancer is the third leading cause of cancer-related death in both men and women.¹ Colonoscopy is the current gold standard for screening due to the ability to remove precancerous lesions but remains highly dependent on the quality of bowel preparation.² Poor bowel preparation has been associated with impaired adenoma detection as well as increased health care utilization due to the need for a repeat colonoscopy.³

Multiple patient factors are associated with increased risk of poor bowel preparation, including age > 60 years, male sex, diabetes mellitus, and presence of a mental health diagnosis, factors that are prevalent among the veteran population.^3-5 Text messages have been shown to improve the quality of bowel preparation by increasing patients' understanding and adherence with the preparation process. Improved adherence with bowel preparation directions is associated with a cleaner colon prior to colonoscopy, leading to a thorough examination. Studies using text messaging instructions prior to colonoscopies have also shown measurable improvement in adenoma detection rate, patient preparation-associated discomfort, and completion of colonoscopy.^6-10

In 2016, the Veterans Health Administration (VHA) introduced Annie, one of the first automated text messaging services, named after Army Lieutenant Annie Fox, the first woman to receive the Purple Heart for combat. The Annie platform allows for notifications, instructions, and simple data collection. The development of this platform allows VHA practitioners to engage and educate veterans in a similar way to other health care systems using text messaging protocols. Annie text messages have been piloted for the use of hepatitis C treatment, demonstrating promise of improved medication adherence and patient satisfaction.¹¹ We aimed to develop and pilot the Annie bowel preparation protocol to improve the quality of colonoscopy bowel preparation for outpatients at the Minneapolis Veterans Affairs Medical Center (MVAMC) in Minnesota. A secondary goal included measuring patient satisfaction with the text messaging instructions for outpatient colonoscopy preparation.

Methods

We conducted a single center, prospective, endoscopist-blinded, study with two 3-month long Plan-Do-Study-Act (PDSA) cycles to improve the text messaging bowel preparation protocol at MVAMC between January 2019 and April 2020. The MVAMC Institutional Review Board determined the quality improvement project was exempt. Veterans who had outpatient colonoscopies scheduled were included. Veterans undergoing inpatient colonoscopies or outpatients who could not be reached to obtain informed consent, lacked text message capability, declined participation, or required extended colonoscopy preparation were excluded. Per MVAMC procedures, extended colonoscopy preparation was provided to patients receiving general or monitored anesthesia care, with a history of poor bowel preparation, or with risk factors for poor preparation as determined by the ordering health care professional (HCP). Standard bowel preparation involves ingestion of 4 L of polyethylene glycol 3350 with electrolytes; extended bowel preparation requires ingestion of an additional 2 L to total 6 L and uses a different set of instructions. Additionally, the patient population requiring extended bowel preparation also includes patients with spinal cord injuries, who often are admitted for assistance with extended preparation. Patients who consented to receiving text messages were placed in the Annie intervention group, and all others were placed in the control group.

The control group received standardized patient education, including a mailed copy of bowel preparation instructions and a phone call from a gastroenterology service nurse about 1 to 2 weeks before the procedure. Current MVAMC standard of care involves a phone call from a nurse to confirm that patients have received the polyethylene glycol preparation solution, the mailed instructions, have an escort and transportation, and to answer any questions. Both the usual care and intervention group received the phone call. During this call, the Annie text messaging bowel preparation protocol was introduced; if the veteran chose to participate, consent and enrollment were completed.

On the day of the colonoscopy, veterans in the intervention group were surveyed in the waiting room about their experience receiving the text messages and soliciting feedback for improvement or surveyed via telephone call within 3 days of their procedure. Patient satisfaction was quantified with a scale from 1 (low) to 10 (high), including questions about how helpful the texts were in relation to total number, timing, and content of messages as well as whether veterans would like to receive the text messages again for future procedures.

We reviewed individual charts and collected Boston Bowel Preparation Scale (BBPS) scores to determine adequate preparation. BBPS assigns a score of 0 to 3 for the right, transverse, and left colon applied upon withdrawal after flushing and suctioning have been completed.¹² Adequate preparation is considered a total score of ≥ 6 with no segment scoring < 2. This method of preparation assessment is preferred due to its ability to account for difference in preparation quality among colonic segments, well-defined scoring characteristics, and several studies validating its use showing inter- and intraobserver reliability.¹² Follow-up studies have shown validity of the BBPS when compared with relevant outcomes such as polyp detection rate and recommended timing for repeat procedure.¹³ Variables associated with poor bowel preparation (ie, gender, prior abdominal surgery, impaired mobility, high body mass index, diabetes mellitus, stroke, dementia, any neurologic diagnosis, cirrhosis, smoking, polypharmacy [> 8 active medications], and narcotic or tricyclic antidepressant medication use) were also collected through chart review.^3-5 We note that immobility was defined by International Classification of Diseases (ICD)-9 and ICD-10 codes and prescriptions for assistive devices (ie, canes, wheelchairs, 4-wheeled walkers).

Veterans assent to be enrolled in Annie. After enrollment, veterans must text back a specific word response to an initial text message to receive the protocolized messages from the Annie program. A contact phone number to the gastrointestinal nurse line was provided for questions during business hours. The start date for the text message protocol is 6 days prior to the procedure date. If a patient rescheduled their colonoscopy, the Annie database was updated manually.

Statistical Analysis

We used both Pearson χ² test and 2-sample t test analyses to compare demographic information and patient satisfaction scores between the control and intervention groups. We compared continuous BBPS scores between Annie intervention vs control group using parametric and nonparametric independent t tests using the Mann-Whitney U test. We repeated this analysis controlling for both mental health diagnoses and age using linear regression. We were unable to survey 61 of the 187 veterans who received Annie text messages. 

RESULTS

During PDSA cycles 1 and 2, 640 veterans were scheduled for outpatient colonoscopy: 453 veterans were in the control group; 187 veterans were in the intervention group, of which 126 were surveyed. A significant percentage of veterans declined participation because they felt like they did not need reinforced education; others were not eligible for Annie due to requirement for extended bowel preparation, cancelled colonoscopy, inability to physically read text messages, or lack of cell phone.

The mean (SD) age was 65 (8) years; 184 (28.8%) had a diabetes mellitus diagnosis, and the mean (SD) body mass index was 31.6 (6.4). The Annie group was slightly more likely to have mental health diagnoses and lower age compared with the control group (Table 1).

Patient Feedback

We collected feedback from veterans after each PDSA cycle to identify areas for improvement by both in-person and telephone surveys. Based on feedback from PDSA cycle 1, we decreased the total number of text messages to create a more succinct set of instructions. The most frequently requested change involved timing the text messages to align with the exact morning a specific instruction should take place.

Patient satisfaction with the Annie text messaging service was high.

DISCUSSION

To our knowledge, this is the first report of using Annie at a VAMC for colonoscopy bowel preparation improvement. We found a statistically significant improvement in the average BBPS in those receiving Annie text messages compared with the routine care control group. We also found high levels of patient satisfaction with most patients requesting to receive them again for future procedures.

The clinical significance of a BBPS of 7.8 vs 8.2 is unclear, although any score > 6 is considered to be adequate. However, subjectively speaking, the higher the BBPS the cleaner the colon, and theoretically the easier it is to see small or flat polyps. Future steps could include calculating adenoma detection rates for those enrolled in the Annie program vs the control group.

We have received inquiries regarding potential program implementation at other facilities. Success and sustainability of the program will require long-term commitment and ideally protected time for staff. It is helpful to remember that for each person who chooses to enroll in the intervention, the program currently requires that a brief consent note is placed in the patient’s chart. Thus, depending on the facilities’ resources, it is ideal for one staff member to be the designated lead to help oversee, troubleshoot, and train additional personnel. Surveys can be intermittently used to obtain feedback for improvement but are not required for sustainability. Automated text messaging is a promising addition to medicine for clinical education and communication. Future studies should examine the clinical significance (ie, adenoma detection rates) of text messaging bowel preparation protocols.

Limitations

Our study has several limitations. First, this was a single center study, thus generalizability is limited. MVAMC represents a predominantly White, male, and rural population. Second, data are likely an underestimation of the true impact of intervention, because results do not account for patients who were turned away on day of procedure (typically still reporting brown stools at time of check-in for procedure) due to poor preparation or aborted procedures secondary to poor preparation. Only about one-third of the 640 veterans opted to receive Annie text messages.

Studies have shown veterans are willing to use technology for health care; however, access to technology and lack of training remain barriers to use.¹⁴ This has been most robustly studied at the VA in veterans experiencing mental illness and homelessness. Targeted strategies to improve veteran adoption of technology within their health care include supplying veterans with cell phones and paid data plans and providing training on specific technology-based resources.^15-17 Future improvement for the Annie platform should include improved integration with CPRS. Integration will facilitate automatic import of key information such as mobile phone number or colonoscopy procedure date. Unfortunately, this is not currently an automated process, and the manual workload of staff limits sustainability. Since our study ended, the Annie database now allows an “event date” to be programmed in to center the text message series around. This will be entered at the time of Annie enrollment and eliminate manual activation of the protocol. The issue of updating information for rescheduled procedures remains.

Conclusions

There is increasing evidence that automated text messaging is a promising addition to medicine for clinical education and communication. It continues to gain traction as a readily available and acceptable option, and many patients are willing to incorporate the technology platform into their care plan. We found high patient satisfaction with our protocol, and Annie patients had cleaner bowel preparations compared with control patients. Our study supports the use of text message reminders as an effective intervention for improving patient adherence with bowel preparation instructions. We suspect that creation of a text messaging protocol designed for patients requiring outpatient extended bowel preparation will yield great benefit. As technology continues to improve, future implementation of Annie text messaging will become increasingly seamless within the field of gastroenterology and beyond.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck (H&N) cancer.^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia.⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was.⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures.^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume for the lowest dose target volume. NRG H&N trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose  ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for H&N squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as H&N cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the H&N.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for H&N cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy (IMRT). Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 69.96 Gy in 33 fractions, with elective volumes treated to 54.45 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased 1-year dysphagia.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for H&N cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant.

An advantage of contralateral constrictor is that it is independent of planning target volume (PTV) size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with H&N cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with H&N cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck (H&N) cancer.^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia.⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was.⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures.^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume for the lowest dose target volume. NRG H&N trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose  ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for H&N squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as H&N cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the H&N.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for H&N cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy (IMRT). Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 69.96 Gy in 33 fractions, with elective volumes treated to 54.45 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased 1-year dysphagia.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for H&N cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant.

An advantage of contralateral constrictor is that it is independent of planning target volume (PTV) size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with H&N cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with H&N cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck (H&N) cancer.^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia.⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was.⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures.^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume for the lowest dose target volume. NRG H&N trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose  ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for H&N squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as H&N cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the H&N.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for H&N cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy (IMRT). Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 69.96 Gy in 33 fractions, with elective volumes treated to 54.45 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased 1-year dysphagia.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for H&N cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant.

An advantage of contralateral constrictor is that it is independent of planning target volume (PTV) size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with H&N cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with H&N cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

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

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

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

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

The study was published in HIV Medicine.

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

Pregnancies in trials excluding pregnant women

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

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

Pregnancy outcomes

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

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

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

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

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

Planned studies during pregnancy

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

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

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

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

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

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

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

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

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

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

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

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

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

The study was published in HIV Medicine.

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

Pregnancies in trials excluding pregnant women

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

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

Pregnancy outcomes

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

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

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

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

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

Planned studies during pregnancy

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

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

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

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

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

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

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

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

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

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

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

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

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

The study was published in HIV Medicine.

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

Pregnancies in trials excluding pregnant women

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

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

Pregnancy outcomes

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

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

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

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

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

Planned studies during pregnancy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other screening tools

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other screening tools

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other screening tools

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Seizures make matters worse

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

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

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

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

A tip for caregivers

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

Double whammy

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

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

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

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

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

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

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

Seizures make matters worse

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

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

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

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

A tip for caregivers

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

Double whammy

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

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

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

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

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

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

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

Seizures make matters worse

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

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

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

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

A tip for caregivers

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

Double whammy

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

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

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

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

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

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

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

AKT alterations

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

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

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

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

Results

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

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

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

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

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

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

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

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

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

‘Clinically relevant benefit’

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

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

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

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

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

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

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

AKT alterations

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

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

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

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

Results

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

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

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

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

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

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

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

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

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

‘Clinically relevant benefit’

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

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

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

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

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

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

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

AKT alterations

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

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

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

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

Results

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

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

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

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

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

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

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

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

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

‘Clinically relevant benefit’

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Long-term complications

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Long-term complications

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Long-term complications

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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