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Exciting opportunities for tobacco treatment
FROM THE CHEST TOBACCO/VAPING WORK GROUP –
The recent changes enacted by the Centers for Medicare & Medicaid Services (CMS) are creating unprecedented opportunities for pulmonologists and medical centers to help treat people with tobacco use disorder. As we face a critical moment in the fight against tobacco-related morbidity and mortality, it is essential that we leverage these changes. In doing so, CHEST aims to serve as an active bridge, informing health care providers of this unique federal opportunity that benefits both patients and clinicians.
A quick primer on “incident to” services
These CMS changes create an important shift in how “incident to” services can be billed. These are any services that are incident to (occur because of) a provider evaluation. These previously required direct supervision of the provider (in the same building) to be billed at the provider rate. Now “general supervision” suffices, which means the physician can be available by phone/video call. These services can then often be billed at a higher rate. In the case of treating dependence on tobacco products, any tobacco treatment specialist (TTS) employed by a practice who cares for the patient subsequent to the initial encounter can now be reimbursed in an increased manner. Better reimbursement for this vital service will ideally lead to better utilization of these resources and better public health.
The Medicare solution is here
With the CMS rule changes in 2023 and their reaffirmation in 2024, the structure has been put in place to allow physicians, medical centers, and TTSs to create contractual relationships that can significantly improve patient care. TTSs are health care professionals from a wide variety of disciplines who have received specialized training in tobacco and nicotine addiction and treatment strategies. By expanding billing and, thus, service opportunities, these CMS modifications empower health care providers to leverage the existing fee-for-service model, translating to better care and sustainable revenue streams.
Key changes in the CMS 2023 rule
One of the most notable changes involves the supervision requirements for auxiliary personnel, which now permit general supervision. Specifically, physicians are not required to be physically present during clinical encounters but can supervise TTSs virtually through real-time audio/video technology. This is a vital shift that enhances flexibility in patient care and expands the capabilities of health care teams.
According to 42 CFR § 410.26, TTSs qualify as auxiliary health care providers, meaning that they can operate under the supervision of a physician or other designated providers. This revised framework gives practices maximum autonomy in their staffing models and enhances their ability to offer comprehensive care. For example, TTSs can function as patient navigators, ensuring patients using tobacco receive medically appropriate early lung cancer screening and other related medical services.
Expanding access to behavioral health services
The changes aim not only to increase the efficiency of health care delivery but also to reflect a commitment to expanding access to vital behavioral health services. Key takeaways from a summary of the CMS 2023 rule include:
- The goal of these changes is to enhance access to behavioral health services across the board.
- The change in supervision requirements applies to auxiliary personnel offering behavioral health services incident to a physician’s services.
- Both patients and physicians will benefit from an expanded clinical team and improved reimbursement options for the services provided.
By leveraging these opportunities, physicians and their teams can collaborate with TTSs to make significant strides in helping patients address and overcome their dependence on tobacco and nicotine.
The outlook: CMS 2024 rule
The current outlook for 2024 and beyond promises even more opportunities as part of CMS’ ongoing Behavioral Health Strategy. This includes enabling mental health counselors (MHCs) and marriage and family therapists (MFTs) to bill Medicare independently, initiating vital coverage for mental health services that align with tobacco cessation efforts.
Physicians and medical centers can contract with MFTs and MHCs who are TTSs to provide tobacco addiction services. TTSs will serve as essential partners in multidisciplinary care teams, enhancing the overall health care landscape while ensuring that patients receive comprehensive support tailored to their needs.
Telehealth policy changes: Making services accessible
The White House also recently reinforced the importance of telehealth services, providing further avenues for TTSs to reach patients effectively. With expanded geographic locations for service delivery, care can be provided from virtually anywhere, including when the patient is at home.
Key telehealth provisions include:
- Extended telehealth services through 2024
- Elimination of in-person requirements for mental health services
- Expanded eligibility for providers qualified to provide telehealth services
Practical implications for providers
These developments not only simplify the establishment of tobacco treatment programs but also create better avenues to develop partnerships between physicians, hospitals, medical centers, multidisciplinary practices, and TTSs. Importantly, these clinicians will be compensated directly for the tobacco treatment services they provide.
Conclusion
This is a pivotal moment for pulmonologists and TTSs to meaningfully claim their place within the health care space. As we strive to “make smoking history,” we must act on these CMS opportunities. As providers, we must be proactive, collaborate across disciplines, and serve as advocates for our patients.
Together, we can turn the tide against tobacco use and improve health outcomes nationwide.
Call to action
CHEST encourages all health care professionals to engage with the available resources, collaborate with TTSs, and take appropriate advantage of these new policies for the benefit of our patients. Let’s work together to ensure that we seize this moment and make a real difference in the lives of those affected by tobacco addiction.
Those interested in more information—or to access additional resources and assistance in locating TTSs—please contact Matthew Bars at [email protected] or +1 (800) 45-SMOKE.
FROM THE CHEST TOBACCO/VAPING WORK GROUP –
The recent changes enacted by the Centers for Medicare & Medicaid Services (CMS) are creating unprecedented opportunities for pulmonologists and medical centers to help treat people with tobacco use disorder. As we face a critical moment in the fight against tobacco-related morbidity and mortality, it is essential that we leverage these changes. In doing so, CHEST aims to serve as an active bridge, informing health care providers of this unique federal opportunity that benefits both patients and clinicians.
A quick primer on “incident to” services
These CMS changes create an important shift in how “incident to” services can be billed. These are any services that are incident to (occur because of) a provider evaluation. These previously required direct supervision of the provider (in the same building) to be billed at the provider rate. Now “general supervision” suffices, which means the physician can be available by phone/video call. These services can then often be billed at a higher rate. In the case of treating dependence on tobacco products, any tobacco treatment specialist (TTS) employed by a practice who cares for the patient subsequent to the initial encounter can now be reimbursed in an increased manner. Better reimbursement for this vital service will ideally lead to better utilization of these resources and better public health.
The Medicare solution is here
With the CMS rule changes in 2023 and their reaffirmation in 2024, the structure has been put in place to allow physicians, medical centers, and TTSs to create contractual relationships that can significantly improve patient care. TTSs are health care professionals from a wide variety of disciplines who have received specialized training in tobacco and nicotine addiction and treatment strategies. By expanding billing and, thus, service opportunities, these CMS modifications empower health care providers to leverage the existing fee-for-service model, translating to better care and sustainable revenue streams.
Key changes in the CMS 2023 rule
One of the most notable changes involves the supervision requirements for auxiliary personnel, which now permit general supervision. Specifically, physicians are not required to be physically present during clinical encounters but can supervise TTSs virtually through real-time audio/video technology. This is a vital shift that enhances flexibility in patient care and expands the capabilities of health care teams.
According to 42 CFR § 410.26, TTSs qualify as auxiliary health care providers, meaning that they can operate under the supervision of a physician or other designated providers. This revised framework gives practices maximum autonomy in their staffing models and enhances their ability to offer comprehensive care. For example, TTSs can function as patient navigators, ensuring patients using tobacco receive medically appropriate early lung cancer screening and other related medical services.
Expanding access to behavioral health services
The changes aim not only to increase the efficiency of health care delivery but also to reflect a commitment to expanding access to vital behavioral health services. Key takeaways from a summary of the CMS 2023 rule include:
- The goal of these changes is to enhance access to behavioral health services across the board.
- The change in supervision requirements applies to auxiliary personnel offering behavioral health services incident to a physician’s services.
- Both patients and physicians will benefit from an expanded clinical team and improved reimbursement options for the services provided.
By leveraging these opportunities, physicians and their teams can collaborate with TTSs to make significant strides in helping patients address and overcome their dependence on tobacco and nicotine.
The outlook: CMS 2024 rule
The current outlook for 2024 and beyond promises even more opportunities as part of CMS’ ongoing Behavioral Health Strategy. This includes enabling mental health counselors (MHCs) and marriage and family therapists (MFTs) to bill Medicare independently, initiating vital coverage for mental health services that align with tobacco cessation efforts.
Physicians and medical centers can contract with MFTs and MHCs who are TTSs to provide tobacco addiction services. TTSs will serve as essential partners in multidisciplinary care teams, enhancing the overall health care landscape while ensuring that patients receive comprehensive support tailored to their needs.
Telehealth policy changes: Making services accessible
The White House also recently reinforced the importance of telehealth services, providing further avenues for TTSs to reach patients effectively. With expanded geographic locations for service delivery, care can be provided from virtually anywhere, including when the patient is at home.
Key telehealth provisions include:
- Extended telehealth services through 2024
- Elimination of in-person requirements for mental health services
- Expanded eligibility for providers qualified to provide telehealth services
Practical implications for providers
These developments not only simplify the establishment of tobacco treatment programs but also create better avenues to develop partnerships between physicians, hospitals, medical centers, multidisciplinary practices, and TTSs. Importantly, these clinicians will be compensated directly for the tobacco treatment services they provide.
Conclusion
This is a pivotal moment for pulmonologists and TTSs to meaningfully claim their place within the health care space. As we strive to “make smoking history,” we must act on these CMS opportunities. As providers, we must be proactive, collaborate across disciplines, and serve as advocates for our patients.
Together, we can turn the tide against tobacco use and improve health outcomes nationwide.
Call to action
CHEST encourages all health care professionals to engage with the available resources, collaborate with TTSs, and take appropriate advantage of these new policies for the benefit of our patients. Let’s work together to ensure that we seize this moment and make a real difference in the lives of those affected by tobacco addiction.
Those interested in more information—or to access additional resources and assistance in locating TTSs—please contact Matthew Bars at [email protected] or +1 (800) 45-SMOKE.
FROM THE CHEST TOBACCO/VAPING WORK GROUP –
The recent changes enacted by the Centers for Medicare & Medicaid Services (CMS) are creating unprecedented opportunities for pulmonologists and medical centers to help treat people with tobacco use disorder. As we face a critical moment in the fight against tobacco-related morbidity and mortality, it is essential that we leverage these changes. In doing so, CHEST aims to serve as an active bridge, informing health care providers of this unique federal opportunity that benefits both patients and clinicians.
A quick primer on “incident to” services
These CMS changes create an important shift in how “incident to” services can be billed. These are any services that are incident to (occur because of) a provider evaluation. These previously required direct supervision of the provider (in the same building) to be billed at the provider rate. Now “general supervision” suffices, which means the physician can be available by phone/video call. These services can then often be billed at a higher rate. In the case of treating dependence on tobacco products, any tobacco treatment specialist (TTS) employed by a practice who cares for the patient subsequent to the initial encounter can now be reimbursed in an increased manner. Better reimbursement for this vital service will ideally lead to better utilization of these resources and better public health.
The Medicare solution is here
With the CMS rule changes in 2023 and their reaffirmation in 2024, the structure has been put in place to allow physicians, medical centers, and TTSs to create contractual relationships that can significantly improve patient care. TTSs are health care professionals from a wide variety of disciplines who have received specialized training in tobacco and nicotine addiction and treatment strategies. By expanding billing and, thus, service opportunities, these CMS modifications empower health care providers to leverage the existing fee-for-service model, translating to better care and sustainable revenue streams.
Key changes in the CMS 2023 rule
One of the most notable changes involves the supervision requirements for auxiliary personnel, which now permit general supervision. Specifically, physicians are not required to be physically present during clinical encounters but can supervise TTSs virtually through real-time audio/video technology. This is a vital shift that enhances flexibility in patient care and expands the capabilities of health care teams.
According to 42 CFR § 410.26, TTSs qualify as auxiliary health care providers, meaning that they can operate under the supervision of a physician or other designated providers. This revised framework gives practices maximum autonomy in their staffing models and enhances their ability to offer comprehensive care. For example, TTSs can function as patient navigators, ensuring patients using tobacco receive medically appropriate early lung cancer screening and other related medical services.
Expanding access to behavioral health services
The changes aim not only to increase the efficiency of health care delivery but also to reflect a commitment to expanding access to vital behavioral health services. Key takeaways from a summary of the CMS 2023 rule include:
- The goal of these changes is to enhance access to behavioral health services across the board.
- The change in supervision requirements applies to auxiliary personnel offering behavioral health services incident to a physician’s services.
- Both patients and physicians will benefit from an expanded clinical team and improved reimbursement options for the services provided.
By leveraging these opportunities, physicians and their teams can collaborate with TTSs to make significant strides in helping patients address and overcome their dependence on tobacco and nicotine.
The outlook: CMS 2024 rule
The current outlook for 2024 and beyond promises even more opportunities as part of CMS’ ongoing Behavioral Health Strategy. This includes enabling mental health counselors (MHCs) and marriage and family therapists (MFTs) to bill Medicare independently, initiating vital coverage for mental health services that align with tobacco cessation efforts.
Physicians and medical centers can contract with MFTs and MHCs who are TTSs to provide tobacco addiction services. TTSs will serve as essential partners in multidisciplinary care teams, enhancing the overall health care landscape while ensuring that patients receive comprehensive support tailored to their needs.
Telehealth policy changes: Making services accessible
The White House also recently reinforced the importance of telehealth services, providing further avenues for TTSs to reach patients effectively. With expanded geographic locations for service delivery, care can be provided from virtually anywhere, including when the patient is at home.
Key telehealth provisions include:
- Extended telehealth services through 2024
- Elimination of in-person requirements for mental health services
- Expanded eligibility for providers qualified to provide telehealth services
Practical implications for providers
These developments not only simplify the establishment of tobacco treatment programs but also create better avenues to develop partnerships between physicians, hospitals, medical centers, multidisciplinary practices, and TTSs. Importantly, these clinicians will be compensated directly for the tobacco treatment services they provide.
Conclusion
This is a pivotal moment for pulmonologists and TTSs to meaningfully claim their place within the health care space. As we strive to “make smoking history,” we must act on these CMS opportunities. As providers, we must be proactive, collaborate across disciplines, and serve as advocates for our patients.
Together, we can turn the tide against tobacco use and improve health outcomes nationwide.
Call to action
CHEST encourages all health care professionals to engage with the available resources, collaborate with TTSs, and take appropriate advantage of these new policies for the benefit of our patients. Let’s work together to ensure that we seize this moment and make a real difference in the lives of those affected by tobacco addiction.
Those interested in more information—or to access additional resources and assistance in locating TTSs—please contact Matthew Bars at [email protected] or +1 (800) 45-SMOKE.
Top reads from the CHEST journal portfolio
Journal CHEST®
By Claire Launois, MD, PhD, and colleagues
It has long been a critique of studies that evaluate the impact of positive airway pressure (PAP) adherence on positive health outcomes that patients who are more adherent to PAP may also be more adherent to other health behaviors that contribute to those positive outcomes, such as incident cardiac events in patients with OSA. An association was found between multiple proxies of the healthy adherer effect and later PAP adherence in patients with OSA, the highest being related to proxies of cardiovascular health. A preceding reduction in health care costs was also found in these patients. These findings may help contribute to interpretation and validation of new studies to help us better understand the impact of PAP treatment of OSA.
– Commentary by Sreelatha Naik, MD, FCCP, Member of the CHEST Physician Editorial Board
CHEST® Critical Care
By Burton H. Shen, MD, and colleagues
Asthma is a common reason for hospital admission. Between 5% and 35% of patients who are admitted due to asthma are also admitted to the ICU during their hospital stay. For adolescents and young adults, there is variability in admission to the PICU vs adult ICU. This study specifically evaluated patients aged 12 to 26 years old and included hospitals with both a PICU and an adult ICU. The results show us that age, rather than specific clinical characteristics, is the strongest predictor for PICU admission. Patients aged 18 years and younger were more likely to be admitted to the PICU. This is an important consideration, as hospital bedspace is often more limited during viral season in pediatric hospitals and PICUs. This information is also important for outpatient asthma providers to consider as they counsel their patients and provide long-term management before and after these hospital stays.
– Commentary by Lisa Ulrich, MD, Member of the CHEST Physician Editorial Board
CHEST® Pulmonary
Short-Acting Beta-Agonists, Antibiotics, Oral Corticosteroids, and the Associated Burden of COPD
By Mohit Bhutani, MD, FCCP, and colleagues
This study notably highlights the fact that high frequency use of short-acting beta-agonists, antibiotics, and oral corticosteroids may not directly raise the likelihood of an exacerbation but rather may be a sign of worsening disease or poorly managed COPD.
Future studies should investigate the factors that contribute to patients’ frequent prescription use, such as understanding the underlying causes of their exacerbations and other pertinent factors. Additionally, details about patient adherence, a complete clinical history, and the treatment of any further chronic disorders are pivotal for a more complete picture. Enhanced methods for recognizing mild/moderate and severe exacerbations, including patient-reported outcomes, in order to have a better understanding of the influence on drug use and outcomes will be extremely helpful as well. To understand how medications impact results, further studies should look for causal links between medication use and exacerbations.
Lastly, Canadian research on COPD definitely offers insightful information, but when extrapolating these results to the United States, one must take into account variations in the health care system, demographics, and regional patterns along with social determinants of health.
– Commentary by Humayun Anjum, MD, FCCP, Member of the CHEST Physician Editorial Board
Journal CHEST®
By Claire Launois, MD, PhD, and colleagues
It has long been a critique of studies that evaluate the impact of positive airway pressure (PAP) adherence on positive health outcomes that patients who are more adherent to PAP may also be more adherent to other health behaviors that contribute to those positive outcomes, such as incident cardiac events in patients with OSA. An association was found between multiple proxies of the healthy adherer effect and later PAP adherence in patients with OSA, the highest being related to proxies of cardiovascular health. A preceding reduction in health care costs was also found in these patients. These findings may help contribute to interpretation and validation of new studies to help us better understand the impact of PAP treatment of OSA.
– Commentary by Sreelatha Naik, MD, FCCP, Member of the CHEST Physician Editorial Board
CHEST® Critical Care
By Burton H. Shen, MD, and colleagues
Asthma is a common reason for hospital admission. Between 5% and 35% of patients who are admitted due to asthma are also admitted to the ICU during their hospital stay. For adolescents and young adults, there is variability in admission to the PICU vs adult ICU. This study specifically evaluated patients aged 12 to 26 years old and included hospitals with both a PICU and an adult ICU. The results show us that age, rather than specific clinical characteristics, is the strongest predictor for PICU admission. Patients aged 18 years and younger were more likely to be admitted to the PICU. This is an important consideration, as hospital bedspace is often more limited during viral season in pediatric hospitals and PICUs. This information is also important for outpatient asthma providers to consider as they counsel their patients and provide long-term management before and after these hospital stays.
– Commentary by Lisa Ulrich, MD, Member of the CHEST Physician Editorial Board
CHEST® Pulmonary
Short-Acting Beta-Agonists, Antibiotics, Oral Corticosteroids, and the Associated Burden of COPD
By Mohit Bhutani, MD, FCCP, and colleagues
This study notably highlights the fact that high frequency use of short-acting beta-agonists, antibiotics, and oral corticosteroids may not directly raise the likelihood of an exacerbation but rather may be a sign of worsening disease or poorly managed COPD.
Future studies should investigate the factors that contribute to patients’ frequent prescription use, such as understanding the underlying causes of their exacerbations and other pertinent factors. Additionally, details about patient adherence, a complete clinical history, and the treatment of any further chronic disorders are pivotal for a more complete picture. Enhanced methods for recognizing mild/moderate and severe exacerbations, including patient-reported outcomes, in order to have a better understanding of the influence on drug use and outcomes will be extremely helpful as well. To understand how medications impact results, further studies should look for causal links between medication use and exacerbations.
Lastly, Canadian research on COPD definitely offers insightful information, but when extrapolating these results to the United States, one must take into account variations in the health care system, demographics, and regional patterns along with social determinants of health.
– Commentary by Humayun Anjum, MD, FCCP, Member of the CHEST Physician Editorial Board
Journal CHEST®
By Claire Launois, MD, PhD, and colleagues
It has long been a critique of studies that evaluate the impact of positive airway pressure (PAP) adherence on positive health outcomes that patients who are more adherent to PAP may also be more adherent to other health behaviors that contribute to those positive outcomes, such as incident cardiac events in patients with OSA. An association was found between multiple proxies of the healthy adherer effect and later PAP adherence in patients with OSA, the highest being related to proxies of cardiovascular health. A preceding reduction in health care costs was also found in these patients. These findings may help contribute to interpretation and validation of new studies to help us better understand the impact of PAP treatment of OSA.
– Commentary by Sreelatha Naik, MD, FCCP, Member of the CHEST Physician Editorial Board
CHEST® Critical Care
By Burton H. Shen, MD, and colleagues
Asthma is a common reason for hospital admission. Between 5% and 35% of patients who are admitted due to asthma are also admitted to the ICU during their hospital stay. For adolescents and young adults, there is variability in admission to the PICU vs adult ICU. This study specifically evaluated patients aged 12 to 26 years old and included hospitals with both a PICU and an adult ICU. The results show us that age, rather than specific clinical characteristics, is the strongest predictor for PICU admission. Patients aged 18 years and younger were more likely to be admitted to the PICU. This is an important consideration, as hospital bedspace is often more limited during viral season in pediatric hospitals and PICUs. This information is also important for outpatient asthma providers to consider as they counsel their patients and provide long-term management before and after these hospital stays.
– Commentary by Lisa Ulrich, MD, Member of the CHEST Physician Editorial Board
CHEST® Pulmonary
Short-Acting Beta-Agonists, Antibiotics, Oral Corticosteroids, and the Associated Burden of COPD
By Mohit Bhutani, MD, FCCP, and colleagues
This study notably highlights the fact that high frequency use of short-acting beta-agonists, antibiotics, and oral corticosteroids may not directly raise the likelihood of an exacerbation but rather may be a sign of worsening disease or poorly managed COPD.
Future studies should investigate the factors that contribute to patients’ frequent prescription use, such as understanding the underlying causes of their exacerbations and other pertinent factors. Additionally, details about patient adherence, a complete clinical history, and the treatment of any further chronic disorders are pivotal for a more complete picture. Enhanced methods for recognizing mild/moderate and severe exacerbations, including patient-reported outcomes, in order to have a better understanding of the influence on drug use and outcomes will be extremely helpful as well. To understand how medications impact results, further studies should look for causal links between medication use and exacerbations.
Lastly, Canadian research on COPD definitely offers insightful information, but when extrapolating these results to the United States, one must take into account variations in the health care system, demographics, and regional patterns along with social determinants of health.
– Commentary by Humayun Anjum, MD, FCCP, Member of the CHEST Physician Editorial Board
Biomarker use in ARDS resulting from COVID-19 infection
There is renewed interest in the use of immunomodulator therapies in patients with acute hypoxemic respiratory failure.
Beyond COVID-19, studies have also shown corticosteroid therapy improves clinical outcomes in patients with severe community-acquired pneumonia.3 However, the overwhelming majority of studies identifying plasma biomarkers that are associated with clinical outcomes in severe lung injury predate the routine use of corticosteroids.4 Two investigators at Massachusetts General Hospital, Jehan W. Alladina, MD, and George A. Alba, MD, performed a study to assess whether plasma biomarkers previously associated with clinical outcomes in ARDS maintained their predictive value in the setting of widespread immunomodulator therapy in the ICU. Drs. Alladina and Alba are physician-scientists and codirectors of the Program for Advancing Critical Care Translational Science at Massachusetts General Hospital in Boston.
In a study published in CHEST®Critical Care earlier this year, they prospectively enrolled patients with ARDS due to confirmed SARS-CoV-2 infection during the second wave of the COVID-19 pandemic from December 31, 2020, to March 31, 2021, at Massachusetts General Hospital.5 Plasma samples were collected within 24 hours of intubation for mechanical ventilation for protein analysis in 69 patients. Baseline demographics included a mean age of 62 plus or minus 15 years and a BMI of 31 plus or minus 8, and 45% were female. The median PaO2 to FiO2 ratio was 174 mm Hg, consistent with moderate ARDS, and the median duration of ventilation was 17 days. The patients had a median modified sequential organ failure assessment score of 8.5, and in-hospital mortality was 44% by 60 days. Notably, all patients in this cohort received steroids during their ICU stay.
Interestingly, the study investigators found no association between clinical outcomes and circulating proteins implicated in inflammation (eg, interleukin [IL]-6, IL-8), epithelial injury (eg, soluble receptor for advanced glycation end products, surfactant protein D), or coagulation (eg, D-dimer, tissue factor). However, four endothelial biomarkers—von Willebrand factor A2 domain; angiopoietin-2; syndecan-1; and neural precursor cell expressed, developmentally downregulated 9 (NEDD9)—were associated with 60-day mortality after adjusting for age, sex, and severity of illness. A sensitivity analysis, in which patients treated with the IL-6 inhibitor tocilizumab (n=4) were excluded, showed similar results.
Of the endothelial proteins, NEDD9 demonstrated the greatest effect size in its association with mortality in patients with ARDS due to COVID-19 who were treated with immunomodulators. NEDD9 is a scaffolding protein highly expressed in the pulmonary vascular endothelium, but its role in ARDS is not well known. In pulmonary vascular disease, plasma levels are associated with adverse pulmonary hemodynamics and clinical outcomes. Pulmonary artery endothelial NEDD9 is upregulated by cellular hypoxia and can mediate platelet-endothelial adhesion by interacting with P-selectin on the surface of activated platelets.6 Additionally, there is evidence of increased pulmonary endothelial NEDD9 expression and colocalization with fibrin within pulmonary arteries in lung tissue of patients who died from ARDS due to COVID-19.7 Thus, NEDD9 may be an important mediator of pulmonary vascular dysfunction observed in ARDS and could be a novel biomarker for patient subphenotyping and prognostication of clinical outcomes.
In summary, in a cohort of patients with COVID-19 ARDS uniformly treated with corticosteroids, plasma biomarkers of inflammation, coagulation, and epithelial injury were not associated with clinical outcomes, but endothelial biomarkers remained prognostic. It is biologically plausible that immunomodulators could attenuate the association between inflammatory biomarkers and patient outcomes. The findings of this study highlight the association of endothelial biomarkers with clinical outcomes in patients with COVID-19 ARDS treated with immunomodulators and warrant prospective validation, especially with the increasing evidence-based use of antiinflammatory therapy in acute lung injury. However, there are several important limitations to consider, including a small sample size from a single institution that precludes any definitive conclusions regarding any negative associations. Moreover, the single time point studied (the day of initiation of mechanical ventilation) and absence of a comparator group do not allow a comprehensive evaluation of the impact of antiinflammatory therapies across the trajectory of disease. Whether the findings are generalizable to all patients with ARDS treated with immunomodulators also remains unknown.
Overall, these data suggest that circulating signatures previously associated with ARDS, particularly those related to systemic inflammation, may have limited prognostic utility in the era of increasing immunomodulator use in critical illness. A deeper understanding of the pathobiology of ARDS, including the complex interplay with systemic immunomodulation, is needed to identify prognostic biomarkers and targeted therapies that improve patient outcomes.
Both authors work in the Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, in Boston.
References
1. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704.
2. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19. JAMA. 2020;324(13):1-11.
3. Dequin P-F, Meziani F, Quenot J-P, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med. 2023;388(21):1931-1941.
4. Del Valle DM, Kim-Schulze S, Huang H-H, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-1643.
5. Alladina JW, Giacona FL, Haring AM, et al. Circulating biomarkers of endothelial dysfunction associated with ventilatory ratio and mortality in ARDS resulting from SARS-CoV-2 infection treated with antiinflammatory therapies. CHEST Crit Care. 2024;2(2):100054.
6. Alba GA, Samokhin AO, Wang R-S, et al. NEDD9 is a novel and modifiable mediator of platelet-endothelial adhesion in the pulmonary circulation. Am J Respir Crit Care Med. 2021;203(12):1533-1545.
7. Alba GA, Samokhin AO, Wang R-S, et al. Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS‐CoV‐2 infection. Pulm Circ. 2022;12(2):e12071.
There is renewed interest in the use of immunomodulator therapies in patients with acute hypoxemic respiratory failure.
Beyond COVID-19, studies have also shown corticosteroid therapy improves clinical outcomes in patients with severe community-acquired pneumonia.3 However, the overwhelming majority of studies identifying plasma biomarkers that are associated with clinical outcomes in severe lung injury predate the routine use of corticosteroids.4 Two investigators at Massachusetts General Hospital, Jehan W. Alladina, MD, and George A. Alba, MD, performed a study to assess whether plasma biomarkers previously associated with clinical outcomes in ARDS maintained their predictive value in the setting of widespread immunomodulator therapy in the ICU. Drs. Alladina and Alba are physician-scientists and codirectors of the Program for Advancing Critical Care Translational Science at Massachusetts General Hospital in Boston.
In a study published in CHEST®Critical Care earlier this year, they prospectively enrolled patients with ARDS due to confirmed SARS-CoV-2 infection during the second wave of the COVID-19 pandemic from December 31, 2020, to March 31, 2021, at Massachusetts General Hospital.5 Plasma samples were collected within 24 hours of intubation for mechanical ventilation for protein analysis in 69 patients. Baseline demographics included a mean age of 62 plus or minus 15 years and a BMI of 31 plus or minus 8, and 45% were female. The median PaO2 to FiO2 ratio was 174 mm Hg, consistent with moderate ARDS, and the median duration of ventilation was 17 days. The patients had a median modified sequential organ failure assessment score of 8.5, and in-hospital mortality was 44% by 60 days. Notably, all patients in this cohort received steroids during their ICU stay.
Interestingly, the study investigators found no association between clinical outcomes and circulating proteins implicated in inflammation (eg, interleukin [IL]-6, IL-8), epithelial injury (eg, soluble receptor for advanced glycation end products, surfactant protein D), or coagulation (eg, D-dimer, tissue factor). However, four endothelial biomarkers—von Willebrand factor A2 domain; angiopoietin-2; syndecan-1; and neural precursor cell expressed, developmentally downregulated 9 (NEDD9)—were associated with 60-day mortality after adjusting for age, sex, and severity of illness. A sensitivity analysis, in which patients treated with the IL-6 inhibitor tocilizumab (n=4) were excluded, showed similar results.
Of the endothelial proteins, NEDD9 demonstrated the greatest effect size in its association with mortality in patients with ARDS due to COVID-19 who were treated with immunomodulators. NEDD9 is a scaffolding protein highly expressed in the pulmonary vascular endothelium, but its role in ARDS is not well known. In pulmonary vascular disease, plasma levels are associated with adverse pulmonary hemodynamics and clinical outcomes. Pulmonary artery endothelial NEDD9 is upregulated by cellular hypoxia and can mediate platelet-endothelial adhesion by interacting with P-selectin on the surface of activated platelets.6 Additionally, there is evidence of increased pulmonary endothelial NEDD9 expression and colocalization with fibrin within pulmonary arteries in lung tissue of patients who died from ARDS due to COVID-19.7 Thus, NEDD9 may be an important mediator of pulmonary vascular dysfunction observed in ARDS and could be a novel biomarker for patient subphenotyping and prognostication of clinical outcomes.
In summary, in a cohort of patients with COVID-19 ARDS uniformly treated with corticosteroids, plasma biomarkers of inflammation, coagulation, and epithelial injury were not associated with clinical outcomes, but endothelial biomarkers remained prognostic. It is biologically plausible that immunomodulators could attenuate the association between inflammatory biomarkers and patient outcomes. The findings of this study highlight the association of endothelial biomarkers with clinical outcomes in patients with COVID-19 ARDS treated with immunomodulators and warrant prospective validation, especially with the increasing evidence-based use of antiinflammatory therapy in acute lung injury. However, there are several important limitations to consider, including a small sample size from a single institution that precludes any definitive conclusions regarding any negative associations. Moreover, the single time point studied (the day of initiation of mechanical ventilation) and absence of a comparator group do not allow a comprehensive evaluation of the impact of antiinflammatory therapies across the trajectory of disease. Whether the findings are generalizable to all patients with ARDS treated with immunomodulators also remains unknown.
Overall, these data suggest that circulating signatures previously associated with ARDS, particularly those related to systemic inflammation, may have limited prognostic utility in the era of increasing immunomodulator use in critical illness. A deeper understanding of the pathobiology of ARDS, including the complex interplay with systemic immunomodulation, is needed to identify prognostic biomarkers and targeted therapies that improve patient outcomes.
Both authors work in the Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, in Boston.
References
1. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704.
2. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19. JAMA. 2020;324(13):1-11.
3. Dequin P-F, Meziani F, Quenot J-P, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med. 2023;388(21):1931-1941.
4. Del Valle DM, Kim-Schulze S, Huang H-H, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-1643.
5. Alladina JW, Giacona FL, Haring AM, et al. Circulating biomarkers of endothelial dysfunction associated with ventilatory ratio and mortality in ARDS resulting from SARS-CoV-2 infection treated with antiinflammatory therapies. CHEST Crit Care. 2024;2(2):100054.
6. Alba GA, Samokhin AO, Wang R-S, et al. NEDD9 is a novel and modifiable mediator of platelet-endothelial adhesion in the pulmonary circulation. Am J Respir Crit Care Med. 2021;203(12):1533-1545.
7. Alba GA, Samokhin AO, Wang R-S, et al. Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS‐CoV‐2 infection. Pulm Circ. 2022;12(2):e12071.
There is renewed interest in the use of immunomodulator therapies in patients with acute hypoxemic respiratory failure.
Beyond COVID-19, studies have also shown corticosteroid therapy improves clinical outcomes in patients with severe community-acquired pneumonia.3 However, the overwhelming majority of studies identifying plasma biomarkers that are associated with clinical outcomes in severe lung injury predate the routine use of corticosteroids.4 Two investigators at Massachusetts General Hospital, Jehan W. Alladina, MD, and George A. Alba, MD, performed a study to assess whether plasma biomarkers previously associated with clinical outcomes in ARDS maintained their predictive value in the setting of widespread immunomodulator therapy in the ICU. Drs. Alladina and Alba are physician-scientists and codirectors of the Program for Advancing Critical Care Translational Science at Massachusetts General Hospital in Boston.
In a study published in CHEST®Critical Care earlier this year, they prospectively enrolled patients with ARDS due to confirmed SARS-CoV-2 infection during the second wave of the COVID-19 pandemic from December 31, 2020, to March 31, 2021, at Massachusetts General Hospital.5 Plasma samples were collected within 24 hours of intubation for mechanical ventilation for protein analysis in 69 patients. Baseline demographics included a mean age of 62 plus or minus 15 years and a BMI of 31 plus or minus 8, and 45% were female. The median PaO2 to FiO2 ratio was 174 mm Hg, consistent with moderate ARDS, and the median duration of ventilation was 17 days. The patients had a median modified sequential organ failure assessment score of 8.5, and in-hospital mortality was 44% by 60 days. Notably, all patients in this cohort received steroids during their ICU stay.
Interestingly, the study investigators found no association between clinical outcomes and circulating proteins implicated in inflammation (eg, interleukin [IL]-6, IL-8), epithelial injury (eg, soluble receptor for advanced glycation end products, surfactant protein D), or coagulation (eg, D-dimer, tissue factor). However, four endothelial biomarkers—von Willebrand factor A2 domain; angiopoietin-2; syndecan-1; and neural precursor cell expressed, developmentally downregulated 9 (NEDD9)—were associated with 60-day mortality after adjusting for age, sex, and severity of illness. A sensitivity analysis, in which patients treated with the IL-6 inhibitor tocilizumab (n=4) were excluded, showed similar results.
Of the endothelial proteins, NEDD9 demonstrated the greatest effect size in its association with mortality in patients with ARDS due to COVID-19 who were treated with immunomodulators. NEDD9 is a scaffolding protein highly expressed in the pulmonary vascular endothelium, but its role in ARDS is not well known. In pulmonary vascular disease, plasma levels are associated with adverse pulmonary hemodynamics and clinical outcomes. Pulmonary artery endothelial NEDD9 is upregulated by cellular hypoxia and can mediate platelet-endothelial adhesion by interacting with P-selectin on the surface of activated platelets.6 Additionally, there is evidence of increased pulmonary endothelial NEDD9 expression and colocalization with fibrin within pulmonary arteries in lung tissue of patients who died from ARDS due to COVID-19.7 Thus, NEDD9 may be an important mediator of pulmonary vascular dysfunction observed in ARDS and could be a novel biomarker for patient subphenotyping and prognostication of clinical outcomes.
In summary, in a cohort of patients with COVID-19 ARDS uniformly treated with corticosteroids, plasma biomarkers of inflammation, coagulation, and epithelial injury were not associated with clinical outcomes, but endothelial biomarkers remained prognostic. It is biologically plausible that immunomodulators could attenuate the association between inflammatory biomarkers and patient outcomes. The findings of this study highlight the association of endothelial biomarkers with clinical outcomes in patients with COVID-19 ARDS treated with immunomodulators and warrant prospective validation, especially with the increasing evidence-based use of antiinflammatory therapy in acute lung injury. However, there are several important limitations to consider, including a small sample size from a single institution that precludes any definitive conclusions regarding any negative associations. Moreover, the single time point studied (the day of initiation of mechanical ventilation) and absence of a comparator group do not allow a comprehensive evaluation of the impact of antiinflammatory therapies across the trajectory of disease. Whether the findings are generalizable to all patients with ARDS treated with immunomodulators also remains unknown.
Overall, these data suggest that circulating signatures previously associated with ARDS, particularly those related to systemic inflammation, may have limited prognostic utility in the era of increasing immunomodulator use in critical illness. A deeper understanding of the pathobiology of ARDS, including the complex interplay with systemic immunomodulation, is needed to identify prognostic biomarkers and targeted therapies that improve patient outcomes.
Both authors work in the Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, in Boston.
References
1. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704.
2. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19. JAMA. 2020;324(13):1-11.
3. Dequin P-F, Meziani F, Quenot J-P, et al. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med. 2023;388(21):1931-1941.
4. Del Valle DM, Kim-Schulze S, Huang H-H, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-1643.
5. Alladina JW, Giacona FL, Haring AM, et al. Circulating biomarkers of endothelial dysfunction associated with ventilatory ratio and mortality in ARDS resulting from SARS-CoV-2 infection treated with antiinflammatory therapies. CHEST Crit Care. 2024;2(2):100054.
6. Alba GA, Samokhin AO, Wang R-S, et al. NEDD9 is a novel and modifiable mediator of platelet-endothelial adhesion in the pulmonary circulation. Am J Respir Crit Care Med. 2021;203(12):1533-1545.
7. Alba GA, Samokhin AO, Wang R-S, et al. Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS‐CoV‐2 infection. Pulm Circ. 2022;12(2):e12071.
Improved CHEST Physician® coming in 2025
FROM THE CHEST PHYSICIAN EDITORIAL BOARD – There will be some exciting changes happening at the CHEST Physician publication in 2025. We’re building on nearly three decades as a leading source of news and clinical commentary in pulmonary and critical care medicine to roll out several notable improvements.
First, the CHEST Physician website, chestphysician.org, will undergo a complete transformation. With an improved user experience, you’ll be able to more easily find content relevant to your interests and specialties.
Second, a brand-new email newsletter will hit your inbox twice a month, starting in January 2025. These emails will give you a quick look into timely content that may interest you and affect your daily practice. Additionally, this digital-first approach will get you the news and research you rely on sooner.
Lastly, the redesigned CHEST Physician print issue will now be produced and delivered on a quarterly basis. The first issue will arrive in March 2025. These special issues will feature print-exclusive content and graphics, as well as offer a deeper dive into the most relevant news stories from recent months.
Notably, all new CHEST Physician content published in the new year will be tailored to our audience and readership, and it will address the issues and topics that matter to you most as health care providers.
As the CHEST Physician publication undergoes this transformation, we want to hear from you. What topics do you want more of? How can CHEST continue to best serve the chest medicine community? Email [email protected] to share your ideas.
Thank you for being a loyal CHEST Physician reader. We look forward to bringing you elevated content and an enhanced reader experience in the new year.
FROM THE CHEST PHYSICIAN EDITORIAL BOARD – There will be some exciting changes happening at the CHEST Physician publication in 2025. We’re building on nearly three decades as a leading source of news and clinical commentary in pulmonary and critical care medicine to roll out several notable improvements.
First, the CHEST Physician website, chestphysician.org, will undergo a complete transformation. With an improved user experience, you’ll be able to more easily find content relevant to your interests and specialties.
Second, a brand-new email newsletter will hit your inbox twice a month, starting in January 2025. These emails will give you a quick look into timely content that may interest you and affect your daily practice. Additionally, this digital-first approach will get you the news and research you rely on sooner.
Lastly, the redesigned CHEST Physician print issue will now be produced and delivered on a quarterly basis. The first issue will arrive in March 2025. These special issues will feature print-exclusive content and graphics, as well as offer a deeper dive into the most relevant news stories from recent months.
Notably, all new CHEST Physician content published in the new year will be tailored to our audience and readership, and it will address the issues and topics that matter to you most as health care providers.
As the CHEST Physician publication undergoes this transformation, we want to hear from you. What topics do you want more of? How can CHEST continue to best serve the chest medicine community? Email [email protected] to share your ideas.
Thank you for being a loyal CHEST Physician reader. We look forward to bringing you elevated content and an enhanced reader experience in the new year.
FROM THE CHEST PHYSICIAN EDITORIAL BOARD – There will be some exciting changes happening at the CHEST Physician publication in 2025. We’re building on nearly three decades as a leading source of news and clinical commentary in pulmonary and critical care medicine to roll out several notable improvements.
First, the CHEST Physician website, chestphysician.org, will undergo a complete transformation. With an improved user experience, you’ll be able to more easily find content relevant to your interests and specialties.
Second, a brand-new email newsletter will hit your inbox twice a month, starting in January 2025. These emails will give you a quick look into timely content that may interest you and affect your daily practice. Additionally, this digital-first approach will get you the news and research you rely on sooner.
Lastly, the redesigned CHEST Physician print issue will now be produced and delivered on a quarterly basis. The first issue will arrive in March 2025. These special issues will feature print-exclusive content and graphics, as well as offer a deeper dive into the most relevant news stories from recent months.
Notably, all new CHEST Physician content published in the new year will be tailored to our audience and readership, and it will address the issues and topics that matter to you most as health care providers.
As the CHEST Physician publication undergoes this transformation, we want to hear from you. What topics do you want more of? How can CHEST continue to best serve the chest medicine community? Email [email protected] to share your ideas.
Thank you for being a loyal CHEST Physician reader. We look forward to bringing you elevated content and an enhanced reader experience in the new year.
AI in Medicine: Are Large Language Models Ready for the Exam Room?
In seconds, Ravi Parikh, MD, an oncologist at the Emory University School of Medicine in Atlanta, had a summary of his patient’s entire medical history. Normally, Parikh skimmed the cumbersome files before seeing a patient. However, the artificial intelligence (AI) tool his institution was testing could list the highlights he needed in a fraction of the time.
“On the whole, I like it ... it saves me time,” Parikh said of the tool. “But I’d be lying if I told you it was perfect all the time. It’s interpreting the [patient] history in some ways that may be inaccurate,” he said.
Within the first week of testing the tool, Parikh started to notice that the large language model (LLM) made a particular mistake in his patients with prostate cancer. If their prostate-specific antigen test results came back slightly elevated — which is part of normal variation — the LLM recorded it as disease progression. Because Parikh reviews all his notes — with or without using an AI tool — after a visit, he easily caught the mistake before it was added to the chart. “The problem, I think, is if these mistakes go under the hood,” he said.
In the data science world, these mistakes are called hallucinations. And a growing body of research suggests they’re happening more frequently than is safe for healthcare. The industry promised LLMs would alleviate administrative burden and reduce physician burnout. But so far, studies show these AI-tool mistakes often create more work for doctors, not less. To truly help physicians and be safe for patients, some experts say healthcare needs to build its own LLMs from the ground up. And all agree that the field desperately needs a way to vet these algorithms more thoroughly.
Prone to Error
Right now, “I think the industry is focused on taking existing LLMs and forcing them into usage for healthcare,” said Nigam H. Shah, MBBS, PhD, chief data scientist for Stanford Health. However, the value of deploying general LLMs in the healthcare space is questionable. “People are starting to wonder if we’re using these tools wrong,” he told this news organization.
In 2023, Shah and his colleagues evaluated seven LLMs on their ability to answer electronic health record–based questions. For realistic tasks, the error rate in the best cases was about 35%, he said. “To me, that rate seems a bit high ... to adopt for routine use.”
A study earlier this year by the UC San Diego School of Medicine showed that using LLMs to respond to patient messages increased the time doctors spent on messages. And this summer, a study by the clinical AI firm Mendel found that when GPT-4o or Llama-3 were used to summarize patient medical records, almost every summary contained at least one type of hallucination.
“We’ve seen cases where a patient does have drug allergies, but the system says ‘no known drug allergies’ ” in the medical history summary, said Wael Salloum, PhD, cofounder and chief science officer at Mendel. “That’s a serious hallucination.” And if physicians have to constantly verify what the system is telling them, that “defeats the purpose [of summarization],” he said.
A Higher Quality Diet
Part of the trouble with LLMs is that there’s just not enough high-quality information to feed them. The algorithms are insatiable, requiring vast swaths of data for training. GPT-3.5, for instance, was trained on 570 GB of data from the internet, more than 300 billion words. And to train GPT-4o, OpenAI reportedly transcribed more than 1 million hours of YouTube content.
However, the strategies that built these general LLMs don’t always translate well to healthcare. The internet is full of low-quality or misleading health information from wellness sites and supplement advertisements. And even data that are trustworthy, like the millions of clinical studies and the US Food and Drug Administration (FDA) statements, can be outdated, Salloum said. And “an LLM in training can’t distinguish good from bad,” he added.
The good news is that clinicians don’t rely on controversial information in the real world. Medical knowledge is standardized. “Healthcare is a domain rich with explicit knowledge,” Salloum said. So there’s potential to build a more reliable LLM that is guided by robust medical standards and guidelines.
It’s possible that healthcare could use small language models, which are LLM’s pocket-sized cousins, and perform tasks needing only bite-sized datasets requiring fewer resources and easier fine-tuning, according to Microsoft’s website. Shah said training these smaller models on real medical data might be an option, like an LLM meant to respond to patient messages that could be trained with real messages sent by physicians.
Several groups are already working on databases of standardized human medical knowledge or real physician responses. “Perhaps that will work better than using LLMs trained on the general internet. Those studies need to be done,” Shah said.
Jon Tamir, assistant professor of electrical and computer engineering and co-lead of the AI Health Lab at The University of Texas at Austin, said, “The community has recognized that we are entering a new era of AI where the dataset itself is the most important aspect. We need training sets that are highly curated and highly specialized.
“If the dataset is highly specialized, it will definitely help reduce hallucinations,” he said.
Cutting Overconfidence
A major problem with LLM mistakes is that they are often hard to detect. Hallucinations can be highly convincing even if they’re highly inaccurate, according to Tamir.
When Shah, for instance, was recently testing an LLM on de-identified patient data, he asked the LLM which blood test the patient last had. The model responded with “complete blood count [CBC].” But when he asked for the results, the model gave him white blood count and other values. “Turns out that record did not have a CBC done at all! The result was entirely made up,” he said.
Making healthcare LLMs safer and more reliable will mean training AI to acknowledge potential mistakes and uncertainty. Existing LLMs are trained to project confidence and produce a lot of answers, even when there isn’t one, Salloum said. They rarely respond with “I don’t know” even when their prediction has low confidence, he added.
Healthcare stands to benefit from a system that highlights uncertainty and potential errors. For instance, if a patient’s history shows they have smoked, stopped smoking, vaped, and started smoking again. The LLM might call them a smoker but flag the comment as uncertain because the chronology is complicated, Salloum said.
Tamir added that this strategy could improve LLM and doctor collaboration by honing in on where human expertise is needed most.
Too Little Evaluation
For any improvement strategy to work, LLMs — and all AI-assisted healthcare tools — first need a better evaluation framework. So far, LLMs have “been used in really exciting ways but not really well-vetted ways,” Tamir said.
While some AI-assisted tools, particularly in medical imaging, have undergone rigorous FDA evaluations and earned approval, most haven’t. And because the FDA only regulates algorithms that are considered medical devices, Parikh said that most LLMs used for administrative tasks and efficiency don’t fall under the regulatory agency’s purview.
But these algorithms still have access to patient information and can directly influence patient and doctor decisions. Third-party regulatory agencies are expected to emerge, but it’s still unclear who those will be. Before developers can build a safer and more efficient LLM for healthcare, they’ll need better guidelines and guardrails. “Unless we figure out evaluation, how would we know whether the healthcare-appropriate large language models are better or worse?” Shah asked.
A version of this article appeared on Medscape.com.
In seconds, Ravi Parikh, MD, an oncologist at the Emory University School of Medicine in Atlanta, had a summary of his patient’s entire medical history. Normally, Parikh skimmed the cumbersome files before seeing a patient. However, the artificial intelligence (AI) tool his institution was testing could list the highlights he needed in a fraction of the time.
“On the whole, I like it ... it saves me time,” Parikh said of the tool. “But I’d be lying if I told you it was perfect all the time. It’s interpreting the [patient] history in some ways that may be inaccurate,” he said.
Within the first week of testing the tool, Parikh started to notice that the large language model (LLM) made a particular mistake in his patients with prostate cancer. If their prostate-specific antigen test results came back slightly elevated — which is part of normal variation — the LLM recorded it as disease progression. Because Parikh reviews all his notes — with or without using an AI tool — after a visit, he easily caught the mistake before it was added to the chart. “The problem, I think, is if these mistakes go under the hood,” he said.
In the data science world, these mistakes are called hallucinations. And a growing body of research suggests they’re happening more frequently than is safe for healthcare. The industry promised LLMs would alleviate administrative burden and reduce physician burnout. But so far, studies show these AI-tool mistakes often create more work for doctors, not less. To truly help physicians and be safe for patients, some experts say healthcare needs to build its own LLMs from the ground up. And all agree that the field desperately needs a way to vet these algorithms more thoroughly.
Prone to Error
Right now, “I think the industry is focused on taking existing LLMs and forcing them into usage for healthcare,” said Nigam H. Shah, MBBS, PhD, chief data scientist for Stanford Health. However, the value of deploying general LLMs in the healthcare space is questionable. “People are starting to wonder if we’re using these tools wrong,” he told this news organization.
In 2023, Shah and his colleagues evaluated seven LLMs on their ability to answer electronic health record–based questions. For realistic tasks, the error rate in the best cases was about 35%, he said. “To me, that rate seems a bit high ... to adopt for routine use.”
A study earlier this year by the UC San Diego School of Medicine showed that using LLMs to respond to patient messages increased the time doctors spent on messages. And this summer, a study by the clinical AI firm Mendel found that when GPT-4o or Llama-3 were used to summarize patient medical records, almost every summary contained at least one type of hallucination.
“We’ve seen cases where a patient does have drug allergies, but the system says ‘no known drug allergies’ ” in the medical history summary, said Wael Salloum, PhD, cofounder and chief science officer at Mendel. “That’s a serious hallucination.” And if physicians have to constantly verify what the system is telling them, that “defeats the purpose [of summarization],” he said.
A Higher Quality Diet
Part of the trouble with LLMs is that there’s just not enough high-quality information to feed them. The algorithms are insatiable, requiring vast swaths of data for training. GPT-3.5, for instance, was trained on 570 GB of data from the internet, more than 300 billion words. And to train GPT-4o, OpenAI reportedly transcribed more than 1 million hours of YouTube content.
However, the strategies that built these general LLMs don’t always translate well to healthcare. The internet is full of low-quality or misleading health information from wellness sites and supplement advertisements. And even data that are trustworthy, like the millions of clinical studies and the US Food and Drug Administration (FDA) statements, can be outdated, Salloum said. And “an LLM in training can’t distinguish good from bad,” he added.
The good news is that clinicians don’t rely on controversial information in the real world. Medical knowledge is standardized. “Healthcare is a domain rich with explicit knowledge,” Salloum said. So there’s potential to build a more reliable LLM that is guided by robust medical standards and guidelines.
It’s possible that healthcare could use small language models, which are LLM’s pocket-sized cousins, and perform tasks needing only bite-sized datasets requiring fewer resources and easier fine-tuning, according to Microsoft’s website. Shah said training these smaller models on real medical data might be an option, like an LLM meant to respond to patient messages that could be trained with real messages sent by physicians.
Several groups are already working on databases of standardized human medical knowledge or real physician responses. “Perhaps that will work better than using LLMs trained on the general internet. Those studies need to be done,” Shah said.
Jon Tamir, assistant professor of electrical and computer engineering and co-lead of the AI Health Lab at The University of Texas at Austin, said, “The community has recognized that we are entering a new era of AI where the dataset itself is the most important aspect. We need training sets that are highly curated and highly specialized.
“If the dataset is highly specialized, it will definitely help reduce hallucinations,” he said.
Cutting Overconfidence
A major problem with LLM mistakes is that they are often hard to detect. Hallucinations can be highly convincing even if they’re highly inaccurate, according to Tamir.
When Shah, for instance, was recently testing an LLM on de-identified patient data, he asked the LLM which blood test the patient last had. The model responded with “complete blood count [CBC].” But when he asked for the results, the model gave him white blood count and other values. “Turns out that record did not have a CBC done at all! The result was entirely made up,” he said.
Making healthcare LLMs safer and more reliable will mean training AI to acknowledge potential mistakes and uncertainty. Existing LLMs are trained to project confidence and produce a lot of answers, even when there isn’t one, Salloum said. They rarely respond with “I don’t know” even when their prediction has low confidence, he added.
Healthcare stands to benefit from a system that highlights uncertainty and potential errors. For instance, if a patient’s history shows they have smoked, stopped smoking, vaped, and started smoking again. The LLM might call them a smoker but flag the comment as uncertain because the chronology is complicated, Salloum said.
Tamir added that this strategy could improve LLM and doctor collaboration by honing in on where human expertise is needed most.
Too Little Evaluation
For any improvement strategy to work, LLMs — and all AI-assisted healthcare tools — first need a better evaluation framework. So far, LLMs have “been used in really exciting ways but not really well-vetted ways,” Tamir said.
While some AI-assisted tools, particularly in medical imaging, have undergone rigorous FDA evaluations and earned approval, most haven’t. And because the FDA only regulates algorithms that are considered medical devices, Parikh said that most LLMs used for administrative tasks and efficiency don’t fall under the regulatory agency’s purview.
But these algorithms still have access to patient information and can directly influence patient and doctor decisions. Third-party regulatory agencies are expected to emerge, but it’s still unclear who those will be. Before developers can build a safer and more efficient LLM for healthcare, they’ll need better guidelines and guardrails. “Unless we figure out evaluation, how would we know whether the healthcare-appropriate large language models are better or worse?” Shah asked.
A version of this article appeared on Medscape.com.
In seconds, Ravi Parikh, MD, an oncologist at the Emory University School of Medicine in Atlanta, had a summary of his patient’s entire medical history. Normally, Parikh skimmed the cumbersome files before seeing a patient. However, the artificial intelligence (AI) tool his institution was testing could list the highlights he needed in a fraction of the time.
“On the whole, I like it ... it saves me time,” Parikh said of the tool. “But I’d be lying if I told you it was perfect all the time. It’s interpreting the [patient] history in some ways that may be inaccurate,” he said.
Within the first week of testing the tool, Parikh started to notice that the large language model (LLM) made a particular mistake in his patients with prostate cancer. If their prostate-specific antigen test results came back slightly elevated — which is part of normal variation — the LLM recorded it as disease progression. Because Parikh reviews all his notes — with or without using an AI tool — after a visit, he easily caught the mistake before it was added to the chart. “The problem, I think, is if these mistakes go under the hood,” he said.
In the data science world, these mistakes are called hallucinations. And a growing body of research suggests they’re happening more frequently than is safe for healthcare. The industry promised LLMs would alleviate administrative burden and reduce physician burnout. But so far, studies show these AI-tool mistakes often create more work for doctors, not less. To truly help physicians and be safe for patients, some experts say healthcare needs to build its own LLMs from the ground up. And all agree that the field desperately needs a way to vet these algorithms more thoroughly.
Prone to Error
Right now, “I think the industry is focused on taking existing LLMs and forcing them into usage for healthcare,” said Nigam H. Shah, MBBS, PhD, chief data scientist for Stanford Health. However, the value of deploying general LLMs in the healthcare space is questionable. “People are starting to wonder if we’re using these tools wrong,” he told this news organization.
In 2023, Shah and his colleagues evaluated seven LLMs on their ability to answer electronic health record–based questions. For realistic tasks, the error rate in the best cases was about 35%, he said. “To me, that rate seems a bit high ... to adopt for routine use.”
A study earlier this year by the UC San Diego School of Medicine showed that using LLMs to respond to patient messages increased the time doctors spent on messages. And this summer, a study by the clinical AI firm Mendel found that when GPT-4o or Llama-3 were used to summarize patient medical records, almost every summary contained at least one type of hallucination.
“We’ve seen cases where a patient does have drug allergies, but the system says ‘no known drug allergies’ ” in the medical history summary, said Wael Salloum, PhD, cofounder and chief science officer at Mendel. “That’s a serious hallucination.” And if physicians have to constantly verify what the system is telling them, that “defeats the purpose [of summarization],” he said.
A Higher Quality Diet
Part of the trouble with LLMs is that there’s just not enough high-quality information to feed them. The algorithms are insatiable, requiring vast swaths of data for training. GPT-3.5, for instance, was trained on 570 GB of data from the internet, more than 300 billion words. And to train GPT-4o, OpenAI reportedly transcribed more than 1 million hours of YouTube content.
However, the strategies that built these general LLMs don’t always translate well to healthcare. The internet is full of low-quality or misleading health information from wellness sites and supplement advertisements. And even data that are trustworthy, like the millions of clinical studies and the US Food and Drug Administration (FDA) statements, can be outdated, Salloum said. And “an LLM in training can’t distinguish good from bad,” he added.
The good news is that clinicians don’t rely on controversial information in the real world. Medical knowledge is standardized. “Healthcare is a domain rich with explicit knowledge,” Salloum said. So there’s potential to build a more reliable LLM that is guided by robust medical standards and guidelines.
It’s possible that healthcare could use small language models, which are LLM’s pocket-sized cousins, and perform tasks needing only bite-sized datasets requiring fewer resources and easier fine-tuning, according to Microsoft’s website. Shah said training these smaller models on real medical data might be an option, like an LLM meant to respond to patient messages that could be trained with real messages sent by physicians.
Several groups are already working on databases of standardized human medical knowledge or real physician responses. “Perhaps that will work better than using LLMs trained on the general internet. Those studies need to be done,” Shah said.
Jon Tamir, assistant professor of electrical and computer engineering and co-lead of the AI Health Lab at The University of Texas at Austin, said, “The community has recognized that we are entering a new era of AI where the dataset itself is the most important aspect. We need training sets that are highly curated and highly specialized.
“If the dataset is highly specialized, it will definitely help reduce hallucinations,” he said.
Cutting Overconfidence
A major problem with LLM mistakes is that they are often hard to detect. Hallucinations can be highly convincing even if they’re highly inaccurate, according to Tamir.
When Shah, for instance, was recently testing an LLM on de-identified patient data, he asked the LLM which blood test the patient last had. The model responded with “complete blood count [CBC].” But when he asked for the results, the model gave him white blood count and other values. “Turns out that record did not have a CBC done at all! The result was entirely made up,” he said.
Making healthcare LLMs safer and more reliable will mean training AI to acknowledge potential mistakes and uncertainty. Existing LLMs are trained to project confidence and produce a lot of answers, even when there isn’t one, Salloum said. They rarely respond with “I don’t know” even when their prediction has low confidence, he added.
Healthcare stands to benefit from a system that highlights uncertainty and potential errors. For instance, if a patient’s history shows they have smoked, stopped smoking, vaped, and started smoking again. The LLM might call them a smoker but flag the comment as uncertain because the chronology is complicated, Salloum said.
Tamir added that this strategy could improve LLM and doctor collaboration by honing in on where human expertise is needed most.
Too Little Evaluation
For any improvement strategy to work, LLMs — and all AI-assisted healthcare tools — first need a better evaluation framework. So far, LLMs have “been used in really exciting ways but not really well-vetted ways,” Tamir said.
While some AI-assisted tools, particularly in medical imaging, have undergone rigorous FDA evaluations and earned approval, most haven’t. And because the FDA only regulates algorithms that are considered medical devices, Parikh said that most LLMs used for administrative tasks and efficiency don’t fall under the regulatory agency’s purview.
But these algorithms still have access to patient information and can directly influence patient and doctor decisions. Third-party regulatory agencies are expected to emerge, but it’s still unclear who those will be. Before developers can build a safer and more efficient LLM for healthcare, they’ll need better guidelines and guardrails. “Unless we figure out evaluation, how would we know whether the healthcare-appropriate large language models are better or worse?” Shah asked.
A version of this article appeared on Medscape.com.
COPD Updates From CHEST 2024
Efficacy data on ensifentrine, recently FDA-approved for moderate to severe COPD, as well as dupilumab use for symptom control, are key updates in COPD from the CHEST Annual Meeting. Dharani Narendra, MD, FCCP, CHEST Physician Editorial Board Member, from Baylor College of Medicine in Houston, Texas, reports on the findings.
Dr. Narendra begins with a trial examining the role of muscle relaxants in COPD exacerbation. The results showed that patients with COPD who were taking muscle relaxants experienced a rising risk for exacerbations over 1, 3, and 5 years, with a 20% relative risk increase by year 5.
Next, Dr. Narendra reports on ensifentrine efficacy in a subgroup analysis of the ENHANCE phase 3 trial, which provided the basis for FDA approval. Ensifentrine significantly improved peak and average FEV1 at week 12, compared with placebo.
Dr. Narendra discusses a second presentation on ensifentrine — a meta-analysis of six randomized controlled trials of ensifentrine vs placebo in 2,365 patients. Significant improvements were seen in peak FEV1 and average FEV1, confirming ensifentrine efficacy in symptomatic patients with COPD with moderate to severe obstruction.
She also reviews subgroup analyses from the BOREAS and NOTUS trials, which led to the approval of dupilumab. One analysis demonstrated that dupilumab improved respiratory symptoms in patients with COPD with type 2 inflammation. Another showed significant reduction in annual exacerbation rates in patients with and without emphysema.
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Dharani K. Narendra, MD, FCCP, Assistant Professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas
Dharani K. Narendra, MD, FCCP, has disclosed no relevant financial relationships.
Efficacy data on ensifentrine, recently FDA-approved for moderate to severe COPD, as well as dupilumab use for symptom control, are key updates in COPD from the CHEST Annual Meeting. Dharani Narendra, MD, FCCP, CHEST Physician Editorial Board Member, from Baylor College of Medicine in Houston, Texas, reports on the findings.
Dr. Narendra begins with a trial examining the role of muscle relaxants in COPD exacerbation. The results showed that patients with COPD who were taking muscle relaxants experienced a rising risk for exacerbations over 1, 3, and 5 years, with a 20% relative risk increase by year 5.
Next, Dr. Narendra reports on ensifentrine efficacy in a subgroup analysis of the ENHANCE phase 3 trial, which provided the basis for FDA approval. Ensifentrine significantly improved peak and average FEV1 at week 12, compared with placebo.
Dr. Narendra discusses a second presentation on ensifentrine — a meta-analysis of six randomized controlled trials of ensifentrine vs placebo in 2,365 patients. Significant improvements were seen in peak FEV1 and average FEV1, confirming ensifentrine efficacy in symptomatic patients with COPD with moderate to severe obstruction.
She also reviews subgroup analyses from the BOREAS and NOTUS trials, which led to the approval of dupilumab. One analysis demonstrated that dupilumab improved respiratory symptoms in patients with COPD with type 2 inflammation. Another showed significant reduction in annual exacerbation rates in patients with and without emphysema.
--
Dharani K. Narendra, MD, FCCP, Assistant Professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas
Dharani K. Narendra, MD, FCCP, has disclosed no relevant financial relationships.
Efficacy data on ensifentrine, recently FDA-approved for moderate to severe COPD, as well as dupilumab use for symptom control, are key updates in COPD from the CHEST Annual Meeting. Dharani Narendra, MD, FCCP, CHEST Physician Editorial Board Member, from Baylor College of Medicine in Houston, Texas, reports on the findings.
Dr. Narendra begins with a trial examining the role of muscle relaxants in COPD exacerbation. The results showed that patients with COPD who were taking muscle relaxants experienced a rising risk for exacerbations over 1, 3, and 5 years, with a 20% relative risk increase by year 5.
Next, Dr. Narendra reports on ensifentrine efficacy in a subgroup analysis of the ENHANCE phase 3 trial, which provided the basis for FDA approval. Ensifentrine significantly improved peak and average FEV1 at week 12, compared with placebo.
Dr. Narendra discusses a second presentation on ensifentrine — a meta-analysis of six randomized controlled trials of ensifentrine vs placebo in 2,365 patients. Significant improvements were seen in peak FEV1 and average FEV1, confirming ensifentrine efficacy in symptomatic patients with COPD with moderate to severe obstruction.
She also reviews subgroup analyses from the BOREAS and NOTUS trials, which led to the approval of dupilumab. One analysis demonstrated that dupilumab improved respiratory symptoms in patients with COPD with type 2 inflammation. Another showed significant reduction in annual exacerbation rates in patients with and without emphysema.
--
Dharani K. Narendra, MD, FCCP, Assistant Professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas
Dharani K. Narendra, MD, FCCP, has disclosed no relevant financial relationships.
Cybersecurity Concerns Continue to Rise With Ransom, Data Manipulation, AI Risks
From the largest healthcare companies to solo practices, just every organization in medicine faces a risk for costly cyberattacks. In recent years, hackers have threatened to release the personal information of patients and employees — or paralyze online systems — unless they’re paid a ransom.
Should companies pay? It’s not an easy answer, a pair of experts told colleagues in an American Medical Association (AMA) cybersecurity webinar on October 18. It turns out that each choice — pay or don’t pay — can end up being costly.
This is just one of the new challenges facing the American medical system on the cybersecurity front, the speakers said. Others include the possibility that hackers will manipulate patient data — turning a medical test negative, for example, when it’s actually positive — and take advantage of the powers of artificial intelligence (AI).
The AMA held the webinar to educate physicians about cybersecurity risks and defenses, an especially hot topic in the wake of February’s Change Healthcare hack, which cost UnitedHealth Group an estimated $2.5 billion — so far — and deeply disrupted the American healthcare system.
Cautionary tales abound. Greg Garcia, executive director for cybersecurity of the Health Sector Coordinating Council, a coalition of medical industry organizations, pointed to a Pennsylvania clinic that refused to pay a ransom to prevent the release of hundreds of images of patients with breast cancer undressed from the waist up. Garcia told webinar participants that the ransom was $5 million.
Risky Choices
While the Federal Bureau of Investigation recommends against paying a ransom, this can be a risky choice, Garcia said. Hackers released the images, and the center has reportedly agreed to settle a class-action lawsuit for $65 million. “They traded $5 million for $60 million,” Garcia added, slightly misstating the settlement amount.
Health systems have been cagey about whether they’ve paid ransoms to prevent private data from being made public in cyberattacks. If a ransom is demanded, “it’s every organization for itself,” Garcia said.
He highlighted the case of a chain of psychiatry practices in Finland that suffered a ransomware attack in 2020. The hackers “contacted the patients and said: ‘Hey, call your clinic and tell them to pay the ransom. Otherwise, we’re going to release all your psychiatric notes to the public.’ ”
Cyberattacks continue. In October, Boston Children’s Health Physicians announced that it had suffered a “ recent security incident” involving data — possibly including Social Security numbers and treatment information — regarding patients and employees. A hacker group reportedly claimed responsibility and wants the system, which boasts more than 300 clinicians, to pay a ransom or else it will release the stolen information.
Should Paying Ransom Be a Crime?
Christian Dameff, MD, MS, an emergency medicine physician and director of the Center for Healthcare Cybersecurity at the University of California (UC), San Diego, noted that there are efforts to turn paying ransom into a crime. “If people aren’t paying ransoms, then ransomware operators will move to something else that makes them money.”
Dameff urged colleagues to understand we no longer live in a world where clinicians only bother to think of technology when they call the IT department to help them reset their password.
New challenges face clinicians, he said. “How do we develop better strategies, downtime procedures, and safe clinical care in an era where our vital technology may be gone, not just for an hour or 2, but as is the case with these ransomware attacks, sometimes weeks to months.”
Garcia said “cybersecurity is everybody’s responsibility, including frontline clinicians. Because you’re touching data, you’re touching technology, you’re touching patients, and all of those things combine to present some vulnerabilities in the digital world.”
Next Frontier: Hackers May Manipulate Patient Data
Dameff said future hackers may use AI to manipulate individual patient data in ways that threaten patient health. AI makes this easier to accomplish.
“What if I delete your allergies in your electronic health record, or I manipulate your chest x-ray, or I change your lab values so it looks like you’re in diabetic ketoacidosis when you’re not so a clinician gives you insulin when you don’t need it?”
Garcia highlighted another new threat: Phishing efforts that are harder to ignore thanks to AI.
“One of the most successful way that hackers get in, disrupt systems, and steal data is through email phishing, and it’s only going to get better because of artificial intelligence,” he said. “No longer are you going to have typos in that email written by a hacking group in Nigeria or in China. It’s going to be perfect looking.”
What can practices and healthcare systems do? Garcia highlighted federal health agency efforts to encourage organizations to adopt best practices in cybersecurity.
“If you’ve got a data breach, and you can show to the US Department of Health & Human Services [HHS] you have implemented generally recognized cybersecurity controls over the past year, that you have done your best, you did the right thing, and you still got hit, HHS is directed to essentially take it easy on you,” he said. “That’s a positive incentive.”
Ransomware Guide in the Works
Dameff said UC San Diego’s Center for Healthcare Cybersecurity plans to publish a free cybersecurity guide in 2025 that will include specific information about ransomware attacks for medical specialties such as cardiology, trauma surgery, and pediatrics.
“Then, should you ever be ransomed, you can pull out this guide. You’ll know what’s going to kind of happen, and you can better prepare for those effects.”
Will the future president prioritize healthcare cybersecurity? That remains to be seen, but crises do have the capacity to concentrate the mind, experts said.
The nation’s capital “has a very short memory, a short attention span. The policymakers tend to be reactive,” Dameff said. “All it takes is yet another Change Healthcare–like attack that disrupts 30% or more of the nation’s healthcare system for the policymakers to sit up, take notice, and try to come up with solutions.”
In addition, he said, an estimated two data breaches/ransomware attacks are occurring per day. “The fact is that we’re all patients, up to the President of the United States and every member of the Congress is a patient.”
There’s a “very existential, very palpable understanding that cyber safety is patient safety and cyber insecurity is patient insecurity,” Dameff said.
A version of this article appeared on Medscape.com.
From the largest healthcare companies to solo practices, just every organization in medicine faces a risk for costly cyberattacks. In recent years, hackers have threatened to release the personal information of patients and employees — or paralyze online systems — unless they’re paid a ransom.
Should companies pay? It’s not an easy answer, a pair of experts told colleagues in an American Medical Association (AMA) cybersecurity webinar on October 18. It turns out that each choice — pay or don’t pay — can end up being costly.
This is just one of the new challenges facing the American medical system on the cybersecurity front, the speakers said. Others include the possibility that hackers will manipulate patient data — turning a medical test negative, for example, when it’s actually positive — and take advantage of the powers of artificial intelligence (AI).
The AMA held the webinar to educate physicians about cybersecurity risks and defenses, an especially hot topic in the wake of February’s Change Healthcare hack, which cost UnitedHealth Group an estimated $2.5 billion — so far — and deeply disrupted the American healthcare system.
Cautionary tales abound. Greg Garcia, executive director for cybersecurity of the Health Sector Coordinating Council, a coalition of medical industry organizations, pointed to a Pennsylvania clinic that refused to pay a ransom to prevent the release of hundreds of images of patients with breast cancer undressed from the waist up. Garcia told webinar participants that the ransom was $5 million.
Risky Choices
While the Federal Bureau of Investigation recommends against paying a ransom, this can be a risky choice, Garcia said. Hackers released the images, and the center has reportedly agreed to settle a class-action lawsuit for $65 million. “They traded $5 million for $60 million,” Garcia added, slightly misstating the settlement amount.
Health systems have been cagey about whether they’ve paid ransoms to prevent private data from being made public in cyberattacks. If a ransom is demanded, “it’s every organization for itself,” Garcia said.
He highlighted the case of a chain of psychiatry practices in Finland that suffered a ransomware attack in 2020. The hackers “contacted the patients and said: ‘Hey, call your clinic and tell them to pay the ransom. Otherwise, we’re going to release all your psychiatric notes to the public.’ ”
Cyberattacks continue. In October, Boston Children’s Health Physicians announced that it had suffered a “ recent security incident” involving data — possibly including Social Security numbers and treatment information — regarding patients and employees. A hacker group reportedly claimed responsibility and wants the system, which boasts more than 300 clinicians, to pay a ransom or else it will release the stolen information.
Should Paying Ransom Be a Crime?
Christian Dameff, MD, MS, an emergency medicine physician and director of the Center for Healthcare Cybersecurity at the University of California (UC), San Diego, noted that there are efforts to turn paying ransom into a crime. “If people aren’t paying ransoms, then ransomware operators will move to something else that makes them money.”
Dameff urged colleagues to understand we no longer live in a world where clinicians only bother to think of technology when they call the IT department to help them reset their password.
New challenges face clinicians, he said. “How do we develop better strategies, downtime procedures, and safe clinical care in an era where our vital technology may be gone, not just for an hour or 2, but as is the case with these ransomware attacks, sometimes weeks to months.”
Garcia said “cybersecurity is everybody’s responsibility, including frontline clinicians. Because you’re touching data, you’re touching technology, you’re touching patients, and all of those things combine to present some vulnerabilities in the digital world.”
Next Frontier: Hackers May Manipulate Patient Data
Dameff said future hackers may use AI to manipulate individual patient data in ways that threaten patient health. AI makes this easier to accomplish.
“What if I delete your allergies in your electronic health record, or I manipulate your chest x-ray, or I change your lab values so it looks like you’re in diabetic ketoacidosis when you’re not so a clinician gives you insulin when you don’t need it?”
Garcia highlighted another new threat: Phishing efforts that are harder to ignore thanks to AI.
“One of the most successful way that hackers get in, disrupt systems, and steal data is through email phishing, and it’s only going to get better because of artificial intelligence,” he said. “No longer are you going to have typos in that email written by a hacking group in Nigeria or in China. It’s going to be perfect looking.”
What can practices and healthcare systems do? Garcia highlighted federal health agency efforts to encourage organizations to adopt best practices in cybersecurity.
“If you’ve got a data breach, and you can show to the US Department of Health & Human Services [HHS] you have implemented generally recognized cybersecurity controls over the past year, that you have done your best, you did the right thing, and you still got hit, HHS is directed to essentially take it easy on you,” he said. “That’s a positive incentive.”
Ransomware Guide in the Works
Dameff said UC San Diego’s Center for Healthcare Cybersecurity plans to publish a free cybersecurity guide in 2025 that will include specific information about ransomware attacks for medical specialties such as cardiology, trauma surgery, and pediatrics.
“Then, should you ever be ransomed, you can pull out this guide. You’ll know what’s going to kind of happen, and you can better prepare for those effects.”
Will the future president prioritize healthcare cybersecurity? That remains to be seen, but crises do have the capacity to concentrate the mind, experts said.
The nation’s capital “has a very short memory, a short attention span. The policymakers tend to be reactive,” Dameff said. “All it takes is yet another Change Healthcare–like attack that disrupts 30% or more of the nation’s healthcare system for the policymakers to sit up, take notice, and try to come up with solutions.”
In addition, he said, an estimated two data breaches/ransomware attacks are occurring per day. “The fact is that we’re all patients, up to the President of the United States and every member of the Congress is a patient.”
There’s a “very existential, very palpable understanding that cyber safety is patient safety and cyber insecurity is patient insecurity,” Dameff said.
A version of this article appeared on Medscape.com.
From the largest healthcare companies to solo practices, just every organization in medicine faces a risk for costly cyberattacks. In recent years, hackers have threatened to release the personal information of patients and employees — or paralyze online systems — unless they’re paid a ransom.
Should companies pay? It’s not an easy answer, a pair of experts told colleagues in an American Medical Association (AMA) cybersecurity webinar on October 18. It turns out that each choice — pay or don’t pay — can end up being costly.
This is just one of the new challenges facing the American medical system on the cybersecurity front, the speakers said. Others include the possibility that hackers will manipulate patient data — turning a medical test negative, for example, when it’s actually positive — and take advantage of the powers of artificial intelligence (AI).
The AMA held the webinar to educate physicians about cybersecurity risks and defenses, an especially hot topic in the wake of February’s Change Healthcare hack, which cost UnitedHealth Group an estimated $2.5 billion — so far — and deeply disrupted the American healthcare system.
Cautionary tales abound. Greg Garcia, executive director for cybersecurity of the Health Sector Coordinating Council, a coalition of medical industry organizations, pointed to a Pennsylvania clinic that refused to pay a ransom to prevent the release of hundreds of images of patients with breast cancer undressed from the waist up. Garcia told webinar participants that the ransom was $5 million.
Risky Choices
While the Federal Bureau of Investigation recommends against paying a ransom, this can be a risky choice, Garcia said. Hackers released the images, and the center has reportedly agreed to settle a class-action lawsuit for $65 million. “They traded $5 million for $60 million,” Garcia added, slightly misstating the settlement amount.
Health systems have been cagey about whether they’ve paid ransoms to prevent private data from being made public in cyberattacks. If a ransom is demanded, “it’s every organization for itself,” Garcia said.
He highlighted the case of a chain of psychiatry practices in Finland that suffered a ransomware attack in 2020. The hackers “contacted the patients and said: ‘Hey, call your clinic and tell them to pay the ransom. Otherwise, we’re going to release all your psychiatric notes to the public.’ ”
Cyberattacks continue. In October, Boston Children’s Health Physicians announced that it had suffered a “ recent security incident” involving data — possibly including Social Security numbers and treatment information — regarding patients and employees. A hacker group reportedly claimed responsibility and wants the system, which boasts more than 300 clinicians, to pay a ransom or else it will release the stolen information.
Should Paying Ransom Be a Crime?
Christian Dameff, MD, MS, an emergency medicine physician and director of the Center for Healthcare Cybersecurity at the University of California (UC), San Diego, noted that there are efforts to turn paying ransom into a crime. “If people aren’t paying ransoms, then ransomware operators will move to something else that makes them money.”
Dameff urged colleagues to understand we no longer live in a world where clinicians only bother to think of technology when they call the IT department to help them reset their password.
New challenges face clinicians, he said. “How do we develop better strategies, downtime procedures, and safe clinical care in an era where our vital technology may be gone, not just for an hour or 2, but as is the case with these ransomware attacks, sometimes weeks to months.”
Garcia said “cybersecurity is everybody’s responsibility, including frontline clinicians. Because you’re touching data, you’re touching technology, you’re touching patients, and all of those things combine to present some vulnerabilities in the digital world.”
Next Frontier: Hackers May Manipulate Patient Data
Dameff said future hackers may use AI to manipulate individual patient data in ways that threaten patient health. AI makes this easier to accomplish.
“What if I delete your allergies in your electronic health record, or I manipulate your chest x-ray, or I change your lab values so it looks like you’re in diabetic ketoacidosis when you’re not so a clinician gives you insulin when you don’t need it?”
Garcia highlighted another new threat: Phishing efforts that are harder to ignore thanks to AI.
“One of the most successful way that hackers get in, disrupt systems, and steal data is through email phishing, and it’s only going to get better because of artificial intelligence,” he said. “No longer are you going to have typos in that email written by a hacking group in Nigeria or in China. It’s going to be perfect looking.”
What can practices and healthcare systems do? Garcia highlighted federal health agency efforts to encourage organizations to adopt best practices in cybersecurity.
“If you’ve got a data breach, and you can show to the US Department of Health & Human Services [HHS] you have implemented generally recognized cybersecurity controls over the past year, that you have done your best, you did the right thing, and you still got hit, HHS is directed to essentially take it easy on you,” he said. “That’s a positive incentive.”
Ransomware Guide in the Works
Dameff said UC San Diego’s Center for Healthcare Cybersecurity plans to publish a free cybersecurity guide in 2025 that will include specific information about ransomware attacks for medical specialties such as cardiology, trauma surgery, and pediatrics.
“Then, should you ever be ransomed, you can pull out this guide. You’ll know what’s going to kind of happen, and you can better prepare for those effects.”
Will the future president prioritize healthcare cybersecurity? That remains to be seen, but crises do have the capacity to concentrate the mind, experts said.
The nation’s capital “has a very short memory, a short attention span. The policymakers tend to be reactive,” Dameff said. “All it takes is yet another Change Healthcare–like attack that disrupts 30% or more of the nation’s healthcare system for the policymakers to sit up, take notice, and try to come up with solutions.”
In addition, he said, an estimated two data breaches/ransomware attacks are occurring per day. “The fact is that we’re all patients, up to the President of the United States and every member of the Congress is a patient.”
There’s a “very existential, very palpable understanding that cyber safety is patient safety and cyber insecurity is patient insecurity,” Dameff said.
A version of this article appeared on Medscape.com.
Six Tips for Media Interviews
As a physician, you might be contacted by the media to provide your professional opinion and advice. Or you might be looking for media interview opportunities to market your practice or side project. And if you do research, media interviews can be an effective way to spread the word. It’s important to prepare for a media interview so that you achieve the outcome you are looking for.
Keep your message simple. When you are a subject expert, you might think that the basics are obvious or even boring, and that the nuances are more important. However, most of the audience is looking for big-picture information that they can apply to their lives. Consider a few key takeaways, keeping in mind that your interview is likely to be edited to short sound bites or a few quotes. It may help to jot down notes so that you cover the fundamentals clearly. You could even write and rehearse a script beforehand. If there is something complicated or subtle that you want to convey, you can preface it by saying, “This is confusing but very important …” to let the audience know to give extra consideration to what you are about to say.
Avoid extremes and hyperbole. Sometimes, exaggerated statements make their way into medical discussions. Statements such as “it doesn’t matter how many calories you consume — it’s all about the quality” are common oversimplifications. But you might be upset to see your name next to a comment like this because it is not actually correct. Check the phrasing of your key takeaways to avoid being stuck defending or explaining an inaccurate statement when your patients ask you about it later.
Ask the interviewers what they are looking for. Many medical topics have some controversial element, so it is good to know what you’re getting into. Find out the purpose of the article or interview before you decide whether it is right for you. It could be about another doctor in town who is being sued; if you don’t want to be associated with that story, it might be best to decline the interview.
Explain your goals. You might accept or pursue an interview to raise awareness about an underrecognized condition. You might want the public to identify and get help for early symptoms, or you might want to create empathy for people coping with a disease you treat. Consider why you are participating in an interview, and communicate that to the interviewer to ensure that your objective can be part of the final product.
Know whom you’re dealing with. It is good to learn about the publication/media channel before you agree to participate. It may have a political bias, or perhaps the interview is intended to promote a specific product. If you agree with and support their purposes, then you may be happy to lend your opinion. But learning about the “voice” of the publication in advance allows you to make an informed decision about whether you want to be identified with a particular political ideology or product endorsement.
Ask to see your quotes before publication. It’s good to have the opportunity to make corrections in case you are accidentally misquoted or misunderstood. It is best to ask to see quotes before you agree to the interview. Some reporters may agree to (or even prefer) a written question-and-answer format so that they can directly quote your responses without rephrasing your words. You could suggest this, especially if you are too busy for a call or live meeting.
As a physician, your insights and advice can be highly beneficial to others. You can also use media interviews to propel your career forward. Doing your homework can ensure that you will be pleased with the final product and how your words were used.
Dr. Moawad, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
As a physician, you might be contacted by the media to provide your professional opinion and advice. Or you might be looking for media interview opportunities to market your practice or side project. And if you do research, media interviews can be an effective way to spread the word. It’s important to prepare for a media interview so that you achieve the outcome you are looking for.
Keep your message simple. When you are a subject expert, you might think that the basics are obvious or even boring, and that the nuances are more important. However, most of the audience is looking for big-picture information that they can apply to their lives. Consider a few key takeaways, keeping in mind that your interview is likely to be edited to short sound bites or a few quotes. It may help to jot down notes so that you cover the fundamentals clearly. You could even write and rehearse a script beforehand. If there is something complicated or subtle that you want to convey, you can preface it by saying, “This is confusing but very important …” to let the audience know to give extra consideration to what you are about to say.
Avoid extremes and hyperbole. Sometimes, exaggerated statements make their way into medical discussions. Statements such as “it doesn’t matter how many calories you consume — it’s all about the quality” are common oversimplifications. But you might be upset to see your name next to a comment like this because it is not actually correct. Check the phrasing of your key takeaways to avoid being stuck defending or explaining an inaccurate statement when your patients ask you about it later.
Ask the interviewers what they are looking for. Many medical topics have some controversial element, so it is good to know what you’re getting into. Find out the purpose of the article or interview before you decide whether it is right for you. It could be about another doctor in town who is being sued; if you don’t want to be associated with that story, it might be best to decline the interview.
Explain your goals. You might accept or pursue an interview to raise awareness about an underrecognized condition. You might want the public to identify and get help for early symptoms, or you might want to create empathy for people coping with a disease you treat. Consider why you are participating in an interview, and communicate that to the interviewer to ensure that your objective can be part of the final product.
Know whom you’re dealing with. It is good to learn about the publication/media channel before you agree to participate. It may have a political bias, or perhaps the interview is intended to promote a specific product. If you agree with and support their purposes, then you may be happy to lend your opinion. But learning about the “voice” of the publication in advance allows you to make an informed decision about whether you want to be identified with a particular political ideology or product endorsement.
Ask to see your quotes before publication. It’s good to have the opportunity to make corrections in case you are accidentally misquoted or misunderstood. It is best to ask to see quotes before you agree to the interview. Some reporters may agree to (or even prefer) a written question-and-answer format so that they can directly quote your responses without rephrasing your words. You could suggest this, especially if you are too busy for a call or live meeting.
As a physician, your insights and advice can be highly beneficial to others. You can also use media interviews to propel your career forward. Doing your homework can ensure that you will be pleased with the final product and how your words were used.
Dr. Moawad, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
As a physician, you might be contacted by the media to provide your professional opinion and advice. Or you might be looking for media interview opportunities to market your practice or side project. And if you do research, media interviews can be an effective way to spread the word. It’s important to prepare for a media interview so that you achieve the outcome you are looking for.
Keep your message simple. When you are a subject expert, you might think that the basics are obvious or even boring, and that the nuances are more important. However, most of the audience is looking for big-picture information that they can apply to their lives. Consider a few key takeaways, keeping in mind that your interview is likely to be edited to short sound bites or a few quotes. It may help to jot down notes so that you cover the fundamentals clearly. You could even write and rehearse a script beforehand. If there is something complicated or subtle that you want to convey, you can preface it by saying, “This is confusing but very important …” to let the audience know to give extra consideration to what you are about to say.
Avoid extremes and hyperbole. Sometimes, exaggerated statements make their way into medical discussions. Statements such as “it doesn’t matter how many calories you consume — it’s all about the quality” are common oversimplifications. But you might be upset to see your name next to a comment like this because it is not actually correct. Check the phrasing of your key takeaways to avoid being stuck defending or explaining an inaccurate statement when your patients ask you about it later.
Ask the interviewers what they are looking for. Many medical topics have some controversial element, so it is good to know what you’re getting into. Find out the purpose of the article or interview before you decide whether it is right for you. It could be about another doctor in town who is being sued; if you don’t want to be associated with that story, it might be best to decline the interview.
Explain your goals. You might accept or pursue an interview to raise awareness about an underrecognized condition. You might want the public to identify and get help for early symptoms, or you might want to create empathy for people coping with a disease you treat. Consider why you are participating in an interview, and communicate that to the interviewer to ensure that your objective can be part of the final product.
Know whom you’re dealing with. It is good to learn about the publication/media channel before you agree to participate. It may have a political bias, or perhaps the interview is intended to promote a specific product. If you agree with and support their purposes, then you may be happy to lend your opinion. But learning about the “voice” of the publication in advance allows you to make an informed decision about whether you want to be identified with a particular political ideology or product endorsement.
Ask to see your quotes before publication. It’s good to have the opportunity to make corrections in case you are accidentally misquoted or misunderstood. It is best to ask to see quotes before you agree to the interview. Some reporters may agree to (or even prefer) a written question-and-answer format so that they can directly quote your responses without rephrasing your words. You could suggest this, especially if you are too busy for a call or live meeting.
As a physician, your insights and advice can be highly beneficial to others. You can also use media interviews to propel your career forward. Doing your homework can ensure that you will be pleased with the final product and how your words were used.
Dr. Moawad, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Climate Change Linked to Lung Cancer in Never-Smokers
The incidence of lung cancer in never-smokers (LCINS) is increasing, and experts think climate change may be driving the uptick.
LCINS differs histologically and epidemiologically from smoking-related cancers, occurring almost always as adenocarcinomas and mostly affecting women and individuals of Asian ancestry, according to a study published in Nature Reviews Clinical Oncology in January 2024. Cases of LCINS are estimated to be the fifth most common cause of cancer-related deaths worldwide.
These potential culprits are varied and sometimes interrelated — and they underscore the need for continued emphasis on environmental hazards, the panelists agreed.
Focusing on climate change — and taking action at the individual level — is a good place to start, said Leticia M. Nogueira, PhD, scientific director of health services research in the Surveillance and Health Equity Science Department of the American Cancer Society.
Long-Term Exposure to Wildfires Linked to Increased Cancer Risk
Climate change is associated with climate-driven disasters such as more intense hurricanes and more frequent wildfires that can expose populations to environmental carcinogens, Nogueira explained.
Such weather events disrupt the care of patients with cancer and lead to poorer outcomes, according to her own research. They also contribute to the rising incidence of LCINS, she said.
In a population-based study published in The Lancet Planetary Health, long-term exposure to wildfires was associated with an increased risk for lung cancer and brain tumors. Individuals exposed to a wildfire within 50 km of their residential locations in the prior decade has a 4.9% relatively higher incidence of lung cancer and a 10% relatively higher incidence of brain tumors.
“These findings are relevant on a global scale given the anticipated effects of climate change on wildfire frequency and severity,” the authors concluded, noting the study limitations and the need for further research.
How Clinicians Can Help
Nogueira urged attendees to take action to help improve healthcare outcomes.
“Let’s not forget that the healthcare system is one of the most emission-intensive industries in the world. Emissions from the US healthcare system exceed emission from the entire UK, and we can be doing much better.
“There is something for each one of us here today to do: We can champion environmentally responsible efforts at our institutions, we can engage with disaster preparedness and response ... and we can document ongoing suffering to increase awareness and incentivize action,” she said.
In a commentary published in CA: A Cancer Journal for Clinicians, Nogueira and her colleagues further addressed the links between climate change and cancer and listed various sources of greenhouse gas emissions and proposed interventions, including those associated with the healthcare industry.
“If you look at this list and say ‘No way — there is no chance my institution will do any of that,’ let me ask you something: Are you allowed to smoke on campus? How do you think that happened? How do you think that started?” she said, invoking Archimedes’ famous quote, “Give me a lever long enough, and I shall move the world.”
“You most certainly have the power to make a difference,” Nogueira said. “So recognize where your points of influence are – move your lever, move the world.”
A version of this article appeared on Medscape.com.
The incidence of lung cancer in never-smokers (LCINS) is increasing, and experts think climate change may be driving the uptick.
LCINS differs histologically and epidemiologically from smoking-related cancers, occurring almost always as adenocarcinomas and mostly affecting women and individuals of Asian ancestry, according to a study published in Nature Reviews Clinical Oncology in January 2024. Cases of LCINS are estimated to be the fifth most common cause of cancer-related deaths worldwide.
These potential culprits are varied and sometimes interrelated — and they underscore the need for continued emphasis on environmental hazards, the panelists agreed.
Focusing on climate change — and taking action at the individual level — is a good place to start, said Leticia M. Nogueira, PhD, scientific director of health services research in the Surveillance and Health Equity Science Department of the American Cancer Society.
Long-Term Exposure to Wildfires Linked to Increased Cancer Risk
Climate change is associated with climate-driven disasters such as more intense hurricanes and more frequent wildfires that can expose populations to environmental carcinogens, Nogueira explained.
Such weather events disrupt the care of patients with cancer and lead to poorer outcomes, according to her own research. They also contribute to the rising incidence of LCINS, she said.
In a population-based study published in The Lancet Planetary Health, long-term exposure to wildfires was associated with an increased risk for lung cancer and brain tumors. Individuals exposed to a wildfire within 50 km of their residential locations in the prior decade has a 4.9% relatively higher incidence of lung cancer and a 10% relatively higher incidence of brain tumors.
“These findings are relevant on a global scale given the anticipated effects of climate change on wildfire frequency and severity,” the authors concluded, noting the study limitations and the need for further research.
How Clinicians Can Help
Nogueira urged attendees to take action to help improve healthcare outcomes.
“Let’s not forget that the healthcare system is one of the most emission-intensive industries in the world. Emissions from the US healthcare system exceed emission from the entire UK, and we can be doing much better.
“There is something for each one of us here today to do: We can champion environmentally responsible efforts at our institutions, we can engage with disaster preparedness and response ... and we can document ongoing suffering to increase awareness and incentivize action,” she said.
In a commentary published in CA: A Cancer Journal for Clinicians, Nogueira and her colleagues further addressed the links between climate change and cancer and listed various sources of greenhouse gas emissions and proposed interventions, including those associated with the healthcare industry.
“If you look at this list and say ‘No way — there is no chance my institution will do any of that,’ let me ask you something: Are you allowed to smoke on campus? How do you think that happened? How do you think that started?” she said, invoking Archimedes’ famous quote, “Give me a lever long enough, and I shall move the world.”
“You most certainly have the power to make a difference,” Nogueira said. “So recognize where your points of influence are – move your lever, move the world.”
A version of this article appeared on Medscape.com.
The incidence of lung cancer in never-smokers (LCINS) is increasing, and experts think climate change may be driving the uptick.
LCINS differs histologically and epidemiologically from smoking-related cancers, occurring almost always as adenocarcinomas and mostly affecting women and individuals of Asian ancestry, according to a study published in Nature Reviews Clinical Oncology in January 2024. Cases of LCINS are estimated to be the fifth most common cause of cancer-related deaths worldwide.
These potential culprits are varied and sometimes interrelated — and they underscore the need for continued emphasis on environmental hazards, the panelists agreed.
Focusing on climate change — and taking action at the individual level — is a good place to start, said Leticia M. Nogueira, PhD, scientific director of health services research in the Surveillance and Health Equity Science Department of the American Cancer Society.
Long-Term Exposure to Wildfires Linked to Increased Cancer Risk
Climate change is associated with climate-driven disasters such as more intense hurricanes and more frequent wildfires that can expose populations to environmental carcinogens, Nogueira explained.
Such weather events disrupt the care of patients with cancer and lead to poorer outcomes, according to her own research. They also contribute to the rising incidence of LCINS, she said.
In a population-based study published in The Lancet Planetary Health, long-term exposure to wildfires was associated with an increased risk for lung cancer and brain tumors. Individuals exposed to a wildfire within 50 km of their residential locations in the prior decade has a 4.9% relatively higher incidence of lung cancer and a 10% relatively higher incidence of brain tumors.
“These findings are relevant on a global scale given the anticipated effects of climate change on wildfire frequency and severity,” the authors concluded, noting the study limitations and the need for further research.
How Clinicians Can Help
Nogueira urged attendees to take action to help improve healthcare outcomes.
“Let’s not forget that the healthcare system is one of the most emission-intensive industries in the world. Emissions from the US healthcare system exceed emission from the entire UK, and we can be doing much better.
“There is something for each one of us here today to do: We can champion environmentally responsible efforts at our institutions, we can engage with disaster preparedness and response ... and we can document ongoing suffering to increase awareness and incentivize action,” she said.
In a commentary published in CA: A Cancer Journal for Clinicians, Nogueira and her colleagues further addressed the links between climate change and cancer and listed various sources of greenhouse gas emissions and proposed interventions, including those associated with the healthcare industry.
“If you look at this list and say ‘No way — there is no chance my institution will do any of that,’ let me ask you something: Are you allowed to smoke on campus? How do you think that happened? How do you think that started?” she said, invoking Archimedes’ famous quote, “Give me a lever long enough, and I shall move the world.”
“You most certainly have the power to make a difference,” Nogueira said. “So recognize where your points of influence are – move your lever, move the world.”
A version of this article appeared on Medscape.com.
Should First-Line Dual Checkpoint Blockade Be Used for NSCLC With Specific Mutations?
according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.
according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.
according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.