The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.

“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.

The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).

In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.

Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.

Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.

Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.

The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.

Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.

“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.

Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.

Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.

bjancin@mdedge.com

SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.

The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.

“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.

The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).

In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.

Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.

Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.

Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.

The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.

Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.

“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.

Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.

Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.

bjancin@mdedge.com

SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.

The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.

“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.

The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).

In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.

Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.

Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.

Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.

The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.

Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.

“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.

Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.

Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.

bjancin@mdedge.com

SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.

“I do not shrink from this responsibility – I welcome it.” – John F. Kennedy, inaugural address

COVID-19 has changed our world. Social distancing is now the norm and flattening the curve is our motto. Family physicians’ place on the front line of medicine is more important now than it has ever been.

In the Pennsylvania community in which we work, the first person to don protective gear and sample patients for viral testing in a rapidly organized COVID-19 testing site was John Russell, MD, a family physician. When I asked him about his experience, Dr. Russell said: “No one became a fireman to get cats out of trees ... it was to fight fires. As doctors, this is the same idea ... this is a chance to help fight the fires in our community.”

And, of course, it is primary care providers – family physicians, internists, pediatricians, nurse practitioners, physician assistants, and nurses – who day in and day out are putting aside their own fears, while dealing with those of their family, to come to work with a sense of purpose and courage.

The military uses the term “operational tempo” to describe the speed and intensity of actions relative to the speed and intensity of unfolding events in the operational environment. Family physicians are being asked to work at an increased speed in unfamiliar terrain as our environments change by the hour. The challenge is to answer the call – and take care of ourselves – in unprecedented ways. We often use anticipatory guidance with our patients to help prepare them for the challenges they will face. So too must we anticipate the things we will need to be attentive to in the coming months in order to sustain the effort that will be required of us.

With this in mind, we would be wise to consider developing plans in three domains: physical, mental, and social.

With gyms closed and restaurants limiting their offerings to take-out, this is an opportune time to create an exercise regimen at home and experiment with healthy meal options. YouTube videos abound for workouts of every length. And of course, you can simply take a daily walk, go for a run, or take a bike ride. Similarly, good choices can be made with take-out and the foods we prepare at home.

To take care of our mental health, we need to have the discipline to take breaks, delegate when necessary, and use downtime to clear our minds. Need another option? Consider meditation. Google “best meditation apps” and take your pick.

From a social standpoint, we must be proactive about preventing emotional isolation. Technology allows us to connect with others through messaging and face-to-face video. We need to remember to regularly check in with those we care about; few things in life are as affirming as the connections with those who are close to us: ­family, coworkers, and patients.

Out of crisis comes opportunity. Should we be quarantined, we can remind ourselves that Sir Isaac Newton, while in quarantine during the bubonic plague, laid the foundation for classical physics, composed theories on light and optics, and penned his first draft of the law of gravity.¹

Life carries on amidst the ­pandemic. Even though the current focus is on the ­COVID-19 crisis, our many needs, joys, and challenges as human beings remain. Today, someone will find out she is pregnant and someone else will be diagnosed with cancer, plan a wedding, or attend the funeral of a loved one. We, as family physicians, have the training to lead with courage and empathy. We have the expertise gained through years of helping patients though diverse physical and emotional challenges.

We will continue to listen to our patients’ stories, diagnose and treat their diseases, and take steps to bring a sense of calm to the chaos around us. We need to be mindful of our own mindset, because we have a choice. As the psychologist Victor Frankl said in 1946 after being liberated from the concentration camps, “Everything can be taken from a man but one thing: the last of the human freedoms – to choose one’s attitude in any given set of circumstances, to choose one’s own way.”²
 

A version of this commentary originally appeared in the Journal of Family Practice (J Fam Pract. 2020 April;69[3]:119,153).

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Aaron Sutton is a behavioral health consultant and faculty member in the family medicine residency program at Abington Jefferson Health.

References

1. Brockell G. “During a pandemic, Isaac Newton had to work from home, too. He used the time wisely.” The Washington Post. 2020 Mar 12.

2. Frankl VE. “Man’s Search for Meaning.” Boston: Beacon Press, 2006.

“I do not shrink from this responsibility – I welcome it.” – John F. Kennedy, inaugural address

COVID-19 has changed our world. Social distancing is now the norm and flattening the curve is our motto. Family physicians’ place on the front line of medicine is more important now than it has ever been.

In the Pennsylvania community in which we work, the first person to don protective gear and sample patients for viral testing in a rapidly organized COVID-19 testing site was John Russell, MD, a family physician. When I asked him about his experience, Dr. Russell said: “No one became a fireman to get cats out of trees ... it was to fight fires. As doctors, this is the same idea ... this is a chance to help fight the fires in our community.”

And, of course, it is primary care providers – family physicians, internists, pediatricians, nurse practitioners, physician assistants, and nurses – who day in and day out are putting aside their own fears, while dealing with those of their family, to come to work with a sense of purpose and courage.

The military uses the term “operational tempo” to describe the speed and intensity of actions relative to the speed and intensity of unfolding events in the operational environment. Family physicians are being asked to work at an increased speed in unfamiliar terrain as our environments change by the hour. The challenge is to answer the call – and take care of ourselves – in unprecedented ways. We often use anticipatory guidance with our patients to help prepare them for the challenges they will face. So too must we anticipate the things we will need to be attentive to in the coming months in order to sustain the effort that will be required of us.

With this in mind, we would be wise to consider developing plans in three domains: physical, mental, and social.

With gyms closed and restaurants limiting their offerings to take-out, this is an opportune time to create an exercise regimen at home and experiment with healthy meal options. YouTube videos abound for workouts of every length. And of course, you can simply take a daily walk, go for a run, or take a bike ride. Similarly, good choices can be made with take-out and the foods we prepare at home.

To take care of our mental health, we need to have the discipline to take breaks, delegate when necessary, and use downtime to clear our minds. Need another option? Consider meditation. Google “best meditation apps” and take your pick.

From a social standpoint, we must be proactive about preventing emotional isolation. Technology allows us to connect with others through messaging and face-to-face video. We need to remember to regularly check in with those we care about; few things in life are as affirming as the connections with those who are close to us: ­family, coworkers, and patients.

Out of crisis comes opportunity. Should we be quarantined, we can remind ourselves that Sir Isaac Newton, while in quarantine during the bubonic plague, laid the foundation for classical physics, composed theories on light and optics, and penned his first draft of the law of gravity.¹

Life carries on amidst the ­pandemic. Even though the current focus is on the ­COVID-19 crisis, our many needs, joys, and challenges as human beings remain. Today, someone will find out she is pregnant and someone else will be diagnosed with cancer, plan a wedding, or attend the funeral of a loved one. We, as family physicians, have the training to lead with courage and empathy. We have the expertise gained through years of helping patients though diverse physical and emotional challenges.

We will continue to listen to our patients’ stories, diagnose and treat their diseases, and take steps to bring a sense of calm to the chaos around us. We need to be mindful of our own mindset, because we have a choice. As the psychologist Victor Frankl said in 1946 after being liberated from the concentration camps, “Everything can be taken from a man but one thing: the last of the human freedoms – to choose one’s attitude in any given set of circumstances, to choose one’s own way.”²
 

A version of this commentary originally appeared in the Journal of Family Practice (J Fam Pract. 2020 April;69[3]:119,153).

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Aaron Sutton is a behavioral health consultant and faculty member in the family medicine residency program at Abington Jefferson Health.

References

1. Brockell G. “During a pandemic, Isaac Newton had to work from home, too. He used the time wisely.” The Washington Post. 2020 Mar 12.

2. Frankl VE. “Man’s Search for Meaning.” Boston: Beacon Press, 2006.

“I do not shrink from this responsibility – I welcome it.” – John F. Kennedy, inaugural address

COVID-19 has changed our world. Social distancing is now the norm and flattening the curve is our motto. Family physicians’ place on the front line of medicine is more important now than it has ever been.

In the Pennsylvania community in which we work, the first person to don protective gear and sample patients for viral testing in a rapidly organized COVID-19 testing site was John Russell, MD, a family physician. When I asked him about his experience, Dr. Russell said: “No one became a fireman to get cats out of trees ... it was to fight fires. As doctors, this is the same idea ... this is a chance to help fight the fires in our community.”

And, of course, it is primary care providers – family physicians, internists, pediatricians, nurse practitioners, physician assistants, and nurses – who day in and day out are putting aside their own fears, while dealing with those of their family, to come to work with a sense of purpose and courage.

The military uses the term “operational tempo” to describe the speed and intensity of actions relative to the speed and intensity of unfolding events in the operational environment. Family physicians are being asked to work at an increased speed in unfamiliar terrain as our environments change by the hour. The challenge is to answer the call – and take care of ourselves – in unprecedented ways. We often use anticipatory guidance with our patients to help prepare them for the challenges they will face. So too must we anticipate the things we will need to be attentive to in the coming months in order to sustain the effort that will be required of us.

With this in mind, we would be wise to consider developing plans in three domains: physical, mental, and social.

With gyms closed and restaurants limiting their offerings to take-out, this is an opportune time to create an exercise regimen at home and experiment with healthy meal options. YouTube videos abound for workouts of every length. And of course, you can simply take a daily walk, go for a run, or take a bike ride. Similarly, good choices can be made with take-out and the foods we prepare at home.

To take care of our mental health, we need to have the discipline to take breaks, delegate when necessary, and use downtime to clear our minds. Need another option? Consider meditation. Google “best meditation apps” and take your pick.

From a social standpoint, we must be proactive about preventing emotional isolation. Technology allows us to connect with others through messaging and face-to-face video. We need to remember to regularly check in with those we care about; few things in life are as affirming as the connections with those who are close to us: ­family, coworkers, and patients.

Out of crisis comes opportunity. Should we be quarantined, we can remind ourselves that Sir Isaac Newton, while in quarantine during the bubonic plague, laid the foundation for classical physics, composed theories on light and optics, and penned his first draft of the law of gravity.¹

Life carries on amidst the ­pandemic. Even though the current focus is on the ­COVID-19 crisis, our many needs, joys, and challenges as human beings remain. Today, someone will find out she is pregnant and someone else will be diagnosed with cancer, plan a wedding, or attend the funeral of a loved one. We, as family physicians, have the training to lead with courage and empathy. We have the expertise gained through years of helping patients though diverse physical and emotional challenges.

We will continue to listen to our patients’ stories, diagnose and treat their diseases, and take steps to bring a sense of calm to the chaos around us. We need to be mindful of our own mindset, because we have a choice. As the psychologist Victor Frankl said in 1946 after being liberated from the concentration camps, “Everything can be taken from a man but one thing: the last of the human freedoms – to choose one’s attitude in any given set of circumstances, to choose one’s own way.”²
 

A version of this commentary originally appeared in the Journal of Family Practice (J Fam Pract. 2020 April;69[3]:119,153).

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Aaron Sutton is a behavioral health consultant and faculty member in the family medicine residency program at Abington Jefferson Health.

References

1. Brockell G. “During a pandemic, Isaac Newton had to work from home, too. He used the time wisely.” The Washington Post. 2020 Mar 12.

2. Frankl VE. “Man’s Search for Meaning.” Boston: Beacon Press, 2006.

It is becoming increasingly clear that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients.

Newly published data from New York show that, among those aged under 60 years, obesity was twice as likely to result in hospitalization for COVID-19 and also significantly increased the likelihood that a person would end up in intensive care.

“Obesity [in people younger than 60] appears to be a previously unrecognized risk factor for hospital admission and need for critical care. This has important and practical implications when nearly 40% of adults in the U.S. are obese with a body mass index [BMI] of [at least] 30,” wrote Jennifer Lighter, MD, of New York University Langone Health, and colleagues in their research letter published in Clinical Infectious Diseases.

Similar findings in a preprint publication, yet to be peer reviewed, from another New York hospital show that, with the exception of older age, obesity (BMI greater than 40 kg/m²) had the strongest association with hospitalization for COVID-19, increasing the risk more than 500%.

Meanwhile, a new French study shows a high frequency of obesity among patients admitted to one ICU for COVID-19; furthermore, disease severity increased with increasing BMI. One of the authors said in an interview that many of the presenting patients were younger, with their only risk factor being obesity.

“Patients with obesity should avoid any COVID-19 contamination by enforcing all prevention measures during the current pandemic,” wrote the authors, led by Arthur Simonnet, MD, Centre Hospitalier Universitaire de Lille (France).

They also stressed that COVID-19 patients “with severe obesity should be monitored more closely.”
 

Those with obesity are young and become very sick, very quickly

François Pattou, MD, PhD, coauthor of the French article published in Obesity said in an interview that, when patients with COVID-19 began to arrive at their ICU in Lille, there were young patients who did not have any other comorbidities.

“They were just obese,” he observed, adding that they seemed “to have a very specific disease, something different” from that seen before, with patients becoming very sick, very quickly.

In their study, they examined 124 consecutive patients admitted to intensive care with COVID-19 between Feb. 25 and April 5, 2020, and compared them with a historical control group of 306 patients admitted to the ICU at the same hospital for non–COVID-19-related severe acute respiratory disease in 2019.

By April 6, 60 patients with COVID-19 had been discharged from intensive care, 18 had died, and 46 remained in the unit. The majority (73%) were male, and their median age was 60 years. Obesity and severe obesity were significantly more prevalent among the patients with COVID-19, at 47.6% and 28.2% versus 25.2% and 10.8% among historical controls (P < .001 for trend).

A key finding was that those with a BMI greater than 35 had a more than 600% increased risk of requiring mechanical ventilation (odds ratio, 7.36; P = .021), compared with those with a BMI less than 25, even after adjusting for age, diabetes, and hypertension.
 

Obesity in under 60s at least doubles risk of admission in U.S.

The studies out of New York, one of which was stratified by age, paint a similar picture.

Dr. Lighter and colleagues found that, of the 3,615 individuals who tested positive for COVID-19 in their series, 775 (21%) had a BMI of 30-34 and 595 (16%) had a BMI of at least 35. Obesity wasn’t a predictor of admission to hospital or the ICU in those over the age of 60 years, but in those younger than 60 years, it was.

Those under age 60 with a BMI of 30-34 were twice as likely to be admitted to hospital (hazard ratio, 2.0; P < .0001) and critical care (HR, 1.8; P = .006), compared with those under age 60 with a BMI less than 30. Likewise, those under age 60 with a BMI of at least 35 were 2.2 (P < .0001) and 3.6 (P < .0001) times more likely to be admitted to acute and critical care.

“Unfortunately, obesity in people [less than] 60 years is a newly identified epidemiologic risk factor which may contribute to increased morbidity rates [with COVID-19] experienced in the U.S.,” they concluded.

And in the other U.S. study, Christopher M. Petrilli, MD, of New York University, and colleagues looked at 4,103 patients with COVID-19 treated between March 1 and April 2, 2020, and followed to April 7.

Just under half of patients (48.7%) were hospitalized, of whom 22.3% required mechanical ventilation and 14.6% died or were discharged to hospice. The research was published on medRxiv, showing that, apart from age, the strongest predictors of hospitalization were BMI greater than 40 (OR, 6.2) and heart failure (OR, 4.3).

“It is notable that the chronic condition with the strongest association with critical illness was obesity, with a substantially higher odds ratio than any cardiovascular or pulmonary disease,” they noted.
 

Inflammation is a possible culprit

Dr. Pattou believes that the culprit behind the increased risk of disease severity seen with obesity in COVID-19 is inflammation, mediated by fibrin deposits in the circulation, which his colleagues have seen on autopsy, and which “block oxygen passage through the blood.”

This may help explain why mechanical ventilation can be less successful in these patients. “The answer is to get rid of this inflammation,” Dr. Pattou observed.

Dr. Petrilli and colleagues also observed that obesity “is well-recognized to be a proinflammatory condition.”

And their findings showed “the importance of inflammatory markers in distinguishing future critical from noncritical illness,” they said, noting that, among these markers, early elevations in C-reactive protein and D-dimer “had the strongest association with mechanical ventilation or mortality.”

Livio Luzi, MD, of IRCCS MultiMedica, Milan, Italy, has previously written on the relationship between influenza and obesity, and discussed in an interview the potential lessons for the COVID-19 pandemic.

“Obesity is characterized by an impairment of immune response and by a low-grade chronic inflammation. Furthermore, obese subjects have an altered dynamic of pulmonary ventilation, with reduced diaphragmatic excursion,” Dr. Luzi said. These factors, alongside others, “may help to explain” the current results, and stress the importance of close monitoring of those with obesity and COVID-19.

No relevant financial relationships were declared.

This article first appeared on Medscape.com.

It is becoming increasingly clear that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients.

Newly published data from New York show that, among those aged under 60 years, obesity was twice as likely to result in hospitalization for COVID-19 and also significantly increased the likelihood that a person would end up in intensive care.

“Obesity [in people younger than 60] appears to be a previously unrecognized risk factor for hospital admission and need for critical care. This has important and practical implications when nearly 40% of adults in the U.S. are obese with a body mass index [BMI] of [at least] 30,” wrote Jennifer Lighter, MD, of New York University Langone Health, and colleagues in their research letter published in Clinical Infectious Diseases.

Similar findings in a preprint publication, yet to be peer reviewed, from another New York hospital show that, with the exception of older age, obesity (BMI greater than 40 kg/m²) had the strongest association with hospitalization for COVID-19, increasing the risk more than 500%.

Meanwhile, a new French study shows a high frequency of obesity among patients admitted to one ICU for COVID-19; furthermore, disease severity increased with increasing BMI. One of the authors said in an interview that many of the presenting patients were younger, with their only risk factor being obesity.

“Patients with obesity should avoid any COVID-19 contamination by enforcing all prevention measures during the current pandemic,” wrote the authors, led by Arthur Simonnet, MD, Centre Hospitalier Universitaire de Lille (France).

They also stressed that COVID-19 patients “with severe obesity should be monitored more closely.”
 

Those with obesity are young and become very sick, very quickly

François Pattou, MD, PhD, coauthor of the French article published in Obesity said in an interview that, when patients with COVID-19 began to arrive at their ICU in Lille, there were young patients who did not have any other comorbidities.

“They were just obese,” he observed, adding that they seemed “to have a very specific disease, something different” from that seen before, with patients becoming very sick, very quickly.

In their study, they examined 124 consecutive patients admitted to intensive care with COVID-19 between Feb. 25 and April 5, 2020, and compared them with a historical control group of 306 patients admitted to the ICU at the same hospital for non–COVID-19-related severe acute respiratory disease in 2019.

By April 6, 60 patients with COVID-19 had been discharged from intensive care, 18 had died, and 46 remained in the unit. The majority (73%) were male, and their median age was 60 years. Obesity and severe obesity were significantly more prevalent among the patients with COVID-19, at 47.6% and 28.2% versus 25.2% and 10.8% among historical controls (P < .001 for trend).

A key finding was that those with a BMI greater than 35 had a more than 600% increased risk of requiring mechanical ventilation (odds ratio, 7.36; P = .021), compared with those with a BMI less than 25, even after adjusting for age, diabetes, and hypertension.
 

Obesity in under 60s at least doubles risk of admission in U.S.

The studies out of New York, one of which was stratified by age, paint a similar picture.

Dr. Lighter and colleagues found that, of the 3,615 individuals who tested positive for COVID-19 in their series, 775 (21%) had a BMI of 30-34 and 595 (16%) had a BMI of at least 35. Obesity wasn’t a predictor of admission to hospital or the ICU in those over the age of 60 years, but in those younger than 60 years, it was.

Those under age 60 with a BMI of 30-34 were twice as likely to be admitted to hospital (hazard ratio, 2.0; P < .0001) and critical care (HR, 1.8; P = .006), compared with those under age 60 with a BMI less than 30. Likewise, those under age 60 with a BMI of at least 35 were 2.2 (P < .0001) and 3.6 (P < .0001) times more likely to be admitted to acute and critical care.

“Unfortunately, obesity in people [less than] 60 years is a newly identified epidemiologic risk factor which may contribute to increased morbidity rates [with COVID-19] experienced in the U.S.,” they concluded.

And in the other U.S. study, Christopher M. Petrilli, MD, of New York University, and colleagues looked at 4,103 patients with COVID-19 treated between March 1 and April 2, 2020, and followed to April 7.

Just under half of patients (48.7%) were hospitalized, of whom 22.3% required mechanical ventilation and 14.6% died or were discharged to hospice. The research was published on medRxiv, showing that, apart from age, the strongest predictors of hospitalization were BMI greater than 40 (OR, 6.2) and heart failure (OR, 4.3).

“It is notable that the chronic condition with the strongest association with critical illness was obesity, with a substantially higher odds ratio than any cardiovascular or pulmonary disease,” they noted.
 

Inflammation is a possible culprit

Dr. Pattou believes that the culprit behind the increased risk of disease severity seen with obesity in COVID-19 is inflammation, mediated by fibrin deposits in the circulation, which his colleagues have seen on autopsy, and which “block oxygen passage through the blood.”

This may help explain why mechanical ventilation can be less successful in these patients. “The answer is to get rid of this inflammation,” Dr. Pattou observed.

Dr. Petrilli and colleagues also observed that obesity “is well-recognized to be a proinflammatory condition.”

And their findings showed “the importance of inflammatory markers in distinguishing future critical from noncritical illness,” they said, noting that, among these markers, early elevations in C-reactive protein and D-dimer “had the strongest association with mechanical ventilation or mortality.”

Livio Luzi, MD, of IRCCS MultiMedica, Milan, Italy, has previously written on the relationship between influenza and obesity, and discussed in an interview the potential lessons for the COVID-19 pandemic.

“Obesity is characterized by an impairment of immune response and by a low-grade chronic inflammation. Furthermore, obese subjects have an altered dynamic of pulmonary ventilation, with reduced diaphragmatic excursion,” Dr. Luzi said. These factors, alongside others, “may help to explain” the current results, and stress the importance of close monitoring of those with obesity and COVID-19.

No relevant financial relationships were declared.

This article first appeared on Medscape.com.

It is becoming increasingly clear that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients.

Newly published data from New York show that, among those aged under 60 years, obesity was twice as likely to result in hospitalization for COVID-19 and also significantly increased the likelihood that a person would end up in intensive care.

“Obesity [in people younger than 60] appears to be a previously unrecognized risk factor for hospital admission and need for critical care. This has important and practical implications when nearly 40% of adults in the U.S. are obese with a body mass index [BMI] of [at least] 30,” wrote Jennifer Lighter, MD, of New York University Langone Health, and colleagues in their research letter published in Clinical Infectious Diseases.

Similar findings in a preprint publication, yet to be peer reviewed, from another New York hospital show that, with the exception of older age, obesity (BMI greater than 40 kg/m²) had the strongest association with hospitalization for COVID-19, increasing the risk more than 500%.

Meanwhile, a new French study shows a high frequency of obesity among patients admitted to one ICU for COVID-19; furthermore, disease severity increased with increasing BMI. One of the authors said in an interview that many of the presenting patients were younger, with their only risk factor being obesity.

“Patients with obesity should avoid any COVID-19 contamination by enforcing all prevention measures during the current pandemic,” wrote the authors, led by Arthur Simonnet, MD, Centre Hospitalier Universitaire de Lille (France).

They also stressed that COVID-19 patients “with severe obesity should be monitored more closely.”
 

Those with obesity are young and become very sick, very quickly

François Pattou, MD, PhD, coauthor of the French article published in Obesity said in an interview that, when patients with COVID-19 began to arrive at their ICU in Lille, there were young patients who did not have any other comorbidities.

“They were just obese,” he observed, adding that they seemed “to have a very specific disease, something different” from that seen before, with patients becoming very sick, very quickly.

In their study, they examined 124 consecutive patients admitted to intensive care with COVID-19 between Feb. 25 and April 5, 2020, and compared them with a historical control group of 306 patients admitted to the ICU at the same hospital for non–COVID-19-related severe acute respiratory disease in 2019.

By April 6, 60 patients with COVID-19 had been discharged from intensive care, 18 had died, and 46 remained in the unit. The majority (73%) were male, and their median age was 60 years. Obesity and severe obesity were significantly more prevalent among the patients with COVID-19, at 47.6% and 28.2% versus 25.2% and 10.8% among historical controls (P < .001 for trend).

A key finding was that those with a BMI greater than 35 had a more than 600% increased risk of requiring mechanical ventilation (odds ratio, 7.36; P = .021), compared with those with a BMI less than 25, even after adjusting for age, diabetes, and hypertension.
 

Obesity in under 60s at least doubles risk of admission in U.S.

The studies out of New York, one of which was stratified by age, paint a similar picture.

Dr. Lighter and colleagues found that, of the 3,615 individuals who tested positive for COVID-19 in their series, 775 (21%) had a BMI of 30-34 and 595 (16%) had a BMI of at least 35. Obesity wasn’t a predictor of admission to hospital or the ICU in those over the age of 60 years, but in those younger than 60 years, it was.

Those under age 60 with a BMI of 30-34 were twice as likely to be admitted to hospital (hazard ratio, 2.0; P < .0001) and critical care (HR, 1.8; P = .006), compared with those under age 60 with a BMI less than 30. Likewise, those under age 60 with a BMI of at least 35 were 2.2 (P < .0001) and 3.6 (P < .0001) times more likely to be admitted to acute and critical care.

“Unfortunately, obesity in people [less than] 60 years is a newly identified epidemiologic risk factor which may contribute to increased morbidity rates [with COVID-19] experienced in the U.S.,” they concluded.

And in the other U.S. study, Christopher M. Petrilli, MD, of New York University, and colleagues looked at 4,103 patients with COVID-19 treated between March 1 and April 2, 2020, and followed to April 7.

Just under half of patients (48.7%) were hospitalized, of whom 22.3% required mechanical ventilation and 14.6% died or were discharged to hospice. The research was published on medRxiv, showing that, apart from age, the strongest predictors of hospitalization were BMI greater than 40 (OR, 6.2) and heart failure (OR, 4.3).

“It is notable that the chronic condition with the strongest association with critical illness was obesity, with a substantially higher odds ratio than any cardiovascular or pulmonary disease,” they noted.
 

Inflammation is a possible culprit

Dr. Pattou believes that the culprit behind the increased risk of disease severity seen with obesity in COVID-19 is inflammation, mediated by fibrin deposits in the circulation, which his colleagues have seen on autopsy, and which “block oxygen passage through the blood.”

This may help explain why mechanical ventilation can be less successful in these patients. “The answer is to get rid of this inflammation,” Dr. Pattou observed.

Dr. Petrilli and colleagues also observed that obesity “is well-recognized to be a proinflammatory condition.”

And their findings showed “the importance of inflammatory markers in distinguishing future critical from noncritical illness,” they said, noting that, among these markers, early elevations in C-reactive protein and D-dimer “had the strongest association with mechanical ventilation or mortality.”

Livio Luzi, MD, of IRCCS MultiMedica, Milan, Italy, has previously written on the relationship between influenza and obesity, and discussed in an interview the potential lessons for the COVID-19 pandemic.

“Obesity is characterized by an impairment of immune response and by a low-grade chronic inflammation. Furthermore, obese subjects have an altered dynamic of pulmonary ventilation, with reduced diaphragmatic excursion,” Dr. Luzi said. These factors, alongside others, “may help to explain” the current results, and stress the importance of close monitoring of those with obesity and COVID-19.

No relevant financial relationships were declared.

This article first appeared on Medscape.com.

Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.

The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.

“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”

Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.

The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.

After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.

Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.

dbrunk@mdedge.com

SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.

Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.

The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.

“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”

Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.

The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.

After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.

Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.

dbrunk@mdedge.com

SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.

Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.

The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.

“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”

Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.

The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.

After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.

Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.

dbrunk@mdedge.com

SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.

COVID-19 has prompted many changes in pediatric health care. They say necessity is the mother of invention. Sometimes, necessity is the motivator for the long-past-due adoption of a previous invention, such as telemedicine for minor illnesses. And sometimes necessity reminds us about what is really important in a world of high technology.

Nicola Marfisi/AGF/Universal Images Group/Science Source

Unlike our nearly overwhelmed internal medicine, ED, and family physician colleagues, many pediatricians are in a lull that threatens the financial viability of our practices. We are postponing annual well visits. We have fewer sick visits and hospitalizations since respiratory syncytial virus (RSV) and influenza also have been reduced by social distancing. Parents are avoiding the risk of contagion in the waiting room and not bringing their children in for minor complaints. There is more telemedicine – a welcome change in financing and practice whose time has come, but was being delayed by lack of insurance coverage.

Technology has allowed clinicians to respond to the pandemic in ways that would not have been possible a few years ago. Online tools, such as subscription email lists, webinars, and electronic medical news services, provide updates when the information changes weekly on the virus’s contagiousness, asymptomatic and presymptomatic transmission, prevalence, the effectiveness of masks, and experimental treatment options. These changes have been so fast that many journal articles based on data from China were obsolete and contradicted before they appeared in print.

However, technology only helped us to more effectively do what we needed to do in the first place – come together in a world of physical distancing and work toward common goals. In many hospitals, pediatric wards were emptied by reduced RSV admissions and postponed elective surgeries. These units have been converted to accept adult patients up to age 30 or 40 years. Our med-peds colleagues quickly created webinars and online resource packages on topics pediatric hospitalists might need to care for that population. There were refresher courses on ventilator management and reminders that community pediatric hospitalists, who in the winter might have one-third of their admissions with RSV, have more experience managing viral pneumonia than the internists.

Ward teams were created with a pediatric attending and an internal medicine resident. The resident’s familiarity with the names of blood pressure medicines complemented the attending’s years of clinical judgment and bedside manner. People are stepping out of their comfort zones but initial reports from the front lines are that, with each other’s support, we’ve got this.

Mistakes in telemedicine are being made, shared, and learned from. Emergency physicians are collecting anecdotes of situations when things were missed or treatment delayed. Surgeons report seeing increased numbers of cases in which the diagnosis of appendicitis was delayed, which isn’t surprising when a pediatrician cannot lay hands on the belly. Perhaps any case in which a parent calls a second or third time should be seen in the flesh.

Some newborn nurseries are discharging mother and baby at 24 hours after birth and rediscovering what was learned about that practice, which became common in the 1990s. It works well for the vast majority of babies, but we need to be ready to detect the occasional jaundiced baby or the one where breastfeeding isn’t going well. The gray-haired pediatricians can recall those nuances.

Another key role is to help everyone process the frequent deaths during a pandemic. First, there are the families we care for. Children are losing grandparents with little warning. Parents may be overwhelmed with grief while ill themselves. That makes children vulnerable.

Our medical system in 2 months has moved heaven and earth – and significantly harmed the medical care and financial future of our children – trying to assure that every 80-year-old has the right to die while attached to a ventilator, even though only a small fraction of them will survive to discharge. Meanwhile, on the wards, visitation policies have people deteriorating and dying alone. I find this paradigm distressing and antithetical to my training.

Medicine and nursing both have long histories in which the practitioner recognized that there was little they could do to prevent the death. Their role was to compassionately guide the family through it. For some people, this connection is the most precious of the arts of medicine and nursing. We need to reexamine our values. We need to get creative. We need to involve palliative care experts and clergy with the same urgency with which we have automakers making ventilators.

Second, there are our colleagues. Pediatric caregivers, particularly trainees, rarely encounter deaths and can benefit from debriefing sessions, even short ones. There is comfort in having a colleague review the situation and say: “There was nothing you could have done.” Or even: “That minor omission did not alter the outcome.” Even when everything was done properly, deaths cause moral suffering that needs processing and healing. Even if you don’t have magic words to give, just being present aids in the healing. We are all in this, together.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. He has no relevant financial disclosures. Email him at pdnews@mdedge.com.

COVID-19 has prompted many changes in pediatric health care. They say necessity is the mother of invention. Sometimes, necessity is the motivator for the long-past-due adoption of a previous invention, such as telemedicine for minor illnesses. And sometimes necessity reminds us about what is really important in a world of high technology.

Nicola Marfisi/AGF/Universal Images Group/Science Source

Unlike our nearly overwhelmed internal medicine, ED, and family physician colleagues, many pediatricians are in a lull that threatens the financial viability of our practices. We are postponing annual well visits. We have fewer sick visits and hospitalizations since respiratory syncytial virus (RSV) and influenza also have been reduced by social distancing. Parents are avoiding the risk of contagion in the waiting room and not bringing their children in for minor complaints. There is more telemedicine – a welcome change in financing and practice whose time has come, but was being delayed by lack of insurance coverage.

Technology has allowed clinicians to respond to the pandemic in ways that would not have been possible a few years ago. Online tools, such as subscription email lists, webinars, and electronic medical news services, provide updates when the information changes weekly on the virus’s contagiousness, asymptomatic and presymptomatic transmission, prevalence, the effectiveness of masks, and experimental treatment options. These changes have been so fast that many journal articles based on data from China were obsolete and contradicted before they appeared in print.

However, technology only helped us to more effectively do what we needed to do in the first place – come together in a world of physical distancing and work toward common goals. In many hospitals, pediatric wards were emptied by reduced RSV admissions and postponed elective surgeries. These units have been converted to accept adult patients up to age 30 or 40 years. Our med-peds colleagues quickly created webinars and online resource packages on topics pediatric hospitalists might need to care for that population. There were refresher courses on ventilator management and reminders that community pediatric hospitalists, who in the winter might have one-third of their admissions with RSV, have more experience managing viral pneumonia than the internists.

Ward teams were created with a pediatric attending and an internal medicine resident. The resident’s familiarity with the names of blood pressure medicines complemented the attending’s years of clinical judgment and bedside manner. People are stepping out of their comfort zones but initial reports from the front lines are that, with each other’s support, we’ve got this.

Mistakes in telemedicine are being made, shared, and learned from. Emergency physicians are collecting anecdotes of situations when things were missed or treatment delayed. Surgeons report seeing increased numbers of cases in which the diagnosis of appendicitis was delayed, which isn’t surprising when a pediatrician cannot lay hands on the belly. Perhaps any case in which a parent calls a second or third time should be seen in the flesh.

Some newborn nurseries are discharging mother and baby at 24 hours after birth and rediscovering what was learned about that practice, which became common in the 1990s. It works well for the vast majority of babies, but we need to be ready to detect the occasional jaundiced baby or the one where breastfeeding isn’t going well. The gray-haired pediatricians can recall those nuances.

Another key role is to help everyone process the frequent deaths during a pandemic. First, there are the families we care for. Children are losing grandparents with little warning. Parents may be overwhelmed with grief while ill themselves. That makes children vulnerable.

Our medical system in 2 months has moved heaven and earth – and significantly harmed the medical care and financial future of our children – trying to assure that every 80-year-old has the right to die while attached to a ventilator, even though only a small fraction of them will survive to discharge. Meanwhile, on the wards, visitation policies have people deteriorating and dying alone. I find this paradigm distressing and antithetical to my training.

Medicine and nursing both have long histories in which the practitioner recognized that there was little they could do to prevent the death. Their role was to compassionately guide the family through it. For some people, this connection is the most precious of the arts of medicine and nursing. We need to reexamine our values. We need to get creative. We need to involve palliative care experts and clergy with the same urgency with which we have automakers making ventilators.

Second, there are our colleagues. Pediatric caregivers, particularly trainees, rarely encounter deaths and can benefit from debriefing sessions, even short ones. There is comfort in having a colleague review the situation and say: “There was nothing you could have done.” Or even: “That minor omission did not alter the outcome.” Even when everything was done properly, deaths cause moral suffering that needs processing and healing. Even if you don’t have magic words to give, just being present aids in the healing. We are all in this, together.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. He has no relevant financial disclosures. Email him at pdnews@mdedge.com.

COVID-19 has prompted many changes in pediatric health care. They say necessity is the mother of invention. Sometimes, necessity is the motivator for the long-past-due adoption of a previous invention, such as telemedicine for minor illnesses. And sometimes necessity reminds us about what is really important in a world of high technology.

Nicola Marfisi/AGF/Universal Images Group/Science Source

Unlike our nearly overwhelmed internal medicine, ED, and family physician colleagues, many pediatricians are in a lull that threatens the financial viability of our practices. We are postponing annual well visits. We have fewer sick visits and hospitalizations since respiratory syncytial virus (RSV) and influenza also have been reduced by social distancing. Parents are avoiding the risk of contagion in the waiting room and not bringing their children in for minor complaints. There is more telemedicine – a welcome change in financing and practice whose time has come, but was being delayed by lack of insurance coverage.

Technology has allowed clinicians to respond to the pandemic in ways that would not have been possible a few years ago. Online tools, such as subscription email lists, webinars, and electronic medical news services, provide updates when the information changes weekly on the virus’s contagiousness, asymptomatic and presymptomatic transmission, prevalence, the effectiveness of masks, and experimental treatment options. These changes have been so fast that many journal articles based on data from China were obsolete and contradicted before they appeared in print.

However, technology only helped us to more effectively do what we needed to do in the first place – come together in a world of physical distancing and work toward common goals. In many hospitals, pediatric wards were emptied by reduced RSV admissions and postponed elective surgeries. These units have been converted to accept adult patients up to age 30 or 40 years. Our med-peds colleagues quickly created webinars and online resource packages on topics pediatric hospitalists might need to care for that population. There were refresher courses on ventilator management and reminders that community pediatric hospitalists, who in the winter might have one-third of their admissions with RSV, have more experience managing viral pneumonia than the internists.

Ward teams were created with a pediatric attending and an internal medicine resident. The resident’s familiarity with the names of blood pressure medicines complemented the attending’s years of clinical judgment and bedside manner. People are stepping out of their comfort zones but initial reports from the front lines are that, with each other’s support, we’ve got this.

Mistakes in telemedicine are being made, shared, and learned from. Emergency physicians are collecting anecdotes of situations when things were missed or treatment delayed. Surgeons report seeing increased numbers of cases in which the diagnosis of appendicitis was delayed, which isn’t surprising when a pediatrician cannot lay hands on the belly. Perhaps any case in which a parent calls a second or third time should be seen in the flesh.

Some newborn nurseries are discharging mother and baby at 24 hours after birth and rediscovering what was learned about that practice, which became common in the 1990s. It works well for the vast majority of babies, but we need to be ready to detect the occasional jaundiced baby or the one where breastfeeding isn’t going well. The gray-haired pediatricians can recall those nuances.

Another key role is to help everyone process the frequent deaths during a pandemic. First, there are the families we care for. Children are losing grandparents with little warning. Parents may be overwhelmed with grief while ill themselves. That makes children vulnerable.

Our medical system in 2 months has moved heaven and earth – and significantly harmed the medical care and financial future of our children – trying to assure that every 80-year-old has the right to die while attached to a ventilator, even though only a small fraction of them will survive to discharge. Meanwhile, on the wards, visitation policies have people deteriorating and dying alone. I find this paradigm distressing and antithetical to my training.

Medicine and nursing both have long histories in which the practitioner recognized that there was little they could do to prevent the death. Their role was to compassionately guide the family through it. For some people, this connection is the most precious of the arts of medicine and nursing. We need to reexamine our values. We need to get creative. We need to involve palliative care experts and clergy with the same urgency with which we have automakers making ventilators.

Second, there are our colleagues. Pediatric caregivers, particularly trainees, rarely encounter deaths and can benefit from debriefing sessions, even short ones. There is comfort in having a colleague review the situation and say: “There was nothing you could have done.” Or even: “That minor omission did not alter the outcome.” Even when everything was done properly, deaths cause moral suffering that needs processing and healing. Even if you don’t have magic words to give, just being present aids in the healing. We are all in this, together.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. He has no relevant financial disclosures. Email him at pdnews@mdedge.com.

A clofarabine-based treatment was found to be safe and effective in refractory/relapsed acute myeloid leukemia (AML) in the phase 2 CLAM trial.

The CLAM protocol treatment was clofarabine, cytarabine, and mitoxantrone (intravenous infusion, days 1‐5), cytarabine (intravenous infusion starting 4 hours after clofarabine, days 1‐5), and mitoxantrone (intravenous infusion, days 3‐5).

Bone marrow aspiration and trephine biopsy were performed on day 28. A total of 52 patients (16 women), with an age range of 22-65 years and refractory/relapsed AML were treated.

The overall response rate after the first cycle of CLAM was 90.4% (complete remission, 69.2%; CR with incomplete hematologic recovery, 21.2%). In addition, the efficacy of CLAM was not apparently affected by high‐risk karyotypes and genetic mutations among the patients.

Patients with a response (marrow < 5% blasts) received a maximum of two cycles of CLAM consolidation, each at 50% dose reduction, given 6‐8 weeks apart. Responding patients with an HLA‐matched sibling or volunteer‐unrelated donor were offered allogeneic hematopoietic stem cell transplantation (HSCT). Toxicity of CLAM was manageable and did not compromise subsequent allogeneic HSCT, the researchers added.

“In this era of molecular targeting, CLAM might still have a role to play,” according to the researchers. “It offers the advantage of a highly effective regimen that is readily available. It provides a median DOR of 5 months, which is meaningful for organization of HSCT. Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT.”

No disclosures or conflicts of interest were reported.

mlesney@mdedge.com

SOURCE: Gill H et al. Cancer Med. 2020 Mar 20. doi:10.1002/cam4.2865.

A clofarabine-based treatment was found to be safe and effective in refractory/relapsed acute myeloid leukemia (AML) in the phase 2 CLAM trial.

The CLAM protocol treatment was clofarabine, cytarabine, and mitoxantrone (intravenous infusion, days 1‐5), cytarabine (intravenous infusion starting 4 hours after clofarabine, days 1‐5), and mitoxantrone (intravenous infusion, days 3‐5).

Bone marrow aspiration and trephine biopsy were performed on day 28. A total of 52 patients (16 women), with an age range of 22-65 years and refractory/relapsed AML were treated.

The overall response rate after the first cycle of CLAM was 90.4% (complete remission, 69.2%; CR with incomplete hematologic recovery, 21.2%). In addition, the efficacy of CLAM was not apparently affected by high‐risk karyotypes and genetic mutations among the patients.

Patients with a response (marrow < 5% blasts) received a maximum of two cycles of CLAM consolidation, each at 50% dose reduction, given 6‐8 weeks apart. Responding patients with an HLA‐matched sibling or volunteer‐unrelated donor were offered allogeneic hematopoietic stem cell transplantation (HSCT). Toxicity of CLAM was manageable and did not compromise subsequent allogeneic HSCT, the researchers added.

“In this era of molecular targeting, CLAM might still have a role to play,” according to the researchers. “It offers the advantage of a highly effective regimen that is readily available. It provides a median DOR of 5 months, which is meaningful for organization of HSCT. Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT.”

No disclosures or conflicts of interest were reported.

mlesney@mdedge.com

SOURCE: Gill H et al. Cancer Med. 2020 Mar 20. doi:10.1002/cam4.2865.

A clofarabine-based treatment was found to be safe and effective in refractory/relapsed acute myeloid leukemia (AML) in the phase 2 CLAM trial.

The CLAM protocol treatment was clofarabine, cytarabine, and mitoxantrone (intravenous infusion, days 1‐5), cytarabine (intravenous infusion starting 4 hours after clofarabine, days 1‐5), and mitoxantrone (intravenous infusion, days 3‐5).

Bone marrow aspiration and trephine biopsy were performed on day 28. A total of 52 patients (16 women), with an age range of 22-65 years and refractory/relapsed AML were treated.

The overall response rate after the first cycle of CLAM was 90.4% (complete remission, 69.2%; CR with incomplete hematologic recovery, 21.2%). In addition, the efficacy of CLAM was not apparently affected by high‐risk karyotypes and genetic mutations among the patients.

Patients with a response (marrow < 5% blasts) received a maximum of two cycles of CLAM consolidation, each at 50% dose reduction, given 6‐8 weeks apart. Responding patients with an HLA‐matched sibling or volunteer‐unrelated donor were offered allogeneic hematopoietic stem cell transplantation (HSCT). Toxicity of CLAM was manageable and did not compromise subsequent allogeneic HSCT, the researchers added.

“In this era of molecular targeting, CLAM might still have a role to play,” according to the researchers. “It offers the advantage of a highly effective regimen that is readily available. It provides a median DOR of 5 months, which is meaningful for organization of HSCT. Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT.”

No disclosures or conflicts of interest were reported.

mlesney@mdedge.com

SOURCE: Gill H et al. Cancer Med. 2020 Mar 20. doi:10.1002/cam4.2865.

The Diagnosis: Majocchi Granuloma 

Majocchi granuloma (MG) is a dermatophytic infection that reveals hyphal elements within the cornified cells of follicles and most commonly is caused by Trichophyton rubrum. However, occasionally other Trichophyton, Trichosporon, and Aspergillus species are involved.¹  

There typically are 2 forms of MG: (1) the small perifollicular papular form that usually is localized to the dermis and occurs in immunocompetent individuals, and (2) a deep form featuring subcutaneous plaques and nodules that generally occur on the hair-bearing surfaces in immunosuppressed hosts.² Majocchi granuloma also commonly occurs from the use of potent topical steroids on unsuspected tinea.³  

Histopathologically, MG generally presents as granulomatous inflammation with perifollicular neutrophilic infiltration. This polymorphonuclear cell infiltrate was visible clinically as a single pustule overlying the nodular plaque, a clue appreciable only on close inspection. Histopathologic examination revealed segmented branching filaments present within cornified elements of a follicle (Figure). Notably, potassium hydroxide (KOH) preparations are unreliable diagnostic aids in MG, as evidenced by the 2 negative KOH preparations in this case. According to Chou and Hsu,⁴ because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for MG due to deeper invasion of the fungi into the dermal follicular component. In fact, KOH preparations of MG may reveal no hyphae in 23.3% of cases.²  

The initiating factor in MG is not entirely known but is thought to be physical trauma that either directly or indirectly leads to follicle disruption and passive introduction of the organism into the dermis (eg, traumatic implantation via gardening or other recreational activities).² Other proposed mechanisms include the presentation of the membrane-associated ATP-binding cassette transporter on the surface of T rubrum.¹ Dermatophytes evade the host immune system through a variety of mechanisms: (1) cell wall glycoproteins, (2) release of anti-inflammatory cytokines, and (3) generation of immunosuppressive regulatory T cells.¹ 

Collectively, the clinical and histopathologic findings distinguish MG from other cutaneous conditions. Sporotrichosis, a granulomatous infection caused by Sporothrix schenckii, typically is found in tropical regions of the world and often is associated with floriculture.⁵ Sporotrichosis initially presents in a subcutaneous papulonodular form, but unlike MG, it later ulcerates and progresses along adjacent lymphatic chains.⁵ Pathology of sporotrichosis exhibits pseudoepitheliomatous hyperplasia with granulomas, possible foci of suppuration, and yeastlike forms called cigar bodies. Chromoblastomycosis clinically is defined by tumorlike lesions on the skin including verrucous, nodular, or scarlike plaques and typically is associated with traumatic injury and implantation of the microorganism. Histologically, chromoblastomycosis demonstrates pseudoepitheliomatous hyperplasia with granulomas and characteristic darkly pigmented, thick-walled sclerotic cells called Medlar bodies.⁶ Mycobacterium marinum is one cause of nontuberculous mycobacterial skin infections in humans. Clinically, M marinum is associated with improper hygiene techniques and contact with fish tanks and other aqueous environments. Mycobacterium marinum can present histopathologically as early neutrophilic infiltration or late dermal granulomatous inflammation.⁷ Acid-fast bacilli typically are scant, leaving the diagnosis best secured via polymerase chain reaction assay. Nodular Kaposi sarcoma (KS) can present as a dusky nodular plaque on an acral surface but typically is seen in patients with underlying human immunodeficiency virus/AIDS or other immunosuppressive conditions. The pathology for KS shows a proliferation of human herpes virus 8-positive spindle cells with slitlike spaces containing red blood cells instead of granulomatous inflammation. 

Treatment regimens with topical corticosteroids can exacerbate the infection due to local suppression of cell-mediated immunity.⁸ In these scenarios, fungal infection is suspected, and systemic antifungals such as ketoconazole; itraconazole; or terbinafine, which has become the mainstay, are prescribed. Resolution of the infection with these medications usually is seen after 4 weeks.² 

A diagnosis of MG can be elusive and often may take multiple visits. Clinicians should note that MG could demonstrate repeated false-negative KOH preparations; therefore, these tests should not be relied on as the sole determination of a diagnosis. Although chromoblastomycosis, sporotrichosis, nodular KS, and infection with M marinum may all present as nodular plaques with granulomatous pathology, a follicular pustule may be a clinical clue to MG, as its mimics typically lack folliculocentric neutrophils.

The Diagnosis: Majocchi Granuloma 

Majocchi granuloma (MG) is a dermatophytic infection that reveals hyphal elements within the cornified cells of follicles and most commonly is caused by Trichophyton rubrum. However, occasionally other Trichophyton, Trichosporon, and Aspergillus species are involved.¹  

There typically are 2 forms of MG: (1) the small perifollicular papular form that usually is localized to the dermis and occurs in immunocompetent individuals, and (2) a deep form featuring subcutaneous plaques and nodules that generally occur on the hair-bearing surfaces in immunosuppressed hosts.² Majocchi granuloma also commonly occurs from the use of potent topical steroids on unsuspected tinea.³  

Histopathologically, MG generally presents as granulomatous inflammation with perifollicular neutrophilic infiltration. This polymorphonuclear cell infiltrate was visible clinically as a single pustule overlying the nodular plaque, a clue appreciable only on close inspection. Histopathologic examination revealed segmented branching filaments present within cornified elements of a follicle (Figure). Notably, potassium hydroxide (KOH) preparations are unreliable diagnostic aids in MG, as evidenced by the 2 negative KOH preparations in this case. According to Chou and Hsu,⁴ because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for MG due to deeper invasion of the fungi into the dermal follicular component. In fact, KOH preparations of MG may reveal no hyphae in 23.3% of cases.²  

The initiating factor in MG is not entirely known but is thought to be physical trauma that either directly or indirectly leads to follicle disruption and passive introduction of the organism into the dermis (eg, traumatic implantation via gardening or other recreational activities).² Other proposed mechanisms include the presentation of the membrane-associated ATP-binding cassette transporter on the surface of T rubrum.¹ Dermatophytes evade the host immune system through a variety of mechanisms: (1) cell wall glycoproteins, (2) release of anti-inflammatory cytokines, and (3) generation of immunosuppressive regulatory T cells.¹ 

Collectively, the clinical and histopathologic findings distinguish MG from other cutaneous conditions. Sporotrichosis, a granulomatous infection caused by Sporothrix schenckii, typically is found in tropical regions of the world and often is associated with floriculture.⁵ Sporotrichosis initially presents in a subcutaneous papulonodular form, but unlike MG, it later ulcerates and progresses along adjacent lymphatic chains.⁵ Pathology of sporotrichosis exhibits pseudoepitheliomatous hyperplasia with granulomas, possible foci of suppuration, and yeastlike forms called cigar bodies. Chromoblastomycosis clinically is defined by tumorlike lesions on the skin including verrucous, nodular, or scarlike plaques and typically is associated with traumatic injury and implantation of the microorganism. Histologically, chromoblastomycosis demonstrates pseudoepitheliomatous hyperplasia with granulomas and characteristic darkly pigmented, thick-walled sclerotic cells called Medlar bodies.⁶ Mycobacterium marinum is one cause of nontuberculous mycobacterial skin infections in humans. Clinically, M marinum is associated with improper hygiene techniques and contact with fish tanks and other aqueous environments. Mycobacterium marinum can present histopathologically as early neutrophilic infiltration or late dermal granulomatous inflammation.⁷ Acid-fast bacilli typically are scant, leaving the diagnosis best secured via polymerase chain reaction assay. Nodular Kaposi sarcoma (KS) can present as a dusky nodular plaque on an acral surface but typically is seen in patients with underlying human immunodeficiency virus/AIDS or other immunosuppressive conditions. The pathology for KS shows a proliferation of human herpes virus 8-positive spindle cells with slitlike spaces containing red blood cells instead of granulomatous inflammation. 

Treatment regimens with topical corticosteroids can exacerbate the infection due to local suppression of cell-mediated immunity.⁸ In these scenarios, fungal infection is suspected, and systemic antifungals such as ketoconazole; itraconazole; or terbinafine, which has become the mainstay, are prescribed. Resolution of the infection with these medications usually is seen after 4 weeks.² 

A diagnosis of MG can be elusive and often may take multiple visits. Clinicians should note that MG could demonstrate repeated false-negative KOH preparations; therefore, these tests should not be relied on as the sole determination of a diagnosis. Although chromoblastomycosis, sporotrichosis, nodular KS, and infection with M marinum may all present as nodular plaques with granulomatous pathology, a follicular pustule may be a clinical clue to MG, as its mimics typically lack folliculocentric neutrophils.

The Diagnosis: Majocchi Granuloma 

Majocchi granuloma (MG) is a dermatophytic infection that reveals hyphal elements within the cornified cells of follicles and most commonly is caused by Trichophyton rubrum. However, occasionally other Trichophyton, Trichosporon, and Aspergillus species are involved.¹  

There typically are 2 forms of MG: (1) the small perifollicular papular form that usually is localized to the dermis and occurs in immunocompetent individuals, and (2) a deep form featuring subcutaneous plaques and nodules that generally occur on the hair-bearing surfaces in immunosuppressed hosts.² Majocchi granuloma also commonly occurs from the use of potent topical steroids on unsuspected tinea.³  

Histopathologically, MG generally presents as granulomatous inflammation with perifollicular neutrophilic infiltration. This polymorphonuclear cell infiltrate was visible clinically as a single pustule overlying the nodular plaque, a clue appreciable only on close inspection. Histopathologic examination revealed segmented branching filaments present within cornified elements of a follicle (Figure). Notably, potassium hydroxide (KOH) preparations are unreliable diagnostic aids in MG, as evidenced by the 2 negative KOH preparations in this case. According to Chou and Hsu,⁴ because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for MG due to deeper invasion of the fungi into the dermal follicular component. In fact, KOH preparations of MG may reveal no hyphae in 23.3% of cases.²  

The initiating factor in MG is not entirely known but is thought to be physical trauma that either directly or indirectly leads to follicle disruption and passive introduction of the organism into the dermis (eg, traumatic implantation via gardening or other recreational activities).² Other proposed mechanisms include the presentation of the membrane-associated ATP-binding cassette transporter on the surface of T rubrum.¹ Dermatophytes evade the host immune system through a variety of mechanisms: (1) cell wall glycoproteins, (2) release of anti-inflammatory cytokines, and (3) generation of immunosuppressive regulatory T cells.¹ 

Collectively, the clinical and histopathologic findings distinguish MG from other cutaneous conditions. Sporotrichosis, a granulomatous infection caused by Sporothrix schenckii, typically is found in tropical regions of the world and often is associated with floriculture.⁵ Sporotrichosis initially presents in a subcutaneous papulonodular form, but unlike MG, it later ulcerates and progresses along adjacent lymphatic chains.⁵ Pathology of sporotrichosis exhibits pseudoepitheliomatous hyperplasia with granulomas, possible foci of suppuration, and yeastlike forms called cigar bodies. Chromoblastomycosis clinically is defined by tumorlike lesions on the skin including verrucous, nodular, or scarlike plaques and typically is associated with traumatic injury and implantation of the microorganism. Histologically, chromoblastomycosis demonstrates pseudoepitheliomatous hyperplasia with granulomas and characteristic darkly pigmented, thick-walled sclerotic cells called Medlar bodies.⁶ Mycobacterium marinum is one cause of nontuberculous mycobacterial skin infections in humans. Clinically, M marinum is associated with improper hygiene techniques and contact with fish tanks and other aqueous environments. Mycobacterium marinum can present histopathologically as early neutrophilic infiltration or late dermal granulomatous inflammation.⁷ Acid-fast bacilli typically are scant, leaving the diagnosis best secured via polymerase chain reaction assay. Nodular Kaposi sarcoma (KS) can present as a dusky nodular plaque on an acral surface but typically is seen in patients with underlying human immunodeficiency virus/AIDS or other immunosuppressive conditions. The pathology for KS shows a proliferation of human herpes virus 8-positive spindle cells with slitlike spaces containing red blood cells instead of granulomatous inflammation. 

Treatment regimens with topical corticosteroids can exacerbate the infection due to local suppression of cell-mediated immunity.⁸ In these scenarios, fungal infection is suspected, and systemic antifungals such as ketoconazole; itraconazole; or terbinafine, which has become the mainstay, are prescribed. Resolution of the infection with these medications usually is seen after 4 weeks.² 

A diagnosis of MG can be elusive and often may take multiple visits. Clinicians should note that MG could demonstrate repeated false-negative KOH preparations; therefore, these tests should not be relied on as the sole determination of a diagnosis. Although chromoblastomycosis, sporotrichosis, nodular KS, and infection with M marinum may all present as nodular plaques with granulomatous pathology, a follicular pustule may be a clinical clue to MG, as its mimics typically lack folliculocentric neutrophils.

As the COVID-19 pandemic continues, many cancer patients are finding it increasingly difficult to receive the care they need and are facing financial challenges.

Half of the cancer patients and survivors who responded to a recent survey reported changes, delays, or disruptions to the care they were receiving. The survey, with 1,219 respondents, was conducted by the American Cancer Society Cancer Action Network (ACS CAN).

“The circumstances of this virus – from the fact cancer patients are at higher risk of severe complications should they be diagnosed with COVID-19, to the fact many patients are facing serious financial strain caused by the virus’ economic effect – make getting care especially difficult,” Keysha Brooks-Coley, vice president of federal advocacy for ACS CAN, told Medscape Medical News.

Nearly a quarter (24%) of survey respondents reported a delay in care or treatment. The proportion was slightly more (27%) among those currently receiving active treatment.

In addition, 12% (13% in active treatment) stated that not only was their care delayed but that they also have not been told when services would be rescheduled.

As previously reported by Medscape Medical News, many oncology groups have issued new guidelines for cancer care in reaction to the current crisis. These include recommendations to delay cancer treatment in order to avoid exposing cancer patients to the virus.

Half of those in active treatment report disruptions

The survey was initiated by ACS CAN on March 25 and was distributed over a 2-week period. The goal was to gain a better understanding of how COVID-19 was affecting cancer patients and survivors in the United States. Of the 1,219 respondents, half (51%) were cancer patients currently undergoing active treatment.

Among the patients and survivors who were currently in active treatment, 55% reported that there have been changes, delays, or disruptions in their care. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

Financial concerns

Almost all of the survey respondents were covered by some type of insurance; 49% had coverage through an employer, 32% were covered by Medicare, 7% had privately purchased insurance, and 4% were covered through Medicaid.

Many cancer patients had already been having difficulty paying for their care, but for a substantial proportion of survey respondents, the COVID-19 pandemic has exacerbated the problem. More than one-third (38%) stated that COVID-19 “has had a notable impact on their financial situation that affects their ability to pay for health care.”

The most common financial problems that were related to access to care include reduced work hours (14%), reduced investment values (11%), having difficulty affording food and supplies because of staying at home to avoid contracting the virus (9%), and becoming unemployed (8%).

A reduction in work hours and job loss were of particular concern to respondents because of the possible effects these would have on their health insurance coverage. Of those who reported that they or a family member living with them had lost a job, 43% had employer-sponsored health insurance. Additionally, 58% of patients or a family member whose working hours had been reduced also had health insurance through their employer

Among the entire cohort, 28% reported that they were worried that the financial impact of COVID-19 would make it difficult to pay for the health care they need as cancer survivors. This concern was highly correlated with income. Almost half (46%) of patients who earned $30,000 or less reported that they were worried, but even in household with incomes over $110,000 per year, 21% were also concerned about the financial impact.

“Now more than ever, patients need to be able to get, keep, and afford health coverage to treat their disease,” commented Brooks-Coley.
 

Taking action

“ACS CAN is working every day to make clear to Congress and the administration the real and immediate challenges cancer patients and survivors face during this pandemic,” said Brooks-Coley.

With nearly 50 other professional and advocacy groups, ACS CAN has sent letters to congressional leadership and the Secretary of the Department of Health & Human Services asking them to make policy changes that would help patients.

The proposed action points include having insurers allow patients to use providers who are out of network if necessary; waiving site-specific precertification and prior authorization for cancer treatment; utilizing shared decision making between patients and providers in deciding whether to use home infusion without pressure from the insurer; allowing patients to obtain 90-day supplies of medication; increasing funding for state Medicaid programs and assistance for those who have lost employee-sponsored coverage; and improving telehealth services.

“We urge Congress and the administration to keep the needs of cancer patients and survivors in mind as they continue to address the public health crisis,” she said.

This article first appeared on Medscape.com.

As the COVID-19 pandemic continues, many cancer patients are finding it increasingly difficult to receive the care they need and are facing financial challenges.

Half of the cancer patients and survivors who responded to a recent survey reported changes, delays, or disruptions to the care they were receiving. The survey, with 1,219 respondents, was conducted by the American Cancer Society Cancer Action Network (ACS CAN).

“The circumstances of this virus – from the fact cancer patients are at higher risk of severe complications should they be diagnosed with COVID-19, to the fact many patients are facing serious financial strain caused by the virus’ economic effect – make getting care especially difficult,” Keysha Brooks-Coley, vice president of federal advocacy for ACS CAN, told Medscape Medical News.

Nearly a quarter (24%) of survey respondents reported a delay in care or treatment. The proportion was slightly more (27%) among those currently receiving active treatment.

In addition, 12% (13% in active treatment) stated that not only was their care delayed but that they also have not been told when services would be rescheduled.

As previously reported by Medscape Medical News, many oncology groups have issued new guidelines for cancer care in reaction to the current crisis. These include recommendations to delay cancer treatment in order to avoid exposing cancer patients to the virus.

Half of those in active treatment report disruptions

The survey was initiated by ACS CAN on March 25 and was distributed over a 2-week period. The goal was to gain a better understanding of how COVID-19 was affecting cancer patients and survivors in the United States. Of the 1,219 respondents, half (51%) were cancer patients currently undergoing active treatment.

Among the patients and survivors who were currently in active treatment, 55% reported that there have been changes, delays, or disruptions in their care. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

Financial concerns

Almost all of the survey respondents were covered by some type of insurance; 49% had coverage through an employer, 32% were covered by Medicare, 7% had privately purchased insurance, and 4% were covered through Medicaid.

Many cancer patients had already been having difficulty paying for their care, but for a substantial proportion of survey respondents, the COVID-19 pandemic has exacerbated the problem. More than one-third (38%) stated that COVID-19 “has had a notable impact on their financial situation that affects their ability to pay for health care.”

The most common financial problems that were related to access to care include reduced work hours (14%), reduced investment values (11%), having difficulty affording food and supplies because of staying at home to avoid contracting the virus (9%), and becoming unemployed (8%).

A reduction in work hours and job loss were of particular concern to respondents because of the possible effects these would have on their health insurance coverage. Of those who reported that they or a family member living with them had lost a job, 43% had employer-sponsored health insurance. Additionally, 58% of patients or a family member whose working hours had been reduced also had health insurance through their employer

Among the entire cohort, 28% reported that they were worried that the financial impact of COVID-19 would make it difficult to pay for the health care they need as cancer survivors. This concern was highly correlated with income. Almost half (46%) of patients who earned $30,000 or less reported that they were worried, but even in household with incomes over $110,000 per year, 21% were also concerned about the financial impact.

“Now more than ever, patients need to be able to get, keep, and afford health coverage to treat their disease,” commented Brooks-Coley.
 

Taking action

“ACS CAN is working every day to make clear to Congress and the administration the real and immediate challenges cancer patients and survivors face during this pandemic,” said Brooks-Coley.

With nearly 50 other professional and advocacy groups, ACS CAN has sent letters to congressional leadership and the Secretary of the Department of Health & Human Services asking them to make policy changes that would help patients.

The proposed action points include having insurers allow patients to use providers who are out of network if necessary; waiving site-specific precertification and prior authorization for cancer treatment; utilizing shared decision making between patients and providers in deciding whether to use home infusion without pressure from the insurer; allowing patients to obtain 90-day supplies of medication; increasing funding for state Medicaid programs and assistance for those who have lost employee-sponsored coverage; and improving telehealth services.

“We urge Congress and the administration to keep the needs of cancer patients and survivors in mind as they continue to address the public health crisis,” she said.

This article first appeared on Medscape.com.

As the COVID-19 pandemic continues, many cancer patients are finding it increasingly difficult to receive the care they need and are facing financial challenges.

Half of the cancer patients and survivors who responded to a recent survey reported changes, delays, or disruptions to the care they were receiving. The survey, with 1,219 respondents, was conducted by the American Cancer Society Cancer Action Network (ACS CAN).

“The circumstances of this virus – from the fact cancer patients are at higher risk of severe complications should they be diagnosed with COVID-19, to the fact many patients are facing serious financial strain caused by the virus’ economic effect – make getting care especially difficult,” Keysha Brooks-Coley, vice president of federal advocacy for ACS CAN, told Medscape Medical News.

Nearly a quarter (24%) of survey respondents reported a delay in care or treatment. The proportion was slightly more (27%) among those currently receiving active treatment.

In addition, 12% (13% in active treatment) stated that not only was their care delayed but that they also have not been told when services would be rescheduled.

As previously reported by Medscape Medical News, many oncology groups have issued new guidelines for cancer care in reaction to the current crisis. These include recommendations to delay cancer treatment in order to avoid exposing cancer patients to the virus.

Half of those in active treatment report disruptions

The survey was initiated by ACS CAN on March 25 and was distributed over a 2-week period. The goal was to gain a better understanding of how COVID-19 was affecting cancer patients and survivors in the United States. Of the 1,219 respondents, half (51%) were cancer patients currently undergoing active treatment.

Among the patients and survivors who were currently in active treatment, 55% reported that there have been changes, delays, or disruptions in their care. The services most frequently affected included in-person provider visits (50%), supportive services (20%), and imaging procedures to monitor tumor growth (20%).

In addition, 8% reported that their treatment, including chemotherapy and immunotherapy, had been affected by the COVID-19 pandemic.

Financial concerns

Almost all of the survey respondents were covered by some type of insurance; 49% had coverage through an employer, 32% were covered by Medicare, 7% had privately purchased insurance, and 4% were covered through Medicaid.

Many cancer patients had already been having difficulty paying for their care, but for a substantial proportion of survey respondents, the COVID-19 pandemic has exacerbated the problem. More than one-third (38%) stated that COVID-19 “has had a notable impact on their financial situation that affects their ability to pay for health care.”

The most common financial problems that were related to access to care include reduced work hours (14%), reduced investment values (11%), having difficulty affording food and supplies because of staying at home to avoid contracting the virus (9%), and becoming unemployed (8%).

A reduction in work hours and job loss were of particular concern to respondents because of the possible effects these would have on their health insurance coverage. Of those who reported that they or a family member living with them had lost a job, 43% had employer-sponsored health insurance. Additionally, 58% of patients or a family member whose working hours had been reduced also had health insurance through their employer

Among the entire cohort, 28% reported that they were worried that the financial impact of COVID-19 would make it difficult to pay for the health care they need as cancer survivors. This concern was highly correlated with income. Almost half (46%) of patients who earned $30,000 or less reported that they were worried, but even in household with incomes over $110,000 per year, 21% were also concerned about the financial impact.

“Now more than ever, patients need to be able to get, keep, and afford health coverage to treat their disease,” commented Brooks-Coley.
 

Taking action

“ACS CAN is working every day to make clear to Congress and the administration the real and immediate challenges cancer patients and survivors face during this pandemic,” said Brooks-Coley.

With nearly 50 other professional and advocacy groups, ACS CAN has sent letters to congressional leadership and the Secretary of the Department of Health & Human Services asking them to make policy changes that would help patients.

The proposed action points include having insurers allow patients to use providers who are out of network if necessary; waiving site-specific precertification and prior authorization for cancer treatment; utilizing shared decision making between patients and providers in deciding whether to use home infusion without pressure from the insurer; allowing patients to obtain 90-day supplies of medication; increasing funding for state Medicaid programs and assistance for those who have lost employee-sponsored coverage; and improving telehealth services.

“We urge Congress and the administration to keep the needs of cancer patients and survivors in mind as they continue to address the public health crisis,” she said.

This article first appeared on Medscape.com.

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.¹ If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.²

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,³ colorectal adenocarcinomas,⁴ keratoacanthomas,⁵ and other visceral malignancies.⁶ Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.⁵ These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.⁷ This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).⁸ This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.⁹ Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.¹⁰ Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.⁹

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.¹¹ Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.¹² These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.¹³ Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,¹⁴ which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.¹⁵ Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.¹⁶

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.¹⁷ It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.¹⁸

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.¹⁹ Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.²⁰ Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.²¹

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.²² Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.²³

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).²⁴ In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).²⁵ These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.²⁶ A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.²⁷

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.²⁸ In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.²⁹

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.^30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.³⁰ Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.³¹ Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.³²

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.³³ Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.³⁴ The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.³⁴

These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.

Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.^23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.¹³

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.³⁷ As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.³⁸

It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.^17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.¹⁹

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.¹ If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.²

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,³ colorectal adenocarcinomas,⁴ keratoacanthomas,⁵ and other visceral malignancies.⁶ Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.⁵ These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.⁷ This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).⁸ This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.⁹ Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.¹⁰ Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.⁹

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.¹¹ Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.¹² These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.¹³ Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,¹⁴ which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.¹⁵ Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.¹⁶

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.¹⁷ It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.¹⁸

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.¹⁹ Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.²⁰ Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.²¹

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.²² Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.²³

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).²⁴ In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).²⁵ These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.²⁶ A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.²⁷

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.²⁸ In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.²⁹

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.^30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.³⁰ Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.³¹ Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.³²

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.³³ Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.³⁴ The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.³⁴

These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.

Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.^23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.¹³

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.³⁷ As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.³⁸

It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.^17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.¹⁹

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.¹ If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.²

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,³ colorectal adenocarcinomas,⁴ keratoacanthomas,⁵ and other visceral malignancies.⁶ Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.⁵ These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.⁷ This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).⁸ This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.⁹ Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.¹⁰ Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.⁹

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.¹¹ Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.¹² These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.¹³ Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,¹⁴ which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.¹⁵ Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.¹⁶

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.¹⁷ It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.¹⁸

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.¹⁹ Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.²⁰ Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.²¹

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.²² Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.²³

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).²⁴ In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).²⁵ These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.²⁶ A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.²⁷

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.²⁸ In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.²⁹

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.^30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.³⁰ Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.³¹ Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.³²

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.³³ Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.³⁴ The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.³⁴

These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.

Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.^23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.¹³

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.³⁷ As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.³⁸

It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.^17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.¹⁹

Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.

Dr Amanda Nickles Fader

At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Confirmed benefit

The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.

“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”

The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.

“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.

Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
 

PFS, OS, and toxicity

There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.

The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).

In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).

“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).

The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).

Long-term toxicity did not differ between the treatment arms.
 

Applications and next steps

“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”

This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.

“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.

“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.

She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.

“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.

She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.

sworcester@mdedge.com

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.

Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.

Dr Amanda Nickles Fader

At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Confirmed benefit

The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.

“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”

The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.

“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.

Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
 

PFS, OS, and toxicity

There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.

The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).

In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).

“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).

The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).

Long-term toxicity did not differ between the treatment arms.
 

Applications and next steps

“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”

This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.

“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.

“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.

She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.

“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.

She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.

sworcester@mdedge.com

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.

Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.

Dr Amanda Nickles Fader

At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Confirmed benefit

The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.

“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”

The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.

“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.

Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
 

PFS, OS, and toxicity

There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.

The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).

In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).

“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).

The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).

Long-term toxicity did not differ between the treatment arms.
 

Applications and next steps

“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”

This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.

“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.

“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.

She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.

“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.

She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.

sworcester@mdedge.com

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.