Clinical Topics & News

Small cell lung cancer has traditionally been attributed almost exclusively to tobacco exposure, but some recent studies have suggested a higher than expected prevalence among nonsmokers. A new retrospective analysis suggests the disease has a different genomic profile among smokers than nonsmokers, indicating that the subgroups may have unique disease characteristics. Key differences included a lower frequency of TP53 gene mutations and a higher frequency of epidermal growth factor receptor (EGFR) alterations in never smokers.

About 6.9% of small cell lung cancer patients in the CASPIAN study were nonsmokers, as were 3.0% in the IMpower133 study.

“Given that the pathogenesis of small cell lung cancer is often tied to the damaging effects of tobacco, we hypothesized that small cell lung cancer in never-smokers would possess distinct molecular attributes. Our data does not provide any solid evidence for any treatment implications, though it does raise therapeutic questions which we believe deserve further exploration,” said Michael Oh, MD, during a presentation of the study results at the annual meeting of the European Society for Medical Oncology. Dr. Oh is a fellow at the University of California, Los Angeles.

The topic is important clinically, according to Antonio Passaro, MD, PhD, who served as a discussant during the session. He noted that small cell lung cancer in never-smokers is the seventh-most common cause of cancer-related mortality worldwide. In non–small cell lung cancer, rates of tobacco-associated disease have been decreasing, but there are increases in diagnoses among never smokers. Nonsmoking small cell lung cancer patients do not have better prognoses, and novel therapies and advances like immunotherapy and low-dose CT lung cancer screening disproportionately benefit current or former smokers.

Potential risk factors for never-smokers include environmental exposures like radon gas, cooking oil vapors, indoor and outdoor wood burning, and genetic and viral factors. “At the present time we do not have the knowledge to identify the most important factor in development of lung cancer in never-smoking [patients],” said Dr. Passaro, who is a medical oncologist at the European Institute of Oncology in Milan.

He added that the current study results are interesting but need much more follow-up, such as “longitudinal studies combining detailed clinical annotation with tissue and blood sampling. Here there is a need for collaborative efforts.” Key questions include the roles of the genomic landscape in normal lung tissue may play, the lung micro-environment, genetic factors, and environmental exposures.

One key possibility is air pollution. “We know that lung cancer in never-smokers is frequent in some countries, for example in Asian countries and it is more frequent in the United States than in Europe, but to find an explanation to this kind of data is difficult at the present time,” Dr. Passaro said.

The researchers retrospectively analyzed data from 608 current or former smokers and 54 never-smokers with small cell lung cancer, with the latter making up 8% of the total population. 70.4% of never-smokers and 55.1% of current or former smokers were female (P = .031). There was no significant between-group difference with respect to age at diagnosis or race.

Somatic mutations were similar to what has been found in previous studies for current or former smokers. 85.2% had changes in TP53, compared with just 59.3% of never-smokers (Q < .001). Changes to EGFR were more common in never-smokers, occurring in 25.9% versus 2.6% (Q < .001). PIK3CA alterations were also more common in never-smokers (14.8% vs. 3.6%; Q = 0.022). There was no significant difference between the two groups with respect to changes in RB1.

Never smokers had tumors with less immune cell infiltration (P = .008), including fewer CD4+ T cells, CD8+ T cells, and macrophages. Their tumor mutation burden was also lower (median, 2.59 vs. 4.99; P < .001).

Dr. Oh has no relevant financial disclosures. Dr. Passaro has consulted, advised, and received research funding from a wide range of pharmaceutical companies.

Small cell lung cancer has traditionally been attributed almost exclusively to tobacco exposure, but some recent studies have suggested a higher than expected prevalence among nonsmokers. A new retrospective analysis suggests the disease has a different genomic profile among smokers than nonsmokers, indicating that the subgroups may have unique disease characteristics. Key differences included a lower frequency of TP53 gene mutations and a higher frequency of epidermal growth factor receptor (EGFR) alterations in never smokers.

About 6.9% of small cell lung cancer patients in the CASPIAN study were nonsmokers, as were 3.0% in the IMpower133 study.

“Given that the pathogenesis of small cell lung cancer is often tied to the damaging effects of tobacco, we hypothesized that small cell lung cancer in never-smokers would possess distinct molecular attributes. Our data does not provide any solid evidence for any treatment implications, though it does raise therapeutic questions which we believe deserve further exploration,” said Michael Oh, MD, during a presentation of the study results at the annual meeting of the European Society for Medical Oncology. Dr. Oh is a fellow at the University of California, Los Angeles.

The topic is important clinically, according to Antonio Passaro, MD, PhD, who served as a discussant during the session. He noted that small cell lung cancer in never-smokers is the seventh-most common cause of cancer-related mortality worldwide. In non–small cell lung cancer, rates of tobacco-associated disease have been decreasing, but there are increases in diagnoses among never smokers. Nonsmoking small cell lung cancer patients do not have better prognoses, and novel therapies and advances like immunotherapy and low-dose CT lung cancer screening disproportionately benefit current or former smokers.

Potential risk factors for never-smokers include environmental exposures like radon gas, cooking oil vapors, indoor and outdoor wood burning, and genetic and viral factors. “At the present time we do not have the knowledge to identify the most important factor in development of lung cancer in never-smoking [patients],” said Dr. Passaro, who is a medical oncologist at the European Institute of Oncology in Milan.

He added that the current study results are interesting but need much more follow-up, such as “longitudinal studies combining detailed clinical annotation with tissue and blood sampling. Here there is a need for collaborative efforts.” Key questions include the roles of the genomic landscape in normal lung tissue may play, the lung micro-environment, genetic factors, and environmental exposures.

One key possibility is air pollution. “We know that lung cancer in never-smokers is frequent in some countries, for example in Asian countries and it is more frequent in the United States than in Europe, but to find an explanation to this kind of data is difficult at the present time,” Dr. Passaro said.

The researchers retrospectively analyzed data from 608 current or former smokers and 54 never-smokers with small cell lung cancer, with the latter making up 8% of the total population. 70.4% of never-smokers and 55.1% of current or former smokers were female (P = .031). There was no significant between-group difference with respect to age at diagnosis or race.

Somatic mutations were similar to what has been found in previous studies for current or former smokers. 85.2% had changes in TP53, compared with just 59.3% of never-smokers (Q < .001). Changes to EGFR were more common in never-smokers, occurring in 25.9% versus 2.6% (Q < .001). PIK3CA alterations were also more common in never-smokers (14.8% vs. 3.6%; Q = 0.022). There was no significant difference between the two groups with respect to changes in RB1.

Never smokers had tumors with less immune cell infiltration (P = .008), including fewer CD4+ T cells, CD8+ T cells, and macrophages. Their tumor mutation burden was also lower (median, 2.59 vs. 4.99; P < .001).

Dr. Oh has no relevant financial disclosures. Dr. Passaro has consulted, advised, and received research funding from a wide range of pharmaceutical companies.

Small cell lung cancer has traditionally been attributed almost exclusively to tobacco exposure, but some recent studies have suggested a higher than expected prevalence among nonsmokers. A new retrospective analysis suggests the disease has a different genomic profile among smokers than nonsmokers, indicating that the subgroups may have unique disease characteristics. Key differences included a lower frequency of TP53 gene mutations and a higher frequency of epidermal growth factor receptor (EGFR) alterations in never smokers.

About 6.9% of small cell lung cancer patients in the CASPIAN study were nonsmokers, as were 3.0% in the IMpower133 study.

“Given that the pathogenesis of small cell lung cancer is often tied to the damaging effects of tobacco, we hypothesized that small cell lung cancer in never-smokers would possess distinct molecular attributes. Our data does not provide any solid evidence for any treatment implications, though it does raise therapeutic questions which we believe deserve further exploration,” said Michael Oh, MD, during a presentation of the study results at the annual meeting of the European Society for Medical Oncology. Dr. Oh is a fellow at the University of California, Los Angeles.

The topic is important clinically, according to Antonio Passaro, MD, PhD, who served as a discussant during the session. He noted that small cell lung cancer in never-smokers is the seventh-most common cause of cancer-related mortality worldwide. In non–small cell lung cancer, rates of tobacco-associated disease have been decreasing, but there are increases in diagnoses among never smokers. Nonsmoking small cell lung cancer patients do not have better prognoses, and novel therapies and advances like immunotherapy and low-dose CT lung cancer screening disproportionately benefit current or former smokers.

Potential risk factors for never-smokers include environmental exposures like radon gas, cooking oil vapors, indoor and outdoor wood burning, and genetic and viral factors. “At the present time we do not have the knowledge to identify the most important factor in development of lung cancer in never-smoking [patients],” said Dr. Passaro, who is a medical oncologist at the European Institute of Oncology in Milan.

He added that the current study results are interesting but need much more follow-up, such as “longitudinal studies combining detailed clinical annotation with tissue and blood sampling. Here there is a need for collaborative efforts.” Key questions include the roles of the genomic landscape in normal lung tissue may play, the lung micro-environment, genetic factors, and environmental exposures.

One key possibility is air pollution. “We know that lung cancer in never-smokers is frequent in some countries, for example in Asian countries and it is more frequent in the United States than in Europe, but to find an explanation to this kind of data is difficult at the present time,” Dr. Passaro said.

The researchers retrospectively analyzed data from 608 current or former smokers and 54 never-smokers with small cell lung cancer, with the latter making up 8% of the total population. 70.4% of never-smokers and 55.1% of current or former smokers were female (P = .031). There was no significant between-group difference with respect to age at diagnosis or race.

Somatic mutations were similar to what has been found in previous studies for current or former smokers. 85.2% had changes in TP53, compared with just 59.3% of never-smokers (Q < .001). Changes to EGFR were more common in never-smokers, occurring in 25.9% versus 2.6% (Q < .001). PIK3CA alterations were also more common in never-smokers (14.8% vs. 3.6%; Q = 0.022). There was no significant difference between the two groups with respect to changes in RB1.

Never smokers had tumors with less immune cell infiltration (P = .008), including fewer CD4+ T cells, CD8+ T cells, and macrophages. Their tumor mutation burden was also lower (median, 2.59 vs. 4.99; P < .001).

Dr. Oh has no relevant financial disclosures. Dr. Passaro has consulted, advised, and received research funding from a wide range of pharmaceutical companies.

Chronic lack of exercise – dubbed “exercise deficiency” – is associated with cardiac atrophy, reduced cardiac output and chamber size, and diminished cardiorespiratory fitness (CRF) in a subgroup of patients with heart failure with preserved ejection fraction (HFpEF), researchers say.

Increasing the physical activity levels of these sedentary individuals could be an effective preventive strategy, particularly for those who are younger and middle-aged, they suggest.

Thinking of HFpEF as an exercise deficiency syndrome leading to a small heart “flies in the face of decades of cardiovascular teaching, because traditionally, we’ve thought of heart failure as the big floppy heart,” Andre La Gerche, MBBS, PhD, of the Baker Heart and Diabetes Institute, Melbourne, told this news organization.

“While it is true that some people with HFpEF have thick, stiff hearts, we propose that another subset has a normal heart, except it’s small because it’s been underexercised,” he said.

The article, published online  as part of a Focus Seminar series in the Journal of the American College of Cardiology, has “gone viral on social media,” Jason C. Kovacic, MBBS, PhD, of the Victor Chang Cardiac Research Institute, Darlinghurst, Australia, told this news organization.

Dr. Kovacic is a JACC section editor and the coordinating and senior author of the series, which covers other issues surrounding physical activity, both in athletes and the general public.
 

‘Coin-dropping moment’

To support their hypothesis that HFpEF is an exercise deficiency in certain patients, Dr. La Gerche and colleagues conducted a literature review that highlights the following points:

• There is a strong association between physical activity and both CRF and heart function.
• Exercise deficiency is a major risk factor for HFpEF in a subset of patients.
• Increasing physical activity is associated with greater cardiac mass, stroke volumes, cardiac output, and peak oxygen consumption.
• Physical inactivity leads to loss of heart muscle, reduced output and chamber size, and less ability to improve cardiac performance with exercise.
• Aging results in a smaller, stiffer heart; however, this effect is mitigated by regular exercise.
• Individuals who are sedentary throughout life cannot attenuate age-related reductions in heart size and have increasing chamber stiffness.

“When we explain it, it’s like a coin-dropping moment, because it’s actually a really simple concept,” Dr. La Gerche said. “A small heart has a small stroke volume. A patient with a small heart with a maximal stroke volume of 60 mL can generate a cardiac output of 9 L/min at a heart rate of 150 beats/min during exercise – an output that just isn’t enough. It’s like trying to drive a truck with a 50cc motorbike engine.”

“Plus,” Dr. La Gerche added, “exercise deficiency also sets the stage for comorbidities such as obesity, diabetes, and high blood pressure, all of which can ultimately lead to HFpEF.”

Considering HFpEF as an exercise deficiency syndrome has two clinical implications, Dr. La Gerche said. “First, it helps us understand the condition and diagnose more cases. For example, I think practitioners will start to recognize that breathlessness in some of their patients is associated with a small heart.”

“Second,” he said, “if it’s an exercise deficiency syndrome, the treatment is exercise. For most people, that means exercising regularly before the age of 60 to prevent HFpEF, because studies have found that after the age of 60, the heart is a bit fixed and harder to remodel. That doesn’t mean you shouldn’t try after 60 or that you won’t get benefit. But the real sweet spot is in middle age and younger.”
 

The bigger picture

The JACC Focus Seminar series starts with an article that underscores the benefits of regular physical activity. “The key is getting our patients to meet the guidelines: 150 to 300 minutes of moderate intensity exercise per week, or 75 to 250 minutes of vigorous activity per week,” Dr. Kovacic emphasized.

“Yes, we can give a statin to lower cholesterol. Yes, we can give a blood pressure medication to lower blood pressure. But when you prescribe exercise, you impact patients’ blood pressure, their cholesterol, their weight, their sense of well-being,” he said. “It cuts across so many different aspects of people’s lives that it’s important to underscore the value of exercise to everybody.”

That includes physicians, he affirmed. “It behooves all physicians to be leading by example. I would encourage those who are overweight or aren’t exercising as much as they should be to make the time to be healthy and to exercise. If you don’t, then bad health will force you to make the time to deal with bad health issues.”

Other articles in the series deal with the athlete’s heart. Christopher Semsarian, MBBS, PhD, MPH, University of Sydney, and colleagues discuss emerging data on hypertrophic cardiomyopathy and other genetic cardiovascular diseases, with the conclusion that it is probably okay for more athletes with these conditions to participate in recreational and competitive sports than was previously thought – another paradigm shift, according to Dr. Kovacic.

The final article addresses some of the challenges and controversies related to the athlete’s heart, including whether extreme exercise is associated with vulnerability to atrial fibrillation and other arrhythmias, and the impact of gender on the cardiac response to exercise, which can’t be determined now because of a paucity of data on women in sports.

Overall, Dr. Kovacic said, the series makes for “compelling” reading that should encourage readers to embark on their own studies to add to the data and support exercise prescription across the board.

No commercial funding or relevant conflicts of interest were reported.

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

Chronic lack of exercise – dubbed “exercise deficiency” – is associated with cardiac atrophy, reduced cardiac output and chamber size, and diminished cardiorespiratory fitness (CRF) in a subgroup of patients with heart failure with preserved ejection fraction (HFpEF), researchers say.

Increasing the physical activity levels of these sedentary individuals could be an effective preventive strategy, particularly for those who are younger and middle-aged, they suggest.

Thinking of HFpEF as an exercise deficiency syndrome leading to a small heart “flies in the face of decades of cardiovascular teaching, because traditionally, we’ve thought of heart failure as the big floppy heart,” Andre La Gerche, MBBS, PhD, of the Baker Heart and Diabetes Institute, Melbourne, told this news organization.

“While it is true that some people with HFpEF have thick, stiff hearts, we propose that another subset has a normal heart, except it’s small because it’s been underexercised,” he said.

The article, published online  as part of a Focus Seminar series in the Journal of the American College of Cardiology, has “gone viral on social media,” Jason C. Kovacic, MBBS, PhD, of the Victor Chang Cardiac Research Institute, Darlinghurst, Australia, told this news organization.

Dr. Kovacic is a JACC section editor and the coordinating and senior author of the series, which covers other issues surrounding physical activity, both in athletes and the general public.
 

‘Coin-dropping moment’

To support their hypothesis that HFpEF is an exercise deficiency in certain patients, Dr. La Gerche and colleagues conducted a literature review that highlights the following points:

• There is a strong association between physical activity and both CRF and heart function.
• Exercise deficiency is a major risk factor for HFpEF in a subset of patients.
• Increasing physical activity is associated with greater cardiac mass, stroke volumes, cardiac output, and peak oxygen consumption.
• Physical inactivity leads to loss of heart muscle, reduced output and chamber size, and less ability to improve cardiac performance with exercise.
• Aging results in a smaller, stiffer heart; however, this effect is mitigated by regular exercise.
• Individuals who are sedentary throughout life cannot attenuate age-related reductions in heart size and have increasing chamber stiffness.

“When we explain it, it’s like a coin-dropping moment, because it’s actually a really simple concept,” Dr. La Gerche said. “A small heart has a small stroke volume. A patient with a small heart with a maximal stroke volume of 60 mL can generate a cardiac output of 9 L/min at a heart rate of 150 beats/min during exercise – an output that just isn’t enough. It’s like trying to drive a truck with a 50cc motorbike engine.”

“Plus,” Dr. La Gerche added, “exercise deficiency also sets the stage for comorbidities such as obesity, diabetes, and high blood pressure, all of which can ultimately lead to HFpEF.”

Considering HFpEF as an exercise deficiency syndrome has two clinical implications, Dr. La Gerche said. “First, it helps us understand the condition and diagnose more cases. For example, I think practitioners will start to recognize that breathlessness in some of their patients is associated with a small heart.”

“Second,” he said, “if it’s an exercise deficiency syndrome, the treatment is exercise. For most people, that means exercising regularly before the age of 60 to prevent HFpEF, because studies have found that after the age of 60, the heart is a bit fixed and harder to remodel. That doesn’t mean you shouldn’t try after 60 or that you won’t get benefit. But the real sweet spot is in middle age and younger.”
 

The bigger picture

The JACC Focus Seminar series starts with an article that underscores the benefits of regular physical activity. “The key is getting our patients to meet the guidelines: 150 to 300 minutes of moderate intensity exercise per week, or 75 to 250 minutes of vigorous activity per week,” Dr. Kovacic emphasized.

“Yes, we can give a statin to lower cholesterol. Yes, we can give a blood pressure medication to lower blood pressure. But when you prescribe exercise, you impact patients’ blood pressure, their cholesterol, their weight, their sense of well-being,” he said. “It cuts across so many different aspects of people’s lives that it’s important to underscore the value of exercise to everybody.”

That includes physicians, he affirmed. “It behooves all physicians to be leading by example. I would encourage those who are overweight or aren’t exercising as much as they should be to make the time to be healthy and to exercise. If you don’t, then bad health will force you to make the time to deal with bad health issues.”

Other articles in the series deal with the athlete’s heart. Christopher Semsarian, MBBS, PhD, MPH, University of Sydney, and colleagues discuss emerging data on hypertrophic cardiomyopathy and other genetic cardiovascular diseases, with the conclusion that it is probably okay for more athletes with these conditions to participate in recreational and competitive sports than was previously thought – another paradigm shift, according to Dr. Kovacic.

The final article addresses some of the challenges and controversies related to the athlete’s heart, including whether extreme exercise is associated with vulnerability to atrial fibrillation and other arrhythmias, and the impact of gender on the cardiac response to exercise, which can’t be determined now because of a paucity of data on women in sports.

Overall, Dr. Kovacic said, the series makes for “compelling” reading that should encourage readers to embark on their own studies to add to the data and support exercise prescription across the board.

No commercial funding or relevant conflicts of interest were reported.

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

Chronic lack of exercise – dubbed “exercise deficiency” – is associated with cardiac atrophy, reduced cardiac output and chamber size, and diminished cardiorespiratory fitness (CRF) in a subgroup of patients with heart failure with preserved ejection fraction (HFpEF), researchers say.

Increasing the physical activity levels of these sedentary individuals could be an effective preventive strategy, particularly for those who are younger and middle-aged, they suggest.

Thinking of HFpEF as an exercise deficiency syndrome leading to a small heart “flies in the face of decades of cardiovascular teaching, because traditionally, we’ve thought of heart failure as the big floppy heart,” Andre La Gerche, MBBS, PhD, of the Baker Heart and Diabetes Institute, Melbourne, told this news organization.

“While it is true that some people with HFpEF have thick, stiff hearts, we propose that another subset has a normal heart, except it’s small because it’s been underexercised,” he said.

The article, published online  as part of a Focus Seminar series in the Journal of the American College of Cardiology, has “gone viral on social media,” Jason C. Kovacic, MBBS, PhD, of the Victor Chang Cardiac Research Institute, Darlinghurst, Australia, told this news organization.

Dr. Kovacic is a JACC section editor and the coordinating and senior author of the series, which covers other issues surrounding physical activity, both in athletes and the general public.
 

‘Coin-dropping moment’

To support their hypothesis that HFpEF is an exercise deficiency in certain patients, Dr. La Gerche and colleagues conducted a literature review that highlights the following points:

• There is a strong association between physical activity and both CRF and heart function.
• Exercise deficiency is a major risk factor for HFpEF in a subset of patients.
• Increasing physical activity is associated with greater cardiac mass, stroke volumes, cardiac output, and peak oxygen consumption.
• Physical inactivity leads to loss of heart muscle, reduced output and chamber size, and less ability to improve cardiac performance with exercise.
• Aging results in a smaller, stiffer heart; however, this effect is mitigated by regular exercise.
• Individuals who are sedentary throughout life cannot attenuate age-related reductions in heart size and have increasing chamber stiffness.

“When we explain it, it’s like a coin-dropping moment, because it’s actually a really simple concept,” Dr. La Gerche said. “A small heart has a small stroke volume. A patient with a small heart with a maximal stroke volume of 60 mL can generate a cardiac output of 9 L/min at a heart rate of 150 beats/min during exercise – an output that just isn’t enough. It’s like trying to drive a truck with a 50cc motorbike engine.”

“Plus,” Dr. La Gerche added, “exercise deficiency also sets the stage for comorbidities such as obesity, diabetes, and high blood pressure, all of which can ultimately lead to HFpEF.”

Considering HFpEF as an exercise deficiency syndrome has two clinical implications, Dr. La Gerche said. “First, it helps us understand the condition and diagnose more cases. For example, I think practitioners will start to recognize that breathlessness in some of their patients is associated with a small heart.”

“Second,” he said, “if it’s an exercise deficiency syndrome, the treatment is exercise. For most people, that means exercising regularly before the age of 60 to prevent HFpEF, because studies have found that after the age of 60, the heart is a bit fixed and harder to remodel. That doesn’t mean you shouldn’t try after 60 or that you won’t get benefit. But the real sweet spot is in middle age and younger.”
 

The bigger picture

The JACC Focus Seminar series starts with an article that underscores the benefits of regular physical activity. “The key is getting our patients to meet the guidelines: 150 to 300 minutes of moderate intensity exercise per week, or 75 to 250 minutes of vigorous activity per week,” Dr. Kovacic emphasized.

“Yes, we can give a statin to lower cholesterol. Yes, we can give a blood pressure medication to lower blood pressure. But when you prescribe exercise, you impact patients’ blood pressure, their cholesterol, their weight, their sense of well-being,” he said. “It cuts across so many different aspects of people’s lives that it’s important to underscore the value of exercise to everybody.”

That includes physicians, he affirmed. “It behooves all physicians to be leading by example. I would encourage those who are overweight or aren’t exercising as much as they should be to make the time to be healthy and to exercise. If you don’t, then bad health will force you to make the time to deal with bad health issues.”

Other articles in the series deal with the athlete’s heart. Christopher Semsarian, MBBS, PhD, MPH, University of Sydney, and colleagues discuss emerging data on hypertrophic cardiomyopathy and other genetic cardiovascular diseases, with the conclusion that it is probably okay for more athletes with these conditions to participate in recreational and competitive sports than was previously thought – another paradigm shift, according to Dr. Kovacic.

The final article addresses some of the challenges and controversies related to the athlete’s heart, including whether extreme exercise is associated with vulnerability to atrial fibrillation and other arrhythmias, and the impact of gender on the cardiac response to exercise, which can’t be determined now because of a paucity of data on women in sports.

Overall, Dr. Kovacic said, the series makes for “compelling” reading that should encourage readers to embark on their own studies to add to the data and support exercise prescription across the board.

No commercial funding or relevant conflicts of interest were reported.

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

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

An Italian study of women diagnosed with breast cancer reported that around 50% experienced body image disturbance and 20% noted a negative impact on their sex life. And while meeting with a specialist in psycho-oncology was universally viewed as an acceptable option, only one out of four patients considered consulting a sexologist. All these women should be encouraged to face and address issues related to sexuality so that they can truly regain a good quality of life, the study suggests.

The study, which was conducted at the breast unit of Santa Maria Goretti Hospital in Latina, Italy, enrolled 141 patients who had undergone breast cancer surgery. Participants were asked to complete a questionnaire that included questions regarding self-image, sexual activity, and sexual satisfaction, and it analyzed these aspects before and after treatment. The participants were then asked whether they felt that they needed to see a sexologist or a specialist in psycho-oncology.

The findings clearly showed a worsening in terms of body image perception. When the women were asked about the relationship they had with their body, femininity, and beauty prior to being diagnosed, 37.4% characterized it as very good and 58.9% as “normal,” with ups and downs but nothing that they would term “conflictual.” After diagnosis, 48.9% noted that the disease had an impact on their body image with a partial conditioning about their femininity and beauty. However, 7.2% had difficulty when it came to recognizing their own body, and their relationship with femininity also became difficult.

On the topic of sexuality, 71.2% of patients were completely satisfied with their sex life before they were diagnosed with breast cancer, 23.7% were partially satisfied, and 5.0% were unsatisfied. As for their sex life after diagnosis and surgery, 20.1% stated that it continued to be fulfilling and 55.4% said that it had gotten worse; 18.8% reported significant sexual dissatisfaction.

The participants were asked whether consulting a professional would be warranted, and whether that would provide useful support for overcoming the difficulties and challenges arising from the disease and the related treatments. In response, 97.1% said they would go to a specialist in psycho-oncology, but only 27.3% would seek help from a sexologist.

“Despite the negative impact on body image and on sexuality, few patients would seek the help of a sexologist; nearly all of the patients, however, would seek the help of a specialist in psycho-oncology. This was very surprising to us,” write the authors. They went on to note that they are carrying out another project to understand the reason for this disparity.

In addition, they advised clinicians to encourage communication about sexuality – a topic that is regularly overlooked and not included in discussions with patients, mostly because of cultural barriers. Often, physicians aren’t comfortable talking about sexuality, as they don’t feel they have the proper training to do so. Patients who are experiencing issues related to sexuality also often have difficulty asking for help. And so, in their conclusion, the authors point out that “collaborating together in the right direction is the basis of change and good communication.”

This article was translated from Univadis Italy and appeared on Medscape.com.

An Italian study of women diagnosed with breast cancer reported that around 50% experienced body image disturbance and 20% noted a negative impact on their sex life. And while meeting with a specialist in psycho-oncology was universally viewed as an acceptable option, only one out of four patients considered consulting a sexologist. All these women should be encouraged to face and address issues related to sexuality so that they can truly regain a good quality of life, the study suggests.

The study, which was conducted at the breast unit of Santa Maria Goretti Hospital in Latina, Italy, enrolled 141 patients who had undergone breast cancer surgery. Participants were asked to complete a questionnaire that included questions regarding self-image, sexual activity, and sexual satisfaction, and it analyzed these aspects before and after treatment. The participants were then asked whether they felt that they needed to see a sexologist or a specialist in psycho-oncology.

The findings clearly showed a worsening in terms of body image perception. When the women were asked about the relationship they had with their body, femininity, and beauty prior to being diagnosed, 37.4% characterized it as very good and 58.9% as “normal,” with ups and downs but nothing that they would term “conflictual.” After diagnosis, 48.9% noted that the disease had an impact on their body image with a partial conditioning about their femininity and beauty. However, 7.2% had difficulty when it came to recognizing their own body, and their relationship with femininity also became difficult.

On the topic of sexuality, 71.2% of patients were completely satisfied with their sex life before they were diagnosed with breast cancer, 23.7% were partially satisfied, and 5.0% were unsatisfied. As for their sex life after diagnosis and surgery, 20.1% stated that it continued to be fulfilling and 55.4% said that it had gotten worse; 18.8% reported significant sexual dissatisfaction.

The participants were asked whether consulting a professional would be warranted, and whether that would provide useful support for overcoming the difficulties and challenges arising from the disease and the related treatments. In response, 97.1% said they would go to a specialist in psycho-oncology, but only 27.3% would seek help from a sexologist.

“Despite the negative impact on body image and on sexuality, few patients would seek the help of a sexologist; nearly all of the patients, however, would seek the help of a specialist in psycho-oncology. This was very surprising to us,” write the authors. They went on to note that they are carrying out another project to understand the reason for this disparity.

In addition, they advised clinicians to encourage communication about sexuality – a topic that is regularly overlooked and not included in discussions with patients, mostly because of cultural barriers. Often, physicians aren’t comfortable talking about sexuality, as they don’t feel they have the proper training to do so. Patients who are experiencing issues related to sexuality also often have difficulty asking for help. And so, in their conclusion, the authors point out that “collaborating together in the right direction is the basis of change and good communication.”

This article was translated from Univadis Italy and appeared on Medscape.com.

An Italian study of women diagnosed with breast cancer reported that around 50% experienced body image disturbance and 20% noted a negative impact on their sex life. And while meeting with a specialist in psycho-oncology was universally viewed as an acceptable option, only one out of four patients considered consulting a sexologist. All these women should be encouraged to face and address issues related to sexuality so that they can truly regain a good quality of life, the study suggests.

The study, which was conducted at the breast unit of Santa Maria Goretti Hospital in Latina, Italy, enrolled 141 patients who had undergone breast cancer surgery. Participants were asked to complete a questionnaire that included questions regarding self-image, sexual activity, and sexual satisfaction, and it analyzed these aspects before and after treatment. The participants were then asked whether they felt that they needed to see a sexologist or a specialist in psycho-oncology.

The findings clearly showed a worsening in terms of body image perception. When the women were asked about the relationship they had with their body, femininity, and beauty prior to being diagnosed, 37.4% characterized it as very good and 58.9% as “normal,” with ups and downs but nothing that they would term “conflictual.” After diagnosis, 48.9% noted that the disease had an impact on their body image with a partial conditioning about their femininity and beauty. However, 7.2% had difficulty when it came to recognizing their own body, and their relationship with femininity also became difficult.

On the topic of sexuality, 71.2% of patients were completely satisfied with their sex life before they were diagnosed with breast cancer, 23.7% were partially satisfied, and 5.0% were unsatisfied. As for their sex life after diagnosis and surgery, 20.1% stated that it continued to be fulfilling and 55.4% said that it had gotten worse; 18.8% reported significant sexual dissatisfaction.

The participants were asked whether consulting a professional would be warranted, and whether that would provide useful support for overcoming the difficulties and challenges arising from the disease and the related treatments. In response, 97.1% said they would go to a specialist in psycho-oncology, but only 27.3% would seek help from a sexologist.

“Despite the negative impact on body image and on sexuality, few patients would seek the help of a sexologist; nearly all of the patients, however, would seek the help of a specialist in psycho-oncology. This was very surprising to us,” write the authors. They went on to note that they are carrying out another project to understand the reason for this disparity.

In addition, they advised clinicians to encourage communication about sexuality – a topic that is regularly overlooked and not included in discussions with patients, mostly because of cultural barriers. Often, physicians aren’t comfortable talking about sexuality, as they don’t feel they have the proper training to do so. Patients who are experiencing issues related to sexuality also often have difficulty asking for help. And so, in their conclusion, the authors point out that “collaborating together in the right direction is the basis of change and good communication.”

This article was translated from Univadis Italy and appeared on Medscape.com.

Experiencing psychological distress prior to becoming infected with SARS-CoV-2 is tied to an increased risk for post-COVID conditions often called “long COVID,” new research suggests.

In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.

Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.

“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.

“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.

The findings were published online in JAMA Psychiatry.
 

‘Poorly understood’

Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.

Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.

Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.

To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).

They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.

Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.

The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.

Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
 

Inflammation, immune dysregulation implicated?

The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).

Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.

The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.

For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.

During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.

Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.

The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).

Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.

In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).

Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).

Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.

However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
 

Contributes to the field

Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.

Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.

He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”

Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.

More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.

The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.

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

Experiencing psychological distress prior to becoming infected with SARS-CoV-2 is tied to an increased risk for post-COVID conditions often called “long COVID,” new research suggests.

In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.

Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.

“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.

“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.

The findings were published online in JAMA Psychiatry.
 

‘Poorly understood’

Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.

Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.

Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.

To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).

They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.

Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.

The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.

Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
 

Inflammation, immune dysregulation implicated?

The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).

Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.

The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.

For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.

During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.

Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.

The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).

Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.

In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).

Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).

Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.

However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
 

Contributes to the field

Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.

Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.

He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”

Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.

More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.

The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.

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

Experiencing psychological distress prior to becoming infected with SARS-CoV-2 is tied to an increased risk for post-COVID conditions often called “long COVID,” new research suggests.

In an analysis of almost 55,000 adult participants in three ongoing studies, having depression, anxiety, worry, perceived stress, or loneliness early in the pandemic, before SARS-CoV-2 infection, was associated with a 50% increased risk for developing long COVID. These types of psychological distress were also associated with a 15% to 51% greater risk for impairment in daily life among individuals with long COVID.

Psychological distress was even more strongly associated with developing long COVID than were physical health risk factors, and the increased risk was not explained by health behaviors such as smoking or physical comorbidities, researchers note.

“Our findings suggest the need to consider psychological health in addition to physical health as risk factors of long COVID-19,” lead author Siwen Wang, MD, postdoctoral fellow, department of nutrition, Harvard T. H. Chan School of Public Health, Boston, said in an interview.

“We need to increase public awareness of the importance of mental health and focus on getting mental health care for people who need it, increasing the supply of mental health clinicians and improving access to care,” she said.

The findings were published online in JAMA Psychiatry.
 

‘Poorly understood’

Postacute sequelae of SARS-CoV-2 (“long COVID”), which are “signs and symptoms consistent with COVID-19 that extend beyond 4 weeks from onset of infection” constitute “an emerging health issue,” the investigators write.

Dr. Wang noted that it has been estimated that 8-23 million Americans have developed long COVID. However, “despite the high prevalence and daily life impairment associated with long COVID, it is still poorly understood, and few risk factors have been established,” she said.

Although psychological distress may be implicated in long COVID, only three previous studies investigated psychological factors as potential contributors, the researchers note. Also, no study has investigated the potential role of other common manifestations of distress that have increased during the pandemic, such as loneliness and perceived stress, they add.

To investigate these issues, the researchers turned to three large ongoing longitudinal studies: the Nurses’ Health Study II (NSHII), the Nurses’ Health study 3 (NHS3), and the Growing Up Today Study (GUTS).

They analyzed data on 54,960 total participants (96.6% women; mean age, 57.5 years). Of the full group, 38% were active health care workers.

Participants completed an online COVID-19 questionnaire from April 2020 to Sept. 1, 2020 (baseline), and monthly surveys thereafter. Beginning in August 2020, surveys were administered quarterly. The end of follow-up was in November 2021.

The COVID questionnaires included questions about positive SARS-CoV-2 test results, COVID symptoms and hospitalization since March 1, 2020, and the presence of long-term COVID symptoms, such as fatigue, respiratory problems, persistent cough, muscle/joint/chest pain, smell/taste problems, confusion/disorientation/brain fog, depression/anxiety/changes in mood, headache, and memory problems.

Participants who reported these post-COVID conditions were asked about the frequency of symptoms and the degree of impairment in daily life.
 

Inflammation, immune dysregulation implicated?

The Patient Health Questionnaire–4 (PHQ-4) was used to assess for anxiety and depressive symptoms in the past 2 weeks. It consists of a two-item depression measure (PHQ-2) and a two-item Generalized Anxiety Disorder Scale (GAD-2).

Non–health care providers completed two additional assessments of psychological distress: the four-item Perceived Stress Scale and the three-item UCLA Loneliness Scale.

The researchers included demographic factors, weight, smoking status, marital status, and medical conditions, including diabetes, hypertension, hypercholesterolemia, asthma, and cancer, and socioeconomic factors as covariates.

For each participant, the investigators calculated the number of types of distress experienced at a high level, including probable depression, probable anxiety, worry about COVID-19, being in the top quartile of perceived stress, and loneliness.

During the 19 months of follow-up (1-47 weeks after baseline), 6% of respondents reported a positive result on a SARS-CoV-2 antibody, antigen, or polymerase chain reaction test.

Of these, 43.9% reported long-COVID conditions, with most reporting that symptoms lasted 2 months or longer; 55.8% reported at least occasional daily life impairment.

The most common post-COVID conditions were fatigue (reported by 56%), loss of smell or taste problems (44.6%), shortness of breath (25.5%), confusion/disorientation/ brain fog (24.5%), and memory issues (21.8%).

Among patients who had been infected, there was a considerably higher rate of preinfection psychological distress after adjusting for sociodemographic factors, health behaviors, and comorbidities. Each type of distress was associated with post-COVID conditions.

In addition, participants who had experienced at least two types of distress prior to infection were at nearly 50% increased risk for post–COVID conditions (risk ratio, 1.49; 95% confidence interval, 1.23-1.80).

Among those with post-COVID conditions, all types of distress were associated with increased risk for daily life impairment (RR range, 1.15-1.51).

Senior author Andrea Roberts, PhD, senior research scientist at the Harvard T. H. Chan School of Public Health, Boston, noted that the investigators did not examine biological mechanisms potentially underlying the association they found.

However, “based on prior research, it may be that inflammation and immune dysregulation related to psychological distress play a role in the association of distress with long COVID, but we can’t be sure,” Dr. Roberts said.
 

Contributes to the field

Commenting for this article, Yapeng Su, PhD, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center in Seattle, called the study “great work contributing to the long-COVID research field and revealing important connections” with psychological stress prior to infection.

Dr. Su, who was not involved with the study, was previously at the Institute for Systems Biology, also in Seattle, and has written about long COVID.

He noted that the “biological mechanism of such intriguing linkage is definitely the important next step, which will likely require deep phenotyping of biological specimens from these patients longitudinally.”

Dr. Wang pointed to past research suggesting that some patients with mental illness “sometimes develop autoantibodies that have also been associated with increased risk of long COVID.” In addition, depression “affects the brain in ways that may explain certain cognitive symptoms in long COVID,” she added.

More studies are now needed to understand how psychological distress increases the risk for long COVID, said Dr. Wang.

The research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Dean’s Fund for Scientific Advancement Acceleration Award from the Harvard T. H. Chan School of Public Health, the Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award, and the Veterans Affairs Health Services Research and Development Service funds. Dr. Wang and Dr. Roberts have reported no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Su reports no relevant financial relationships.

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

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Dr. Inés Gracia-Darder

Known association, but not much data

“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.

“So we assume that also has an effect on melanoma-specific survival,” she added.

That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
 

Retrospective cohort analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
 

Independent association with overall survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.
 

Time to recommend vitamin D supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.

Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”

The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

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

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Dr. Inés Gracia-Darder

Known association, but not much data

“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.

“So we assume that also has an effect on melanoma-specific survival,” she added.

That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
 

Retrospective cohort analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
 

Independent association with overall survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.
 

Time to recommend vitamin D supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.

Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”

The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

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

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Dr. Inés Gracia-Darder

Known association, but not much data

“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.

“So we assume that also has an effect on melanoma-specific survival,” she added.

That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
 

Retrospective cohort analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
 

Independent association with overall survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.
 

Time to recommend vitamin D supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.

Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”

The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

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