Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.

The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”

The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.

The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.

“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”

Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.

And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”

Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”

An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”

But they pointed out some limitations of the current study.

“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”

The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”

Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.

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

Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.

The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”

The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.

The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.

“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”

Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.

And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”

Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”

An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”

But they pointed out some limitations of the current study.

“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”

The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”

Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.

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

Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.

The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”

The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.

The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.

“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”

Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.

And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”

Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”

An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”

But they pointed out some limitations of the current study.

“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”

The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”

Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.

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

Adults with rosacea had a significantly higher prevalence of multiple risk factors for cardiometabolic disease, according to the results of a meta-analysis of more than 50,000 patients.

To date, “mounting comorbidities of rosacea have been identified, suggesting that rosacea is not simply a skin disease but has links to multiple systemic illnesses,” wrote Qi Chen, MD, of Central South University, Changsha, China, and colleagues. The association with rosacea and cardiometabolic disease has been controversial, they added.

In a study published in the Journal of the American Academy of Dermatology, they identified 13 studies including 50,442 rosacea patients and 1,525,864 controls. Approximately 71% of the rosacea patients were women.

Overall, patients with rosacea showed a statistically significant association for hypertension (risk ratio, 1.20; 95% confidence interval, 1.08-1.34; P = .001) and dyslipidemia (RR, 1.32; 95% CI, 1.10-1.58; P = .002). Specifically, rosacea patients averaged higher standard mean differences of systolic and diastolic blood pressure, total cholesterol, HDL cholesterol and LDL cholesterol, and triglycerides, compared with controls.

Rosacea was not significantly associated with an increased risk for ischemic heart disease, stroke, or diabetes, although the rosacea patients showed significantly increased risk of higher fasting blood glucose, compared with controls.
 

Findings don’t show causality

The study findings were limited by several factors, including the observational nature of some of the studies and the inability to perform subgroup analyses based on subtype and disease severity, the researchers noted. In addition, most of the rosacea patients were outpatients. “Further investigations are warranted to identify the relationship between rosacea and [cardiometabolic disease] in general populations to further validate the significance of our findings.”

However, the results support the value of screening for cardiometabolic disease in rosacea patients to facilitate diagnosis and treatment of disease at an early stage, they concluded.

“Rosacea has been linked statistically to many comorbidities including depression, anxiety, hypertension, and diabetes mellitus,” Julie Harper, MD, of the Dermatology and Skin Care Center of Birmingham (Alabama), said in an interview.

“This study looked more specifically at cardiometabolic disease and found a statistically significant correlation between rosacea and hypertension, higher total cholesterol, higher triglycerides and higher fasting blood glucose,” she said. However, “while there is an association present in this meta-analysis, we cannot assume a cause-and-effect relationship.”

Although the analysis does not prove causality, the key message for clinicians is that cardiometabolic disease is quite common in rosacea patients, and risk factors should be identified and treated early, said Dr. Harper. “Our patients with and without rosacea will benefit from age-appropriate screening, physical examination, and laboratory evaluation with a primary care physician. For rosacea patients in particular, we can advise them that early research suggests that individuals with rosacea might have an increased risk of hypertension and/or high cholesterol and triglycerides. It never hurts to make an appointment with primary care and to be checked.”

“We need more confirmatory studies that minimize the influence of confounding,” Dr. Harper added. Rosacea also has also been linked to obesity, which is another risk factor for cardiometabolic disease.

The study was supported by multiple grants from the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Harper had no relevant financial conflicts to disclose.

SOURCE: Chen Q et al. J Am Acad Dermatol. 2020 Nov;83(5):1331-40.

Adults with rosacea had a significantly higher prevalence of multiple risk factors for cardiometabolic disease, according to the results of a meta-analysis of more than 50,000 patients.

To date, “mounting comorbidities of rosacea have been identified, suggesting that rosacea is not simply a skin disease but has links to multiple systemic illnesses,” wrote Qi Chen, MD, of Central South University, Changsha, China, and colleagues. The association with rosacea and cardiometabolic disease has been controversial, they added.

In a study published in the Journal of the American Academy of Dermatology, they identified 13 studies including 50,442 rosacea patients and 1,525,864 controls. Approximately 71% of the rosacea patients were women.

Overall, patients with rosacea showed a statistically significant association for hypertension (risk ratio, 1.20; 95% confidence interval, 1.08-1.34; P = .001) and dyslipidemia (RR, 1.32; 95% CI, 1.10-1.58; P = .002). Specifically, rosacea patients averaged higher standard mean differences of systolic and diastolic blood pressure, total cholesterol, HDL cholesterol and LDL cholesterol, and triglycerides, compared with controls.

Rosacea was not significantly associated with an increased risk for ischemic heart disease, stroke, or diabetes, although the rosacea patients showed significantly increased risk of higher fasting blood glucose, compared with controls.
 

Findings don’t show causality

The study findings were limited by several factors, including the observational nature of some of the studies and the inability to perform subgroup analyses based on subtype and disease severity, the researchers noted. In addition, most of the rosacea patients were outpatients. “Further investigations are warranted to identify the relationship between rosacea and [cardiometabolic disease] in general populations to further validate the significance of our findings.”

However, the results support the value of screening for cardiometabolic disease in rosacea patients to facilitate diagnosis and treatment of disease at an early stage, they concluded.

“Rosacea has been linked statistically to many comorbidities including depression, anxiety, hypertension, and diabetes mellitus,” Julie Harper, MD, of the Dermatology and Skin Care Center of Birmingham (Alabama), said in an interview.

“This study looked more specifically at cardiometabolic disease and found a statistically significant correlation between rosacea and hypertension, higher total cholesterol, higher triglycerides and higher fasting blood glucose,” she said. However, “while there is an association present in this meta-analysis, we cannot assume a cause-and-effect relationship.”

Although the analysis does not prove causality, the key message for clinicians is that cardiometabolic disease is quite common in rosacea patients, and risk factors should be identified and treated early, said Dr. Harper. “Our patients with and without rosacea will benefit from age-appropriate screening, physical examination, and laboratory evaluation with a primary care physician. For rosacea patients in particular, we can advise them that early research suggests that individuals with rosacea might have an increased risk of hypertension and/or high cholesterol and triglycerides. It never hurts to make an appointment with primary care and to be checked.”

“We need more confirmatory studies that minimize the influence of confounding,” Dr. Harper added. Rosacea also has also been linked to obesity, which is another risk factor for cardiometabolic disease.

The study was supported by multiple grants from the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Harper had no relevant financial conflicts to disclose.

SOURCE: Chen Q et al. J Am Acad Dermatol. 2020 Nov;83(5):1331-40.

Adults with rosacea had a significantly higher prevalence of multiple risk factors for cardiometabolic disease, according to the results of a meta-analysis of more than 50,000 patients.

To date, “mounting comorbidities of rosacea have been identified, suggesting that rosacea is not simply a skin disease but has links to multiple systemic illnesses,” wrote Qi Chen, MD, of Central South University, Changsha, China, and colleagues. The association with rosacea and cardiometabolic disease has been controversial, they added.

In a study published in the Journal of the American Academy of Dermatology, they identified 13 studies including 50,442 rosacea patients and 1,525,864 controls. Approximately 71% of the rosacea patients were women.

Overall, patients with rosacea showed a statistically significant association for hypertension (risk ratio, 1.20; 95% confidence interval, 1.08-1.34; P = .001) and dyslipidemia (RR, 1.32; 95% CI, 1.10-1.58; P = .002). Specifically, rosacea patients averaged higher standard mean differences of systolic and diastolic blood pressure, total cholesterol, HDL cholesterol and LDL cholesterol, and triglycerides, compared with controls.

Rosacea was not significantly associated with an increased risk for ischemic heart disease, stroke, or diabetes, although the rosacea patients showed significantly increased risk of higher fasting blood glucose, compared with controls.
 

Findings don’t show causality

The study findings were limited by several factors, including the observational nature of some of the studies and the inability to perform subgroup analyses based on subtype and disease severity, the researchers noted. In addition, most of the rosacea patients were outpatients. “Further investigations are warranted to identify the relationship between rosacea and [cardiometabolic disease] in general populations to further validate the significance of our findings.”

However, the results support the value of screening for cardiometabolic disease in rosacea patients to facilitate diagnosis and treatment of disease at an early stage, they concluded.

“Rosacea has been linked statistically to many comorbidities including depression, anxiety, hypertension, and diabetes mellitus,” Julie Harper, MD, of the Dermatology and Skin Care Center of Birmingham (Alabama), said in an interview.

“This study looked more specifically at cardiometabolic disease and found a statistically significant correlation between rosacea and hypertension, higher total cholesterol, higher triglycerides and higher fasting blood glucose,” she said. However, “while there is an association present in this meta-analysis, we cannot assume a cause-and-effect relationship.”

Although the analysis does not prove causality, the key message for clinicians is that cardiometabolic disease is quite common in rosacea patients, and risk factors should be identified and treated early, said Dr. Harper. “Our patients with and without rosacea will benefit from age-appropriate screening, physical examination, and laboratory evaluation with a primary care physician. For rosacea patients in particular, we can advise them that early research suggests that individuals with rosacea might have an increased risk of hypertension and/or high cholesterol and triglycerides. It never hurts to make an appointment with primary care and to be checked.”

“We need more confirmatory studies that minimize the influence of confounding,” Dr. Harper added. Rosacea also has also been linked to obesity, which is another risk factor for cardiometabolic disease.

The study was supported by multiple grants from the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose. Dr. Harper had no relevant financial conflicts to disclose.

SOURCE: Chen Q et al. J Am Acad Dermatol. 2020 Nov;83(5):1331-40.

Children with epilepsy with no previous psychiatric diagnosis have alarmingly high rates of suicidal thoughts and behaviors, new research suggests. In a study of more than 100 youth with the disorder, more than 40% had depression, 30% had anxiety, and about 1 in 10 exhibited signs of suicidal thoughts and behaviors.

These rates “are really worrisome” and highlight the need to screen all children and young adults with epilepsy for psychiatric disorders, said study author Tatiana Falcone, MD, assistant professor of neurology and child and adolescent psychiatry at the Cleveland Clinic.

“It’s very important to screen for suicidality and for depression and anxiety, even when patients aren’t reporting symptoms,” said Dr. Falcone.

Previous research shows children with epilepsy will attend the emergency room with symptoms such as headache or stomachache “when the main reason for the visit was the kid was suicidal,” Dr. Falcone said. “Unless you ask the specific question: ‘Are you having thoughts about hurting yourself?’ this will go unreported,” she added.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Red flag

Not much is known about suicidality in children and youth with epilepsy except that depression and anxiety – the most common psychiatric comorbidities in this population – appear to contribute to suicidal thoughts.

Dr. Falcone said that she and her colleagues often see children and adolescents with epilepsy in their clinic who have attempted suicide. In recent years, the clinicians have increased efforts to try to identify them before they carry out a successful suicide attempt, said lead investigator Anjali Dagar, MD, clinical research psychiatry fellow at Cleveland Clinic.

The study included 119 patients aged 10-24 years (mean age, 15.8 years; 54.6% female). All attended an epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and did not have a psychiatric diagnosis.

Epilepsy severity ranged among study participants. About half were drug resistant and were at the center for surgical evaluation and the others were newly diagnosed.

Participants filled out questionnaires to self-report psychiatric conditions. The validated screening tools included the Center for Epidemiological Studies Depression Scale for Children (CES-DC), the Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Ask Suicide–Screening Questions (ASQ).

A score of 15 or higher on the CES-DC indicates a risk for depression. On the SCARED test, a score higher than 32 indicates anxiety. Recent research has shown that anxiety is a main risk factor “in moving people from contemplating suicide to actually carrying it out,” Dr. Falcone said.

The ASQ includes four questions about suicidal thoughts and whether respondents have tried to hurt themselves. Dr. Dagar noted that a positive response to any of these questions should raise a red flag.
 

Very high rates

Results showed that almost one-third (30.2%) of the participants scored positive for anxiety on SCARED and 41.2% scored positive for depression on the CSE-DC. These are “very high” rates, Dr. Falcone said. For comparison, the rate of reported anxiety is less than 10% in school surveys.

In addition, the Centers for Disease Control and Prevention reports about 3% of 2- to 17-year-olds in the general population have depression. Even compared with other chronic illnesses (including diabetes, heart disease, and cancer), children with epilepsy have a higher rate of depression, said Dr. Falcone.

More than 1 in 10 (10.9%) participants in the study exhibited signs of suicidality, as shown by having at least one positive response on the ASQ. “That’s a lot,” and much higher than the estimated rate in the general teen population, Dr. Falcone noted.

She noted that “these are just general kids with epilepsy” who had not been previously diagnosed with a psychiatric disorder.

“Depression, anxiety, and suicidality are very frequent comorbidities in patients with epilepsy; and even if a patient is not reporting any symptoms, we should be asking these questions to help them,” she said.

Study participants who had at least one positive response on the ASQ had a mean score of 32.1 on the SCARED, compared with a mean score of 18.3 for those who did not have a positive response on the ASQ (P = .003).

“We wanted to see if there was a direct association in our sample between anxiety and suicidal thoughts, and we found [that] yes there was,” Dr. Falcone said. There was also an association with depression. More than 26% of participants who scored 16 or higher on the CES-DC indicated at least one positive response on the ASQ. This is significantly higher than those who scored 15 or below on the CES-DC (P < .0001).
 

Bidirectional relationship

The findings suggest that either depression or anxiety may contribute to suicidal thoughts or behaviors, Dr. Dagar said. “It’s like two hands. It could be anxiety leading to suicidality, or it could be depression, or it could be both.”

Dr. Falcone noted that children with epilepsy who aren’t sure when they’ll get their next seizure, or who are bullied at school for being different, may be especially prone to anxiety or depression.

There’s a bit of a “chicken-and-egg” relationship between depression and epilepsy, a disorder affecting electrical signals in the brain, she said. Previous research has shown that a “bidirectional relationship” is involved.

“Even in patients with depression who are not diagnosed with epilepsy, the incidence of epilepsy is 3% higher just because you have depression,” Dr. Falcone said.

Suicidal youth tend to attempt suicide more than once. Dr. Falcone and colleagues are trying to intervene “at different levels,” be that in the hospital or as an outpatient, to prevent this from happening. “We want to find out what different things we can do to engage them and improve the probability they don’t reattempt,” she said.

All children and youth with epilepsy should be screened for anxiety, depression, and suicidal thoughts and behaviors. From age 10 years, children with epilepsy should be screened at least once a year, but those with a psychiatric disorder should be screened more often, Dr. Falcone added. The investigators note their findings need to be confirmed in larger, more diverse studies.
 

Importance of screening

Michael Privitera, MD, director of the Epilepsy Center and professor of neurology at the University of Cincinnati Gardner Neuroscience Institute, said the findings reinforce that, as with adults, depression and anxiety are common in children with epilepsy.

“Neurologists should take advantage of the many psychiatric screening tools available to identify these problems in their pediatric and adult patients,” Dr. Privitera said. Even more importantly, screening may help identify those who may be at highest risk of suicide.

The study was funded by the Health Resources Services Administration. The investigators and Dr. Privitera have disclosed no relevant financial relationships.

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

Children with epilepsy with no previous psychiatric diagnosis have alarmingly high rates of suicidal thoughts and behaviors, new research suggests. In a study of more than 100 youth with the disorder, more than 40% had depression, 30% had anxiety, and about 1 in 10 exhibited signs of suicidal thoughts and behaviors.

These rates “are really worrisome” and highlight the need to screen all children and young adults with epilepsy for psychiatric disorders, said study author Tatiana Falcone, MD, assistant professor of neurology and child and adolescent psychiatry at the Cleveland Clinic.

“It’s very important to screen for suicidality and for depression and anxiety, even when patients aren’t reporting symptoms,” said Dr. Falcone.

Previous research shows children with epilepsy will attend the emergency room with symptoms such as headache or stomachache “when the main reason for the visit was the kid was suicidal,” Dr. Falcone said. “Unless you ask the specific question: ‘Are you having thoughts about hurting yourself?’ this will go unreported,” she added.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Red flag

Not much is known about suicidality in children and youth with epilepsy except that depression and anxiety – the most common psychiatric comorbidities in this population – appear to contribute to suicidal thoughts.

Dr. Falcone said that she and her colleagues often see children and adolescents with epilepsy in their clinic who have attempted suicide. In recent years, the clinicians have increased efforts to try to identify them before they carry out a successful suicide attempt, said lead investigator Anjali Dagar, MD, clinical research psychiatry fellow at Cleveland Clinic.

The study included 119 patients aged 10-24 years (mean age, 15.8 years; 54.6% female). All attended an epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and did not have a psychiatric diagnosis.

Epilepsy severity ranged among study participants. About half were drug resistant and were at the center for surgical evaluation and the others were newly diagnosed.

Participants filled out questionnaires to self-report psychiatric conditions. The validated screening tools included the Center for Epidemiological Studies Depression Scale for Children (CES-DC), the Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Ask Suicide–Screening Questions (ASQ).

A score of 15 or higher on the CES-DC indicates a risk for depression. On the SCARED test, a score higher than 32 indicates anxiety. Recent research has shown that anxiety is a main risk factor “in moving people from contemplating suicide to actually carrying it out,” Dr. Falcone said.

The ASQ includes four questions about suicidal thoughts and whether respondents have tried to hurt themselves. Dr. Dagar noted that a positive response to any of these questions should raise a red flag.
 

Very high rates

Results showed that almost one-third (30.2%) of the participants scored positive for anxiety on SCARED and 41.2% scored positive for depression on the CSE-DC. These are “very high” rates, Dr. Falcone said. For comparison, the rate of reported anxiety is less than 10% in school surveys.

In addition, the Centers for Disease Control and Prevention reports about 3% of 2- to 17-year-olds in the general population have depression. Even compared with other chronic illnesses (including diabetes, heart disease, and cancer), children with epilepsy have a higher rate of depression, said Dr. Falcone.

More than 1 in 10 (10.9%) participants in the study exhibited signs of suicidality, as shown by having at least one positive response on the ASQ. “That’s a lot,” and much higher than the estimated rate in the general teen population, Dr. Falcone noted.

She noted that “these are just general kids with epilepsy” who had not been previously diagnosed with a psychiatric disorder.

“Depression, anxiety, and suicidality are very frequent comorbidities in patients with epilepsy; and even if a patient is not reporting any symptoms, we should be asking these questions to help them,” she said.

Study participants who had at least one positive response on the ASQ had a mean score of 32.1 on the SCARED, compared with a mean score of 18.3 for those who did not have a positive response on the ASQ (P = .003).

“We wanted to see if there was a direct association in our sample between anxiety and suicidal thoughts, and we found [that] yes there was,” Dr. Falcone said. There was also an association with depression. More than 26% of participants who scored 16 or higher on the CES-DC indicated at least one positive response on the ASQ. This is significantly higher than those who scored 15 or below on the CES-DC (P < .0001).
 

Bidirectional relationship

The findings suggest that either depression or anxiety may contribute to suicidal thoughts or behaviors, Dr. Dagar said. “It’s like two hands. It could be anxiety leading to suicidality, or it could be depression, or it could be both.”

Dr. Falcone noted that children with epilepsy who aren’t sure when they’ll get their next seizure, or who are bullied at school for being different, may be especially prone to anxiety or depression.

There’s a bit of a “chicken-and-egg” relationship between depression and epilepsy, a disorder affecting electrical signals in the brain, she said. Previous research has shown that a “bidirectional relationship” is involved.

“Even in patients with depression who are not diagnosed with epilepsy, the incidence of epilepsy is 3% higher just because you have depression,” Dr. Falcone said.

Suicidal youth tend to attempt suicide more than once. Dr. Falcone and colleagues are trying to intervene “at different levels,” be that in the hospital or as an outpatient, to prevent this from happening. “We want to find out what different things we can do to engage them and improve the probability they don’t reattempt,” she said.

All children and youth with epilepsy should be screened for anxiety, depression, and suicidal thoughts and behaviors. From age 10 years, children with epilepsy should be screened at least once a year, but those with a psychiatric disorder should be screened more often, Dr. Falcone added. The investigators note their findings need to be confirmed in larger, more diverse studies.
 

Importance of screening

Michael Privitera, MD, director of the Epilepsy Center and professor of neurology at the University of Cincinnati Gardner Neuroscience Institute, said the findings reinforce that, as with adults, depression and anxiety are common in children with epilepsy.

“Neurologists should take advantage of the many psychiatric screening tools available to identify these problems in their pediatric and adult patients,” Dr. Privitera said. Even more importantly, screening may help identify those who may be at highest risk of suicide.

The study was funded by the Health Resources Services Administration. The investigators and Dr. Privitera have disclosed no relevant financial relationships.

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

Children with epilepsy with no previous psychiatric diagnosis have alarmingly high rates of suicidal thoughts and behaviors, new research suggests. In a study of more than 100 youth with the disorder, more than 40% had depression, 30% had anxiety, and about 1 in 10 exhibited signs of suicidal thoughts and behaviors.

These rates “are really worrisome” and highlight the need to screen all children and young adults with epilepsy for psychiatric disorders, said study author Tatiana Falcone, MD, assistant professor of neurology and child and adolescent psychiatry at the Cleveland Clinic.

“It’s very important to screen for suicidality and for depression and anxiety, even when patients aren’t reporting symptoms,” said Dr. Falcone.

Previous research shows children with epilepsy will attend the emergency room with symptoms such as headache or stomachache “when the main reason for the visit was the kid was suicidal,” Dr. Falcone said. “Unless you ask the specific question: ‘Are you having thoughts about hurting yourself?’ this will go unreported,” she added.

The findings were presented at the American Epilepsy Society’s 74th Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

Red flag

Not much is known about suicidality in children and youth with epilepsy except that depression and anxiety – the most common psychiatric comorbidities in this population – appear to contribute to suicidal thoughts.

Dr. Falcone said that she and her colleagues often see children and adolescents with epilepsy in their clinic who have attempted suicide. In recent years, the clinicians have increased efforts to try to identify them before they carry out a successful suicide attempt, said lead investigator Anjali Dagar, MD, clinical research psychiatry fellow at Cleveland Clinic.

The study included 119 patients aged 10-24 years (mean age, 15.8 years; 54.6% female). All attended an epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and did not have a psychiatric diagnosis.

Epilepsy severity ranged among study participants. About half were drug resistant and were at the center for surgical evaluation and the others were newly diagnosed.

Participants filled out questionnaires to self-report psychiatric conditions. The validated screening tools included the Center for Epidemiological Studies Depression Scale for Children (CES-DC), the Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Ask Suicide–Screening Questions (ASQ).

A score of 15 or higher on the CES-DC indicates a risk for depression. On the SCARED test, a score higher than 32 indicates anxiety. Recent research has shown that anxiety is a main risk factor “in moving people from contemplating suicide to actually carrying it out,” Dr. Falcone said.

The ASQ includes four questions about suicidal thoughts and whether respondents have tried to hurt themselves. Dr. Dagar noted that a positive response to any of these questions should raise a red flag.
 

Very high rates

Results showed that almost one-third (30.2%) of the participants scored positive for anxiety on SCARED and 41.2% scored positive for depression on the CSE-DC. These are “very high” rates, Dr. Falcone said. For comparison, the rate of reported anxiety is less than 10% in school surveys.

In addition, the Centers for Disease Control and Prevention reports about 3% of 2- to 17-year-olds in the general population have depression. Even compared with other chronic illnesses (including diabetes, heart disease, and cancer), children with epilepsy have a higher rate of depression, said Dr. Falcone.

More than 1 in 10 (10.9%) participants in the study exhibited signs of suicidality, as shown by having at least one positive response on the ASQ. “That’s a lot,” and much higher than the estimated rate in the general teen population, Dr. Falcone noted.

She noted that “these are just general kids with epilepsy” who had not been previously diagnosed with a psychiatric disorder.

“Depression, anxiety, and suicidality are very frequent comorbidities in patients with epilepsy; and even if a patient is not reporting any symptoms, we should be asking these questions to help them,” she said.

Study participants who had at least one positive response on the ASQ had a mean score of 32.1 on the SCARED, compared with a mean score of 18.3 for those who did not have a positive response on the ASQ (P = .003).

“We wanted to see if there was a direct association in our sample between anxiety and suicidal thoughts, and we found [that] yes there was,” Dr. Falcone said. There was also an association with depression. More than 26% of participants who scored 16 or higher on the CES-DC indicated at least one positive response on the ASQ. This is significantly higher than those who scored 15 or below on the CES-DC (P < .0001).
 

Bidirectional relationship

The findings suggest that either depression or anxiety may contribute to suicidal thoughts or behaviors, Dr. Dagar said. “It’s like two hands. It could be anxiety leading to suicidality, or it could be depression, or it could be both.”

Dr. Falcone noted that children with epilepsy who aren’t sure when they’ll get their next seizure, or who are bullied at school for being different, may be especially prone to anxiety or depression.

There’s a bit of a “chicken-and-egg” relationship between depression and epilepsy, a disorder affecting electrical signals in the brain, she said. Previous research has shown that a “bidirectional relationship” is involved.

“Even in patients with depression who are not diagnosed with epilepsy, the incidence of epilepsy is 3% higher just because you have depression,” Dr. Falcone said.

Suicidal youth tend to attempt suicide more than once. Dr. Falcone and colleagues are trying to intervene “at different levels,” be that in the hospital or as an outpatient, to prevent this from happening. “We want to find out what different things we can do to engage them and improve the probability they don’t reattempt,” she said.

All children and youth with epilepsy should be screened for anxiety, depression, and suicidal thoughts and behaviors. From age 10 years, children with epilepsy should be screened at least once a year, but those with a psychiatric disorder should be screened more often, Dr. Falcone added. The investigators note their findings need to be confirmed in larger, more diverse studies.
 

Importance of screening

Michael Privitera, MD, director of the Epilepsy Center and professor of neurology at the University of Cincinnati Gardner Neuroscience Institute, said the findings reinforce that, as with adults, depression and anxiety are common in children with epilepsy.

“Neurologists should take advantage of the many psychiatric screening tools available to identify these problems in their pediatric and adult patients,” Dr. Privitera said. Even more importantly, screening may help identify those who may be at highest risk of suicide.

The study was funded by the Health Resources Services Administration. The investigators and Dr. Privitera have disclosed no relevant financial relationships.

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

Osteoarthritis patients report significant pain relief after treatment with cooled radiofrequency ablation, a new technique that “stuns” sensory nerves in shoulder and hip joints to reduce – and sometimes eliminate – pain.

“We send a small current to the sensory nerve to heat up the tissue and disrupt the fibers,” study lead author Felix Gonzalez, MD, of Emory University, Atlanta, said in an interview. “The effect is that the transmission of pain is significantly slowed or halted altogether.

“We damage something to fix something,” Dr. Gonzalez continued. “We target only the problematic nerve and get a very localized effect.”
 

Two-phase treatment

The treatment is performed in two phases. First, patients with shoulder pain are given an anesthetic to block their suprascapular, lateral pectoral, and axillary sensory articular nerves. Patients with hip pain have their obturator and femoral sensory articular nerves blocked.

A week or two later, the same nerves are treated with cooled radiofrequency ablation. Guided by x-ray imaging, a clinician heats up the affected nerve tissue using the tip of a needle, which is pointed at the nerve. “It’s a 22-gauge needle, slightly thicker than an acupuncture needle,” Dr. Gonzalez explained. “We heat up the nerve for about 2 minutes to about 60 degrees Celsius – it stuns the nerve,” he said.

“The result disrupts or slows down pain transmission while leaving the nerve intact.”

To test the efficacy of the technique, researchers treated 12 shoulders in patients with an average age of 61 years, and 11 hips in patients with an average age of 62 years.

Three months after treatment, patients with hip pain reported improvement in Hip Disability and Osteoarthritis Outcome Score (HOOS) from a baseline of 17.0 to 52.9 (P < .0001).

Shoulder pain was also reduced significantly. Using the American Shoulder and Elbow Surgeons (ASES) score, researchers reported an improvement from 17.2 (±6.6) at baseline to 65.7 (±5.9) at 3 months (P < .0001).

“We are targeting a subset of patients for this that don’t qualify for surgery,” Dr. Gonzalez noted. For patients with a body mass index above 35, or a history of hypertension, heart disease, or multiple strokes, opioids are the most common treatment, he said.

These patients “fall through the cracks,” he explained. Those who have mild to moderate pain are managed with physical therapy and injections, and those with severe pain go into surgery. “But what about the ones in the middle ... who are not eligible for surgery? They are at risk for opioid overuse,” he said. “So this treatment is a good option for them.”
 

Treats the symptoms, not the cause

“This study shows the efficacy of this method in taking care of shoulder and hip pain,” Luca Maria Sconfienza, MD, PhD, of Galeazzi Orthopedic Hospital in Milan, said in an interview. Dr. Sconfienza was not involved in Dr. Gonzalez’s study.

However, like corticosteroid injections, “the drawback of radiofrequency ablation is the fact that it only treats the symptoms and not the cause, and efficacy is usually limited over time,” she said.

Dr. Sconfienza said this study leaves her with three pertinent questions. “First, whether pain control extends beyond the 3-month follow-up reported by authors in the abstract; second, [what] is the efficacy of this method compared to other interventions (e.g., physical therapy, injections) or to doing nothing; and last, radiofrequency ablation is usually not a cheap treatment, thus a cost-efficacy analysis would be desirable, especially in comparison to other procedures.”

Dr. Gonzalez and Dr. Sconfienza have nothing relevant to disclose.

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

Osteoarthritis patients report significant pain relief after treatment with cooled radiofrequency ablation, a new technique that “stuns” sensory nerves in shoulder and hip joints to reduce – and sometimes eliminate – pain.

“We send a small current to the sensory nerve to heat up the tissue and disrupt the fibers,” study lead author Felix Gonzalez, MD, of Emory University, Atlanta, said in an interview. “The effect is that the transmission of pain is significantly slowed or halted altogether.

“We damage something to fix something,” Dr. Gonzalez continued. “We target only the problematic nerve and get a very localized effect.”
 

Two-phase treatment

The treatment is performed in two phases. First, patients with shoulder pain are given an anesthetic to block their suprascapular, lateral pectoral, and axillary sensory articular nerves. Patients with hip pain have their obturator and femoral sensory articular nerves blocked.

A week or two later, the same nerves are treated with cooled radiofrequency ablation. Guided by x-ray imaging, a clinician heats up the affected nerve tissue using the tip of a needle, which is pointed at the nerve. “It’s a 22-gauge needle, slightly thicker than an acupuncture needle,” Dr. Gonzalez explained. “We heat up the nerve for about 2 minutes to about 60 degrees Celsius – it stuns the nerve,” he said.

“The result disrupts or slows down pain transmission while leaving the nerve intact.”

To test the efficacy of the technique, researchers treated 12 shoulders in patients with an average age of 61 years, and 11 hips in patients with an average age of 62 years.

Three months after treatment, patients with hip pain reported improvement in Hip Disability and Osteoarthritis Outcome Score (HOOS) from a baseline of 17.0 to 52.9 (P < .0001).

Shoulder pain was also reduced significantly. Using the American Shoulder and Elbow Surgeons (ASES) score, researchers reported an improvement from 17.2 (±6.6) at baseline to 65.7 (±5.9) at 3 months (P < .0001).

“We are targeting a subset of patients for this that don’t qualify for surgery,” Dr. Gonzalez noted. For patients with a body mass index above 35, or a history of hypertension, heart disease, or multiple strokes, opioids are the most common treatment, he said.

These patients “fall through the cracks,” he explained. Those who have mild to moderate pain are managed with physical therapy and injections, and those with severe pain go into surgery. “But what about the ones in the middle ... who are not eligible for surgery? They are at risk for opioid overuse,” he said. “So this treatment is a good option for them.”
 

Treats the symptoms, not the cause

“This study shows the efficacy of this method in taking care of shoulder and hip pain,” Luca Maria Sconfienza, MD, PhD, of Galeazzi Orthopedic Hospital in Milan, said in an interview. Dr. Sconfienza was not involved in Dr. Gonzalez’s study.

However, like corticosteroid injections, “the drawback of radiofrequency ablation is the fact that it only treats the symptoms and not the cause, and efficacy is usually limited over time,” she said.

Dr. Sconfienza said this study leaves her with three pertinent questions. “First, whether pain control extends beyond the 3-month follow-up reported by authors in the abstract; second, [what] is the efficacy of this method compared to other interventions (e.g., physical therapy, injections) or to doing nothing; and last, radiofrequency ablation is usually not a cheap treatment, thus a cost-efficacy analysis would be desirable, especially in comparison to other procedures.”

Dr. Gonzalez and Dr. Sconfienza have nothing relevant to disclose.

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

Osteoarthritis patients report significant pain relief after treatment with cooled radiofrequency ablation, a new technique that “stuns” sensory nerves in shoulder and hip joints to reduce – and sometimes eliminate – pain.

“We send a small current to the sensory nerve to heat up the tissue and disrupt the fibers,” study lead author Felix Gonzalez, MD, of Emory University, Atlanta, said in an interview. “The effect is that the transmission of pain is significantly slowed or halted altogether.

“We damage something to fix something,” Dr. Gonzalez continued. “We target only the problematic nerve and get a very localized effect.”
 

Two-phase treatment

The treatment is performed in two phases. First, patients with shoulder pain are given an anesthetic to block their suprascapular, lateral pectoral, and axillary sensory articular nerves. Patients with hip pain have their obturator and femoral sensory articular nerves blocked.

A week or two later, the same nerves are treated with cooled radiofrequency ablation. Guided by x-ray imaging, a clinician heats up the affected nerve tissue using the tip of a needle, which is pointed at the nerve. “It’s a 22-gauge needle, slightly thicker than an acupuncture needle,” Dr. Gonzalez explained. “We heat up the nerve for about 2 minutes to about 60 degrees Celsius – it stuns the nerve,” he said.

“The result disrupts or slows down pain transmission while leaving the nerve intact.”

To test the efficacy of the technique, researchers treated 12 shoulders in patients with an average age of 61 years, and 11 hips in patients with an average age of 62 years.

Three months after treatment, patients with hip pain reported improvement in Hip Disability and Osteoarthritis Outcome Score (HOOS) from a baseline of 17.0 to 52.9 (P < .0001).

Shoulder pain was also reduced significantly. Using the American Shoulder and Elbow Surgeons (ASES) score, researchers reported an improvement from 17.2 (±6.6) at baseline to 65.7 (±5.9) at 3 months (P < .0001).

“We are targeting a subset of patients for this that don’t qualify for surgery,” Dr. Gonzalez noted. For patients with a body mass index above 35, or a history of hypertension, heart disease, or multiple strokes, opioids are the most common treatment, he said.

These patients “fall through the cracks,” he explained. Those who have mild to moderate pain are managed with physical therapy and injections, and those with severe pain go into surgery. “But what about the ones in the middle ... who are not eligible for surgery? They are at risk for opioid overuse,” he said. “So this treatment is a good option for them.”
 

Treats the symptoms, not the cause

“This study shows the efficacy of this method in taking care of shoulder and hip pain,” Luca Maria Sconfienza, MD, PhD, of Galeazzi Orthopedic Hospital in Milan, said in an interview. Dr. Sconfienza was not involved in Dr. Gonzalez’s study.

However, like corticosteroid injections, “the drawback of radiofrequency ablation is the fact that it only treats the symptoms and not the cause, and efficacy is usually limited over time,” she said.

Dr. Sconfienza said this study leaves her with three pertinent questions. “First, whether pain control extends beyond the 3-month follow-up reported by authors in the abstract; second, [what] is the efficacy of this method compared to other interventions (e.g., physical therapy, injections) or to doing nothing; and last, radiofrequency ablation is usually not a cheap treatment, thus a cost-efficacy analysis would be desirable, especially in comparison to other procedures.”

Dr. Gonzalez and Dr. Sconfienza have nothing relevant to disclose.

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

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

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

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

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

Patients who are profoundly immunosuppressed after extensive cancer treatment, and who fall ill with COVID-19, can shed viable SARS-CoV-2 virus for at least 2 months after symptom onset and may need extended periods of isolation.

Live-virus shedding was detected in 18 patients who had undergone hematopoietic stem cell transplants or chimeric antigen receptor (CAR) T-cell therapy and in 2 patients with lymphoma. 

The finding was reported Dec. 1 in a research letter in the New England Journal of Medicine. 

Individuals who are otherwise healthy when they get COVID-19 are “no longer infectious after the first week of illness,” said lead author Mini Kamboj, MD, chief medical epidemiologist, Memorial Sloan Kettering Cancer Center, New York. 

“We need to keep an open mind about how [much] longer immunocompromised patients could pose an infection risk to others,” she added.

Dr. Kamboj said in an interview that her team’s previous experience with stem cell transplant recipients had suggested that severely immunocompromised patients shed other viruses (such as respiratory syncytial virus, parainfluenza, and influenza) for longer periods of time than do healthy controls.

Based on their latest findings, the investigators suggest that current guidelines for COVID-19 isolation precautions may need to be revised for immunocompromised patients. Even if only a small proportion of patients with cancer who have COVID-19 remain contagious for prolonged periods of time, “it’s a residual risk that we need to address,” Dr. Kamboj said. 

Dr. Kamboj also suggested that physicians follow test-based criteria to determine when a patient undergoing transplant can be released from isolation.
 

Shedding of viable virus

For this study, the investigators used cell cultures to detect viable virus in serially collected nasopharyngeal and sputum samples from 20 immunocompromised patients who had COVID-19 (diagnosed with COVID-19 between March 10 and April 20).  

Patients had lymphoma (n = 8), multiple myeloma (n= 7), acute leukemia/myelodysplastic syndrome (n = 4), and chronic leukemia (n = 1). There were 16 patients who had undergone transplant, 2 who had received CAR T-cell therapy, and 2 who had received other therapy.

There were 15 patients receiving active treatment or chemotherapy, and 11 developed severe COVID-19 infection. 

In total, 78 respiratory samples were collected.

“Viral RNA was detected for up to 78 days after the onset of symptoms,” the researchers reported, “[and] viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing.”

Five patients were followed up, and from these patients, the team grew virus in culture for up to 61 days after symptom onset. Two among this small group of five patients had received allogenic hematopoietic stem cell transplantation and one patient had been treated with CAR T-cell therapy within the previous 6 months. This patient remained seronegative for antibodies to the coronavirus.

For 11 patients, the team obtained serial sample genomes and found that  “each patient was infected by a distinct virus and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates.” These findings were consistent with persistent infection, they noted.

The authors have disclosed no relevant financial relationships.

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

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

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

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

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

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

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

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

The World Health Organization estimates that 14.9 million of 57 million annual deaths worldwide (25%) are related directly to diseases caused by bacterial and/or viral infections.

The first crucial step in order to build a successful surveillance system is to accurately identify and diagnose disease, Ivana Pennisi reminded the audience at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. A problem, particularly in primary care, is differentiating between patients with bacterial infections who might benefit from antibiotics and those with viral infections where supportive treatment is generally required. One solution might a rapid point-of-care tool.

Ms. Pennisi described early experiences of using microchip technology to detect RNA biomarkers in the blood rather than look for the pathogen itself. Early results suggest high diagnostic accuracy at low cost.

It is known that when a bacteria or virus enters the body, it stimulates the immune system in a unique way leading to the expression of different genes in the host blood. As part of the Personalized Management of Febrile Illnesses study, researchers have demonstrated a number of high correlated transcripts. Of current interest are two genes which are upregulated in childhood febrile illnesses.

Ms. Pennisi, a PhD student working as part of a multidisciplinary at the department of infectious disease and Centre for Bioinspired Technology at Imperial College, London, developed loop-mediated isothermal amplification (LAMP) assays to detect for the first time host RNA signatures on a nucleic acid–based point-of-care handheld system to discriminate bacterial from viral infection. The amplification reaction is then combined with microchip technology in the well of a portable point-of-care device named Lacewing. It translates the nucleic acid amplification signal into a quantitative electrochemical signal without the need for a thermal cycler.

The combination of genomic expertise in the section of paediatrics lead by Michael Levin, PhD, and microchip-based technologies in the department of electrical and electronic engineering under the guidance of Pantelis Georgiou, PhD, enabled the team overcome many clinical challenges.

Ms. Pennisi presented her team’s early experiences with clinical samples from 455 febrile children. First, transcription isothermal amplification techniques were employed to confirm bacterial and viral infections. Results were then validated using standard fluorescent-based quantitative polymerase chain reaction (PCR) instruments. In order to define a decision boundary between bacterial and viral patients, cutoff levels were determined using multivariate logistic regression analysis. Results then were evaluated using microarrays, reverse transcriptase PCR (RT-PCR), and the eLAMP to confirm comparability with preferred techniques.

In conclusion, Ms. Pennisi reported that the two-gene signature combined with the use of eLAMP technology in a point-of-care tool offered the potential of low cost and accurate discrimination between bacterial and viral infection in febrile children. She outlined her vision for the future: “The patient sample and reagent are loaded into a disposable cartridge. This is then placed into a device to monitor in real time the reaction and share all the data via a Bluetooth to a dedicated app on a smart phone. All data and location of the outbreak are then stored in [the] cloud, making it easier for epidemiological studies and tracking of new outbreaks. We hope that by enhancing the capability of our platform, we contribute to better patient care.”

“Distinguishing between bacterial and viral infections remains one of the key questions in the daily pediatric acute care,” commented Lauri Ivaska, MD, from the department of pediatrics and adolescent medicine at Turku (Finland) University Hospital. “One of the most promising laboratory methods to do this is by measuring quantities of two specific host RNA transcripts from a blood sample. It would be of great importance if this could be done reliably by using a fast and cheap method as presented here by Ivana Pennisi.”

Ms. Pennisi had no relevant financial disclosures.

Higher doses of vitamin D supplementation not only show no benefit in the prevention of falls in older adults at increased risk of falling, compared with the lowest doses, but they appear to increase the risk, new research shows.

Zbynek Pospisil/iStock/Getty Images

Based on the findings, supplemental vitamin D above the minimum dose of 200 IU/day likely has little benefit, lead author Lawrence J. Appel, MD, MPH, told this news organization.

“In the absence of any benefit of 1,000 IU/day versus 2,000 IU/day [of vitamin D supplementation] on falls, along with the potential for harm from doses above 1,000 IU/day, it is hard to recommend a dose above 200 IU/day in older-aged persons, unless there is a compelling reason,” asserted Dr. Appel, director of the Welch Center for Prevention, Epidemiology, and Clinical Research at Johns Hopkins Bloomberg School of Public Health in Baltimore.

“More is not always better – and it may even be worse,” when it comes to vitamin D’s role in the prevention of falls, he said.

The research, published in Annals of Internal Medicine, adds important evidence in the ongoing struggle to prevent falls, says Bruce R. Troen, MD, in an accompanying editorial.

“Falls and their deleterious consequences remain a substantial risk for older adults and a huge challenge for health care teams,” writes Dr. Troen, a physician-investigator with the Veterans Affairs Western New York Healthcare System.

However, commenting in an interview, Dr. Troen cautions: “There are many epidemiological studies that are correlative, not causative, that do show a likelihood for benefit [with vitamin D supplementation]. … Therefore, there’s no reason for clinicians to discontinue vitamin D in individuals because of this study.”

“If you’re monitoring an older adult who is frail and has multiple comorbidities, you want to know what their vitamin D level is [and] provide them an appropriate supplement if needed,” he emphasized.

Some guidelines already reflect the lack of evidence of any role of vitamin D supplementation in the prevention of falls, including those of the 2018 U.S. Preventive Services Task Force, which, in a reversal of its 2012 recommendation, now does not recommend vitamin D supplementation for fall prevention in older persons without osteoporosis or vitamin D deficiency, Dr. Appel and colleagues note.
 

No prevention of falls regardless of baseline vitamin D

As part of STURDY (Study to understand fall reduction and vitamin D in you), Dr. Appel and colleagues enrolled 688 community-dwelling participants who had an elevated risk of falling, defined as a serum 25-hydroxyvitamin D [25(OH)D] level of 25 to 72.5 nmol/L (10-29 ng/dL).

Participants were a mean age of 77.2 years and had a mean total 25(OH)D level of 55.3 nmol/L at enrollment.

They were randomized to one of four doses of vitamin D₃, including 200 IU/day (the control group), or 1,000, 2,000, or 4,000 IU/day.

The highest doses were found to be associated with worse – not better – outcomes including a shorter time to hospitalization or death, compared with the 1,000-IU/day group. The higher-dose groups were therefore switched to a dose of 1,000 IU/day or lower, and all participants were followed for up to 2 years.

Overall, 63% experienced falls over the course of the study, which, though high, was consistent with the study’s criteria of participants having an elevated fall risk.

Of the 667 participants who completed the trial, no benefit in prevention of falling was seen across any of the doses, compared with the control group dose of 200 IU/day, regardless of participants’ baseline vitamin D levels.

Safety analyses showed that even in the 1,000-IU/day group, a higher risk of first serious fall and first fall with hospitalization was seen compared with the 200-IU/day group.

A limitation is that the study did not have a placebo group, however, “200 IU/day is a very small dose, probably homeopathic,” Dr. Appel said. “It was likely close to a placebo,” he said.
 

Caveats: comorbidities, subgroups

In his editorial, Dr. Troen notes other studies, including VITAL (Vitamin D and Omega-3 Trial) also found no reduction in falls with higher vitamin D doses; however, that study did not show any significant risks with the higher doses.

He adds that the current study lacks information on subsets of participants.

“We don’t have enough information about the existing comorbidities and medications that these people are on to be able to pull back the layers. Maybe there is a subgroup that should not be getting 4,000 IU, whereas another subgroup may not be harmed and you may decide that patient can benefit,” he said.

Furthermore, the trial doesn’t address groups such as nursing home residents.

“I have, for instance, 85-year-olds with vitamin D levels of maybe 20 nmol/L with multiple medical issues, but levels that low were not included in the study, so this is a tricky business, but the bottom line is first, do no harm,” he said.

“We really need trials that factor in the multiple different aspects so we can come up, hopefully, with a holistic and interdisciplinary approach, which is usually the best way to optimize care for frail older adults,” he concluded.

The study received funding from the National Institute of Aging.
 

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

Higher doses of vitamin D supplementation not only show no benefit in the prevention of falls in older adults at increased risk of falling, compared with the lowest doses, but they appear to increase the risk, new research shows.

Zbynek Pospisil/iStock/Getty Images

Based on the findings, supplemental vitamin D above the minimum dose of 200 IU/day likely has little benefit, lead author Lawrence J. Appel, MD, MPH, told this news organization.

“In the absence of any benefit of 1,000 IU/day versus 2,000 IU/day [of vitamin D supplementation] on falls, along with the potential for harm from doses above 1,000 IU/day, it is hard to recommend a dose above 200 IU/day in older-aged persons, unless there is a compelling reason,” asserted Dr. Appel, director of the Welch Center for Prevention, Epidemiology, and Clinical Research at Johns Hopkins Bloomberg School of Public Health in Baltimore.

“More is not always better – and it may even be worse,” when it comes to vitamin D’s role in the prevention of falls, he said.

The research, published in Annals of Internal Medicine, adds important evidence in the ongoing struggle to prevent falls, says Bruce R. Troen, MD, in an accompanying editorial.

“Falls and their deleterious consequences remain a substantial risk for older adults and a huge challenge for health care teams,” writes Dr. Troen, a physician-investigator with the Veterans Affairs Western New York Healthcare System.

However, commenting in an interview, Dr. Troen cautions: “There are many epidemiological studies that are correlative, not causative, that do show a likelihood for benefit [with vitamin D supplementation]. … Therefore, there’s no reason for clinicians to discontinue vitamin D in individuals because of this study.”

“If you’re monitoring an older adult who is frail and has multiple comorbidities, you want to know what their vitamin D level is [and] provide them an appropriate supplement if needed,” he emphasized.

Some guidelines already reflect the lack of evidence of any role of vitamin D supplementation in the prevention of falls, including those of the 2018 U.S. Preventive Services Task Force, which, in a reversal of its 2012 recommendation, now does not recommend vitamin D supplementation for fall prevention in older persons without osteoporosis or vitamin D deficiency, Dr. Appel and colleagues note.
 

No prevention of falls regardless of baseline vitamin D

As part of STURDY (Study to understand fall reduction and vitamin D in you), Dr. Appel and colleagues enrolled 688 community-dwelling participants who had an elevated risk of falling, defined as a serum 25-hydroxyvitamin D [25(OH)D] level of 25 to 72.5 nmol/L (10-29 ng/dL).

Participants were a mean age of 77.2 years and had a mean total 25(OH)D level of 55.3 nmol/L at enrollment.

They were randomized to one of four doses of vitamin D₃, including 200 IU/day (the control group), or 1,000, 2,000, or 4,000 IU/day.

The highest doses were found to be associated with worse – not better – outcomes including a shorter time to hospitalization or death, compared with the 1,000-IU/day group. The higher-dose groups were therefore switched to a dose of 1,000 IU/day or lower, and all participants were followed for up to 2 years.

Overall, 63% experienced falls over the course of the study, which, though high, was consistent with the study’s criteria of participants having an elevated fall risk.

Of the 667 participants who completed the trial, no benefit in prevention of falling was seen across any of the doses, compared with the control group dose of 200 IU/day, regardless of participants’ baseline vitamin D levels.

Safety analyses showed that even in the 1,000-IU/day group, a higher risk of first serious fall and first fall with hospitalization was seen compared with the 200-IU/day group.

A limitation is that the study did not have a placebo group, however, “200 IU/day is a very small dose, probably homeopathic,” Dr. Appel said. “It was likely close to a placebo,” he said.
 

Caveats: comorbidities, subgroups

In his editorial, Dr. Troen notes other studies, including VITAL (Vitamin D and Omega-3 Trial) also found no reduction in falls with higher vitamin D doses; however, that study did not show any significant risks with the higher doses.

He adds that the current study lacks information on subsets of participants.

“We don’t have enough information about the existing comorbidities and medications that these people are on to be able to pull back the layers. Maybe there is a subgroup that should not be getting 4,000 IU, whereas another subgroup may not be harmed and you may decide that patient can benefit,” he said.

Furthermore, the trial doesn’t address groups such as nursing home residents.

“I have, for instance, 85-year-olds with vitamin D levels of maybe 20 nmol/L with multiple medical issues, but levels that low were not included in the study, so this is a tricky business, but the bottom line is first, do no harm,” he said.

“We really need trials that factor in the multiple different aspects so we can come up, hopefully, with a holistic and interdisciplinary approach, which is usually the best way to optimize care for frail older adults,” he concluded.

The study received funding from the National Institute of Aging.
 

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

Higher doses of vitamin D supplementation not only show no benefit in the prevention of falls in older adults at increased risk of falling, compared with the lowest doses, but they appear to increase the risk, new research shows.

Zbynek Pospisil/iStock/Getty Images

Based on the findings, supplemental vitamin D above the minimum dose of 200 IU/day likely has little benefit, lead author Lawrence J. Appel, MD, MPH, told this news organization.

“In the absence of any benefit of 1,000 IU/day versus 2,000 IU/day [of vitamin D supplementation] on falls, along with the potential for harm from doses above 1,000 IU/day, it is hard to recommend a dose above 200 IU/day in older-aged persons, unless there is a compelling reason,” asserted Dr. Appel, director of the Welch Center for Prevention, Epidemiology, and Clinical Research at Johns Hopkins Bloomberg School of Public Health in Baltimore.

“More is not always better – and it may even be worse,” when it comes to vitamin D’s role in the prevention of falls, he said.

The research, published in Annals of Internal Medicine, adds important evidence in the ongoing struggle to prevent falls, says Bruce R. Troen, MD, in an accompanying editorial.

“Falls and their deleterious consequences remain a substantial risk for older adults and a huge challenge for health care teams,” writes Dr. Troen, a physician-investigator with the Veterans Affairs Western New York Healthcare System.

However, commenting in an interview, Dr. Troen cautions: “There are many epidemiological studies that are correlative, not causative, that do show a likelihood for benefit [with vitamin D supplementation]. … Therefore, there’s no reason for clinicians to discontinue vitamin D in individuals because of this study.”

“If you’re monitoring an older adult who is frail and has multiple comorbidities, you want to know what their vitamin D level is [and] provide them an appropriate supplement if needed,” he emphasized.

Some guidelines already reflect the lack of evidence of any role of vitamin D supplementation in the prevention of falls, including those of the 2018 U.S. Preventive Services Task Force, which, in a reversal of its 2012 recommendation, now does not recommend vitamin D supplementation for fall prevention in older persons without osteoporosis or vitamin D deficiency, Dr. Appel and colleagues note.
 

No prevention of falls regardless of baseline vitamin D

As part of STURDY (Study to understand fall reduction and vitamin D in you), Dr. Appel and colleagues enrolled 688 community-dwelling participants who had an elevated risk of falling, defined as a serum 25-hydroxyvitamin D [25(OH)D] level of 25 to 72.5 nmol/L (10-29 ng/dL).

Participants were a mean age of 77.2 years and had a mean total 25(OH)D level of 55.3 nmol/L at enrollment.

They were randomized to one of four doses of vitamin D₃, including 200 IU/day (the control group), or 1,000, 2,000, or 4,000 IU/day.

The highest doses were found to be associated with worse – not better – outcomes including a shorter time to hospitalization or death, compared with the 1,000-IU/day group. The higher-dose groups were therefore switched to a dose of 1,000 IU/day or lower, and all participants were followed for up to 2 years.

Overall, 63% experienced falls over the course of the study, which, though high, was consistent with the study’s criteria of participants having an elevated fall risk.

Of the 667 participants who completed the trial, no benefit in prevention of falling was seen across any of the doses, compared with the control group dose of 200 IU/day, regardless of participants’ baseline vitamin D levels.

Safety analyses showed that even in the 1,000-IU/day group, a higher risk of first serious fall and first fall with hospitalization was seen compared with the 200-IU/day group.

A limitation is that the study did not have a placebo group, however, “200 IU/day is a very small dose, probably homeopathic,” Dr. Appel said. “It was likely close to a placebo,” he said.
 

Caveats: comorbidities, subgroups

In his editorial, Dr. Troen notes other studies, including VITAL (Vitamin D and Omega-3 Trial) also found no reduction in falls with higher vitamin D doses; however, that study did not show any significant risks with the higher doses.

He adds that the current study lacks information on subsets of participants.

“We don’t have enough information about the existing comorbidities and medications that these people are on to be able to pull back the layers. Maybe there is a subgroup that should not be getting 4,000 IU, whereas another subgroup may not be harmed and you may decide that patient can benefit,” he said.

Furthermore, the trial doesn’t address groups such as nursing home residents.

“I have, for instance, 85-year-olds with vitamin D levels of maybe 20 nmol/L with multiple medical issues, but levels that low were not included in the study, so this is a tricky business, but the bottom line is first, do no harm,” he said.

“We really need trials that factor in the multiple different aspects so we can come up, hopefully, with a holistic and interdisciplinary approach, which is usually the best way to optimize care for frail older adults,” he concluded.

The study received funding from the National Institute of Aging.
 

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

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Every medical oncologist who has described a combination chemotherapy regimen to a patient with advanced cancer has likely been asked whether the benefits of tumor shrinkage, disease-free survival (DFS), and overall survival are worth the risks of adverse events (AEs).

Single-agent immunotherapy and, more recently, combinations of immunotherapy drugs have been approved for a variety of metastatic tumors. In general, combination immunotherapy regimens have more AEs and a higher frequency of premature treatment discontinuation for toxicity.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, reflected on new ways to evaluate the benefits and risks of immunotherapy combinations during a plenary session on novel combinations at the American Association for Cancer Research’s Virtual Special Conference on Tumor Immunology and Immunotherapy.
 

Potential targets

As with chemotherapy drugs, immunotherapy combinations make the most sense when drugs targeting independent processes are employed.

As described in a paper published in Nature in 2011, the process for recruiting the immune system to combat cancer is as follows:

• Dendritic cells must sample antigens derived from the tumor.
• The dendritic cells must receive an activation signal so they promote immunity rather than tolerance.
• The tumor antigen–loaded dendritic cells need to generate protective T-cell responses, instead of T-regulatory responses, in lymphoid tissues.
• Cancer antigen–specific T cells must enter tumor tissues.
• Tumor-derived mechanisms for promoting immunosuppression need to be circumvented.

Since each step in the cascade is a potential therapeutic target, there are large numbers of potential drug combinations.
 

Measuring impact

Conventional measurements of tumor response may not be adequately sensitive to the impact from immunotherapy drugs. A case in point is sipuleucel-T, which is approved to treat advanced prostate cancer.

In the pivotal phase 3 trial, only 1 of 341 patients receiving sipuleucel-T achieved a partial response by RECIST criteria. Only 2.6% of patients had a 50% reduction in prostate-specific antigen levels. Nonetheless, a 4.1-month improvement in median overall survival was achieved. These results were published in the New England Journal of Medicine.

The discrepancy between tumor shrinkage and survival benefit for immunotherapy is not unexpected. As many as 10% of patients treated with ipilimumab (ipi) for stage IV malignant melanoma have progressive disease by tumor size but experience prolongation of survival, according to guidelines published in Clinical Cancer Research.

Accurate assessment of the ultimate efficacy of immunotherapy over time would benefit patients and clinicians since immune checkpoint inhibitors are often administered for several years, are financially costly, and treatment-associated AEs emerge unpredictably at any time.

Curtailing the duration of ineffective treatment could be valuable from many perspectives.
 

Immunotherapy combinations in metastatic melanoma

In the CheckMate 067 study, there was an improvement in response, progression-free survival (PFS), and overall survival for nivolumab (nivo) plus ipi or nivo alone, in comparison with ipi alone, in patients with advanced melanoma. Initial results from this trial were published in the New England Journal of Medicine in 2017.

At a minimum follow-up of 60 months, the 5-year overall survival was 52% for the nivo/ipi regimen, 44% for nivo alone, and 26% for ipi alone. These results were published in the New England Journal of Medicine in 2019.

The trial was not statistically powered to conclude whether the overall survival for the combination was superior to that of single-agent nivo alone, but both nivo regimens were superior to ipi alone.

Unfortunately, the combination also produced the highest treatment-related AE rates – 59% with nivo/ipi, 23% with nivo, and 28% with ipi in 2019. In the 2017 report, the combination regimen had more than twice as many premature treatment discontinuations as the other two study arms.

Is there a better way to quantify the risk-benefit ratio and explain it to patients?
 

Alternative strategies for assessing benefit: Treatment-free survival

Researchers have proposed treatment-free survival (TFS) as a potential new metric to characterize not only antitumor activity but also toxicity experienced after the cessation of therapy and before initiation of subsequent systemic therapy or death.

TFS is defined as the area between Kaplan-Meier curves from immunotherapy cessation until the reinitiation of systemic therapy or death. All patients who began immunotherapy are included – not just those achieving response or concluding a predefined number of cycles of treatment.

The curves can be partitioned into states with and without toxicity to establish a unique endpoint: time to cessation of both immunotherapy and toxicity.

Researchers conducted a pooled analysis of 3-year follow-up data from the 1,077 patients who participated in CheckMate 069, testing nivo/ipi versus nivo alone, and CheckMate 067, comparing nivo/ipi, nivo alone, and ipi alone. The results were published in the Journal of Clinical Oncology.

The TFS without grade 3 or higher AEs was 28% for nivo/ipi, 11% for nivo alone, and 23% for ipi alone. The restricted mean time without either treatment or grade 3 or greater AEs was 10.1 months, 4.1 months, and 8.5 months, respectively.

TFS incentivizes the use of regimens that have:

• A short duration of treatment
• Prolonged time to subsequent therapy or death
• Only mild AEs of brief duration.

A higher TFS corresponds with the goals that patients and their providers would have for a treatment regimen.
 

Adaptive models provide clues about benefit from extended therapy

In contrast to cytotoxic chemotherapy and molecularly targeted agents, benefit from immune-targeted therapy can deepen and persist after treatment discontinuation.

In advanced melanoma, researchers observed that overall survival was similar for patients who discontinued nivo/ipi because of AEs during the induction phase of treatment and those who did not. These results were published in the Journal of Clinical Oncology.

This observation has led to an individualized, adaptive approach to de-escalating combination immunotherapy, described in Clinical Cancer Research. The approach is dubbed “SMART,” which stands for sequential multiple assignment randomized trial designs.

With the SMART approach, each stage of a trial corresponds to an important treatment decision point. The goal is to define the population of patients who can safely discontinue treatment based on response, rather than doing so after the development of AEs.

In the Adapt-IT prospective study, 60 patients with advanced melanoma with poor prognostic features were given two doses of nivo/ipi followed by a CT scan at week 6. They were triaged to stopping ipi and proceeding with maintenance therapy with nivo alone or continuing the combination for an additional two cycles of treatment. Results from this trial were presented at ASCO 2020 (abstract 10003).

The investigators found that 68% of patients had no tumor burden increase at week 6 and could discontinue ipi. For those patients, their response rate of 57% approached the expected results from a full course of ipi.

At median follow-up of 22.3 months, median response duration, PFS, and overall survival had not been reached for the responders who received an abbreviated course of the combination regimen.

There were two observations that suggested the first two cycles of treatment drove not only toxicity but also tumor control:

• The rate of grade 3-4 toxicity from only two cycles was high (57%).
• Of the 19 patients (32% of the original 60 patients) who had progressive disease after two cycles of nivo/ipi, there were no responders with continued therapy.

Dr. Postow commented that, in correlative studies conducted as part of Adapt-IT, the Ki-67 of CD8-positive T cells increased after the initial dose of nivo/ipi. However, proliferation did not continue with subsequent cycles (that is, Ki-67 did not continue to rise).

When they examined markers of T-cell stimulation such as inducible costimulator of CD8-positive T cells, the researchers observed the same effect. The “immune boost” occurred with cycle one but not after subsequent doses of the nivo/ipi combination.

Although unproven in clinical trials at this time, these data suggest that response and risks of toxicity may not support giving patients more than one cycle of combination treatment.
 

More nuanced ways of assessing tumor growth

Dr. Postow noted that judgment about treatment effects over time are often made by displaying spider plots of changes from baseline tumor size from “time zero” – the time at which combination therapy is commenced.

He speculated that it might be worthwhile to give a dose or two of immune-targeted monotherapy (such as a PD-1 or PD-L1 inhibitor alone) before time zero, measure tumor growth prior to and after the single agent, and reserve using combination immunotherapy only for those patients who do not experience a dampening of the growth curve.

Patients whose tumor growth kinetics are improved with single-agent treatment could be spared the additional toxicity (and uncertain additive benefit) from the second agent.
 

Treatment optimization: More than ‘messaging’

Oncology practice has passed through a long era of “more is better,” an era that gave rise to intensive cytotoxic chemotherapy for hematologic and solid tumors in the metastatic and adjuvant settings. In some cases, that approach proved to be curative, but not in all.

More recently, because of better staging, improved outcomes with newer technology and treatments, and concern about immediate- and late-onset health risks, there has been an effort to deintensify therapy when it can be done safely.

Once a treatment regimen and treatment duration become established, however, patients and their physicians are reluctant to deintensity therapy.

Dr. Postow’s presentation demonstrated that, with regard to immunotherapy combinations – as in other realms of medical practice – science can lead the way to treatment optimization for individual patients.

We have the potential to reassure patients that treatment de-escalation is a rational and personalized component of treatment optimization through the combination of:

• Identifying new endpoints to quantify treatment benefits and risks.
• SMART trial designs.
• Innovative ways to assess tumor response during each phase of a treatment course.

Precision assessment of immunotherapy effect in individual patients can be a key part of precision medicine.

Dr. Postow disclosed relationships with Aduro, Array BioPharma, Bristol Myers Squibb, Eisai, Incyte, Infinity, Merck, NewLink Genetics, Novartis, and RGenix.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.