Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.

Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.

Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.

Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.

And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.

This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.

“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
 

Diabetes and hyperglycemia worsen COVID-19 outcomes

The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.

Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.

Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.

Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.

In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
 

Antibody response similar in patients with and without diabetes

The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.

After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).

“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).

These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.

They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”

“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”

“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.

The authors have reported no relevant financial relationships.
 

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

Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.

Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.

Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.

Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.

And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.

This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.

“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
 

Diabetes and hyperglycemia worsen COVID-19 outcomes

The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.

Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.

Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.

Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.

In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
 

Antibody response similar in patients with and without diabetes

The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.

After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).

“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).

These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.

They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”

“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”

“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.

The authors have reported no relevant financial relationships.
 

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

Neither diabetes per se nor hyperglycemia appear to impair the antibody response to SARS-CoV-2, suggesting that a COVID-19 vaccine would be just as effective in people with diabetes as in those without, new research finds.

Results from a study involving 480 patients with confirmed COVID-19 seen at an Italian hospital between February 25 and April 19 were published online October 8 in Diabetologia by Vito Lampasona, MD, and colleagues.

Antibody responses against multiple SARS-CoV-2 antigens among the 27% of patients with COVID-19 and diabetes (preexisting and newly diagnosed) were similar with regard to timing, titers, and classes to those of patients with COVID-19 and without diabetes, and the results did not differ by glucose levels.

Moreover, positivity for immunoglobulin G (IgG) against the SARS-CoV-2 spike receptor-binding domain (RBD) was associated with improved survival regardless of diabetes status.

And as previously shown, high blood glucose levels were strongly associated with greater COVID-19 mortality even in those without diabetes.

This is the first study of the immunologic humoral response against SARS-CoV-2 in patients with hyperglycemia, the authors say.

“The immunological response to a future SARS-CoV-2 vaccine will be assessed when the vaccine becomes available. However, our data allow a cautious optimism regarding effective immunization in individuals with diabetes, as well as in the general population,” wrote Dr. Lampasona of San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele in Milan, and colleagues.
 

Diabetes and hyperglycemia worsen COVID-19 outcomes

The investigators analyzed the presence of three types of antibody to multiple SARS-CoV-2 antigens in 509 participants: IgG, which is evidence of past infection; IgM, which indicates more recent or current infection; and IgA, which is involved in the mucosal immune response, for example, in the nose where the virus enters the body.

Overall, 452 (88.8%) patients were hospitalized, 79 (15.5%) patients were admitted to intensive care, and 93 (18.3%) patients died during follow-up.

Of the 139 patients with diabetes, 90 (17.7% of the study cohort) already had a diagnosis of diabetes, and 49 (9.6%) were newly diagnosed.

Those with diabetes were older, had a higher body mass index (BMI), and were more likely to have cardiovascular comorbidities, hypertension, and chronic kidney disease. As has been previously reported for diabetes and COVID-19, diabetes was also associated with increased levels of inflammatory biomarkers, hypercoagulopathy, leukocytosis, and neutrophilia.

In multivariate analysis, diabetes status (hazard ratio, 2.32; P = .001), mean fasting plasma glucose (P < .001), and glucose variability (P = .002) were all independently associated with increased mortality and ICU admission. And fasting plasma glucose was associated with increased mortality risk even among those without diabetes (P < .001).
 

Antibody response similar in patients with and without diabetes

The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable in terms of timing and antibody titers to that of patients without diabetes, with marginal differences, and was not influenced by glucose levels.

After adjustment for sex, age, and diabetes status and stratification by symptom duration at time of sampling, the development of SARS-CoV-2 RBD IgG antibodies was associated with improved survival, with an HR for time to death of 0.4 (P = .002).

“Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival rate, both in the presence or absence of diabetes,” the authors stressed, with similar HRs for those with diabetes (0.37; P = .013) and without diabetes (0.43; P = .038).

These data confirm “the relevance for patient survival rate of the specific antigen response against spike RBD even in the presence of diabetes, and it underlines how the mechanism explaining the worse clinical outcome in patients with diabetes is unrelated to the antibody response,” they explain.

They added, “This, together with evidence that increased blood glucose levels do predict a poor prognosis even in nondiabetic individuals and the association with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leukocytosis and neutrophilia, support the speculation that glucose per se could be an independent biological negative factor, acting as a direct regulator of innate immunity.”

“The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycemia was not the result of an impaired humoral response against SARS-CoV-2.”

“RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARS-COV-2 in people with diabetes,” they reiterated.

The authors have reported no relevant financial relationships.
 

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

Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.

CoRus13/Wikimedia Commons/Creative Commons 4.0

Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.

These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.

The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
 

Promising results for many

There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.

With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.

The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).

Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.

“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.

The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.

[email protected]

SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.

Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.

CoRus13/Wikimedia Commons/Creative Commons 4.0

Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.

These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.

The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
 

Promising results for many

There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.

With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.

The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).

Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.

“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.

The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.

[email protected]

SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.

Patients with B-cell lymphoma are immunocompromised because of the disease and its treatments. This presents the question of their outcomes upon infection with SARS-CoV-2. Researchers assessed the characteristics of patients with lymphoma hospitalized for COVID-19 and analyzed determinants of mortality in a retrospective database study. The investigators looked at data from adult patients with lymphoma who were hospitalized for COVID-19 in March and April 2020 in three French regions.

CoRus13/Wikimedia Commons/Creative Commons 4.0

Older age and relapsed/refractory (r/r) disease in B-cell lymphoma patients were both found to be independent risk factors of increased death rate from COVID-19, according to the online report in EClinicalMedicine, published by The Lancet.

These results encourage “the application of standard Covid-19 treatment, including intubation, for lymphoma patients with Covid-19 lymphoma diagnosis, under first- or second-line chemotherapy, or in remission,” according to Sylvain Lamure, MD, of Montellier (France) University, and colleagues.

The study examined a series of 89 consecutive patients from three French regions who had lymphoma and were hospitalized for COVID-19 in March and April 2020. The population was homogeneous; most patients were diagnosed with B-cell non-Hodgkin lymphoma (NHL) and had been treated for their lymphoma within 1 year.
 

Promising results for many

There were a significant associations between 30-day mortality and increasing age (over age 70 years) and r/r lymphoma. However, in the absence of those factors, mortality of the lymphoma patients with COVID-19 was comparable with that of the reference French COVID-19 population. In addition, there was no significant impact of active lymphoma treatment that had been given within 1 year, except for those patients who received bendamustine, which was associated with greater mortality, according to the researchers.

With a median follow-up of 33 days from admission, the Kaplan-Meier estimate of 30-day overall survival was 71% (95% confidence interval, 62%-81%). According to histological type of the lymphoma, 30-day overall survival rates were 80% (95% CI, 45%-100%) for Hodgkin lymphoma, 71% (95% CI, 61%-82%) for B-cell non-Hodgkin Lymphoma, and 71% (95% CI, 38%-100%) for T-cell non-Hodgkin Lymphoma.

The main factors associated with mortality were age 70 years and older (hazard ratio, 3.78; 95% CI, 1.73-8.25; P = .0009), hypertension (HR, 2.20; 95% CI, 1.06-4.59; P = .03), previous cancer (HR, 2.11; 95% CI, 0.90-4.92; P = .08), use of bendamustine within 12 months before admission to hospital (HR, 3.05; 95% CI, 1.31-7.11; P = .01), and r/r lymphoma (HR, 2.62; 95% CI, 1.20-5.72; P = .02).

Overall, the Kaplan-Meier estimates of 30-day overall survival were 61% for patients with r/r lymphoma, 52% in patients age 70 years with non–r/r lymphoma, and 88% for patients younger than 70 years with non–r/r, which was comparable with general population survival data among French populations, according to the researchers.

“Longer term clinical follow-up and biological monitoring of immune responses is warranted to explore the impact of lymphoma and its treatment on the immunity and prolonged outcome of Covid-19 patients,” they concluded.

The study was unsponsored. Several of the authors reported financial relationships with a number of biotechnology and pharmaceutical companies.

[email protected]

SOURCE: Lamure S et al. EClinicalMedicine. 2020 Oct 12. doi: 10.1016/j.eclinm.2020.100549.

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

No hint of increased mortality risk in association with the use of paclitaxel-coated devices for treatment of peripheral artery disease was detected in VOYAGER PAD, a multithousand-patient randomized trial with long-term follow-up and ascertainment of vital status in 99.6% of participants.

Observers opined that the VOYAGER PAD findings effectively put to rest a nearly 2-year-old controversy over whether paclitaxel-coated devices for treatment of peripheral artery disease (PAD) carry an increased mortality risk. The imbroglio, which was ignited by a meta-analysis of clinical trials with substantial amounts of missing follow-up data, triggered an Food and Drug Administration warning letter to health care providers which threw the field of vascular medicine into disarray.

“Although as a community we’ve continued to struggle with this issue of paclitaxel and mortality, VOYAGER PAD does fill many of the gaps and addresses many of the limitations of currently available data,” Connie N. Hess, MD, said in reporting results of a prespecified analysis of the trial at the Transcatheter Cardiovascular Research Therapeutics virtual annual meeting. “I think these are the most definitive data to date supporting the safety of drug-coated device use.”

VOYAGER PAD was a double-blind, placebo-controlled clinical trial in which 6,564 patients undergoing lower-extremity revascularization for symptomatic PAD were randomized to rivaroxaban at 2.5 mg twice daily or placebo on top of background low-dose aspirin. In the previously reported primary outcome, the group on rivaroxaban plus aspirin had a significant 15% reduction in the risk of the composite endpoint of cardiovascular death, acute limb ischemia, MI, ischemic stroke, or major amputation for vascular causes.

Of the 4,316 patients included in the prespecified analysis by Dr. Hess, a cardiologist at the University of Colorado at Denver, Aurora, 31% received a paclitaxel-coated device. At 3.5 years of follow-up, they had a 10.2% all-cause mortality rate, significantly less than the 13.5% rate in patients who didn’t get a drug-coated device. But since study participants weren’t randomized for drug-coated device use, the investigators utilized a rigorous form of propensity adjustment called inverse probability treatment weighting to neutralize all between-group differences in potentially confounding baseline characteristics, including statin use, prevalence of claudication, and target lesion length.

In the weighted analysis, the all-cause mortality rate at 3.5 years was 12.1% in paclitaxel-coated device recipients and 12.6% in those who didn’t get such devices. The difference was not statistically significant, and the hazard ratio of 0.95 had tight confidence intervals.

“We don’t see a mortality benefit, but I think more importantly, we don’t see any risk for mortality,” the cardiologist observed at the meeting sponsored by the Cardiovascular Research Foundation.

There was no between-group difference in causes of mortality. Nor did all-cause mortality differ by device type, be it paclitaxel-coated balloon versus plain balloon angioplasty, or drug-eluting stent versus bare-metal stent.

Also, the benefit of rivaroxaban plus aspirin over aspirin alone in terms of cardiovascular and ischemic limb outcomes was consistent regardless of whether patients got a drug-coated device or not.

Discussant Robert Lookstein, MD, praised Dr. Hess for “a really enlightening presentation.”

“The entire vascular community has been waiting for a prospective, independently adjudicated trial to try to make determinations of whether we can put this issue behind us, and I think this trial is it,” said Dr. Lookstein, professor of interventional radiology and surgery at the Icahn School of Medicine at Mount Sinai, New York.

“Personally, I think this is probably the most impactful data seen regarding the paclitaxel issue in almost 2 years because it is randomized data, it’s prospectively collected data, and – most importantly from my perspective – they were able to collect vital statistics on more than 99.5% of the patients,” he added. “I think this is incredibly impactful to my practice.”

Frank Veith, MD, professor of surgery at New York University, concurred, declaring, “I think this study is a game changer. And I think the paclitaxel game is over.”

The VOYAGER PAD study was funded by institutional research grants from Bayer and Janssen.

[email protected]

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

Patients with severe melancholic or psychotic depression are more likely to respond to ECT, and preliminary evidence indicates they’re also protected against ECT-induced cognitive impairment, Linda van Diermen, MD, PhD, reported at the virtual congress of the European College of Neuropsychopharmacology.

Over the decades many small, underpowered studies have looked at possible predictors of ECT response and remission, with no consensus being reached. In an effort to bring a measure of clarity, Dr. van Diermen and her coinvestigators performed a meta-analysis of 34 published studies in accord with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols) guidelines and published their findings in the British Journal of Psychiatry. They scrutinized three potential predictors of response: the presence of psychotic features, melancholic depression with psychomotor symptoms, and older age.

Psychotic depression was associated with a 1.7-fold increased likelihood of response to ECT and a 1.5-fold increased odds of remission, compared with that of ECT-treated patients without psychotic depression. Older age was also a statistically significant predictor of response. However, the findings on melancholic depression were inconclusive, with only five studies with inconsistent results being available, said Dr. van Diermen, a psychiatrist at the University of Antwerp (Belgium).

She was quick to point out that, although psychotic depression and older age were statistically significant predictors of heightened likelihood of ECT response, they are of only limited clinical significance in treatment decision-making. The ECT response rate was 79% in patients with psychotic depression but still quite good at 71% in those without psychotic depression. Moreover, the average age of remitters was 59.7 years, compared with 55.4 years in nonresponders, a difference too small to be useful in guiding clinical treatment decisions.

“Age is not a valuable ECT predictor,” she said. “Although we did a meta-analysis in more than 3,200 patients that confirmed the superior effects of ECT in older patients and we recommended it at that time as one of the elements to guide decision-making when you consider ECT, our present, more detailed look at the interdependence of the predictors leads us to reconsider this statement. We now venture that age has been given too much weight in the past decades.”
 

A closer look at ECT response predictors

The studies included in the meta-analysis assessed psychotic depression and melancholic features as ECT response predictors in the typical binary way employed in clinical practice: yes/no, either present or absent. Dr. van Diermer hypothesized that a more in-depth assessment of the severity of those factors would boost their predictive power.

She found that this was indeed the case for melancholic depression as evaluated by three tools for measuring psychomotor symptoms, a core feature of this form of depression. She and her coinvestigators assessed psychomotor functioning in 65 adults with major depressive disorder before, during, and after ECT using the clinician-rated CORE scale, which measures psychomotor retardation, agitation, and noninteractiveness. In addition, the investigators had the subjects wear an accelerometer and complete a timed fine-motor drawing test.

The 41 patients with melancholic depression with psychomotor symptoms as defined by a CORE score of 8 or more were 4.9-fold more likely to reach an ECT response than were those with nonmelancholic depression. A lower baseline daytime activity level as assessed by accelerometer was also a significant predictor of increased likelihood of response, as were slower times on the drawing test.

In contrast, the investigators found that more detailed assessment of psychotic depression using the validated Psychotic Depression Assessment Scale (PDAS) was predictive of the likelihood of ECT response, but not any more so than the simple presence or absence of psychotic symptoms (J ECT. 2019 Dec;35[4]:238-44).

“In our sample, better measurement of psychotic symptoms did not improve prediction, but better measurement of psychomotor symptoms did seem to be valuable,” according to the psychiatrist.
 

Protection against ECT’s cognitive side effects?

Dr. van Diermen and colleagues assessed short- and long-term changes in global cognitive functioning in 65 consecutive patients treated with ECT for a major depressive episode by administering the Montreal Cognitive Assessment (MoCA) at baseline, before the third ECT session, and 1 week, 3 months, and 6 months after completing their treatment course.

During ECT, the investigators documented a limited decrease in cognitive functioning at the group level, which rebounded during the 6 months after ECT. But although there was no significant difference between MoCA scores at baseline and 6 months follow-up after ECT in the overall group of study participants, that doesn’t tell the full story. Six months after completing their course of ECT, 18% of patients demonstrated improved cognitive functioning, compared with baseline, but 8% had significantly worse cognitive functioning than pretreatment.

“Saying that ECT has no cognitive effects seems to be somewhat wrong to me. It has cognitive effects for certain people, and it will be interesting to know which people,” Dr. van Diermen said.

In what she termed “a very, very preliminary analysis,” she found that the patients with psychotic or melancholic depression were markedly less likely to have long-term cognitive impairment as defined by a worse MoCA score, compared with baseline, both at 6 months and one or more intermediate time points. Only 1 of 31 patients with psychotic depression fell into that poor cognitive outcome category, as did 4 patients with melancholic depression, compared with 12 patients without psychotic depression and 9 without melancholic depression. This, Dr. van Diermen believes, is the first report of an apparent protective effect of melancholic or psychotic depression against ECT-induced long-term cognitive worsening.

“Replication of our results is definitely necessary in larger patient samples,” she cautioned.

Dr. van Diermen reported having no financial conflicts regarding her presentation.

[email protected]

SOURCE: van Diermen L. ECNP 2020, Session EDU03.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

Non-White patient participation in phase 3 therapeutic trials for plaque psoriasis is less than 15%, according to a recently published analysis of data from the ClinicalTrials.gov database.

The exact figure drawn from the survey of 82 trials was 14.2%, but 20 (24%) of the trials did not include ethnoracial data at all, and only 65% of those with data had complete data, according to a report in the British Journal of Dermatology by a team of investigators from the department of dermatology at the University of California, San Francisco.

“The remaining studies reported the percentage of white participants only or white participants and one additional ethnoracial group,” reported the investigators, led by Vidhatha D. Reddy, a medical student at UCSF.

The investigators broke down participation by race in all phase 3 plaque psoriasis trials that enrolled adults and had posted results by May 2020. Data from trials of medications yet to be approved were excluded.

Most trials were multinational. The medications evaluated included 11 biologics, 10 topicals, 2 oral systemic agents, and a phosphodiesterase type-4 inhibitor. The 82 trials included in this analysis enrolled 48,846 collectively.

From trials that identified race, 85.8% of 39,161 participants were White, 3.09% of 25,565 patients were Black, 19.55% of 11,364 patients were Hispanic or Latino, and 9.21% of 30,009 patients were Asian. Of trials that included Native Americans or Pacific Islanders, fewer than 2% of participants represented this category.

Non-White patients remain underrepresented even when recognizing differences in the prevalence of psoriasis. For example, one recent survey found the U.S, prevalence of psoriasis to be about half as great in Blacks as it is in Whites (1.9% vs. 3.9%), but the representation of Blacks in the phase 3 trials evaluated by Mr. Reddy and colleagues was more than 20 times lower.

There are many reasons to suspect that lack of diversification in psoriasis trials is impeding optimal care in those underrepresented. Of several examples offered by the authors, one involved differential responses to adalimumab among patients with hidradenitis suppurativa with genetic variants in the BCL2 gene, but the authors reported racially associated genetic differences are not uncommon.

“Estimates have shown that approximately one-fifth of newly developed medications demonstrate interracial/ethnic variability in regard to various factors, such as pharmacokinetics, safety and efficacy profiles, dosing, and pharmacogenetics,” Mr. Reddy and his coinvestigators stated.

Although racial diversity in the design and recruitment for clinical trials has not been a priority in trials involving psoriasis, other skin diseases, or most diseases in general, the authors cited some evidence that this is changing.

“Since 2017, research funded by the National Institutes of Health has been required to report race and ethnicity of participants following an amendment to the Health Revitalization Act,” according to the authors, who suggested that other such initiatives are needed. They advocated “explicit goals to increase recruitment of people of color” as a standard step in clinical trial conduct.

Hypertension trials were cited as an example in which diversity has made a difference.

“Although Black patients are at an elevated risk of developing hypertension, it was not until the enrollment of a substantial proportion of black participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) that enough data on Black patients were available to make specific treatment recommendations in this population,” they noted.
 

Impossible to know treatment benefits without ethnoracial data

Penn Medicine

Another investigator who has considered this issue, Junko Takeshita, MD, PhD, an assistant professor of dermatology at the University of Pennsylvania, Philadelphia, agreed.

“Lack of diversity among participants in phase 3 clinical trials for psoriasis is a problem,” said Dr. Takeshita, who led a study of racial differences in perceptions of psoriasis therapies that was published last year.

In that study, “my research group not only found differences in perceptions about biologics between Black and White patients with psoriasis, but we have also shown that Black patients with psoriasis are less likely to receive biologic treatment,” she reported. There are many explanations. For example, she found in another study that Black patients are underrepresented in direct-to-consumer advertisements for biologics.

This problem is not unique to psoriasis. Underrepresentation of Blacks and other ethnoracial groups is true of other skin diseases and many diseases in general, according to Dr. Takeshita. However, she cautioned that the 3% figure for Black participation in psoriasis trials reported by Mr. Reddy and colleagues is not necessarily reflective of trials in the United States.

“This study included international study sites that are recruiting patients from populations with different demographics than the U.S.,” she noted. By including sites with only Asian patients or countries with few Blacks in the population, it dilutes Black representation. She would expect the exact proportion of Black participants to be somewhat higher even if they are “still likely to be underrepresented” if the analysis has been limited to U.S. data.

The research had no funding source. Three of the nine authors reported financial relationships with pharmaceutical companies.

SOURCE: Reddy VD et al. Br J Dermatol. 2020 Sep 17. doi: 10.1111/bjd.19468.

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

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

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

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

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

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

Irritability appears to be a potent independent predictor of increased risk for suicidality in children and adolescents with ADHD, Tomer Levy, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

While there is ample evidence that ADHD is associated with increased suicidality, Dr. Levy’s recent study involving 1,516 youths aged 6-17 years attending an outpatient ADHD clinic demonstrated that this increased risk is mediated by depression and irritability in roughly equal measures. Moreover, upon controlling for those two factors in a multivariate analysis, ADHD symptoms, per se, had no direct effect on risk of suicidality as defined by suidical ideation, attempts, or self-harm.

The clinical take-home message is that assessing irritability, as well as depression, may bolster an estimate of suicidality and help in managing suicidal risk in ADHD, according to Dr. Levy, a child and adolescent psychiatrist at the Hospital for Sick Children, Toronto, and head of behavioral regulation services at the Geha Mental Health Center in Petah Tikva, Israel.

The study included separate parent- and teacher-structured reports of the youths’ ADHD symptoms, suicidality, depression, irritability, and anxiety. Parents reported suicidality in 12.1% of the pediatric patients, significantly higher than the 3.8% rate reported by teachers.

In multivariate analyses, parent-reported depression accounted for 39.1% of the association between ADHD symptoms and suicidality, while irritability symptoms mediated 36.8% of the total effect. In the teachers’ reports, depression and irritability symptoms accounted for 45.3% and 38.4% of the association. Anxiety symptoms mediated 19% of the relationship between ADHD and suicidality by parental report but had no significant impact on the association according to teacher report in the recently published study.

Dr. Levy noted that, in the DSM-5, irritability cuts across diagnostic categories. It is not only a core dimension of ADHD, but of the other externalizing disorders – conduct disorder and oppositional defiant disorder – as well, and also of neurodevelopmental, internalizing, and stress-related disorders.

Interventional studies aimed at dampening irritability as a potential strategy to reduce suicidality haven’t yet been done, but they deserve research priority status, in Dr. Levy’s view. Numerous functional dimensions that influence irritability are potential targets, including aggression, negative affect, low tolerance of frustration, skewed threat perception, and impaired self-regulation, according to the psychiatrist.

Most suicidal youths are attempting to cope with mental disorders. The most prevalent of these are major depressive disorder and dysthymia, followed by externalizing disorders. And among the externalizing disorders, conduct disorder stands out in terms of the magnitude of associated suicidality risk. In a large Taiwanese national study including 3,711 adolescents with conduct disorder and 14,844 age- and sex-matched controls, conduct disorder was associated with an adjusted 5.17-fold increased risk of subsequent suicide attempts over the next 10 years in a multivariate regression analysis adjusted for other psychiatric comorbidities and demographics.

In addition to depression, irritability symptoms, and conduct problems, other risk factors that should be part of a suicidality assessment in children and adolescents with ADHD include substance use, anxiety, poor family support, and bullying and/or being bullied. But, perhaps surprisingly, not impulsivity, Dr. Levy said.

“There is a widely held perception that impulsivity imparts a risk for suicidality, and especially in the transition from ideation to attempt. However, more recent evidence fails to show a convincing association,” according to Dr. Levy.

He reported having no financial conflicts regarding his presentation.

[email protected]

SOURCE: Levy T. ECNP 2020, Session EDU.02.

Irritability appears to be a potent independent predictor of increased risk for suicidality in children and adolescents with ADHD, Tomer Levy, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

While there is ample evidence that ADHD is associated with increased suicidality, Dr. Levy’s recent study involving 1,516 youths aged 6-17 years attending an outpatient ADHD clinic demonstrated that this increased risk is mediated by depression and irritability in roughly equal measures. Moreover, upon controlling for those two factors in a multivariate analysis, ADHD symptoms, per se, had no direct effect on risk of suicidality as defined by suidical ideation, attempts, or self-harm.

The clinical take-home message is that assessing irritability, as well as depression, may bolster an estimate of suicidality and help in managing suicidal risk in ADHD, according to Dr. Levy, a child and adolescent psychiatrist at the Hospital for Sick Children, Toronto, and head of behavioral regulation services at the Geha Mental Health Center in Petah Tikva, Israel.

The study included separate parent- and teacher-structured reports of the youths’ ADHD symptoms, suicidality, depression, irritability, and anxiety. Parents reported suicidality in 12.1% of the pediatric patients, significantly higher than the 3.8% rate reported by teachers.

In multivariate analyses, parent-reported depression accounted for 39.1% of the association between ADHD symptoms and suicidality, while irritability symptoms mediated 36.8% of the total effect. In the teachers’ reports, depression and irritability symptoms accounted for 45.3% and 38.4% of the association. Anxiety symptoms mediated 19% of the relationship between ADHD and suicidality by parental report but had no significant impact on the association according to teacher report in the recently published study.

Dr. Levy noted that, in the DSM-5, irritability cuts across diagnostic categories. It is not only a core dimension of ADHD, but of the other externalizing disorders – conduct disorder and oppositional defiant disorder – as well, and also of neurodevelopmental, internalizing, and stress-related disorders.

Interventional studies aimed at dampening irritability as a potential strategy to reduce suicidality haven’t yet been done, but they deserve research priority status, in Dr. Levy’s view. Numerous functional dimensions that influence irritability are potential targets, including aggression, negative affect, low tolerance of frustration, skewed threat perception, and impaired self-regulation, according to the psychiatrist.

Most suicidal youths are attempting to cope with mental disorders. The most prevalent of these are major depressive disorder and dysthymia, followed by externalizing disorders. And among the externalizing disorders, conduct disorder stands out in terms of the magnitude of associated suicidality risk. In a large Taiwanese national study including 3,711 adolescents with conduct disorder and 14,844 age- and sex-matched controls, conduct disorder was associated with an adjusted 5.17-fold increased risk of subsequent suicide attempts over the next 10 years in a multivariate regression analysis adjusted for other psychiatric comorbidities and demographics.

In addition to depression, irritability symptoms, and conduct problems, other risk factors that should be part of a suicidality assessment in children and adolescents with ADHD include substance use, anxiety, poor family support, and bullying and/or being bullied. But, perhaps surprisingly, not impulsivity, Dr. Levy said.

“There is a widely held perception that impulsivity imparts a risk for suicidality, and especially in the transition from ideation to attempt. However, more recent evidence fails to show a convincing association,” according to Dr. Levy.

He reported having no financial conflicts regarding his presentation.

[email protected]

SOURCE: Levy T. ECNP 2020, Session EDU.02.

Irritability appears to be a potent independent predictor of increased risk for suicidality in children and adolescents with ADHD, Tomer Levy, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

While there is ample evidence that ADHD is associated with increased suicidality, Dr. Levy’s recent study involving 1,516 youths aged 6-17 years attending an outpatient ADHD clinic demonstrated that this increased risk is mediated by depression and irritability in roughly equal measures. Moreover, upon controlling for those two factors in a multivariate analysis, ADHD symptoms, per se, had no direct effect on risk of suicidality as defined by suidical ideation, attempts, or self-harm.

The clinical take-home message is that assessing irritability, as well as depression, may bolster an estimate of suicidality and help in managing suicidal risk in ADHD, according to Dr. Levy, a child and adolescent psychiatrist at the Hospital for Sick Children, Toronto, and head of behavioral regulation services at the Geha Mental Health Center in Petah Tikva, Israel.

The study included separate parent- and teacher-structured reports of the youths’ ADHD symptoms, suicidality, depression, irritability, and anxiety. Parents reported suicidality in 12.1% of the pediatric patients, significantly higher than the 3.8% rate reported by teachers.

In multivariate analyses, parent-reported depression accounted for 39.1% of the association between ADHD symptoms and suicidality, while irritability symptoms mediated 36.8% of the total effect. In the teachers’ reports, depression and irritability symptoms accounted for 45.3% and 38.4% of the association. Anxiety symptoms mediated 19% of the relationship between ADHD and suicidality by parental report but had no significant impact on the association according to teacher report in the recently published study.

Dr. Levy noted that, in the DSM-5, irritability cuts across diagnostic categories. It is not only a core dimension of ADHD, but of the other externalizing disorders – conduct disorder and oppositional defiant disorder – as well, and also of neurodevelopmental, internalizing, and stress-related disorders.

Interventional studies aimed at dampening irritability as a potential strategy to reduce suicidality haven’t yet been done, but they deserve research priority status, in Dr. Levy’s view. Numerous functional dimensions that influence irritability are potential targets, including aggression, negative affect, low tolerance of frustration, skewed threat perception, and impaired self-regulation, according to the psychiatrist.

Most suicidal youths are attempting to cope with mental disorders. The most prevalent of these are major depressive disorder and dysthymia, followed by externalizing disorders. And among the externalizing disorders, conduct disorder stands out in terms of the magnitude of associated suicidality risk. In a large Taiwanese national study including 3,711 adolescents with conduct disorder and 14,844 age- and sex-matched controls, conduct disorder was associated with an adjusted 5.17-fold increased risk of subsequent suicide attempts over the next 10 years in a multivariate regression analysis adjusted for other psychiatric comorbidities and demographics.

In addition to depression, irritability symptoms, and conduct problems, other risk factors that should be part of a suicidality assessment in children and adolescents with ADHD include substance use, anxiety, poor family support, and bullying and/or being bullied. But, perhaps surprisingly, not impulsivity, Dr. Levy said.

“There is a widely held perception that impulsivity imparts a risk for suicidality, and especially in the transition from ideation to attempt. However, more recent evidence fails to show a convincing association,” according to Dr. Levy.

He reported having no financial conflicts regarding his presentation.

[email protected]

SOURCE: Levy T. ECNP 2020, Session EDU.02.

The COVID-19 pandemic has thrown a monkey wrench into the medical education landscape across the entire health care spectrum, disrupting the plans of medical students, residents, fellows, and program directors.

As cases of COVID-19 spread across the United States in early 2020, it became clear to training program directors that immediate action was required to meet the needs of medical learners. The challenges were unlike those surrounding the Ebola virus in 2014, “where we could more easily prevent students and trainees from exposure due to the fact that there were simply not significant numbers of cases in the United States,” Tiffany Murano, MD, said at a Society for Critical Care virtual meeting: COVID-19: What’s Next. Dr. Murano is professor of emergency medicine at Rutgers New Jersey Medical School, Newark, and president-elect of the Council of Residency Directors in Emergency Medicine. “COVID was a completely different scenario. We quickly realized that not only was personal protective equipment in short supply, but we also lacked the testing and tracking capabilities for potential exposures. Medical students and other supportive workers who were considered nonessential were removed from the clinical setting. This was after a trial of limiting who the students saw, essentially dampening the risk of exposure. But this proved to be flawed as COVID patients presented with symptoms that were unexpected.”

To complicate matters, she continued, many medical clinics either shut down, had limited access, or converted to telemedicine. Elective surgeries were canceled. This led to an overall pause in clinical medical student rotations and no direct patient care activities. As social distancing mandates were instituted, licensing examination testing centers were closed, and exams and on-campus activities were postponed.
 

Limiting trainee exposure

On the graduate medical education front, some training programs attempted to limit exposure of their trainees to persons under investigation for COVID-19. “As the number of COVID cases grew and encompassed most of what we were seeing in the hospital, it was obvious that residents had to play a vital part in the care of these patients,” said Dr. Murano, who is also a member of the American Council of Graduate Medical Education’s emergency review and recognition committee. “However, there was a consensus among all of the specialties that the procedures that posed the highest risk of exposure would be limited to the most senior or experienced trainees or professionals, and closely supervised by the faculty.”

ACGME activities such as accreditation site visits, clinical environment learning reviews, self-study, and resident and faculty surveys were suspended, postponed, or modified in some way, she said. The ACGME created stages of COVID status to guide sponsoring institutions to suspend learning curricula in order for patients to be cared for. Stage 1 was business as usual, “so there was no significant impact on patient care,” Dr. Murano said. “Stage 2 was increased but manageable clinical demand, while stage 3 was pandemic emergency status, where there were extraordinary circumstances where the clinical demand was so high and strenuous that the routine patient care and education really needed to be reconfigured in order to care for the patients.”

New requirements to manage training

The ACGME also implemented four requirements to manage training that were consistent among institutions, regardless of their COVID stage status. These included making sure that trainees continued to be held to work-hour limit requirements, ensuring adequate resources for training, ensuring that all residents had the appropriate level of supervision at all times, and allowing fellows to function in the core specialty in which they completed their residency training. “This was only possible if the fellows were ABMS [American Board of Medical Specialties] or AOA [American Osteopathic Association] board-eligible, or certified in their core specialty,” Dr. Murano said. “The fellows had to be appointed to the medical staff at the sponsoring institution, and their time spent on the core specialty service would be limited to 20% of their annual education time in any academic year.”

Mindful that there may have been trainees who required a 2-week quarantine period following exposure or potential exposure to COVID-19, some specialty boards showed leniency in residency time required to sit for the written exam. “Testing centers were being forced to close to observe social distancing requirements and heed sanitation recommendations, so exams were either canceled or postponed,” Dr. Murano said. “This posed a special concern for the board certification process, and those specialties with oral examinations had to make a heavy decision regarding whether or not they would allow these exams to take place. Naturally, travel among institutions was suspended or limited, or had quarantine requirements upon returning home from endemic areas. Conferences were either being canceled or converted to virtual formats.”

Subani Chandra, MD, FCCP, of the division of pulmonary, allergy, and critical care medicine at Columbia University, New York, is the internal medicine residency program director and the associate vice-chair of education for the department of medicine, and she recognized the problem created for medical trainees by the changes necessitated by the pandemic.

“The variability in caseloads and clinical exposure has given thrust to the move toward competency-based assessments rather than number- or time-based criteria for determining proficiency and graduation,” she wrote in an email interview. In addition, she noted the impact on medical meetings and the need to adapt. “Early on, before large regional and national conferences adapted to a virtual format, many were canceled altogether. Students, residents, and fellows expecting to have the opportunity to present their scholarly work were suddenly no longer able to do so. Understanding the importance of scholarly interaction, the virtual format of CHEST 2020 is designed with opportunities to present, interact with experts in the field, ask questions, network, and meet mentors.”

No return to ‘normal’

By April 2020, cases in the northeast continued to rise, particularly in the New York, New Jersey, and Connecticut region. “These states were essentially shut down in order to contain spread of the virus,” she said. “This was a real turning point because we realized that things were not going to return to ‘normal’ in the foreseeable future.” With the clinical experience essentially halted for medical students during this time, some medical schools allowed their senior students who met requirements to graduate early. “There were a lot of mixed feelings about this, recognizing that PPE [personal protective equipment] was still in short supply in many areas,” Dr. Murano said. “So, institutions took on these early graduates into roles in which they were not learners in particular, but rather medical workers. They were helping with informatics and technology, telehealth, virtual or telephone call follow-ups, and other tasks like this. There was a movement to virtual learning for the preclinical undergraduate learners, so classes were now online, recorded, or livestreamed.”
 

Early graduation, matching, and residencies

On April 3, the ACGME released a statement regarding graduating students early and appointing them early to the clinical learning environment. “They pointed out that institutions that were in emergency pandemic status lacked the ability to offer the comprehensive orientation and training in PPE and direct supervision required for new residents at the start of their residency,” Dr. Murano said. “Their opinion maintained that graduating medical students matriculate in their previously matched program, the National Resident Match Program start date, or other date that would be nationally determined to be the beginning of the 2020-2021 academic year.”

As May 2020 rolled around, the overriding feeling was uncertainty regarding when, if, and how medical schools were going to open in the early summer and fall. “There was also uncertainty about how graduating medical students were going to function in their new role as residents,” she said. “Same for the graduating residents. There were some who had signed contracts for jobs months before, and had them rescinded, and physicians were being furloughed due to financial hardships that institutions faced. There was also postponement of board certification exams, so people were uncertain about when they would become board certified.”

July 2020 ushered in what Dr. Murano characterized as “a whole new level of stress.” For medical students in particular, “we were entering the application season for residency positions,” she said. “Due to travel restrictions placed by various states and institutions, away rotations were limited or nonexistent. Application release dates through the Electronic Residency Application Service were moved to later in the year. The United States Medical Licensing Examination clinical skills exam was suspended, and there were modifications made for Education Commission for Foreign Medical Graduates requirements. Letters of recommendation were also going to be limited, so there had to be some degree of leniency within specialties to take a more holistic approach to review of applications for residencies.”

On the graduate medical education front, the ACGME sunsetted the initial stages and created two categories: nonemergency, which was formerly stages 1 and 2, and emergency, which was formerly stage 3. “All emergency stages are applied for and granted at 1-month intervals,” Dr. Murano said. Board certification exams were modified to accommodate either later exams or online formats, and specialties with oral examinations faced the task of potentially creating virtual oral exams.

Despite the challenges, Dr. Chandra has seen medical training programs respond with new ideas. “The flexibility and agile adaptability of the entire educational enterprise has been remarkable. The inherent uncertainty in a very dynamic and changing learning environment can be challenging. Recognizing this, many programs are creating additional ways to support the mental, emotional, physical, and financial health of students, residents, and fellows and all health care workers. The importance of this innovative response cannot be overstated.”
 

New learning formats

The pandemic forced Dr. Murano and other medical educators to consider unorthodox learning formats, and virtual learning took center stage. “Residency programs had shared national livestream conferences and grand rounds, and there were virtual curricula made for medical students as well as virtual simulation,” she said. “Telemedicine and telehealth really became important parts of education as well, as this may have been the only face-to-face contact that students and residents had with patients who had non–COVID-related complaints.”

To level the playing field for medical residents during this unprecedented time, a work group of the Coalition for Physician Accountability developed a set of recommendations that include limiting the number of letters of recommendation accepted, limiting the number of away rotations, and allowing alternative or less conventional letters of recommendation. “Keeping an open mind and taking a more holistic approach to applicants has really been needed during this time,” Dr. Murano said. “Virtual interview days have been agreed upon for all specialties. They’re safer, and they allow for students to virtually meet faculty and residents from distant programs that in the past would have been a deterrent due to distance and travel costs. This is not without its own downside, as it’s difficult to determine how well a student will fit into a program without [him or her] actually visiting the institution.”

Dr. Chandra agreed that virtual interviews are necessary but have inherent limitations. However, “we will all learn a lot, and very likely the future process will blend the benefits of both virtual and in-person interviews.”
 

‘We need to keep moving forward’

Dr. Murano concluded her presentation by noting that the COVID-19 pandemic has created opportunities for growth and innovation in medical education, “so we need to keep moving forward. I’ve heard many say that they can’t wait for things to go back to normal. But I think it’s important to go ahead to new and better ways of learning. We’re now thinking outside of the typical education model and are embracing technology and alternative means of education. We don’t know yet if this education is better, worse, or equivalent to traditional methods, but that will be determined and studied in months and years to come, so we’re certainly looking to the future.”

Dr. Murano and Dr. Chandra reported having no financial disclosures.

[email protected]

The COVID-19 pandemic has thrown a monkey wrench into the medical education landscape across the entire health care spectrum, disrupting the plans of medical students, residents, fellows, and program directors.

As cases of COVID-19 spread across the United States in early 2020, it became clear to training program directors that immediate action was required to meet the needs of medical learners. The challenges were unlike those surrounding the Ebola virus in 2014, “where we could more easily prevent students and trainees from exposure due to the fact that there were simply not significant numbers of cases in the United States,” Tiffany Murano, MD, said at a Society for Critical Care virtual meeting: COVID-19: What’s Next. Dr. Murano is professor of emergency medicine at Rutgers New Jersey Medical School, Newark, and president-elect of the Council of Residency Directors in Emergency Medicine. “COVID was a completely different scenario. We quickly realized that not only was personal protective equipment in short supply, but we also lacked the testing and tracking capabilities for potential exposures. Medical students and other supportive workers who were considered nonessential were removed from the clinical setting. This was after a trial of limiting who the students saw, essentially dampening the risk of exposure. But this proved to be flawed as COVID patients presented with symptoms that were unexpected.”

To complicate matters, she continued, many medical clinics either shut down, had limited access, or converted to telemedicine. Elective surgeries were canceled. This led to an overall pause in clinical medical student rotations and no direct patient care activities. As social distancing mandates were instituted, licensing examination testing centers were closed, and exams and on-campus activities were postponed.
 

Limiting trainee exposure

On the graduate medical education front, some training programs attempted to limit exposure of their trainees to persons under investigation for COVID-19. “As the number of COVID cases grew and encompassed most of what we were seeing in the hospital, it was obvious that residents had to play a vital part in the care of these patients,” said Dr. Murano, who is also a member of the American Council of Graduate Medical Education’s emergency review and recognition committee. “However, there was a consensus among all of the specialties that the procedures that posed the highest risk of exposure would be limited to the most senior or experienced trainees or professionals, and closely supervised by the faculty.”

ACGME activities such as accreditation site visits, clinical environment learning reviews, self-study, and resident and faculty surveys were suspended, postponed, or modified in some way, she said. The ACGME created stages of COVID status to guide sponsoring institutions to suspend learning curricula in order for patients to be cared for. Stage 1 was business as usual, “so there was no significant impact on patient care,” Dr. Murano said. “Stage 2 was increased but manageable clinical demand, while stage 3 was pandemic emergency status, where there were extraordinary circumstances where the clinical demand was so high and strenuous that the routine patient care and education really needed to be reconfigured in order to care for the patients.”

New requirements to manage training

The ACGME also implemented four requirements to manage training that were consistent among institutions, regardless of their COVID stage status. These included making sure that trainees continued to be held to work-hour limit requirements, ensuring adequate resources for training, ensuring that all residents had the appropriate level of supervision at all times, and allowing fellows to function in the core specialty in which they completed their residency training. “This was only possible if the fellows were ABMS [American Board of Medical Specialties] or AOA [American Osteopathic Association] board-eligible, or certified in their core specialty,” Dr. Murano said. “The fellows had to be appointed to the medical staff at the sponsoring institution, and their time spent on the core specialty service would be limited to 20% of their annual education time in any academic year.”

Mindful that there may have been trainees who required a 2-week quarantine period following exposure or potential exposure to COVID-19, some specialty boards showed leniency in residency time required to sit for the written exam. “Testing centers were being forced to close to observe social distancing requirements and heed sanitation recommendations, so exams were either canceled or postponed,” Dr. Murano said. “This posed a special concern for the board certification process, and those specialties with oral examinations had to make a heavy decision regarding whether or not they would allow these exams to take place. Naturally, travel among institutions was suspended or limited, or had quarantine requirements upon returning home from endemic areas. Conferences were either being canceled or converted to virtual formats.”

Subani Chandra, MD, FCCP, of the division of pulmonary, allergy, and critical care medicine at Columbia University, New York, is the internal medicine residency program director and the associate vice-chair of education for the department of medicine, and she recognized the problem created for medical trainees by the changes necessitated by the pandemic.

“The variability in caseloads and clinical exposure has given thrust to the move toward competency-based assessments rather than number- or time-based criteria for determining proficiency and graduation,” she wrote in an email interview. In addition, she noted the impact on medical meetings and the need to adapt. “Early on, before large regional and national conferences adapted to a virtual format, many were canceled altogether. Students, residents, and fellows expecting to have the opportunity to present their scholarly work were suddenly no longer able to do so. Understanding the importance of scholarly interaction, the virtual format of CHEST 2020 is designed with opportunities to present, interact with experts in the field, ask questions, network, and meet mentors.”

No return to ‘normal’

By April 2020, cases in the northeast continued to rise, particularly in the New York, New Jersey, and Connecticut region. “These states were essentially shut down in order to contain spread of the virus,” she said. “This was a real turning point because we realized that things were not going to return to ‘normal’ in the foreseeable future.” With the clinical experience essentially halted for medical students during this time, some medical schools allowed their senior students who met requirements to graduate early. “There were a lot of mixed feelings about this, recognizing that PPE [personal protective equipment] was still in short supply in many areas,” Dr. Murano said. “So, institutions took on these early graduates into roles in which they were not learners in particular, but rather medical workers. They were helping with informatics and technology, telehealth, virtual or telephone call follow-ups, and other tasks like this. There was a movement to virtual learning for the preclinical undergraduate learners, so classes were now online, recorded, or livestreamed.”
 

Early graduation, matching, and residencies

On April 3, the ACGME released a statement regarding graduating students early and appointing them early to the clinical learning environment. “They pointed out that institutions that were in emergency pandemic status lacked the ability to offer the comprehensive orientation and training in PPE and direct supervision required for new residents at the start of their residency,” Dr. Murano said. “Their opinion maintained that graduating medical students matriculate in their previously matched program, the National Resident Match Program start date, or other date that would be nationally determined to be the beginning of the 2020-2021 academic year.”

As May 2020 rolled around, the overriding feeling was uncertainty regarding when, if, and how medical schools were going to open in the early summer and fall. “There was also uncertainty about how graduating medical students were going to function in their new role as residents,” she said. “Same for the graduating residents. There were some who had signed contracts for jobs months before, and had them rescinded, and physicians were being furloughed due to financial hardships that institutions faced. There was also postponement of board certification exams, so people were uncertain about when they would become board certified.”

July 2020 ushered in what Dr. Murano characterized as “a whole new level of stress.” For medical students in particular, “we were entering the application season for residency positions,” she said. “Due to travel restrictions placed by various states and institutions, away rotations were limited or nonexistent. Application release dates through the Electronic Residency Application Service were moved to later in the year. The United States Medical Licensing Examination clinical skills exam was suspended, and there were modifications made for Education Commission for Foreign Medical Graduates requirements. Letters of recommendation were also going to be limited, so there had to be some degree of leniency within specialties to take a more holistic approach to review of applications for residencies.”

On the graduate medical education front, the ACGME sunsetted the initial stages and created two categories: nonemergency, which was formerly stages 1 and 2, and emergency, which was formerly stage 3. “All emergency stages are applied for and granted at 1-month intervals,” Dr. Murano said. Board certification exams were modified to accommodate either later exams or online formats, and specialties with oral examinations faced the task of potentially creating virtual oral exams.

Despite the challenges, Dr. Chandra has seen medical training programs respond with new ideas. “The flexibility and agile adaptability of the entire educational enterprise has been remarkable. The inherent uncertainty in a very dynamic and changing learning environment can be challenging. Recognizing this, many programs are creating additional ways to support the mental, emotional, physical, and financial health of students, residents, and fellows and all health care workers. The importance of this innovative response cannot be overstated.”
 

New learning formats

The pandemic forced Dr. Murano and other medical educators to consider unorthodox learning formats, and virtual learning took center stage. “Residency programs had shared national livestream conferences and grand rounds, and there were virtual curricula made for medical students as well as virtual simulation,” she said. “Telemedicine and telehealth really became important parts of education as well, as this may have been the only face-to-face contact that students and residents had with patients who had non–COVID-related complaints.”

To level the playing field for medical residents during this unprecedented time, a work group of the Coalition for Physician Accountability developed a set of recommendations that include limiting the number of letters of recommendation accepted, limiting the number of away rotations, and allowing alternative or less conventional letters of recommendation. “Keeping an open mind and taking a more holistic approach to applicants has really been needed during this time,” Dr. Murano said. “Virtual interview days have been agreed upon for all specialties. They’re safer, and they allow for students to virtually meet faculty and residents from distant programs that in the past would have been a deterrent due to distance and travel costs. This is not without its own downside, as it’s difficult to determine how well a student will fit into a program without [him or her] actually visiting the institution.”

Dr. Chandra agreed that virtual interviews are necessary but have inherent limitations. However, “we will all learn a lot, and very likely the future process will blend the benefits of both virtual and in-person interviews.”
 

‘We need to keep moving forward’

Dr. Murano concluded her presentation by noting that the COVID-19 pandemic has created opportunities for growth and innovation in medical education, “so we need to keep moving forward. I’ve heard many say that they can’t wait for things to go back to normal. But I think it’s important to go ahead to new and better ways of learning. We’re now thinking outside of the typical education model and are embracing technology and alternative means of education. We don’t know yet if this education is better, worse, or equivalent to traditional methods, but that will be determined and studied in months and years to come, so we’re certainly looking to the future.”

Dr. Murano and Dr. Chandra reported having no financial disclosures.

[email protected]

The COVID-19 pandemic has thrown a monkey wrench into the medical education landscape across the entire health care spectrum, disrupting the plans of medical students, residents, fellows, and program directors.

As cases of COVID-19 spread across the United States in early 2020, it became clear to training program directors that immediate action was required to meet the needs of medical learners. The challenges were unlike those surrounding the Ebola virus in 2014, “where we could more easily prevent students and trainees from exposure due to the fact that there were simply not significant numbers of cases in the United States,” Tiffany Murano, MD, said at a Society for Critical Care virtual meeting: COVID-19: What’s Next. Dr. Murano is professor of emergency medicine at Rutgers New Jersey Medical School, Newark, and president-elect of the Council of Residency Directors in Emergency Medicine. “COVID was a completely different scenario. We quickly realized that not only was personal protective equipment in short supply, but we also lacked the testing and tracking capabilities for potential exposures. Medical students and other supportive workers who were considered nonessential were removed from the clinical setting. This was after a trial of limiting who the students saw, essentially dampening the risk of exposure. But this proved to be flawed as COVID patients presented with symptoms that were unexpected.”

To complicate matters, she continued, many medical clinics either shut down, had limited access, or converted to telemedicine. Elective surgeries were canceled. This led to an overall pause in clinical medical student rotations and no direct patient care activities. As social distancing mandates were instituted, licensing examination testing centers were closed, and exams and on-campus activities were postponed.
 

Limiting trainee exposure

On the graduate medical education front, some training programs attempted to limit exposure of their trainees to persons under investigation for COVID-19. “As the number of COVID cases grew and encompassed most of what we were seeing in the hospital, it was obvious that residents had to play a vital part in the care of these patients,” said Dr. Murano, who is also a member of the American Council of Graduate Medical Education’s emergency review and recognition committee. “However, there was a consensus among all of the specialties that the procedures that posed the highest risk of exposure would be limited to the most senior or experienced trainees or professionals, and closely supervised by the faculty.”

ACGME activities such as accreditation site visits, clinical environment learning reviews, self-study, and resident and faculty surveys were suspended, postponed, or modified in some way, she said. The ACGME created stages of COVID status to guide sponsoring institutions to suspend learning curricula in order for patients to be cared for. Stage 1 was business as usual, “so there was no significant impact on patient care,” Dr. Murano said. “Stage 2 was increased but manageable clinical demand, while stage 3 was pandemic emergency status, where there were extraordinary circumstances where the clinical demand was so high and strenuous that the routine patient care and education really needed to be reconfigured in order to care for the patients.”

New requirements to manage training

The ACGME also implemented four requirements to manage training that were consistent among institutions, regardless of their COVID stage status. These included making sure that trainees continued to be held to work-hour limit requirements, ensuring adequate resources for training, ensuring that all residents had the appropriate level of supervision at all times, and allowing fellows to function in the core specialty in which they completed their residency training. “This was only possible if the fellows were ABMS [American Board of Medical Specialties] or AOA [American Osteopathic Association] board-eligible, or certified in their core specialty,” Dr. Murano said. “The fellows had to be appointed to the medical staff at the sponsoring institution, and their time spent on the core specialty service would be limited to 20% of their annual education time in any academic year.”

Mindful that there may have been trainees who required a 2-week quarantine period following exposure or potential exposure to COVID-19, some specialty boards showed leniency in residency time required to sit for the written exam. “Testing centers were being forced to close to observe social distancing requirements and heed sanitation recommendations, so exams were either canceled or postponed,” Dr. Murano said. “This posed a special concern for the board certification process, and those specialties with oral examinations had to make a heavy decision regarding whether or not they would allow these exams to take place. Naturally, travel among institutions was suspended or limited, or had quarantine requirements upon returning home from endemic areas. Conferences were either being canceled or converted to virtual formats.”

Subani Chandra, MD, FCCP, of the division of pulmonary, allergy, and critical care medicine at Columbia University, New York, is the internal medicine residency program director and the associate vice-chair of education for the department of medicine, and she recognized the problem created for medical trainees by the changes necessitated by the pandemic.

“The variability in caseloads and clinical exposure has given thrust to the move toward competency-based assessments rather than number- or time-based criteria for determining proficiency and graduation,” she wrote in an email interview. In addition, she noted the impact on medical meetings and the need to adapt. “Early on, before large regional and national conferences adapted to a virtual format, many were canceled altogether. Students, residents, and fellows expecting to have the opportunity to present their scholarly work were suddenly no longer able to do so. Understanding the importance of scholarly interaction, the virtual format of CHEST 2020 is designed with opportunities to present, interact with experts in the field, ask questions, network, and meet mentors.”

No return to ‘normal’

By April 2020, cases in the northeast continued to rise, particularly in the New York, New Jersey, and Connecticut region. “These states were essentially shut down in order to contain spread of the virus,” she said. “This was a real turning point because we realized that things were not going to return to ‘normal’ in the foreseeable future.” With the clinical experience essentially halted for medical students during this time, some medical schools allowed their senior students who met requirements to graduate early. “There were a lot of mixed feelings about this, recognizing that PPE [personal protective equipment] was still in short supply in many areas,” Dr. Murano said. “So, institutions took on these early graduates into roles in which they were not learners in particular, but rather medical workers. They were helping with informatics and technology, telehealth, virtual or telephone call follow-ups, and other tasks like this. There was a movement to virtual learning for the preclinical undergraduate learners, so classes were now online, recorded, or livestreamed.”
 

Early graduation, matching, and residencies

On April 3, the ACGME released a statement regarding graduating students early and appointing them early to the clinical learning environment. “They pointed out that institutions that were in emergency pandemic status lacked the ability to offer the comprehensive orientation and training in PPE and direct supervision required for new residents at the start of their residency,” Dr. Murano said. “Their opinion maintained that graduating medical students matriculate in their previously matched program, the National Resident Match Program start date, or other date that would be nationally determined to be the beginning of the 2020-2021 academic year.”

As May 2020 rolled around, the overriding feeling was uncertainty regarding when, if, and how medical schools were going to open in the early summer and fall. “There was also uncertainty about how graduating medical students were going to function in their new role as residents,” she said. “Same for the graduating residents. There were some who had signed contracts for jobs months before, and had them rescinded, and physicians were being furloughed due to financial hardships that institutions faced. There was also postponement of board certification exams, so people were uncertain about when they would become board certified.”

July 2020 ushered in what Dr. Murano characterized as “a whole new level of stress.” For medical students in particular, “we were entering the application season for residency positions,” she said. “Due to travel restrictions placed by various states and institutions, away rotations were limited or nonexistent. Application release dates through the Electronic Residency Application Service were moved to later in the year. The United States Medical Licensing Examination clinical skills exam was suspended, and there were modifications made for Education Commission for Foreign Medical Graduates requirements. Letters of recommendation were also going to be limited, so there had to be some degree of leniency within specialties to take a more holistic approach to review of applications for residencies.”

On the graduate medical education front, the ACGME sunsetted the initial stages and created two categories: nonemergency, which was formerly stages 1 and 2, and emergency, which was formerly stage 3. “All emergency stages are applied for and granted at 1-month intervals,” Dr. Murano said. Board certification exams were modified to accommodate either later exams or online formats, and specialties with oral examinations faced the task of potentially creating virtual oral exams.

Despite the challenges, Dr. Chandra has seen medical training programs respond with new ideas. “The flexibility and agile adaptability of the entire educational enterprise has been remarkable. The inherent uncertainty in a very dynamic and changing learning environment can be challenging. Recognizing this, many programs are creating additional ways to support the mental, emotional, physical, and financial health of students, residents, and fellows and all health care workers. The importance of this innovative response cannot be overstated.”
 

New learning formats

The pandemic forced Dr. Murano and other medical educators to consider unorthodox learning formats, and virtual learning took center stage. “Residency programs had shared national livestream conferences and grand rounds, and there were virtual curricula made for medical students as well as virtual simulation,” she said. “Telemedicine and telehealth really became important parts of education as well, as this may have been the only face-to-face contact that students and residents had with patients who had non–COVID-related complaints.”

To level the playing field for medical residents during this unprecedented time, a work group of the Coalition for Physician Accountability developed a set of recommendations that include limiting the number of letters of recommendation accepted, limiting the number of away rotations, and allowing alternative or less conventional letters of recommendation. “Keeping an open mind and taking a more holistic approach to applicants has really been needed during this time,” Dr. Murano said. “Virtual interview days have been agreed upon for all specialties. They’re safer, and they allow for students to virtually meet faculty and residents from distant programs that in the past would have been a deterrent due to distance and travel costs. This is not without its own downside, as it’s difficult to determine how well a student will fit into a program without [him or her] actually visiting the institution.”

Dr. Chandra agreed that virtual interviews are necessary but have inherent limitations. However, “we will all learn a lot, and very likely the future process will blend the benefits of both virtual and in-person interviews.”
 

‘We need to keep moving forward’

Dr. Murano concluded her presentation by noting that the COVID-19 pandemic has created opportunities for growth and innovation in medical education, “so we need to keep moving forward. I’ve heard many say that they can’t wait for things to go back to normal. But I think it’s important to go ahead to new and better ways of learning. We’re now thinking outside of the typical education model and are embracing technology and alternative means of education. We don’t know yet if this education is better, worse, or equivalent to traditional methods, but that will be determined and studied in months and years to come, so we’re certainly looking to the future.”

Dr. Murano and Dr. Chandra reported having no financial disclosures.

[email protected]

The Diagnosis: Acrodermatitis Enteropathica 

Acrodermatitis enteropathica (AE) was the presumptive diagnosis. Oral supplementation with zinc sulfate 3 mg/kg/d was started immediately after a zinc level was ordered. A low zinc level of 15 µg/dL (reference range, 56-134 µg/dL) eventually was obtained. The lesions began to fade in 2 days along with return of normal feeding and disposition, and the patient was discharged with continued zinc supplementation.  

Acrodermatitis enteropathica is an autosomal-recessive condition resulting in severe zinc deficiency caused by a defect of dietary zinc absorption in the duodenum and jejunum.¹ It occurs in 1 in 500,000 individuals with no gender or racial predilection. It can be acquired or inherited.² Recognition of clinical symptoms is essential due to potential death if untreated. Zinc is an important trace element required for the proper functioning of all cells and plays a large role in the metabolism of protein, carbohydrates, and vitamin A. Zinc deficiency impairs immune function, leading to bacterial infections. It also is a cofactor of numerous metal enzymes such as alkaline phosphatase, RNA polymerase, and numerous digestive enzymes.³  

Our laboratory analysis revealed low alkaline phosphatase and zinc levels, which led to the diagnosis of AE; unfortunately, these levels can be ambiguous.⁴ There are many causes of acquired zinc deficiency, including premature birth, low birth weight, zinc deficiency in maternal milk, exclusive parenteral nutrition, malabsorption syndromes such as Crohn disease and celiac disease, alcoholism, low calcium and phytate (cereal grain) diet, and kwashiorkor.⁵ The hereditary deficiency of zinc classically is known as AE and is caused by an autosomal-recessive mutation of the SLC39A4 gene on chromosome arm 8q24.3, which determines a congenital partial or total deficiency of the zinc transporter protein ZIP4.⁶  

The clinical manifestations of acquired zinc deficiency and AE are similar and consist of 3 essential symptoms: periorificial dermatitis, alopecia, and diarrhea. Unfortunately, this clinical triad is complete in only 20% of patients with AE.³ For example, our patient was too young for an alopecia determination. The disease typically presents with eczematous papules and sometimes vesiculobullous or pustular lesions located around perioral and acral areas (Figure 1) as well as the anogenital region (Figures 2 and 3). The severity of the skin lesions is variable.⁷ Our patient also presented with eczematous truncal papules on the chest (Figure 4). Acrodermatitis enteropathica usually presents during childhood after weaning. Along with the aforementioned skin findings, other symptoms in infancy can include diarrhea, mood changes, and anorexia. In school-aged children and toddlers, zinc deficiency is characterized by growth retardation, alopecia, weight loss, and recurrent infections.  

In the differential diagnosis, the clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails, and central nervous system (eg, seizures, ataxia, deafness).⁸ Cystic fibrosis presentation depends on the multiorgan involvement, but neonates often present with failure to thrive.⁹ Essential fatty acid deficiency presents clinically as dermatitis, alopecia, and thrombocytopenia, but a complete blood cell count with platelets was within reference range in our patient.¹⁰ Langerhans cell histiocytosis presents with perineal and postauricular lesions, but the skin biopsy did not confirm this diagnosis in our patient.¹¹ Histopathologic examination of the buttock biopsy in our patient revealed nonspecific epidermal hyperplasia with acanthosis as well as clustered necrotic keratinocytes with vacuolization and parakeratosis.  

Most clinicians who suspect AE treat with a therapeutic supplementation of zinc sulfate 3 mg/kg/d while awaiting laboratory results. Acrodermatitis enteropathica is a rare condition, and early recognition of skin findings is important because misdiagnosis can lead to infections, malnutrition, and possibly death.  

The Diagnosis: Acrodermatitis Enteropathica 

Acrodermatitis enteropathica (AE) was the presumptive diagnosis. Oral supplementation with zinc sulfate 3 mg/kg/d was started immediately after a zinc level was ordered. A low zinc level of 15 µg/dL (reference range, 56-134 µg/dL) eventually was obtained. The lesions began to fade in 2 days along with return of normal feeding and disposition, and the patient was discharged with continued zinc supplementation.  

Acrodermatitis enteropathica is an autosomal-recessive condition resulting in severe zinc deficiency caused by a defect of dietary zinc absorption in the duodenum and jejunum.¹ It occurs in 1 in 500,000 individuals with no gender or racial predilection. It can be acquired or inherited.² Recognition of clinical symptoms is essential due to potential death if untreated. Zinc is an important trace element required for the proper functioning of all cells and plays a large role in the metabolism of protein, carbohydrates, and vitamin A. Zinc deficiency impairs immune function, leading to bacterial infections. It also is a cofactor of numerous metal enzymes such as alkaline phosphatase, RNA polymerase, and numerous digestive enzymes.³  

Our laboratory analysis revealed low alkaline phosphatase and zinc levels, which led to the diagnosis of AE; unfortunately, these levels can be ambiguous.⁴ There are many causes of acquired zinc deficiency, including premature birth, low birth weight, zinc deficiency in maternal milk, exclusive parenteral nutrition, malabsorption syndromes such as Crohn disease and celiac disease, alcoholism, low calcium and phytate (cereal grain) diet, and kwashiorkor.⁵ The hereditary deficiency of zinc classically is known as AE and is caused by an autosomal-recessive mutation of the SLC39A4 gene on chromosome arm 8q24.3, which determines a congenital partial or total deficiency of the zinc transporter protein ZIP4.⁶  

The clinical manifestations of acquired zinc deficiency and AE are similar and consist of 3 essential symptoms: periorificial dermatitis, alopecia, and diarrhea. Unfortunately, this clinical triad is complete in only 20% of patients with AE.³ For example, our patient was too young for an alopecia determination. The disease typically presents with eczematous papules and sometimes vesiculobullous or pustular lesions located around perioral and acral areas (Figure 1) as well as the anogenital region (Figures 2 and 3). The severity of the skin lesions is variable.⁷ Our patient also presented with eczematous truncal papules on the chest (Figure 4). Acrodermatitis enteropathica usually presents during childhood after weaning. Along with the aforementioned skin findings, other symptoms in infancy can include diarrhea, mood changes, and anorexia. In school-aged children and toddlers, zinc deficiency is characterized by growth retardation, alopecia, weight loss, and recurrent infections.  

In the differential diagnosis, the clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails, and central nervous system (eg, seizures, ataxia, deafness).⁸ Cystic fibrosis presentation depends on the multiorgan involvement, but neonates often present with failure to thrive.⁹ Essential fatty acid deficiency presents clinically as dermatitis, alopecia, and thrombocytopenia, but a complete blood cell count with platelets was within reference range in our patient.¹⁰ Langerhans cell histiocytosis presents with perineal and postauricular lesions, but the skin biopsy did not confirm this diagnosis in our patient.¹¹ Histopathologic examination of the buttock biopsy in our patient revealed nonspecific epidermal hyperplasia with acanthosis as well as clustered necrotic keratinocytes with vacuolization and parakeratosis.  

Most clinicians who suspect AE treat with a therapeutic supplementation of zinc sulfate 3 mg/kg/d while awaiting laboratory results. Acrodermatitis enteropathica is a rare condition, and early recognition of skin findings is important because misdiagnosis can lead to infections, malnutrition, and possibly death.  

The Diagnosis: Acrodermatitis Enteropathica 

Acrodermatitis enteropathica (AE) was the presumptive diagnosis. Oral supplementation with zinc sulfate 3 mg/kg/d was started immediately after a zinc level was ordered. A low zinc level of 15 µg/dL (reference range, 56-134 µg/dL) eventually was obtained. The lesions began to fade in 2 days along with return of normal feeding and disposition, and the patient was discharged with continued zinc supplementation.  

Acrodermatitis enteropathica is an autosomal-recessive condition resulting in severe zinc deficiency caused by a defect of dietary zinc absorption in the duodenum and jejunum.¹ It occurs in 1 in 500,000 individuals with no gender or racial predilection. It can be acquired or inherited.² Recognition of clinical symptoms is essential due to potential death if untreated. Zinc is an important trace element required for the proper functioning of all cells and plays a large role in the metabolism of protein, carbohydrates, and vitamin A. Zinc deficiency impairs immune function, leading to bacterial infections. It also is a cofactor of numerous metal enzymes such as alkaline phosphatase, RNA polymerase, and numerous digestive enzymes.³  

Our laboratory analysis revealed low alkaline phosphatase and zinc levels, which led to the diagnosis of AE; unfortunately, these levels can be ambiguous.⁴ There are many causes of acquired zinc deficiency, including premature birth, low birth weight, zinc deficiency in maternal milk, exclusive parenteral nutrition, malabsorption syndromes such as Crohn disease and celiac disease, alcoholism, low calcium and phytate (cereal grain) diet, and kwashiorkor.⁵ The hereditary deficiency of zinc classically is known as AE and is caused by an autosomal-recessive mutation of the SLC39A4 gene on chromosome arm 8q24.3, which determines a congenital partial or total deficiency of the zinc transporter protein ZIP4.⁶  

The clinical manifestations of acquired zinc deficiency and AE are similar and consist of 3 essential symptoms: periorificial dermatitis, alopecia, and diarrhea. Unfortunately, this clinical triad is complete in only 20% of patients with AE.³ For example, our patient was too young for an alopecia determination. The disease typically presents with eczematous papules and sometimes vesiculobullous or pustular lesions located around perioral and acral areas (Figure 1) as well as the anogenital region (Figures 2 and 3). The severity of the skin lesions is variable.⁷ Our patient also presented with eczematous truncal papules on the chest (Figure 4). Acrodermatitis enteropathica usually presents during childhood after weaning. Along with the aforementioned skin findings, other symptoms in infancy can include diarrhea, mood changes, and anorexia. In school-aged children and toddlers, zinc deficiency is characterized by growth retardation, alopecia, weight loss, and recurrent infections.  

In the differential diagnosis, the clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails, and central nervous system (eg, seizures, ataxia, deafness).⁸ Cystic fibrosis presentation depends on the multiorgan involvement, but neonates often present with failure to thrive.⁹ Essential fatty acid deficiency presents clinically as dermatitis, alopecia, and thrombocytopenia, but a complete blood cell count with platelets was within reference range in our patient.¹⁰ Langerhans cell histiocytosis presents with perineal and postauricular lesions, but the skin biopsy did not confirm this diagnosis in our patient.¹¹ Histopathologic examination of the buttock biopsy in our patient revealed nonspecific epidermal hyperplasia with acanthosis as well as clustered necrotic keratinocytes with vacuolization and parakeratosis.  

Most clinicians who suspect AE treat with a therapeutic supplementation of zinc sulfate 3 mg/kg/d while awaiting laboratory results. Acrodermatitis enteropathica is a rare condition, and early recognition of skin findings is important because misdiagnosis can lead to infections, malnutrition, and possibly death.  

In the 1970s, cancer survival was poor for young children and older adults in the United States, as shown by data published in the Journal of the National Cancer Institute.

Great progress has been made since the 1970s, but improvements in outcome have been less impressive for cancer patients aged 15-39 years, as shown by research published in Cancer.

Factors that contribute to the AYA gap

About 89,000 AYAs are diagnosed with cancer each year in the United States, according to data from the National Cancer Institute (NCI). Lymphomas and thyroid cancer are the most common cancers among younger AYAs, aged 15-24 years.

In a report commissioned by the NIH in 2006, many factors contributing to the AYA gap were identified. Chief among them were:

• Limitations in access to care.
• Delayed diagnosis.
• Inconsistency in treatment and follow-up.
• Long-term toxicity (fertility, second malignancies, and cardiovascular disease).

These factors compromise health-related survival, even when cancer-specific survival is improved.

Panelist Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., noted that there are additional unique challenges for AYAs with cancer. These include:

• Pubertal changes.
• Developmental transition to independence.
• Societal impediments such as insurance coverage and disparities in access to specialized centers.
• Psychosocial factors such as health literacy and adherence to treatment and follow-up.

Focusing on lymphoma specifically, Dr. Kelly noted that lymphoma biology differs across the age spectrum and by race and ethnicity. Both tumor and host factors require further study, she said.
 

Clinical trial access for AYAs

Dr. Kelly emphasized that, unfortunately, clinical research participation is low among AYAs. A major impediment is that adult clinical trials historically required participants to be at least 18 years old.

In addition, there has not been a focused effort to educate AYAs about regulatory safeguards to ensure safety and the promise of enhanced benefit to them in NCI Cancer Trials Network (NCTN) trials. As a result, the refusal rate is high.

A multi-stakeholder workshop, convened in May 2016 by the American Society of Clinical Oncology and Friends of Cancer Research, outlined opportunities for expanding trial eligibility to include children younger than 18 years in first-in-human and other adult cancer clinical trials, enhancing their access to new agents, without compromising safety.

Recently, collaborative efforts between the adult and children’s NCTN research groups have included AYAs in studies addressing cancers that span the age spectrum, including lymphoma.

However, as Dr. Kelly noted, there are differences in AYA lymphoid malignancy types with a transition from more pediatric to more adult types.
 

Hodgkin lymphoma and primary mediastinal B-cell lymphoma

Panelist Lisa G. Roth, MD, of Weill Cornell Medicine, New York, reviewed the genomic landscape of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).

Dr. Roth explained that both HL and PMBCL are derived from thymic B cells, predominantly affect the mediastinum, and are CD30-positive lymphomas. Both are characterized by upregulation of JAK/STAT and NF-kappaB as well as overexpression of PD-L1.

Dr. Roth noted that HL is challenging to sequence by standard methods because Reed Sternberg (HRS) cells represent less than 1% of the cellular infiltrate. Recurrently mutated genes in HL cluster by histologic subtype.

Whole-exome sequencing of HRS cells show loss of beta-2 microglobulin and MHC-1 expression, HLA-B, NF-kappaB signaling, and JAK-STAT signaling, according to data published in Blood Advances in 2019.

Dr. Roth’s lab performed immunohistochemistry on tissue microarrays in 145 cases of HL (unpublished data). Results showed that loss of beta-2 microglobulin is more common in younger HL patients. For other alterations, there were too few cases to know.

Dr. Roth’s lab is a member of a pediatric/AYA HL sequencing multi-institutional consortium that has been able to extract DNA and RNA from samples submitted for whole-exome sequencing. The consortium’s goal is to shed light on implications of other genomic alterations that may differ by age in HL patients.

Dr. Roth cited research showing that PMBCL shares molecular alterations similar to those of HL. Alterations in PMBCL suggest dysregulated cellular signaling and immune evasion mechanisms (e.g., deletions in MHC type 1 and 2, beta-2 microglobulin, JAK-STAT, and NF-kappaB mutations) that provide opportunities to study novel agents, according to data published in Blood in 2019.

By early 2021, the S1826 and ANHL1931 studies, which have no age restriction, will be available to AYA lymphoma patients with HL and PMBCL, respectively, Dr. Roth said.
 

Follicular lymphoma: Clinical features by age

Panelist Abner Louissaint Jr, MD, PhD, of Massachusetts General Hospital in Boston, discussed age-related differences in follicular lymphoma (FL).

He noted that FL typically presents at an advanced stage, with low- or high-grade histology. It is increasingly common in adults in their 50s and 60s, representing 20% of all lymphomas. FL is rare in children and AYAs.

Dr. Louissaint explained that the typical flow cytometric findings in FL are BCL2 translocations, occurring in up to 85%-90% of low-grade and 50% of high-grade cases. The t(14;18)(q32;q21) translocation juxtaposes BCL2 on 18q21 to regulatory sequences and enhances the expression of elements of the Ig heavy chain.

Malignant cells in FL patients express CD20, CD10, CD21, and BCL2 (in contrast to normal germinal centers) and overexpress BCL6 (in contrast to normal follicles), Dr. Louissaint noted. He said the Ki-67 proliferative index of the malignant cells is typically low.

Pediatric-type FL is rare, but case series show clinical, pathologic, and molecular features that are distinctive from adult FL, Dr. Louissaint explained.

He then discussed the features of pediatric-type FL in multiple domains. In the clinical domain, there is a male predilection, and stage tends to be low. There is frequent involvement of nodes of the head and neck region and rare involvement of internal lymph node chains.

Pathologically, the malignant cells appear high grade, with architectural effacement, expansile follicular pattern, large lymphocyte size, and an elevated proliferation index. In contrast to adult FL, malignant cells in pediatric-type FL lack aberrant BCL2 expression.

Most importantly, for pediatric-type FL, the prognosis is excellent with durable remissions after surgical excision, Dr. Louissaint said.
 

Follicular lymphoma: Molecular features by age

Because of the excellent prognosis in pediatric-type FL, it is important to assess whether young adults with FL have adult-type or pediatric-type lesions, Dr. Louissaint said.

He cited many studies showing differences in adult and pediatric-type FL. In adult FL, the mutational landscape is characterized by frequent chromatin-modifying mutations in genes such as CREBBP, KM22D, and EP300.

In contrast, in pediatric-type FL, there are frequent activating MAPK pathway mutations, including mutations in the negative regulatory domain of MAP2K1. These mutations are not seen in adult FL.

Dr. Louissaint noted that there may be mutations in epigenetic modifiers (CREBBP, TNFRSF14) in both adult and pediatric-type FL. However, CREBBP is very unusual in pediatric-type FL and common in adult FL. This suggests the alterations in pediatric-type FL do not simply represent an early stage of the same disease as adult FL.

Despite a high proliferating fraction and absence of BCL2/BCL6/IRF4 rearrangements in pediatric-type FL, the presence of these features was associated with dramatic difference in progression-free survival, according to research published in Blood in 2012.
 

A distinct entity

In 2016, the World Health Organization recognized pediatric-type FL as a distinct entity, with the following diagnostic criteria (published in Blood):

• At least partial effacement of nodal architecture, expansile follicles, intermediate-size blastoid cells, and no component of diffuse large B-cell lymphoma.
• Immunohistochemistry showing BCL6 positivity, BCL2 negativity or weak positivity, and a high proliferative fraction.
• Genomic studies showing no BCL2 amplification.
• Clinical features of nodal disease in the head and neck region, early clinical stage, age younger than 40 years, typically in a male with no internal nodes involved.

When FL occurs in AYAs, the diagnostic findings of pediatric-type FL suggest the patient will do well with conservative management (e.g., excision alone), Dr. Louissaint noted.
 

Two sizes do not fit all

The strategies that have improved cancer outcomes since the 1970s for children and older adults have been much less successful for AYAs with cancer.

As an oncologic community, we should not allow the AYA gap to persist. As always, the solutions are likely to involve focused clinical research, education, and communication. Effort will need to be targeted specifically to the AYA population.

Since health-related mortality is high even when cancer-specific outcomes improve, adopting and maintaining a healthy lifestyle must be a key part of the discussion with these young patients.

The biologic differences associated with AYA lymphomas demand participation in clinical trials.

Oncologists should vigorously support removing impediments to the participation of AYAs in prospective clinical trials, stratified (but unrestricted) by age, with careful analysis of patient-reported outcomes, late adverse effects, and biospecimen collection.

As Dr. Kelly noted in the question-and-answer period, the Children’s Oncology Group has an existing biobank of paraffin-embedded tumor samples, DNA from lymphoma specimens, plasma, and sera with clinically annotated data that can be given to investigators upon request and justification.
 

Going beyond eligibility for clinical trials

Unfortunately, we will likely find that broadening eligibility criteria is the “low-hanging fruit.” There are protocol-, patient-, and physician-related obstacles, according to a review published in Cancer in 2019.

Patient-related obstacles include fear of toxicity, uncertainty about placebos, a steep learning curve for health literacy, insurance-related impediments, and other access-related issues.

Discussions will need to be tailored to the AYA population. Frank, early conversations about fertility, sexuality, financial hardship, career advancement, work-life balance, and cognitive risks may not only facilitate treatment planning but also encourage the trust that is essential for patients to enroll in trials.

The investment in time, multidisciplinary staff and physician involvement, and potential delays in treatment initiation may be painful and inconvenient, but the benefits for long-term health outcomes and personal-professional relationships will be gratifying beyond measure.

Dr. Smith disclosed relationships with Genentech/Roche, Celgene, TGTX, Karyopharm, Janssen, and Bantem. Dr. Roth disclosed relationships with Janssen, ADC Therapeutics, and Celgene. Dr. Kelly and Dr. Louissaint had no financial relationships to disclose.



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.

In the 1970s, cancer survival was poor for young children and older adults in the United States, as shown by data published in the Journal of the National Cancer Institute.

Great progress has been made since the 1970s, but improvements in outcome have been less impressive for cancer patients aged 15-39 years, as shown by research published in Cancer.

Factors that contribute to the AYA gap

About 89,000 AYAs are diagnosed with cancer each year in the United States, according to data from the National Cancer Institute (NCI). Lymphomas and thyroid cancer are the most common cancers among younger AYAs, aged 15-24 years.

In a report commissioned by the NIH in 2006, many factors contributing to the AYA gap were identified. Chief among them were:

• Limitations in access to care.
• Delayed diagnosis.
• Inconsistency in treatment and follow-up.
• Long-term toxicity (fertility, second malignancies, and cardiovascular disease).

These factors compromise health-related survival, even when cancer-specific survival is improved.

Panelist Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., noted that there are additional unique challenges for AYAs with cancer. These include:

• Pubertal changes.
• Developmental transition to independence.
• Societal impediments such as insurance coverage and disparities in access to specialized centers.
• Psychosocial factors such as health literacy and adherence to treatment and follow-up.

Focusing on lymphoma specifically, Dr. Kelly noted that lymphoma biology differs across the age spectrum and by race and ethnicity. Both tumor and host factors require further study, she said.
 

Clinical trial access for AYAs

Dr. Kelly emphasized that, unfortunately, clinical research participation is low among AYAs. A major impediment is that adult clinical trials historically required participants to be at least 18 years old.

In addition, there has not been a focused effort to educate AYAs about regulatory safeguards to ensure safety and the promise of enhanced benefit to them in NCI Cancer Trials Network (NCTN) trials. As a result, the refusal rate is high.

A multi-stakeholder workshop, convened in May 2016 by the American Society of Clinical Oncology and Friends of Cancer Research, outlined opportunities for expanding trial eligibility to include children younger than 18 years in first-in-human and other adult cancer clinical trials, enhancing their access to new agents, without compromising safety.

Recently, collaborative efforts between the adult and children’s NCTN research groups have included AYAs in studies addressing cancers that span the age spectrum, including lymphoma.

However, as Dr. Kelly noted, there are differences in AYA lymphoid malignancy types with a transition from more pediatric to more adult types.
 

Hodgkin lymphoma and primary mediastinal B-cell lymphoma

Panelist Lisa G. Roth, MD, of Weill Cornell Medicine, New York, reviewed the genomic landscape of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).

Dr. Roth explained that both HL and PMBCL are derived from thymic B cells, predominantly affect the mediastinum, and are CD30-positive lymphomas. Both are characterized by upregulation of JAK/STAT and NF-kappaB as well as overexpression of PD-L1.

Dr. Roth noted that HL is challenging to sequence by standard methods because Reed Sternberg (HRS) cells represent less than 1% of the cellular infiltrate. Recurrently mutated genes in HL cluster by histologic subtype.

Whole-exome sequencing of HRS cells show loss of beta-2 microglobulin and MHC-1 expression, HLA-B, NF-kappaB signaling, and JAK-STAT signaling, according to data published in Blood Advances in 2019.

Dr. Roth’s lab performed immunohistochemistry on tissue microarrays in 145 cases of HL (unpublished data). Results showed that loss of beta-2 microglobulin is more common in younger HL patients. For other alterations, there were too few cases to know.

Dr. Roth’s lab is a member of a pediatric/AYA HL sequencing multi-institutional consortium that has been able to extract DNA and RNA from samples submitted for whole-exome sequencing. The consortium’s goal is to shed light on implications of other genomic alterations that may differ by age in HL patients.

Dr. Roth cited research showing that PMBCL shares molecular alterations similar to those of HL. Alterations in PMBCL suggest dysregulated cellular signaling and immune evasion mechanisms (e.g., deletions in MHC type 1 and 2, beta-2 microglobulin, JAK-STAT, and NF-kappaB mutations) that provide opportunities to study novel agents, according to data published in Blood in 2019.

By early 2021, the S1826 and ANHL1931 studies, which have no age restriction, will be available to AYA lymphoma patients with HL and PMBCL, respectively, Dr. Roth said.
 

Follicular lymphoma: Clinical features by age

Panelist Abner Louissaint Jr, MD, PhD, of Massachusetts General Hospital in Boston, discussed age-related differences in follicular lymphoma (FL).

He noted that FL typically presents at an advanced stage, with low- or high-grade histology. It is increasingly common in adults in their 50s and 60s, representing 20% of all lymphomas. FL is rare in children and AYAs.

Dr. Louissaint explained that the typical flow cytometric findings in FL are BCL2 translocations, occurring in up to 85%-90% of low-grade and 50% of high-grade cases. The t(14;18)(q32;q21) translocation juxtaposes BCL2 on 18q21 to regulatory sequences and enhances the expression of elements of the Ig heavy chain.

Malignant cells in FL patients express CD20, CD10, CD21, and BCL2 (in contrast to normal germinal centers) and overexpress BCL6 (in contrast to normal follicles), Dr. Louissaint noted. He said the Ki-67 proliferative index of the malignant cells is typically low.

Pediatric-type FL is rare, but case series show clinical, pathologic, and molecular features that are distinctive from adult FL, Dr. Louissaint explained.

He then discussed the features of pediatric-type FL in multiple domains. In the clinical domain, there is a male predilection, and stage tends to be low. There is frequent involvement of nodes of the head and neck region and rare involvement of internal lymph node chains.

Pathologically, the malignant cells appear high grade, with architectural effacement, expansile follicular pattern, large lymphocyte size, and an elevated proliferation index. In contrast to adult FL, malignant cells in pediatric-type FL lack aberrant BCL2 expression.

Most importantly, for pediatric-type FL, the prognosis is excellent with durable remissions after surgical excision, Dr. Louissaint said.
 

Follicular lymphoma: Molecular features by age

Because of the excellent prognosis in pediatric-type FL, it is important to assess whether young adults with FL have adult-type or pediatric-type lesions, Dr. Louissaint said.

He cited many studies showing differences in adult and pediatric-type FL. In adult FL, the mutational landscape is characterized by frequent chromatin-modifying mutations in genes such as CREBBP, KM22D, and EP300.

In contrast, in pediatric-type FL, there are frequent activating MAPK pathway mutations, including mutations in the negative regulatory domain of MAP2K1. These mutations are not seen in adult FL.

Dr. Louissaint noted that there may be mutations in epigenetic modifiers (CREBBP, TNFRSF14) in both adult and pediatric-type FL. However, CREBBP is very unusual in pediatric-type FL and common in adult FL. This suggests the alterations in pediatric-type FL do not simply represent an early stage of the same disease as adult FL.

Despite a high proliferating fraction and absence of BCL2/BCL6/IRF4 rearrangements in pediatric-type FL, the presence of these features was associated with dramatic difference in progression-free survival, according to research published in Blood in 2012.
 

A distinct entity

In 2016, the World Health Organization recognized pediatric-type FL as a distinct entity, with the following diagnostic criteria (published in Blood):

• At least partial effacement of nodal architecture, expansile follicles, intermediate-size blastoid cells, and no component of diffuse large B-cell lymphoma.
• Immunohistochemistry showing BCL6 positivity, BCL2 negativity or weak positivity, and a high proliferative fraction.
• Genomic studies showing no BCL2 amplification.
• Clinical features of nodal disease in the head and neck region, early clinical stage, age younger than 40 years, typically in a male with no internal nodes involved.

When FL occurs in AYAs, the diagnostic findings of pediatric-type FL suggest the patient will do well with conservative management (e.g., excision alone), Dr. Louissaint noted.
 

Two sizes do not fit all

The strategies that have improved cancer outcomes since the 1970s for children and older adults have been much less successful for AYAs with cancer.

As an oncologic community, we should not allow the AYA gap to persist. As always, the solutions are likely to involve focused clinical research, education, and communication. Effort will need to be targeted specifically to the AYA population.

Since health-related mortality is high even when cancer-specific outcomes improve, adopting and maintaining a healthy lifestyle must be a key part of the discussion with these young patients.

The biologic differences associated with AYA lymphomas demand participation in clinical trials.

Oncologists should vigorously support removing impediments to the participation of AYAs in prospective clinical trials, stratified (but unrestricted) by age, with careful analysis of patient-reported outcomes, late adverse effects, and biospecimen collection.

As Dr. Kelly noted in the question-and-answer period, the Children’s Oncology Group has an existing biobank of paraffin-embedded tumor samples, DNA from lymphoma specimens, plasma, and sera with clinically annotated data that can be given to investigators upon request and justification.
 

Going beyond eligibility for clinical trials

Unfortunately, we will likely find that broadening eligibility criteria is the “low-hanging fruit.” There are protocol-, patient-, and physician-related obstacles, according to a review published in Cancer in 2019.

Patient-related obstacles include fear of toxicity, uncertainty about placebos, a steep learning curve for health literacy, insurance-related impediments, and other access-related issues.

Discussions will need to be tailored to the AYA population. Frank, early conversations about fertility, sexuality, financial hardship, career advancement, work-life balance, and cognitive risks may not only facilitate treatment planning but also encourage the trust that is essential for patients to enroll in trials.

The investment in time, multidisciplinary staff and physician involvement, and potential delays in treatment initiation may be painful and inconvenient, but the benefits for long-term health outcomes and personal-professional relationships will be gratifying beyond measure.

Dr. Smith disclosed relationships with Genentech/Roche, Celgene, TGTX, Karyopharm, Janssen, and Bantem. Dr. Roth disclosed relationships with Janssen, ADC Therapeutics, and Celgene. Dr. Kelly and Dr. Louissaint had no financial relationships to disclose.



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.

In the 1970s, cancer survival was poor for young children and older adults in the United States, as shown by data published in the Journal of the National Cancer Institute.

Great progress has been made since the 1970s, but improvements in outcome have been less impressive for cancer patients aged 15-39 years, as shown by research published in Cancer.

Factors that contribute to the AYA gap

About 89,000 AYAs are diagnosed with cancer each year in the United States, according to data from the National Cancer Institute (NCI). Lymphomas and thyroid cancer are the most common cancers among younger AYAs, aged 15-24 years.

In a report commissioned by the NIH in 2006, many factors contributing to the AYA gap were identified. Chief among them were:

• Limitations in access to care.
• Delayed diagnosis.
• Inconsistency in treatment and follow-up.
• Long-term toxicity (fertility, second malignancies, and cardiovascular disease).

These factors compromise health-related survival, even when cancer-specific survival is improved.

Panelist Kara Kelly, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., noted that there are additional unique challenges for AYAs with cancer. These include:

• Pubertal changes.
• Developmental transition to independence.
• Societal impediments such as insurance coverage and disparities in access to specialized centers.
• Psychosocial factors such as health literacy and adherence to treatment and follow-up.

Focusing on lymphoma specifically, Dr. Kelly noted that lymphoma biology differs across the age spectrum and by race and ethnicity. Both tumor and host factors require further study, she said.
 

Clinical trial access for AYAs

Dr. Kelly emphasized that, unfortunately, clinical research participation is low among AYAs. A major impediment is that adult clinical trials historically required participants to be at least 18 years old.

In addition, there has not been a focused effort to educate AYAs about regulatory safeguards to ensure safety and the promise of enhanced benefit to them in NCI Cancer Trials Network (NCTN) trials. As a result, the refusal rate is high.

A multi-stakeholder workshop, convened in May 2016 by the American Society of Clinical Oncology and Friends of Cancer Research, outlined opportunities for expanding trial eligibility to include children younger than 18 years in first-in-human and other adult cancer clinical trials, enhancing their access to new agents, without compromising safety.

Recently, collaborative efforts between the adult and children’s NCTN research groups have included AYAs in studies addressing cancers that span the age spectrum, including lymphoma.

However, as Dr. Kelly noted, there are differences in AYA lymphoid malignancy types with a transition from more pediatric to more adult types.
 

Hodgkin lymphoma and primary mediastinal B-cell lymphoma

Panelist Lisa G. Roth, MD, of Weill Cornell Medicine, New York, reviewed the genomic landscape of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL).

Dr. Roth explained that both HL and PMBCL are derived from thymic B cells, predominantly affect the mediastinum, and are CD30-positive lymphomas. Both are characterized by upregulation of JAK/STAT and NF-kappaB as well as overexpression of PD-L1.

Dr. Roth noted that HL is challenging to sequence by standard methods because Reed Sternberg (HRS) cells represent less than 1% of the cellular infiltrate. Recurrently mutated genes in HL cluster by histologic subtype.

Whole-exome sequencing of HRS cells show loss of beta-2 microglobulin and MHC-1 expression, HLA-B, NF-kappaB signaling, and JAK-STAT signaling, according to data published in Blood Advances in 2019.

Dr. Roth’s lab performed immunohistochemistry on tissue microarrays in 145 cases of HL (unpublished data). Results showed that loss of beta-2 microglobulin is more common in younger HL patients. For other alterations, there were too few cases to know.

Dr. Roth’s lab is a member of a pediatric/AYA HL sequencing multi-institutional consortium that has been able to extract DNA and RNA from samples submitted for whole-exome sequencing. The consortium’s goal is to shed light on implications of other genomic alterations that may differ by age in HL patients.

Dr. Roth cited research showing that PMBCL shares molecular alterations similar to those of HL. Alterations in PMBCL suggest dysregulated cellular signaling and immune evasion mechanisms (e.g., deletions in MHC type 1 and 2, beta-2 microglobulin, JAK-STAT, and NF-kappaB mutations) that provide opportunities to study novel agents, according to data published in Blood in 2019.

By early 2021, the S1826 and ANHL1931 studies, which have no age restriction, will be available to AYA lymphoma patients with HL and PMBCL, respectively, Dr. Roth said.
 

Follicular lymphoma: Clinical features by age

Panelist Abner Louissaint Jr, MD, PhD, of Massachusetts General Hospital in Boston, discussed age-related differences in follicular lymphoma (FL).

He noted that FL typically presents at an advanced stage, with low- or high-grade histology. It is increasingly common in adults in their 50s and 60s, representing 20% of all lymphomas. FL is rare in children and AYAs.

Dr. Louissaint explained that the typical flow cytometric findings in FL are BCL2 translocations, occurring in up to 85%-90% of low-grade and 50% of high-grade cases. The t(14;18)(q32;q21) translocation juxtaposes BCL2 on 18q21 to regulatory sequences and enhances the expression of elements of the Ig heavy chain.

Malignant cells in FL patients express CD20, CD10, CD21, and BCL2 (in contrast to normal germinal centers) and overexpress BCL6 (in contrast to normal follicles), Dr. Louissaint noted. He said the Ki-67 proliferative index of the malignant cells is typically low.

Pediatric-type FL is rare, but case series show clinical, pathologic, and molecular features that are distinctive from adult FL, Dr. Louissaint explained.

He then discussed the features of pediatric-type FL in multiple domains. In the clinical domain, there is a male predilection, and stage tends to be low. There is frequent involvement of nodes of the head and neck region and rare involvement of internal lymph node chains.

Pathologically, the malignant cells appear high grade, with architectural effacement, expansile follicular pattern, large lymphocyte size, and an elevated proliferation index. In contrast to adult FL, malignant cells in pediatric-type FL lack aberrant BCL2 expression.

Most importantly, for pediatric-type FL, the prognosis is excellent with durable remissions after surgical excision, Dr. Louissaint said.
 

Follicular lymphoma: Molecular features by age

Because of the excellent prognosis in pediatric-type FL, it is important to assess whether young adults with FL have adult-type or pediatric-type lesions, Dr. Louissaint said.

He cited many studies showing differences in adult and pediatric-type FL. In adult FL, the mutational landscape is characterized by frequent chromatin-modifying mutations in genes such as CREBBP, KM22D, and EP300.

In contrast, in pediatric-type FL, there are frequent activating MAPK pathway mutations, including mutations in the negative regulatory domain of MAP2K1. These mutations are not seen in adult FL.

Dr. Louissaint noted that there may be mutations in epigenetic modifiers (CREBBP, TNFRSF14) in both adult and pediatric-type FL. However, CREBBP is very unusual in pediatric-type FL and common in adult FL. This suggests the alterations in pediatric-type FL do not simply represent an early stage of the same disease as adult FL.

Despite a high proliferating fraction and absence of BCL2/BCL6/IRF4 rearrangements in pediatric-type FL, the presence of these features was associated with dramatic difference in progression-free survival, according to research published in Blood in 2012.
 

A distinct entity

In 2016, the World Health Organization recognized pediatric-type FL as a distinct entity, with the following diagnostic criteria (published in Blood):

• At least partial effacement of nodal architecture, expansile follicles, intermediate-size blastoid cells, and no component of diffuse large B-cell lymphoma.
• Immunohistochemistry showing BCL6 positivity, BCL2 negativity or weak positivity, and a high proliferative fraction.
• Genomic studies showing no BCL2 amplification.
• Clinical features of nodal disease in the head and neck region, early clinical stage, age younger than 40 years, typically in a male with no internal nodes involved.

When FL occurs in AYAs, the diagnostic findings of pediatric-type FL suggest the patient will do well with conservative management (e.g., excision alone), Dr. Louissaint noted.
 

Two sizes do not fit all

The strategies that have improved cancer outcomes since the 1970s for children and older adults have been much less successful for AYAs with cancer.

As an oncologic community, we should not allow the AYA gap to persist. As always, the solutions are likely to involve focused clinical research, education, and communication. Effort will need to be targeted specifically to the AYA population.

Since health-related mortality is high even when cancer-specific outcomes improve, adopting and maintaining a healthy lifestyle must be a key part of the discussion with these young patients.

The biologic differences associated with AYA lymphomas demand participation in clinical trials.

Oncologists should vigorously support removing impediments to the participation of AYAs in prospective clinical trials, stratified (but unrestricted) by age, with careful analysis of patient-reported outcomes, late adverse effects, and biospecimen collection.

As Dr. Kelly noted in the question-and-answer period, the Children’s Oncology Group has an existing biobank of paraffin-embedded tumor samples, DNA from lymphoma specimens, plasma, and sera with clinically annotated data that can be given to investigators upon request and justification.
 

Going beyond eligibility for clinical trials

Unfortunately, we will likely find that broadening eligibility criteria is the “low-hanging fruit.” There are protocol-, patient-, and physician-related obstacles, according to a review published in Cancer in 2019.

Patient-related obstacles include fear of toxicity, uncertainty about placebos, a steep learning curve for health literacy, insurance-related impediments, and other access-related issues.

Discussions will need to be tailored to the AYA population. Frank, early conversations about fertility, sexuality, financial hardship, career advancement, work-life balance, and cognitive risks may not only facilitate treatment planning but also encourage the trust that is essential for patients to enroll in trials.

The investment in time, multidisciplinary staff and physician involvement, and potential delays in treatment initiation may be painful and inconvenient, but the benefits for long-term health outcomes and personal-professional relationships will be gratifying beyond measure.

Dr. Smith disclosed relationships with Genentech/Roche, Celgene, TGTX, Karyopharm, Janssen, and Bantem. Dr. Roth disclosed relationships with Janssen, ADC Therapeutics, and Celgene. Dr. Kelly and Dr. Louissaint had no financial relationships to disclose.



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.