PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

People with type 2 diabetes whose diet followed a “Mediterranean” pattern – high in vegetables, legumes, fish, and unsaturated fats – saw global cognitive improvements over a 2-year period, compared with individuals with different eating patterns, even if the latter incorporated healthy dietary features. In addition, effective glycemic control seemed to have a role in sustaining the benefits associated with the Mediterranean-type diet.

Adults without type 2 diabetes, meanwhile, did not see the cognitive improvements associated with a Mediterranean diet, suggesting that the pathways linking diet to cognition may be different for individuals with and without diabetes, according to Josiemer Mattei, PhD, of the Harvard T.H. Chan School of Public Health in Boston and colleagues.

The investigators used data from the Boston Puerto Rican Health Study, a longitudinal cohort of about 1,499 adults aged 45-75 years who lived in Boston and identified as Puerto Rican, for their research, which was published in Diabetes Care.

At baseline, participants were administered a questionnaire to capture their eating patterns. Four diet-quality scores – Mediterranean Diet Score, Healthy Eating Index, Alternate Healthy Eating Index, and DASH (Dietary Approaches to Stop Hypertension) were analyzed. The participants were also screened for diabetes, and nearly 40% of them were found to have type 2 diabetes at baseline (74% uncontrolled). They underwent a battery of cognitive tests, including the Mini-Mental State Exam and tests for verbal fluency, executive function, word recognition, and figure copying. The study endpoints included 2-year change in global cognitive function as well as executive and memory function. At 2 years, data was available for 913 participants.

Among participants with type 2 diabetes, greater adherence to a Mediterranean-style diet was significantly associated with a higher positive change at the 2-year follow-up in global cognitive function score (0.027 [SD, 0.011]; P = .016), the Mini-Mental State Exam, and other individual tests. The association was significant for those who were under glycemic control at baseline and who remained stable or improved over 2 years, but not for those with poor or worsening glycemic control.

“The Mediterranean diet explained as much or more of the variability in predicting changes in cognitive function in our study as did age, especially for participants with type 2 diabetes under glycemic control. ... This dietary pattern may provide more cognitive benefits [in this patient group] than other modifiable and nonmodifiable factors,” the authors wrote in their analysis. They stressed that a Mediterranean dietary pattern can be realized through foods and dishes that are already standard in many Puerto Rican households.

In participants who did not have diabetes, improvement in memory function measures was seen in association with a Mediterranean diet, but also with adherence to other eating patterns that are deemed healthy. That suggests that for this subgroup, any evidence-based healthy diet – not just the Mediterranean diet – may have some benefits for memory function.

“Dietary recommendations for cognitive health may need to be tailored for individuals with versus without type 2 diabetes,” the authors concluded.

Dr. Mattei and colleagues acknowledged as a limitation of their study its observational design.

The study received funding from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and Harvard University. The authors reported no financial conflicts of interest.

SOURCE: Mattei et al. Diabetes Care. 2019;42(8):1372-9.

People with type 2 diabetes whose diet followed a “Mediterranean” pattern – high in vegetables, legumes, fish, and unsaturated fats – saw global cognitive improvements over a 2-year period, compared with individuals with different eating patterns, even if the latter incorporated healthy dietary features. In addition, effective glycemic control seemed to have a role in sustaining the benefits associated with the Mediterranean-type diet.

Adults without type 2 diabetes, meanwhile, did not see the cognitive improvements associated with a Mediterranean diet, suggesting that the pathways linking diet to cognition may be different for individuals with and without diabetes, according to Josiemer Mattei, PhD, of the Harvard T.H. Chan School of Public Health in Boston and colleagues.

The investigators used data from the Boston Puerto Rican Health Study, a longitudinal cohort of about 1,499 adults aged 45-75 years who lived in Boston and identified as Puerto Rican, for their research, which was published in Diabetes Care.

At baseline, participants were administered a questionnaire to capture their eating patterns. Four diet-quality scores – Mediterranean Diet Score, Healthy Eating Index, Alternate Healthy Eating Index, and DASH (Dietary Approaches to Stop Hypertension) were analyzed. The participants were also screened for diabetes, and nearly 40% of them were found to have type 2 diabetes at baseline (74% uncontrolled). They underwent a battery of cognitive tests, including the Mini-Mental State Exam and tests for verbal fluency, executive function, word recognition, and figure copying. The study endpoints included 2-year change in global cognitive function as well as executive and memory function. At 2 years, data was available for 913 participants.

Among participants with type 2 diabetes, greater adherence to a Mediterranean-style diet was significantly associated with a higher positive change at the 2-year follow-up in global cognitive function score (0.027 [SD, 0.011]; P = .016), the Mini-Mental State Exam, and other individual tests. The association was significant for those who were under glycemic control at baseline and who remained stable or improved over 2 years, but not for those with poor or worsening glycemic control.

“The Mediterranean diet explained as much or more of the variability in predicting changes in cognitive function in our study as did age, especially for participants with type 2 diabetes under glycemic control. ... This dietary pattern may provide more cognitive benefits [in this patient group] than other modifiable and nonmodifiable factors,” the authors wrote in their analysis. They stressed that a Mediterranean dietary pattern can be realized through foods and dishes that are already standard in many Puerto Rican households.

In participants who did not have diabetes, improvement in memory function measures was seen in association with a Mediterranean diet, but also with adherence to other eating patterns that are deemed healthy. That suggests that for this subgroup, any evidence-based healthy diet – not just the Mediterranean diet – may have some benefits for memory function.

“Dietary recommendations for cognitive health may need to be tailored for individuals with versus without type 2 diabetes,” the authors concluded.

Dr. Mattei and colleagues acknowledged as a limitation of their study its observational design.

The study received funding from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and Harvard University. The authors reported no financial conflicts of interest.

SOURCE: Mattei et al. Diabetes Care. 2019;42(8):1372-9.

People with type 2 diabetes whose diet followed a “Mediterranean” pattern – high in vegetables, legumes, fish, and unsaturated fats – saw global cognitive improvements over a 2-year period, compared with individuals with different eating patterns, even if the latter incorporated healthy dietary features. In addition, effective glycemic control seemed to have a role in sustaining the benefits associated with the Mediterranean-type diet.

Adults without type 2 diabetes, meanwhile, did not see the cognitive improvements associated with a Mediterranean diet, suggesting that the pathways linking diet to cognition may be different for individuals with and without diabetes, according to Josiemer Mattei, PhD, of the Harvard T.H. Chan School of Public Health in Boston and colleagues.

The investigators used data from the Boston Puerto Rican Health Study, a longitudinal cohort of about 1,499 adults aged 45-75 years who lived in Boston and identified as Puerto Rican, for their research, which was published in Diabetes Care.

At baseline, participants were administered a questionnaire to capture their eating patterns. Four diet-quality scores – Mediterranean Diet Score, Healthy Eating Index, Alternate Healthy Eating Index, and DASH (Dietary Approaches to Stop Hypertension) were analyzed. The participants were also screened for diabetes, and nearly 40% of them were found to have type 2 diabetes at baseline (74% uncontrolled). They underwent a battery of cognitive tests, including the Mini-Mental State Exam and tests for verbal fluency, executive function, word recognition, and figure copying. The study endpoints included 2-year change in global cognitive function as well as executive and memory function. At 2 years, data was available for 913 participants.

Among participants with type 2 diabetes, greater adherence to a Mediterranean-style diet was significantly associated with a higher positive change at the 2-year follow-up in global cognitive function score (0.027 [SD, 0.011]; P = .016), the Mini-Mental State Exam, and other individual tests. The association was significant for those who were under glycemic control at baseline and who remained stable or improved over 2 years, but not for those with poor or worsening glycemic control.

“The Mediterranean diet explained as much or more of the variability in predicting changes in cognitive function in our study as did age, especially for participants with type 2 diabetes under glycemic control. ... This dietary pattern may provide more cognitive benefits [in this patient group] than other modifiable and nonmodifiable factors,” the authors wrote in their analysis. They stressed that a Mediterranean dietary pattern can be realized through foods and dishes that are already standard in many Puerto Rican households.

In participants who did not have diabetes, improvement in memory function measures was seen in association with a Mediterranean diet, but also with adherence to other eating patterns that are deemed healthy. That suggests that for this subgroup, any evidence-based healthy diet – not just the Mediterranean diet – may have some benefits for memory function.

“Dietary recommendations for cognitive health may need to be tailored for individuals with versus without type 2 diabetes,” the authors concluded.

Dr. Mattei and colleagues acknowledged as a limitation of their study its observational design.

The study received funding from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and Harvard University. The authors reported no financial conflicts of interest.

SOURCE: Mattei et al. Diabetes Care. 2019;42(8):1372-9.

Continuous blood pressure monitoring is significantly better than in-office measurements at predicting the risk of cardiovascular events and death, although the additional prognostic benefit is quite small, wrote Wen-Yi Yang, MD, and colleagues. Their report is in JAMA.

Ingram Publishing/ThinkStock

In light of this finding, 24-hour monitoring is probably best reserved for select patients – especially those with white coat hypertension, and those who self-report hypertension but test within normal parameters in the office, said Philip Greenland, MD, Harry W. Dingman Professor of Cardiology at Northwestern University, Chicago, who wrote a perspective piece published along with the study.

“The good news is that, for the average patient, the office measurement is highly predictive and performs extremely well,” Dr. Greenland said in an interview. “Ambulatory monitoring will get you very little additional information. But if you are getting a 24-hour reading, the measures you probably want to focus on are the nighttime pressures and the overall 24-hour average.”

Dr. Yang of the University of Leuven, Belgium, and his team were “trying to make sense of this huge amount of data that’s available now that ambulatory blood pressure monitoring systems are much more common,” Dr. Greenland said. “The real clinical question is, ‘If I’m getting all this information, how do I interpret it?’ ”

To investigate this, the authors evaluated blood pressure and cardiovascular outcomes among more than 11,000 subjects enrolled in the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome (IDACO).

The median individual follow-up was about 14 years, although some patients were followed up to 22 years. All told, the study posted 153,140 person-years of follow-up. These patients were a mean of 55 years old at enrollment; almost 12% had a history of cardiovascular disease. Most (83%) had three automated in-office blood pressure measurements; 5% had two, and 2% had a single measurement. There were 55 24-hour ambulatory readings, 28 for daytime only, and 11 for nighttime.

The mean in-office automated BP was 135/82. The mean 24-hour BP was 123/74; the mean daytime pressure, 130/79; and the mean nighttime pressure, 113/65.

The authors recorded blood pressure–dipping status: 50% were normal, 18% had extreme dipping, 25% had no dipping, and 6% had reverse dipping. The mean dipping ratio was 0.87.

A regression analysis adjusted for sex, age, body mass index, smoking, and alcohol use, serum cholesterol, antihypertensive drugs, cardiovascular disease and diabetes.

Over the entire study period, there were 2,836 deaths and 2,049 cardiovascular events – a rate of 13.4 per 1,000 person-years. Both cardiovascular events and mortality were significantly associated with all ambulatory BP measurements, compared with in-office measurements. For nighttime systolic BP, the hazard ratio for mortality was 1.23 and 1.36 for cardiovascular events. For the 24-hour measure, the HR for mortality was 1.22, and for cardiovascular events, 1.45. Hazard ratios represented the risk associated with a 20–mm Hg higher systolic blood pressure or a 0.10 difference in dipping ratio.

However, the area under the curve for a single, in-office systolic BP was quite good, at 0.83 for mortality and 0.84 for cardiovascular events. Adding 24-hour measurements or nighttime systolic BP to the model resulted only in very, very small “incremental” improvements in AUC of 0.0013 and 0.0027, respectively

“The current population-based study confirmed previous research indicating that ambulatory BP monitoring over and beyond measures taken in clinicians’ offices improved risk stratification among patients with or suspected of having hypertension,” The authors wrote. “It strengthened the notion that nighttime BP measures carry valuable prognostic information.”

However, they admitted that the addition these measures offer to the AUC for BP measurements was “incremental.”

“This metric is not very sensitive in model comparisons if the basic model performs well, as was the case in the current study. … The prevailing perception among experts is that BP is the strongest modifiable risk factor. The small increments in change in the AUC challenge this concept. Thus an important issue in the evaluation of an additional risk prediction marker is how to interpret a small AUC increase, which many researchers believe is an imprecise metric because it increases only slightly with the introduction of an additional marker in multivariable-adjusted models, even if the marker under study carries great risk, as reflected by the odds ratio (or HR).”

One investigator, Krzysztof Narkiewicz, MD, reported receiving lecture fees from numerous pharmaceutical and device companies. No other disclosures were reported.

[email protected]

SOURCE: Yang W et al. JAMA. 2019;322(5):409-20.

Continuous blood pressure monitoring is significantly better than in-office measurements at predicting the risk of cardiovascular events and death, although the additional prognostic benefit is quite small, wrote Wen-Yi Yang, MD, and colleagues. Their report is in JAMA.

Ingram Publishing/ThinkStock

In light of this finding, 24-hour monitoring is probably best reserved for select patients – especially those with white coat hypertension, and those who self-report hypertension but test within normal parameters in the office, said Philip Greenland, MD, Harry W. Dingman Professor of Cardiology at Northwestern University, Chicago, who wrote a perspective piece published along with the study.

“The good news is that, for the average patient, the office measurement is highly predictive and performs extremely well,” Dr. Greenland said in an interview. “Ambulatory monitoring will get you very little additional information. But if you are getting a 24-hour reading, the measures you probably want to focus on are the nighttime pressures and the overall 24-hour average.”

Dr. Yang of the University of Leuven, Belgium, and his team were “trying to make sense of this huge amount of data that’s available now that ambulatory blood pressure monitoring systems are much more common,” Dr. Greenland said. “The real clinical question is, ‘If I’m getting all this information, how do I interpret it?’ ”

To investigate this, the authors evaluated blood pressure and cardiovascular outcomes among more than 11,000 subjects enrolled in the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome (IDACO).

The median individual follow-up was about 14 years, although some patients were followed up to 22 years. All told, the study posted 153,140 person-years of follow-up. These patients were a mean of 55 years old at enrollment; almost 12% had a history of cardiovascular disease. Most (83%) had three automated in-office blood pressure measurements; 5% had two, and 2% had a single measurement. There were 55 24-hour ambulatory readings, 28 for daytime only, and 11 for nighttime.

The mean in-office automated BP was 135/82. The mean 24-hour BP was 123/74; the mean daytime pressure, 130/79; and the mean nighttime pressure, 113/65.

The authors recorded blood pressure–dipping status: 50% were normal, 18% had extreme dipping, 25% had no dipping, and 6% had reverse dipping. The mean dipping ratio was 0.87.

A regression analysis adjusted for sex, age, body mass index, smoking, and alcohol use, serum cholesterol, antihypertensive drugs, cardiovascular disease and diabetes.

Over the entire study period, there were 2,836 deaths and 2,049 cardiovascular events – a rate of 13.4 per 1,000 person-years. Both cardiovascular events and mortality were significantly associated with all ambulatory BP measurements, compared with in-office measurements. For nighttime systolic BP, the hazard ratio for mortality was 1.23 and 1.36 for cardiovascular events. For the 24-hour measure, the HR for mortality was 1.22, and for cardiovascular events, 1.45. Hazard ratios represented the risk associated with a 20–mm Hg higher systolic blood pressure or a 0.10 difference in dipping ratio.

However, the area under the curve for a single, in-office systolic BP was quite good, at 0.83 for mortality and 0.84 for cardiovascular events. Adding 24-hour measurements or nighttime systolic BP to the model resulted only in very, very small “incremental” improvements in AUC of 0.0013 and 0.0027, respectively

“The current population-based study confirmed previous research indicating that ambulatory BP monitoring over and beyond measures taken in clinicians’ offices improved risk stratification among patients with or suspected of having hypertension,” The authors wrote. “It strengthened the notion that nighttime BP measures carry valuable prognostic information.”

However, they admitted that the addition these measures offer to the AUC for BP measurements was “incremental.”

“This metric is not very sensitive in model comparisons if the basic model performs well, as was the case in the current study. … The prevailing perception among experts is that BP is the strongest modifiable risk factor. The small increments in change in the AUC challenge this concept. Thus an important issue in the evaluation of an additional risk prediction marker is how to interpret a small AUC increase, which many researchers believe is an imprecise metric because it increases only slightly with the introduction of an additional marker in multivariable-adjusted models, even if the marker under study carries great risk, as reflected by the odds ratio (or HR).”

One investigator, Krzysztof Narkiewicz, MD, reported receiving lecture fees from numerous pharmaceutical and device companies. No other disclosures were reported.

[email protected]

SOURCE: Yang W et al. JAMA. 2019;322(5):409-20.

Continuous blood pressure monitoring is significantly better than in-office measurements at predicting the risk of cardiovascular events and death, although the additional prognostic benefit is quite small, wrote Wen-Yi Yang, MD, and colleagues. Their report is in JAMA.

Ingram Publishing/ThinkStock

In light of this finding, 24-hour monitoring is probably best reserved for select patients – especially those with white coat hypertension, and those who self-report hypertension but test within normal parameters in the office, said Philip Greenland, MD, Harry W. Dingman Professor of Cardiology at Northwestern University, Chicago, who wrote a perspective piece published along with the study.

“The good news is that, for the average patient, the office measurement is highly predictive and performs extremely well,” Dr. Greenland said in an interview. “Ambulatory monitoring will get you very little additional information. But if you are getting a 24-hour reading, the measures you probably want to focus on are the nighttime pressures and the overall 24-hour average.”

Dr. Yang of the University of Leuven, Belgium, and his team were “trying to make sense of this huge amount of data that’s available now that ambulatory blood pressure monitoring systems are much more common,” Dr. Greenland said. “The real clinical question is, ‘If I’m getting all this information, how do I interpret it?’ ”

To investigate this, the authors evaluated blood pressure and cardiovascular outcomes among more than 11,000 subjects enrolled in the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome (IDACO).

The median individual follow-up was about 14 years, although some patients were followed up to 22 years. All told, the study posted 153,140 person-years of follow-up. These patients were a mean of 55 years old at enrollment; almost 12% had a history of cardiovascular disease. Most (83%) had three automated in-office blood pressure measurements; 5% had two, and 2% had a single measurement. There were 55 24-hour ambulatory readings, 28 for daytime only, and 11 for nighttime.

The mean in-office automated BP was 135/82. The mean 24-hour BP was 123/74; the mean daytime pressure, 130/79; and the mean nighttime pressure, 113/65.

The authors recorded blood pressure–dipping status: 50% were normal, 18% had extreme dipping, 25% had no dipping, and 6% had reverse dipping. The mean dipping ratio was 0.87.

A regression analysis adjusted for sex, age, body mass index, smoking, and alcohol use, serum cholesterol, antihypertensive drugs, cardiovascular disease and diabetes.

Over the entire study period, there were 2,836 deaths and 2,049 cardiovascular events – a rate of 13.4 per 1,000 person-years. Both cardiovascular events and mortality were significantly associated with all ambulatory BP measurements, compared with in-office measurements. For nighttime systolic BP, the hazard ratio for mortality was 1.23 and 1.36 for cardiovascular events. For the 24-hour measure, the HR for mortality was 1.22, and for cardiovascular events, 1.45. Hazard ratios represented the risk associated with a 20–mm Hg higher systolic blood pressure or a 0.10 difference in dipping ratio.

However, the area under the curve for a single, in-office systolic BP was quite good, at 0.83 for mortality and 0.84 for cardiovascular events. Adding 24-hour measurements or nighttime systolic BP to the model resulted only in very, very small “incremental” improvements in AUC of 0.0013 and 0.0027, respectively

“The current population-based study confirmed previous research indicating that ambulatory BP monitoring over and beyond measures taken in clinicians’ offices improved risk stratification among patients with or suspected of having hypertension,” The authors wrote. “It strengthened the notion that nighttime BP measures carry valuable prognostic information.”

However, they admitted that the addition these measures offer to the AUC for BP measurements was “incremental.”

“This metric is not very sensitive in model comparisons if the basic model performs well, as was the case in the current study. … The prevailing perception among experts is that BP is the strongest modifiable risk factor. The small increments in change in the AUC challenge this concept. Thus an important issue in the evaluation of an additional risk prediction marker is how to interpret a small AUC increase, which many researchers believe is an imprecise metric because it increases only slightly with the introduction of an additional marker in multivariable-adjusted models, even if the marker under study carries great risk, as reflected by the odds ratio (or HR).”

One investigator, Krzysztof Narkiewicz, MD, reported receiving lecture fees from numerous pharmaceutical and device companies. No other disclosures were reported.

[email protected]

SOURCE: Yang W et al. JAMA. 2019;322(5):409-20.

As psychiatry mourns Carl Compton Bell, MD, a giant in our field, we pay homage to his legacy of leadership and productivity.

Dr. Bell wore many hats: community psychiatrist par excellence, award-winning researcher, clinician, public health advocate, mentor, and activist. Eschewing the mold of the stereotypical psychiatrist, he lectured in cowboy hats, baseball caps, message T-shirts, and shades – all conveying his youthful, down-to-earth, yet serious, psychiatrist-of-the-people style. He demonstrated that scholarship could combat racial inequities and made it clear that he had much to accomplish yet little to prove.

Dr. Bell implored physicians to not only treat health problems but also to rectify “upstream” issues. He encouraged their engagement in “bent-nail research,” empirical study directly in the communities where they work – even with limited resources. This approach, rooted in public health and prevention, undergirds his groundbreaking work in the treatment of fetal alcohol exposure with choline and folic acid. HIV prevention in South Africa was another area of study where he developed innovative strategies with successful outcomes. In his study of trauma in youth, he underscored that “risk factors are not predictive factors because of protective factors.”

He promoted social fabric, an adult protective shield, connectedness, self-esteem, self-efficacy, and social skills as protective. He understood that, with treatment and community supports, children exposed to violence were not doomed to a life of aberrant behavior.

A prolific author, Dr. Bell’s peer-reviewed articles are often cited and have become the gospel for community mental health. He bemoaned the insufficient translation of published research into reality in the community. His writings suggested that psychiatry should not assume that its standards of diagnosis and treatment apply entirely to nonwhite populations. This fact remains a call to action for those of us he leaves behind.

As a clinician, Dr. Bell listened intently to his patients to understand their current situations, histories, family histories, and contexts in which they lived. He was so dedicated to their care that, when a mental health center he led for years abruptly closed its doors, he set up a makeshift office on the front sidewalk to serve patients who might not have known about its closure.

Dr. Bell was active in organized psychiatry, serving as past chair of the American Psychiatric Association Council on Social Issues and Public Psychiatry. He inspired the creation of the APA’s Transformational Leadership in Public Psychiatry Fellowship for early- and mid-career psychiatrists. A loyal member of the Black Psychiatrists of America, he took pride in having saved all of BPA’s newsletters dating back to its founding in 1969.

His participation in those associations and in the National Medical Association was an avenue through which his robust scholarship encouraged the next generations of black psychiatrists. Those countless psychiatrists who trusted Dr. Bell’s wise counsel have gone on to become leaders. They are proof that his extraordinary accomplishments and spirit will live on through the multiplier effect of their contributions to the field and mentorship of future psychiatrists for years to come.
 

Dr. Gordon-Achebe is a child, adolescent, and adult psychiatrist practicing in the Baltimore metropolitan area. She is the immediate past president of the American Psychiatric Association’s Caucus of Black Psychiatrists and vice chair for the Council on Children, Adolescents and Their Families.

Dr. Hairston is the psychiatry residency training director at Howard University in Washington. She is the newly elected president of the American Psychiatric Association’s Caucus of Black Psychiatrists and the scientific program committee chair for the Black Psychiatrists of America.

Dr. Starks is a geriatric psychiatrist and Health and Aging Policy Fellow currently working on Capitol Hill in Washington. He is the representative to the assembly for the APA Caucus of Black Psychiatrists. He has nurtured a keen interest in understanding the cultural and social effects of geriatric mental health conditions on the lives of patients and families.

Dr. Primm, a community psychiatrist based in Baltimore, is senior medical director of the Steve Fund, which is focused on the mental health and emotional well-being of young people of color, including college students. She formerly served as deputy medical director of the APA and director of APA’s division of diversity and health equity, previously known as the Office of Minority and National Affairs.

As psychiatry mourns Carl Compton Bell, MD, a giant in our field, we pay homage to his legacy of leadership and productivity.

Dr. Bell wore many hats: community psychiatrist par excellence, award-winning researcher, clinician, public health advocate, mentor, and activist. Eschewing the mold of the stereotypical psychiatrist, he lectured in cowboy hats, baseball caps, message T-shirts, and shades – all conveying his youthful, down-to-earth, yet serious, psychiatrist-of-the-people style. He demonstrated that scholarship could combat racial inequities and made it clear that he had much to accomplish yet little to prove.

Dr. Bell implored physicians to not only treat health problems but also to rectify “upstream” issues. He encouraged their engagement in “bent-nail research,” empirical study directly in the communities where they work – even with limited resources. This approach, rooted in public health and prevention, undergirds his groundbreaking work in the treatment of fetal alcohol exposure with choline and folic acid. HIV prevention in South Africa was another area of study where he developed innovative strategies with successful outcomes. In his study of trauma in youth, he underscored that “risk factors are not predictive factors because of protective factors.”

He promoted social fabric, an adult protective shield, connectedness, self-esteem, self-efficacy, and social skills as protective. He understood that, with treatment and community supports, children exposed to violence were not doomed to a life of aberrant behavior.

A prolific author, Dr. Bell’s peer-reviewed articles are often cited and have become the gospel for community mental health. He bemoaned the insufficient translation of published research into reality in the community. His writings suggested that psychiatry should not assume that its standards of diagnosis and treatment apply entirely to nonwhite populations. This fact remains a call to action for those of us he leaves behind.

As a clinician, Dr. Bell listened intently to his patients to understand their current situations, histories, family histories, and contexts in which they lived. He was so dedicated to their care that, when a mental health center he led for years abruptly closed its doors, he set up a makeshift office on the front sidewalk to serve patients who might not have known about its closure.

Dr. Bell was active in organized psychiatry, serving as past chair of the American Psychiatric Association Council on Social Issues and Public Psychiatry. He inspired the creation of the APA’s Transformational Leadership in Public Psychiatry Fellowship for early- and mid-career psychiatrists. A loyal member of the Black Psychiatrists of America, he took pride in having saved all of BPA’s newsletters dating back to its founding in 1969.

His participation in those associations and in the National Medical Association was an avenue through which his robust scholarship encouraged the next generations of black psychiatrists. Those countless psychiatrists who trusted Dr. Bell’s wise counsel have gone on to become leaders. They are proof that his extraordinary accomplishments and spirit will live on through the multiplier effect of their contributions to the field and mentorship of future psychiatrists for years to come.
 

Dr. Gordon-Achebe is a child, adolescent, and adult psychiatrist practicing in the Baltimore metropolitan area. She is the immediate past president of the American Psychiatric Association’s Caucus of Black Psychiatrists and vice chair for the Council on Children, Adolescents and Their Families.

Dr. Hairston is the psychiatry residency training director at Howard University in Washington. She is the newly elected president of the American Psychiatric Association’s Caucus of Black Psychiatrists and the scientific program committee chair for the Black Psychiatrists of America.

Dr. Starks is a geriatric psychiatrist and Health and Aging Policy Fellow currently working on Capitol Hill in Washington. He is the representative to the assembly for the APA Caucus of Black Psychiatrists. He has nurtured a keen interest in understanding the cultural and social effects of geriatric mental health conditions on the lives of patients and families.

Dr. Primm, a community psychiatrist based in Baltimore, is senior medical director of the Steve Fund, which is focused on the mental health and emotional well-being of young people of color, including college students. She formerly served as deputy medical director of the APA and director of APA’s division of diversity and health equity, previously known as the Office of Minority and National Affairs.

As psychiatry mourns Carl Compton Bell, MD, a giant in our field, we pay homage to his legacy of leadership and productivity.

Dr. Bell wore many hats: community psychiatrist par excellence, award-winning researcher, clinician, public health advocate, mentor, and activist. Eschewing the mold of the stereotypical psychiatrist, he lectured in cowboy hats, baseball caps, message T-shirts, and shades – all conveying his youthful, down-to-earth, yet serious, psychiatrist-of-the-people style. He demonstrated that scholarship could combat racial inequities and made it clear that he had much to accomplish yet little to prove.

Dr. Bell implored physicians to not only treat health problems but also to rectify “upstream” issues. He encouraged their engagement in “bent-nail research,” empirical study directly in the communities where they work – even with limited resources. This approach, rooted in public health and prevention, undergirds his groundbreaking work in the treatment of fetal alcohol exposure with choline and folic acid. HIV prevention in South Africa was another area of study where he developed innovative strategies with successful outcomes. In his study of trauma in youth, he underscored that “risk factors are not predictive factors because of protective factors.”

He promoted social fabric, an adult protective shield, connectedness, self-esteem, self-efficacy, and social skills as protective. He understood that, with treatment and community supports, children exposed to violence were not doomed to a life of aberrant behavior.

A prolific author, Dr. Bell’s peer-reviewed articles are often cited and have become the gospel for community mental health. He bemoaned the insufficient translation of published research into reality in the community. His writings suggested that psychiatry should not assume that its standards of diagnosis and treatment apply entirely to nonwhite populations. This fact remains a call to action for those of us he leaves behind.

As a clinician, Dr. Bell listened intently to his patients to understand their current situations, histories, family histories, and contexts in which they lived. He was so dedicated to their care that, when a mental health center he led for years abruptly closed its doors, he set up a makeshift office on the front sidewalk to serve patients who might not have known about its closure.

Dr. Bell was active in organized psychiatry, serving as past chair of the American Psychiatric Association Council on Social Issues and Public Psychiatry. He inspired the creation of the APA’s Transformational Leadership in Public Psychiatry Fellowship for early- and mid-career psychiatrists. A loyal member of the Black Psychiatrists of America, he took pride in having saved all of BPA’s newsletters dating back to its founding in 1969.

His participation in those associations and in the National Medical Association was an avenue through which his robust scholarship encouraged the next generations of black psychiatrists. Those countless psychiatrists who trusted Dr. Bell’s wise counsel have gone on to become leaders. They are proof that his extraordinary accomplishments and spirit will live on through the multiplier effect of their contributions to the field and mentorship of future psychiatrists for years to come.
 

Dr. Gordon-Achebe is a child, adolescent, and adult psychiatrist practicing in the Baltimore metropolitan area. She is the immediate past president of the American Psychiatric Association’s Caucus of Black Psychiatrists and vice chair for the Council on Children, Adolescents and Their Families.

Dr. Hairston is the psychiatry residency training director at Howard University in Washington. She is the newly elected president of the American Psychiatric Association’s Caucus of Black Psychiatrists and the scientific program committee chair for the Black Psychiatrists of America.

Dr. Starks is a geriatric psychiatrist and Health and Aging Policy Fellow currently working on Capitol Hill in Washington. He is the representative to the assembly for the APA Caucus of Black Psychiatrists. He has nurtured a keen interest in understanding the cultural and social effects of geriatric mental health conditions on the lives of patients and families.

Dr. Primm, a community psychiatrist based in Baltimore, is senior medical director of the Steve Fund, which is focused on the mental health and emotional well-being of young people of color, including college students. She formerly served as deputy medical director of the APA and director of APA’s division of diversity and health equity, previously known as the Office of Minority and National Affairs.

BANGKOK – It’s high time for the prediction of seizure outcomes after epilepsy surgery to step into the 21st century, Lara Jehi, MD, asserted at the International Epilepsy Congress.

Bruce Jancin/MDedge News

She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.

“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.

Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.

“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.

Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.

The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).

However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.

Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).

“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.

The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.

[email protected]

BANGKOK – It’s high time for the prediction of seizure outcomes after epilepsy surgery to step into the 21st century, Lara Jehi, MD, asserted at the International Epilepsy Congress.

Bruce Jancin/MDedge News

She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.

“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.

Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.

“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.

Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.

The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).

However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.

Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).

“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.

The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.

[email protected]

BANGKOK – It’s high time for the prediction of seizure outcomes after epilepsy surgery to step into the 21st century, Lara Jehi, MD, asserted at the International Epilepsy Congress.

Bruce Jancin/MDedge News

She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.

“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.

Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.

“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.

Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.

The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).

However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.

Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).

“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.

The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.

[email protected]

LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.

After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.

Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.

The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.

The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.

Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.

The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”

Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.

Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.

Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.

Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.

Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.

“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.

Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.

“It’s something of great interest, we think, and deserves to be investigated.”

[email protected]

SOURCE: Missling C et al. AAIC 2019, Abstract 32260.

LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.

After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.

Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.

The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.

The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.

Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.

The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”

Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.

Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.

Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.

Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.

Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.

“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.

Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.

“It’s something of great interest, we think, and deserves to be investigated.”

[email protected]

SOURCE: Missling C et al. AAIC 2019, Abstract 32260.

LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.

After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.

Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.

The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.

The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.

Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.

Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.

The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”

Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.

Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.

Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.

Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.

Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.

“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.

Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.

“It’s something of great interest, we think, and deserves to be investigated.”

[email protected]

SOURCE: Missling C et al. AAIC 2019, Abstract 32260.

LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.

Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.

“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.

The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.

Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m² on days 8, 15, and 22, every 35 days.

A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).

In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.

A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.

Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.

Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.

The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.

Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.

Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.

SOURCE: Falchi L et al. 15-ICML, Abstract 129.

LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.

Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.

“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.

The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.

Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m² on days 8, 15, and 22, every 35 days.

A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).

In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.

A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.

Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.

Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.

The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.

Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.

Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.

SOURCE: Falchi L et al. 15-ICML, Abstract 129.

LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.

Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.

“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.

The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.

Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m² on days 8, 15, and 22, every 35 days.

A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).

In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.

A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.

Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.

Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.

The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.

Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.

Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.

SOURCE: Falchi L et al. 15-ICML, Abstract 129.

Paclitaxel-coated devices, which are used to treat peripheral artery disease (PAD), appear to have a nearly 60% higher mortality risk than uncoated devices, according to a letter to health care providers from the Food and Drug Administration.

This letter updates details about long-term follow-up data and panel conclusions reviewed by the Food and Drug Administration, as well as recommendations from the agency regarding these devices. On Jan. 17, 2019, the FDA notified providers regarding an apparent increased late mortality risk seen with paclitaxel-eluting stents and paclitaxel-coated balloons placed in the femoropopliteal artery in patients with PAD. The agency issued an update March 15.

In a public meeting June 19-20, the Circulatory System Devices Panel of the Medical Devices Advisory Committee discussed long-term follow-up data that demonstrated a 57% relative increase in mortality among PAD patients treated with paclitaxel-coated devices when compared with those receiving uncoated devices. The panel concluded that the late mortality signal was real and warranted further study and action, a conclusion with which the FDA has concurred.

Among other recommendations issued by the FDA, health care professionals should continue to closely monitor patients who’ve already received the devices and fully discuss the risks and benefits of these devices with patients. The FDA has decided that, given the demonstrated short-term benefits of these devices, clinical studies may continue and should collect long-term safety and effectiveness data.

The magnitude of this late mortality signal should be interpreted with caution, the FDA noted in the update, because of the wide confidence intervals (although the relative risk was 1.57, the 95% confidence interval was 1.16-2.13, which translates to 16%-113% higher relative risk), pooling studies of different devices that weren’t meant to be combined, missing data, and other reasons.

The full letter, including more detailed data and the full list of recommendations, is available on the FDA’s website.

[email protected]

Paclitaxel-coated devices, which are used to treat peripheral artery disease (PAD), appear to have a nearly 60% higher mortality risk than uncoated devices, according to a letter to health care providers from the Food and Drug Administration.

This letter updates details about long-term follow-up data and panel conclusions reviewed by the Food and Drug Administration, as well as recommendations from the agency regarding these devices. On Jan. 17, 2019, the FDA notified providers regarding an apparent increased late mortality risk seen with paclitaxel-eluting stents and paclitaxel-coated balloons placed in the femoropopliteal artery in patients with PAD. The agency issued an update March 15.

In a public meeting June 19-20, the Circulatory System Devices Panel of the Medical Devices Advisory Committee discussed long-term follow-up data that demonstrated a 57% relative increase in mortality among PAD patients treated with paclitaxel-coated devices when compared with those receiving uncoated devices. The panel concluded that the late mortality signal was real and warranted further study and action, a conclusion with which the FDA has concurred.

Among other recommendations issued by the FDA, health care professionals should continue to closely monitor patients who’ve already received the devices and fully discuss the risks and benefits of these devices with patients. The FDA has decided that, given the demonstrated short-term benefits of these devices, clinical studies may continue and should collect long-term safety and effectiveness data.

The magnitude of this late mortality signal should be interpreted with caution, the FDA noted in the update, because of the wide confidence intervals (although the relative risk was 1.57, the 95% confidence interval was 1.16-2.13, which translates to 16%-113% higher relative risk), pooling studies of different devices that weren’t meant to be combined, missing data, and other reasons.

The full letter, including more detailed data and the full list of recommendations, is available on the FDA’s website.

[email protected]

Paclitaxel-coated devices, which are used to treat peripheral artery disease (PAD), appear to have a nearly 60% higher mortality risk than uncoated devices, according to a letter to health care providers from the Food and Drug Administration.

This letter updates details about long-term follow-up data and panel conclusions reviewed by the Food and Drug Administration, as well as recommendations from the agency regarding these devices. On Jan. 17, 2019, the FDA notified providers regarding an apparent increased late mortality risk seen with paclitaxel-eluting stents and paclitaxel-coated balloons placed in the femoropopliteal artery in patients with PAD. The agency issued an update March 15.

In a public meeting June 19-20, the Circulatory System Devices Panel of the Medical Devices Advisory Committee discussed long-term follow-up data that demonstrated a 57% relative increase in mortality among PAD patients treated with paclitaxel-coated devices when compared with those receiving uncoated devices. The panel concluded that the late mortality signal was real and warranted further study and action, a conclusion with which the FDA has concurred.

Among other recommendations issued by the FDA, health care professionals should continue to closely monitor patients who’ve already received the devices and fully discuss the risks and benefits of these devices with patients. The FDA has decided that, given the demonstrated short-term benefits of these devices, clinical studies may continue and should collect long-term safety and effectiveness data.

The magnitude of this late mortality signal should be interpreted with caution, the FDA noted in the update, because of the wide confidence intervals (although the relative risk was 1.57, the 95% confidence interval was 1.16-2.13, which translates to 16%-113% higher relative risk), pooling studies of different devices that weren’t meant to be combined, missing data, and other reasons.

The full letter, including more detailed data and the full list of recommendations, is available on the FDA’s website.

[email protected]

To the Editor:

In the April 2019 Cutis article by John and Lipner,¹ the authors critiqued the American Academy of Dermatology Basic Dermatology Curriculum (BDC) for not providing an adequate scaffolding of nail findings on which dermatology residents can build their knowledge base; however, that criticism belies a misunderstanding of the BDC’s purpose. It was carefully designed to address the needs of undifferentiated medical students and primary care learners based on needs assessments from practicing primary care physicians and experienced dermatology educators.^2,3 Given the limited amount of time to teach, a basic curriculum must focus on the most high-yield items. The BDC work group developed goals and objectives based on needs assessments for primary care practice with 38 core dermatology diagnoses, including 3 diagnoses with important nail findings: onychomycosis, melanoma, and psoriasis. Much repetition is built into the BDC, and the same diagnosis is used in multiple cases in different modules to encourage retention of information. Therefore, “analysis of nail-related content” should focus on diagnoses rather than cases, and for each diagnosis, note whether the nail findings are a pertinent negative or pertinent positive. In cases of the other 35 diagnoses covered in the BDC, nail findings are omitted for space because they are not relevant (eg, in cases of seborrheic dermatitis or rosacea). Normal nail findings are not pertinent negatives for most diagnoses in the BDC, except in cases with diagnoses for which psoriasis is in the differential, such as nummular dermatitis or pityriasis rosea.

Furthermore, a true analysis of the needs of medical students and primary care learners with regard to nail findings would begin with a needs assessment of the most common nail conditions evaluated in the primary care and urgent care settings. Ingrown nails, paronychia, onychomycosis, and subungual hematomas and other nail traumas are the most common nail conditions encountered in primary care and urgent care,^4-10 but John and Lipner¹ failed to perform analysis or needs assessment based on the incidence of nail diagnoses in these settings.

Other sources for medical students and primary care residents include excellent introductions to nail findings. The newly revised skin chapter of Bates’ Guide to Physical Examination and History Taking¹¹ includes updated photographs of common nail findings and discusses the importance of examining nails in the full-body skin examination. Additionally, Clinical Dermatology: A Color Guide to Diagnosis and Therapy,¹²Lookingbill and Marks’ Principles of Dermatology,¹³ and The Color Atlas and Synopsis of Family Medicine¹⁴ cover nail disease beautifully for medical students and primary care learners. The BDC was never meant to supplant these bountiful resources.

The authors referred to lack of confidence in nail diagnoses among dermatology residents,¹ which is a very real problem that must be addressed by dermatology residency programs. The BDC is not the proper vehicle for training dermatology residents about these conditions; that is the responsibility and challenge of our dermatology residency programs. The authors also suggested teaching how to perform nail biopsies in the BDC.¹ It not reasonable to expect that our primary care colleagues will be performing nail biopsies. A more appropriate level of expectation is that they would know when to refer patients to dermatology; for example, they should know that a pigmented streak on a single nail that is expanding is an indication for referral to a dermatologist.

If the authors or others were to propose an additional nail module to the BDC work group, they would need to include an analysis of the literature regarding the incidence of nail disease seen in primary care and urgent care settings rather than the nail conditions seen by referral bias experienced by consulting dermatologists. The analysis would be worth considering and worthy of the goodwill engendered by the creation of the BDC in the first place.

Sincerely,

Patrick E. McCleskey, MD

From the Department of Dermatology, Kaiser Permanente Oakland Medical Center, California.

Dr. McCleskey previously served as Chair of the American Academy of Dermatology Basic Dermatology Curriculum Work Group (2013-2017) .

Correspondence: Patrick E. McCleskey, MD, 3701 Broadway, 4th Floor, Oakland, CA 94611 ([email protected]).
 

References

1. John JJ, Lipner SR. Analysis of nail-related content in the basic dermatology curriculum. Cutis. 2019;103:214-216.

2. Hansra NK, O’Sullivan P, Chen CL, et al. Medical school dermatology curriculum: are we adequately preparing primary care physicians? J Am Acad Dermatol. 2009;61:23-29.

3. McCleskey PE, Gilson RT, Devillez R. Medical student core curriculum in dermatology survey. J Am Acad Dermatol. 2009;61:30-35.

4. Vierhoeven EWM, Kraaimaat FW, van Wheel C, et al. Skin diseases in family medicine: prevalence and health care use. Ann Fam Med. 2008;6:349-354.

5. Fleisher AB, Herbert CR, Feldman SR, et al. Diagnosis of skin disease by non-dermatologists. Am J Manag Care. 2000;6;1149-1156.

6. Akbas A, Kilinc F, Yakut HI, et al. Nail disorders in children, a clinical study. Our Dermatol Online. 2016;7:149-154.

7. Nadkarni A, Domeisen N, Hill D, et al. The most common dermatology diagnoses in the emergency department. J Am Acad Dermatol. 2016;75:1261-1262.

8. Baibergenova A, Shear NH. Skin conditions that bring patients to emergency departments. Arch Dermatol. 2011;147:118-120.

9. Wang E, Lim BL, Than KY. Dermatological conditions presenting at an emergency department in Singapore. Singapore Med J. 2009;50:881-884.

10. Lai-Kwon J, Weiland TJ, Chong AH, et al. Which dermatological conditions present to an emergency department in Australia? Emerg Med Int. 2014;2014:463026.

11. McCleskey PE. The skin, hair, and nails. In: Bickley L, ed. Bates’ Guide to Physical Examination and History Taking. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017:173-214.

12. Habif TP. Nail diseases. In: Habif TP, ed. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 6th ed. China: Elsevier; 2016:960-985.

13. Marks JG, Miller JJ. Nail disorders. In: Marks JG, Miller JJ, eds. Lookingbill and Marks’ Principles of Dermatology. 6th ed. China: Elsevier; 2019:277-282.

14. Mayeaux EJ Jr, Williams J. Hair and nail conditions. In: Usatine RP, Smith MA, Mayeaux EJ Jr, et al. The Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill Education; 2019.

Author Response

I thank Dr. McCleskey for his interest in our article. Although I acknowledge that the Basic Dermatology Curriculum (BDC) serves as an introduction to dermatology for medical students and primary care physicians, I disagree that the current curriculum should be limited to only 3 diagnoses with important nail findings—onychomycosis, melanoma, and psoriasis—and exclude other common and potentially fatal nail diseases.

To characterize the overall nail burden of ambulatory care visits in the United States, data from the National Ambulatory Medical Care Survey from 2007 to 2016 were analyzed and there were more than 20 million outpatient visits for nail concerns during this period; furthermore, although many patients were seen by dermatologists, a considerable number were seen by pediatricians and general practitioners (Lipner SR, Hancock J, Fleischer AB Jr; unpublished data; July 2019). These findings underscore the importance of educating medical students and primary care physicians on the diagnosis and appropriate referral of patients with nail diseases.

Some limited information on nail unit melanomas is included in the BDC, but it is essential that medical students and general practitioners be educated about early diagnosis of squamous cell carcinomas and melanomas of the nail unit, which may help avoid unnecessary amputations and decrease mortality.¹ Unfortunately, the vast majority of nail unit melanomas are diagnosed at stage II or later, which has been partially attributed to clinical knowledge gaps in the understanding of nail disease.²

Several studies have shown that many physicians fail to examine their patients’ nails during physical examinations, either due to concealment with nail polish or lack of clinical awareness. In a survey-based study analyzing patients’ awareness of longitudinal melanonychia and worrisome signs of nail unit melanoma, only 12% of patients (43/363) stated that their dermatologist or internist specifically asked them about nail changes.³ Furthermore, in another survey-based study of nail examinations at a free cancer screening by the American Academy of Dermatology, more than half of female participants (47/87 [54%]) stated that they were wearing nail polish at the time of screening.^4,5 Therefore, examinations of the nails were not performed as part of the total-body skin examination.

In summary, nail diseases are an important concern in clinical practice with aesthetic and functional consequences. There is a strong need to emphasize the importance of nail examinations for diagnostic purposes and to incorporate more expansive nail-related content into the BDC, which can result in longer and more functional lives for our patients.

Sincerely,

Shari R. Lipner, MD, PhD
 

From the Department of Dermatology, Weill Cornell Medicine, New York, New York.

The author reports no conflict of interest.

References

1. Lipner SR. Ulcerated nodule of the fingernail. JAMA. 2018;319:713.

2. Tan KB, Moncrieff M, Thompson JF, et al. Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential pitfalls in diagnosis, and guidelines for histologic reporting. Am J Surg Pathol. 2007;31:1902-1912.

3. Halteh P, Scher R, Artis A, et al. Assessment of patient knowledge of longitudinal melanonychia: a survey study of patients in outpatient clinics. Skin Appendage Disord. 2017;2:156-161.

4. Ko D, Lipner SR. A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening. J Am Acad Dermatol. 2018;79:975-978.

5. Ko D, Lipner SR. Comment on: “The first 30 years of the American Academy of Dermatology skin cancer screening program: 1985-2014.” J Am Acad Dermatol. 2019;80:e23.

To the Editor:

In the April 2019 Cutis article by John and Lipner,¹ the authors critiqued the American Academy of Dermatology Basic Dermatology Curriculum (BDC) for not providing an adequate scaffolding of nail findings on which dermatology residents can build their knowledge base; however, that criticism belies a misunderstanding of the BDC’s purpose. It was carefully designed to address the needs of undifferentiated medical students and primary care learners based on needs assessments from practicing primary care physicians and experienced dermatology educators.^2,3 Given the limited amount of time to teach, a basic curriculum must focus on the most high-yield items. The BDC work group developed goals and objectives based on needs assessments for primary care practice with 38 core dermatology diagnoses, including 3 diagnoses with important nail findings: onychomycosis, melanoma, and psoriasis. Much repetition is built into the BDC, and the same diagnosis is used in multiple cases in different modules to encourage retention of information. Therefore, “analysis of nail-related content” should focus on diagnoses rather than cases, and for each diagnosis, note whether the nail findings are a pertinent negative or pertinent positive. In cases of the other 35 diagnoses covered in the BDC, nail findings are omitted for space because they are not relevant (eg, in cases of seborrheic dermatitis or rosacea). Normal nail findings are not pertinent negatives for most diagnoses in the BDC, except in cases with diagnoses for which psoriasis is in the differential, such as nummular dermatitis or pityriasis rosea.

Furthermore, a true analysis of the needs of medical students and primary care learners with regard to nail findings would begin with a needs assessment of the most common nail conditions evaluated in the primary care and urgent care settings. Ingrown nails, paronychia, onychomycosis, and subungual hematomas and other nail traumas are the most common nail conditions encountered in primary care and urgent care,^4-10 but John and Lipner¹ failed to perform analysis or needs assessment based on the incidence of nail diagnoses in these settings.

Other sources for medical students and primary care residents include excellent introductions to nail findings. The newly revised skin chapter of Bates’ Guide to Physical Examination and History Taking¹¹ includes updated photographs of common nail findings and discusses the importance of examining nails in the full-body skin examination. Additionally, Clinical Dermatology: A Color Guide to Diagnosis and Therapy,¹²Lookingbill and Marks’ Principles of Dermatology,¹³ and The Color Atlas and Synopsis of Family Medicine¹⁴ cover nail disease beautifully for medical students and primary care learners. The BDC was never meant to supplant these bountiful resources.

The authors referred to lack of confidence in nail diagnoses among dermatology residents,¹ which is a very real problem that must be addressed by dermatology residency programs. The BDC is not the proper vehicle for training dermatology residents about these conditions; that is the responsibility and challenge of our dermatology residency programs. The authors also suggested teaching how to perform nail biopsies in the BDC.¹ It not reasonable to expect that our primary care colleagues will be performing nail biopsies. A more appropriate level of expectation is that they would know when to refer patients to dermatology; for example, they should know that a pigmented streak on a single nail that is expanding is an indication for referral to a dermatologist.

If the authors or others were to propose an additional nail module to the BDC work group, they would need to include an analysis of the literature regarding the incidence of nail disease seen in primary care and urgent care settings rather than the nail conditions seen by referral bias experienced by consulting dermatologists. The analysis would be worth considering and worthy of the goodwill engendered by the creation of the BDC in the first place.

Sincerely,

Patrick E. McCleskey, MD

From the Department of Dermatology, Kaiser Permanente Oakland Medical Center, California.

Dr. McCleskey previously served as Chair of the American Academy of Dermatology Basic Dermatology Curriculum Work Group (2013-2017) .

Correspondence: Patrick E. McCleskey, MD, 3701 Broadway, 4th Floor, Oakland, CA 94611 ([email protected]).
 

References

1. John JJ, Lipner SR. Analysis of nail-related content in the basic dermatology curriculum. Cutis. 2019;103:214-216.

2. Hansra NK, O’Sullivan P, Chen CL, et al. Medical school dermatology curriculum: are we adequately preparing primary care physicians? J Am Acad Dermatol. 2009;61:23-29.

3. McCleskey PE, Gilson RT, Devillez R. Medical student core curriculum in dermatology survey. J Am Acad Dermatol. 2009;61:30-35.

4. Vierhoeven EWM, Kraaimaat FW, van Wheel C, et al. Skin diseases in family medicine: prevalence and health care use. Ann Fam Med. 2008;6:349-354.

5. Fleisher AB, Herbert CR, Feldman SR, et al. Diagnosis of skin disease by non-dermatologists. Am J Manag Care. 2000;6;1149-1156.

6. Akbas A, Kilinc F, Yakut HI, et al. Nail disorders in children, a clinical study. Our Dermatol Online. 2016;7:149-154.

7. Nadkarni A, Domeisen N, Hill D, et al. The most common dermatology diagnoses in the emergency department. J Am Acad Dermatol. 2016;75:1261-1262.

8. Baibergenova A, Shear NH. Skin conditions that bring patients to emergency departments. Arch Dermatol. 2011;147:118-120.

9. Wang E, Lim BL, Than KY. Dermatological conditions presenting at an emergency department in Singapore. Singapore Med J. 2009;50:881-884.

10. Lai-Kwon J, Weiland TJ, Chong AH, et al. Which dermatological conditions present to an emergency department in Australia? Emerg Med Int. 2014;2014:463026.

11. McCleskey PE. The skin, hair, and nails. In: Bickley L, ed. Bates’ Guide to Physical Examination and History Taking. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017:173-214.

12. Habif TP. Nail diseases. In: Habif TP, ed. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 6th ed. China: Elsevier; 2016:960-985.

13. Marks JG, Miller JJ. Nail disorders. In: Marks JG, Miller JJ, eds. Lookingbill and Marks’ Principles of Dermatology. 6th ed. China: Elsevier; 2019:277-282.

14. Mayeaux EJ Jr, Williams J. Hair and nail conditions. In: Usatine RP, Smith MA, Mayeaux EJ Jr, et al. The Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill Education; 2019.

Author Response

I thank Dr. McCleskey for his interest in our article. Although I acknowledge that the Basic Dermatology Curriculum (BDC) serves as an introduction to dermatology for medical students and primary care physicians, I disagree that the current curriculum should be limited to only 3 diagnoses with important nail findings—onychomycosis, melanoma, and psoriasis—and exclude other common and potentially fatal nail diseases.

To characterize the overall nail burden of ambulatory care visits in the United States, data from the National Ambulatory Medical Care Survey from 2007 to 2016 were analyzed and there were more than 20 million outpatient visits for nail concerns during this period; furthermore, although many patients were seen by dermatologists, a considerable number were seen by pediatricians and general practitioners (Lipner SR, Hancock J, Fleischer AB Jr; unpublished data; July 2019). These findings underscore the importance of educating medical students and primary care physicians on the diagnosis and appropriate referral of patients with nail diseases.

Some limited information on nail unit melanomas is included in the BDC, but it is essential that medical students and general practitioners be educated about early diagnosis of squamous cell carcinomas and melanomas of the nail unit, which may help avoid unnecessary amputations and decrease mortality.¹ Unfortunately, the vast majority of nail unit melanomas are diagnosed at stage II or later, which has been partially attributed to clinical knowledge gaps in the understanding of nail disease.²

Several studies have shown that many physicians fail to examine their patients’ nails during physical examinations, either due to concealment with nail polish or lack of clinical awareness. In a survey-based study analyzing patients’ awareness of longitudinal melanonychia and worrisome signs of nail unit melanoma, only 12% of patients (43/363) stated that their dermatologist or internist specifically asked them about nail changes.³ Furthermore, in another survey-based study of nail examinations at a free cancer screening by the American Academy of Dermatology, more than half of female participants (47/87 [54%]) stated that they were wearing nail polish at the time of screening.^4,5 Therefore, examinations of the nails were not performed as part of the total-body skin examination.

In summary, nail diseases are an important concern in clinical practice with aesthetic and functional consequences. There is a strong need to emphasize the importance of nail examinations for diagnostic purposes and to incorporate more expansive nail-related content into the BDC, which can result in longer and more functional lives for our patients.

Sincerely,

Shari R. Lipner, MD, PhD
 

From the Department of Dermatology, Weill Cornell Medicine, New York, New York.

The author reports no conflict of interest.

References

1. Lipner SR. Ulcerated nodule of the fingernail. JAMA. 2018;319:713.

2. Tan KB, Moncrieff M, Thompson JF, et al. Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential pitfalls in diagnosis, and guidelines for histologic reporting. Am J Surg Pathol. 2007;31:1902-1912.

3. Halteh P, Scher R, Artis A, et al. Assessment of patient knowledge of longitudinal melanonychia: a survey study of patients in outpatient clinics. Skin Appendage Disord. 2017;2:156-161.

4. Ko D, Lipner SR. A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening. J Am Acad Dermatol. 2018;79:975-978.

5. Ko D, Lipner SR. Comment on: “The first 30 years of the American Academy of Dermatology skin cancer screening program: 1985-2014.” J Am Acad Dermatol. 2019;80:e23.

To the Editor:

In the April 2019 Cutis article by John and Lipner,¹ the authors critiqued the American Academy of Dermatology Basic Dermatology Curriculum (BDC) for not providing an adequate scaffolding of nail findings on which dermatology residents can build their knowledge base; however, that criticism belies a misunderstanding of the BDC’s purpose. It was carefully designed to address the needs of undifferentiated medical students and primary care learners based on needs assessments from practicing primary care physicians and experienced dermatology educators.^2,3 Given the limited amount of time to teach, a basic curriculum must focus on the most high-yield items. The BDC work group developed goals and objectives based on needs assessments for primary care practice with 38 core dermatology diagnoses, including 3 diagnoses with important nail findings: onychomycosis, melanoma, and psoriasis. Much repetition is built into the BDC, and the same diagnosis is used in multiple cases in different modules to encourage retention of information. Therefore, “analysis of nail-related content” should focus on diagnoses rather than cases, and for each diagnosis, note whether the nail findings are a pertinent negative or pertinent positive. In cases of the other 35 diagnoses covered in the BDC, nail findings are omitted for space because they are not relevant (eg, in cases of seborrheic dermatitis or rosacea). Normal nail findings are not pertinent negatives for most diagnoses in the BDC, except in cases with diagnoses for which psoriasis is in the differential, such as nummular dermatitis or pityriasis rosea.

Furthermore, a true analysis of the needs of medical students and primary care learners with regard to nail findings would begin with a needs assessment of the most common nail conditions evaluated in the primary care and urgent care settings. Ingrown nails, paronychia, onychomycosis, and subungual hematomas and other nail traumas are the most common nail conditions encountered in primary care and urgent care,^4-10 but John and Lipner¹ failed to perform analysis or needs assessment based on the incidence of nail diagnoses in these settings.

Other sources for medical students and primary care residents include excellent introductions to nail findings. The newly revised skin chapter of Bates’ Guide to Physical Examination and History Taking¹¹ includes updated photographs of common nail findings and discusses the importance of examining nails in the full-body skin examination. Additionally, Clinical Dermatology: A Color Guide to Diagnosis and Therapy,¹²Lookingbill and Marks’ Principles of Dermatology,¹³ and The Color Atlas and Synopsis of Family Medicine¹⁴ cover nail disease beautifully for medical students and primary care learners. The BDC was never meant to supplant these bountiful resources.

The authors referred to lack of confidence in nail diagnoses among dermatology residents,¹ which is a very real problem that must be addressed by dermatology residency programs. The BDC is not the proper vehicle for training dermatology residents about these conditions; that is the responsibility and challenge of our dermatology residency programs. The authors also suggested teaching how to perform nail biopsies in the BDC.¹ It not reasonable to expect that our primary care colleagues will be performing nail biopsies. A more appropriate level of expectation is that they would know when to refer patients to dermatology; for example, they should know that a pigmented streak on a single nail that is expanding is an indication for referral to a dermatologist.

If the authors or others were to propose an additional nail module to the BDC work group, they would need to include an analysis of the literature regarding the incidence of nail disease seen in primary care and urgent care settings rather than the nail conditions seen by referral bias experienced by consulting dermatologists. The analysis would be worth considering and worthy of the goodwill engendered by the creation of the BDC in the first place.

Sincerely,

Patrick E. McCleskey, MD

From the Department of Dermatology, Kaiser Permanente Oakland Medical Center, California.

Dr. McCleskey previously served as Chair of the American Academy of Dermatology Basic Dermatology Curriculum Work Group (2013-2017) .

Correspondence: Patrick E. McCleskey, MD, 3701 Broadway, 4th Floor, Oakland, CA 94611 ([email protected]).
 

References

1. John JJ, Lipner SR. Analysis of nail-related content in the basic dermatology curriculum. Cutis. 2019;103:214-216.

2. Hansra NK, O’Sullivan P, Chen CL, et al. Medical school dermatology curriculum: are we adequately preparing primary care physicians? J Am Acad Dermatol. 2009;61:23-29.

3. McCleskey PE, Gilson RT, Devillez R. Medical student core curriculum in dermatology survey. J Am Acad Dermatol. 2009;61:30-35.

4. Vierhoeven EWM, Kraaimaat FW, van Wheel C, et al. Skin diseases in family medicine: prevalence and health care use. Ann Fam Med. 2008;6:349-354.

5. Fleisher AB, Herbert CR, Feldman SR, et al. Diagnosis of skin disease by non-dermatologists. Am J Manag Care. 2000;6;1149-1156.

6. Akbas A, Kilinc F, Yakut HI, et al. Nail disorders in children, a clinical study. Our Dermatol Online. 2016;7:149-154.

7. Nadkarni A, Domeisen N, Hill D, et al. The most common dermatology diagnoses in the emergency department. J Am Acad Dermatol. 2016;75:1261-1262.

8. Baibergenova A, Shear NH. Skin conditions that bring patients to emergency departments. Arch Dermatol. 2011;147:118-120.

9. Wang E, Lim BL, Than KY. Dermatological conditions presenting at an emergency department in Singapore. Singapore Med J. 2009;50:881-884.

10. Lai-Kwon J, Weiland TJ, Chong AH, et al. Which dermatological conditions present to an emergency department in Australia? Emerg Med Int. 2014;2014:463026.

11. McCleskey PE. The skin, hair, and nails. In: Bickley L, ed. Bates’ Guide to Physical Examination and History Taking. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017:173-214.

12. Habif TP. Nail diseases. In: Habif TP, ed. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 6th ed. China: Elsevier; 2016:960-985.

13. Marks JG, Miller JJ. Nail disorders. In: Marks JG, Miller JJ, eds. Lookingbill and Marks’ Principles of Dermatology. 6th ed. China: Elsevier; 2019:277-282.

14. Mayeaux EJ Jr, Williams J. Hair and nail conditions. In: Usatine RP, Smith MA, Mayeaux EJ Jr, et al. The Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill Education; 2019.

Author Response

I thank Dr. McCleskey for his interest in our article. Although I acknowledge that the Basic Dermatology Curriculum (BDC) serves as an introduction to dermatology for medical students and primary care physicians, I disagree that the current curriculum should be limited to only 3 diagnoses with important nail findings—onychomycosis, melanoma, and psoriasis—and exclude other common and potentially fatal nail diseases.

To characterize the overall nail burden of ambulatory care visits in the United States, data from the National Ambulatory Medical Care Survey from 2007 to 2016 were analyzed and there were more than 20 million outpatient visits for nail concerns during this period; furthermore, although many patients were seen by dermatologists, a considerable number were seen by pediatricians and general practitioners (Lipner SR, Hancock J, Fleischer AB Jr; unpublished data; July 2019). These findings underscore the importance of educating medical students and primary care physicians on the diagnosis and appropriate referral of patients with nail diseases.

Some limited information on nail unit melanomas is included in the BDC, but it is essential that medical students and general practitioners be educated about early diagnosis of squamous cell carcinomas and melanomas of the nail unit, which may help avoid unnecessary amputations and decrease mortality.¹ Unfortunately, the vast majority of nail unit melanomas are diagnosed at stage II or later, which has been partially attributed to clinical knowledge gaps in the understanding of nail disease.²

Several studies have shown that many physicians fail to examine their patients’ nails during physical examinations, either due to concealment with nail polish or lack of clinical awareness. In a survey-based study analyzing patients’ awareness of longitudinal melanonychia and worrisome signs of nail unit melanoma, only 12% of patients (43/363) stated that their dermatologist or internist specifically asked them about nail changes.³ Furthermore, in another survey-based study of nail examinations at a free cancer screening by the American Academy of Dermatology, more than half of female participants (47/87 [54%]) stated that they were wearing nail polish at the time of screening.^4,5 Therefore, examinations of the nails were not performed as part of the total-body skin examination.

In summary, nail diseases are an important concern in clinical practice with aesthetic and functional consequences. There is a strong need to emphasize the importance of nail examinations for diagnostic purposes and to incorporate more expansive nail-related content into the BDC, which can result in longer and more functional lives for our patients.

Sincerely,

Shari R. Lipner, MD, PhD
 

From the Department of Dermatology, Weill Cornell Medicine, New York, New York.

The author reports no conflict of interest.

References

1. Lipner SR. Ulcerated nodule of the fingernail. JAMA. 2018;319:713.

2. Tan KB, Moncrieff M, Thompson JF, et al. Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential pitfalls in diagnosis, and guidelines for histologic reporting. Am J Surg Pathol. 2007;31:1902-1912.

3. Halteh P, Scher R, Artis A, et al. Assessment of patient knowledge of longitudinal melanonychia: a survey study of patients in outpatient clinics. Skin Appendage Disord. 2017;2:156-161.

4. Ko D, Lipner SR. A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening. J Am Acad Dermatol. 2018;79:975-978.

5. Ko D, Lipner SR. Comment on: “The first 30 years of the American Academy of Dermatology skin cancer screening program: 1985-2014.” J Am Acad Dermatol. 2019;80:e23.