ORLANDO – Is painless photodynamic therapy possible? Maybe, said James Spencer, MD, at the Orlando Dermatology Aesthetic and Clinical Conference.

Dr. Spencer, who practices in St. Petersburg, Fla., and is cochair of the conference, gave attendees a roundup of what’s new in adjuncts and delivery methods for photodynamic therapy (PDT). Among the updates is the promise of PDT delivered by means of an ultrashort incubation time of 10-20 minutes, followed by prolonged blue light exposure time of 1 hour. “The idea is that the enzymatic conversion is occurring during the light exposure,” Dr. Spencer said, adding that reports of this approach are mostly anecdotal.

A variation on the ultrashort incubation adds microneedling, he said. In one recent study, 33 patients who had facial actinic keratoses (AKs) were randomized to 10 or 20 minutes of incubation after application of aminolevulinic acid (ALA), followed by 1,000 seconds of exposure to blue light. However, in this split-face study, participants each had one side of their faces treated with microneedling and the other half with a sham treatment before ALA was applied.


Those who had the shorter incubation time had 43% of AKs cleared on the side that received microneedling, compared with 38% on the sham side. For those who received 20 minutes of ALA incubation, rates were higher, with 76% AK clearance on the treated side and 58% on the sham side. “Patients reported that the procedure was virtually painless on both sides,” said Dr. Spencer.

Though the addition of microneedling to PDT is a newer trend, there’s one that’s been a mainstay in Europe for some time: daylight PDT. He cited a review article published in 2016, which identified 17 studies on the use of daylight PDT (Dermatol Surg. 2016 Mar;42[3]:286-95).

Advantages of daylight PDT, he said, include less time in the office for patients and “supposedly less pain.” European protocols vary, but most use methyl aminolevulinate, which he said is a “little more lipophilic than ALA,” with incubation times ranging from 0 to 30 minutes. Exposure time is also variable, but will usually range from 1.5 to 2.5 hours. Most patients receive just one treatment, but some protocols will include up to three treatments.

Overall, studies show a range from 46% to almost 90% complete response rates when AKs are treated with daylight PDT. One study that looked at daylight PDT for small basal cell carcinomas showed that 94% of patients had clinical clearance of their lesions after two treatment sessions; however, the recurrence rate at 12 months post therapy was 21%, Dr. Spencer said.


He shared results of a recent head-to-head study of conventional and daylight PDT; conducted in Greece, the study enrolled patients with “high sun exposure” and used a split-face design.

Of the 46 patients who received MAL on both sides of their faces, response rates were similar at both 3 and 12 months, with slightly numerically higher clearance rates for conventional versus daylight PDT. The 3-month clearance rate for conventional PDT was 80.6%, compared with 78.0% for daylight PDT. At 12 months, the respective clearance rates were 73.7% and 71.8% (J Eur Acad Dermatol Venereol. 2018 Apr;32[4]:595-600). However, “significantly less pain was reported with daylight PDT,” Dr. Spencer said.

Daylight PDT hasn’t caught on the United States. Physicians have concern about the lack of control of UV dosing, and, he pointed out, “this, of course, is not billable.”

Dr. Spencer reported that he serves on the speakers bureau for Genentech.

koakes@mdedge.com

ORLANDO – Is painless photodynamic therapy possible? Maybe, said James Spencer, MD, at the Orlando Dermatology Aesthetic and Clinical Conference.

Dr. Spencer, who practices in St. Petersburg, Fla., and is cochair of the conference, gave attendees a roundup of what’s new in adjuncts and delivery methods for photodynamic therapy (PDT). Among the updates is the promise of PDT delivered by means of an ultrashort incubation time of 10-20 minutes, followed by prolonged blue light exposure time of 1 hour. “The idea is that the enzymatic conversion is occurring during the light exposure,” Dr. Spencer said, adding that reports of this approach are mostly anecdotal.

A variation on the ultrashort incubation adds microneedling, he said. In one recent study, 33 patients who had facial actinic keratoses (AKs) were randomized to 10 or 20 minutes of incubation after application of aminolevulinic acid (ALA), followed by 1,000 seconds of exposure to blue light. However, in this split-face study, participants each had one side of their faces treated with microneedling and the other half with a sham treatment before ALA was applied.


Those who had the shorter incubation time had 43% of AKs cleared on the side that received microneedling, compared with 38% on the sham side. For those who received 20 minutes of ALA incubation, rates were higher, with 76% AK clearance on the treated side and 58% on the sham side. “Patients reported that the procedure was virtually painless on both sides,” said Dr. Spencer.

Though the addition of microneedling to PDT is a newer trend, there’s one that’s been a mainstay in Europe for some time: daylight PDT. He cited a review article published in 2016, which identified 17 studies on the use of daylight PDT (Dermatol Surg. 2016 Mar;42[3]:286-95).

Advantages of daylight PDT, he said, include less time in the office for patients and “supposedly less pain.” European protocols vary, but most use methyl aminolevulinate, which he said is a “little more lipophilic than ALA,” with incubation times ranging from 0 to 30 minutes. Exposure time is also variable, but will usually range from 1.5 to 2.5 hours. Most patients receive just one treatment, but some protocols will include up to three treatments.

Overall, studies show a range from 46% to almost 90% complete response rates when AKs are treated with daylight PDT. One study that looked at daylight PDT for small basal cell carcinomas showed that 94% of patients had clinical clearance of their lesions after two treatment sessions; however, the recurrence rate at 12 months post therapy was 21%, Dr. Spencer said.


He shared results of a recent head-to-head study of conventional and daylight PDT; conducted in Greece, the study enrolled patients with “high sun exposure” and used a split-face design.

Of the 46 patients who received MAL on both sides of their faces, response rates were similar at both 3 and 12 months, with slightly numerically higher clearance rates for conventional versus daylight PDT. The 3-month clearance rate for conventional PDT was 80.6%, compared with 78.0% for daylight PDT. At 12 months, the respective clearance rates were 73.7% and 71.8% (J Eur Acad Dermatol Venereol. 2018 Apr;32[4]:595-600). However, “significantly less pain was reported with daylight PDT,” Dr. Spencer said.

Daylight PDT hasn’t caught on the United States. Physicians have concern about the lack of control of UV dosing, and, he pointed out, “this, of course, is not billable.”

Dr. Spencer reported that he serves on the speakers bureau for Genentech.

koakes@mdedge.com

ORLANDO – Is painless photodynamic therapy possible? Maybe, said James Spencer, MD, at the Orlando Dermatology Aesthetic and Clinical Conference.

Dr. Spencer, who practices in St. Petersburg, Fla., and is cochair of the conference, gave attendees a roundup of what’s new in adjuncts and delivery methods for photodynamic therapy (PDT). Among the updates is the promise of PDT delivered by means of an ultrashort incubation time of 10-20 minutes, followed by prolonged blue light exposure time of 1 hour. “The idea is that the enzymatic conversion is occurring during the light exposure,” Dr. Spencer said, adding that reports of this approach are mostly anecdotal.

A variation on the ultrashort incubation adds microneedling, he said. In one recent study, 33 patients who had facial actinic keratoses (AKs) were randomized to 10 or 20 minutes of incubation after application of aminolevulinic acid (ALA), followed by 1,000 seconds of exposure to blue light. However, in this split-face study, participants each had one side of their faces treated with microneedling and the other half with a sham treatment before ALA was applied.


Those who had the shorter incubation time had 43% of AKs cleared on the side that received microneedling, compared with 38% on the sham side. For those who received 20 minutes of ALA incubation, rates were higher, with 76% AK clearance on the treated side and 58% on the sham side. “Patients reported that the procedure was virtually painless on both sides,” said Dr. Spencer.

Though the addition of microneedling to PDT is a newer trend, there’s one that’s been a mainstay in Europe for some time: daylight PDT. He cited a review article published in 2016, which identified 17 studies on the use of daylight PDT (Dermatol Surg. 2016 Mar;42[3]:286-95).

Advantages of daylight PDT, he said, include less time in the office for patients and “supposedly less pain.” European protocols vary, but most use methyl aminolevulinate, which he said is a “little more lipophilic than ALA,” with incubation times ranging from 0 to 30 minutes. Exposure time is also variable, but will usually range from 1.5 to 2.5 hours. Most patients receive just one treatment, but some protocols will include up to three treatments.

Overall, studies show a range from 46% to almost 90% complete response rates when AKs are treated with daylight PDT. One study that looked at daylight PDT for small basal cell carcinomas showed that 94% of patients had clinical clearance of their lesions after two treatment sessions; however, the recurrence rate at 12 months post therapy was 21%, Dr. Spencer said.


He shared results of a recent head-to-head study of conventional and daylight PDT; conducted in Greece, the study enrolled patients with “high sun exposure” and used a split-face design.

Of the 46 patients who received MAL on both sides of their faces, response rates were similar at both 3 and 12 months, with slightly numerically higher clearance rates for conventional versus daylight PDT. The 3-month clearance rate for conventional PDT was 80.6%, compared with 78.0% for daylight PDT. At 12 months, the respective clearance rates were 73.7% and 71.8% (J Eur Acad Dermatol Venereol. 2018 Apr;32[4]:595-600). However, “significantly less pain was reported with daylight PDT,” Dr. Spencer said.

Daylight PDT hasn’t caught on the United States. Physicians have concern about the lack of control of UV dosing, and, he pointed out, “this, of course, is not billable.”

Dr. Spencer reported that he serves on the speakers bureau for Genentech.

koakes@mdedge.com

Helping patients with atrial fibrillation understand what they can realistically expect from ablationby way of benefit as well as awareness of the warning signals heralding serious late complications. Also today, a theory of relativity for rosacea patients, long-term opioid use is substantial in elderly adults prior to total joint replacement, and pediatricians get more guidance to be proactive on the use of e-cigarettes among youth.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Helping patients with atrial fibrillation understand what they can realistically expect from ablationby way of benefit as well as awareness of the warning signals heralding serious late complications. Also today, a theory of relativity for rosacea patients, long-term opioid use is substantial in elderly adults prior to total joint replacement, and pediatricians get more guidance to be proactive on the use of e-cigarettes among youth.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Helping patients with atrial fibrillation understand what they can realistically expect from ablationby way of benefit as well as awareness of the warning signals heralding serious late complications. Also today, a theory of relativity for rosacea patients, long-term opioid use is substantial in elderly adults prior to total joint replacement, and pediatricians get more guidance to be proactive on the use of e-cigarettes among youth.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Although many families still resort to spanking when “No!” isn’t working, pediatricians and child psychologists are unified in their condemnation of physical discipline. However, when it comes to timeout, child behavior specialists have failed to reach consensus. In a recent Washington Post article, Claire Gillespie quotes several experts who feel that timeout is ineffective at best and damaging and dangerous at its worst. (Timeouts are a dated and ineffective parenting strategy. So what’s a good alternative? Washington Post, Nov. 29, 2019.)

Comstock/Thinkstock

How do you feel about timeouts? Do you think they are effective? Do you think that brief periods of isolation in a home setting will increase a child’s anxiety? Will the threat of isolation create long-lasting psychological harm? Or do you believe that properly done timeout can be a safe consequence when a child misbehaves?

The disagreement seems to be another one of those issues of apples and oranges. Do I believe that solitary confinement in a prison or chained to a metal cot in the basement of mentally deranged and obsessive parent will leave psychological scars? Of course I do. But, do I believe that a few minutes alone in a child’s own room in a home in which her parents frequently express their affection will cause any harm? Not for a moment. It’s not so much where the child is. It’s where she isn’t. Of course, she doesn’t want to be isolated from the family and that sends a powerful but not harmful message. A big hug and a kiss at the end of the timeout wipes the slate clear.

Some critics believe that timeout should be condemned because it is a punishment. Here again, it’s a case of semantics. Punishments in my mind are inhumane, “a pound of flesh” or “an eye for an eye” response. A well-done timeout is a harmless consequence and one that particularly makes sense when the misbehavior has been or is creating an unpleasant atmosphere in the family.

Other critics will claim that timeouts aren’t an effective deterrent. Correct! They aren’t meant to be a deterrent. A detailed discussion, more likely a lecture, about the misbehavior before and even immediately after a timeout is a waste of time. If timeouts are a deterrent it is because of their safety. Parents will be more likely to use them as a consequence, and most importantly to follow up on their threats. A parent whose words can be believed is his or her own best deterrent.

Finally, many parents who have tried timeouts will claim that they don’t work. This is true if they were talking about deterrent value. Maybe the timeouts have been too long or too short. About 30-60 seconds after the child stops crying may be enough. However, if the parents mean that the child wouldn’t stay in timeout in his room, then they have not taken the difficult final step. If the parent doesn’t have the stamina to keep walking the child back into his room, then it is time to put a latch on the door. Whoops. ... I may have lost some of you who up to this point have been nodding agreement along with my rationale. I know, I know it smacks of prison. It may be used only once or twice, but it will remain as a tangible reminder that sometimes enough is enough. Frequent trips into the room to help the child self-calm make it clear he hasn’t been abandoned.

It’s hard to provide a fully nuanced argument for including timeout in the consequence arsenal in 500 words. I’m eager to hear how you feel on the subject. I can take the heat.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.

Although many families still resort to spanking when “No!” isn’t working, pediatricians and child psychologists are unified in their condemnation of physical discipline. However, when it comes to timeout, child behavior specialists have failed to reach consensus. In a recent Washington Post article, Claire Gillespie quotes several experts who feel that timeout is ineffective at best and damaging and dangerous at its worst. (Timeouts are a dated and ineffective parenting strategy. So what’s a good alternative? Washington Post, Nov. 29, 2019.)

Comstock/Thinkstock

How do you feel about timeouts? Do you think they are effective? Do you think that brief periods of isolation in a home setting will increase a child’s anxiety? Will the threat of isolation create long-lasting psychological harm? Or do you believe that properly done timeout can be a safe consequence when a child misbehaves?

The disagreement seems to be another one of those issues of apples and oranges. Do I believe that solitary confinement in a prison or chained to a metal cot in the basement of mentally deranged and obsessive parent will leave psychological scars? Of course I do. But, do I believe that a few minutes alone in a child’s own room in a home in which her parents frequently express their affection will cause any harm? Not for a moment. It’s not so much where the child is. It’s where she isn’t. Of course, she doesn’t want to be isolated from the family and that sends a powerful but not harmful message. A big hug and a kiss at the end of the timeout wipes the slate clear.

Some critics believe that timeout should be condemned because it is a punishment. Here again, it’s a case of semantics. Punishments in my mind are inhumane, “a pound of flesh” or “an eye for an eye” response. A well-done timeout is a harmless consequence and one that particularly makes sense when the misbehavior has been or is creating an unpleasant atmosphere in the family.

Other critics will claim that timeouts aren’t an effective deterrent. Correct! They aren’t meant to be a deterrent. A detailed discussion, more likely a lecture, about the misbehavior before and even immediately after a timeout is a waste of time. If timeouts are a deterrent it is because of their safety. Parents will be more likely to use them as a consequence, and most importantly to follow up on their threats. A parent whose words can be believed is his or her own best deterrent.

Finally, many parents who have tried timeouts will claim that they don’t work. This is true if they were talking about deterrent value. Maybe the timeouts have been too long or too short. About 30-60 seconds after the child stops crying may be enough. However, if the parents mean that the child wouldn’t stay in timeout in his room, then they have not taken the difficult final step. If the parent doesn’t have the stamina to keep walking the child back into his room, then it is time to put a latch on the door. Whoops. ... I may have lost some of you who up to this point have been nodding agreement along with my rationale. I know, I know it smacks of prison. It may be used only once or twice, but it will remain as a tangible reminder that sometimes enough is enough. Frequent trips into the room to help the child self-calm make it clear he hasn’t been abandoned.

It’s hard to provide a fully nuanced argument for including timeout in the consequence arsenal in 500 words. I’m eager to hear how you feel on the subject. I can take the heat.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.

Although many families still resort to spanking when “No!” isn’t working, pediatricians and child psychologists are unified in their condemnation of physical discipline. However, when it comes to timeout, child behavior specialists have failed to reach consensus. In a recent Washington Post article, Claire Gillespie quotes several experts who feel that timeout is ineffective at best and damaging and dangerous at its worst. (Timeouts are a dated and ineffective parenting strategy. So what’s a good alternative? Washington Post, Nov. 29, 2019.)

Comstock/Thinkstock

How do you feel about timeouts? Do you think they are effective? Do you think that brief periods of isolation in a home setting will increase a child’s anxiety? Will the threat of isolation create long-lasting psychological harm? Or do you believe that properly done timeout can be a safe consequence when a child misbehaves?

The disagreement seems to be another one of those issues of apples and oranges. Do I believe that solitary confinement in a prison or chained to a metal cot in the basement of mentally deranged and obsessive parent will leave psychological scars? Of course I do. But, do I believe that a few minutes alone in a child’s own room in a home in which her parents frequently express their affection will cause any harm? Not for a moment. It’s not so much where the child is. It’s where she isn’t. Of course, she doesn’t want to be isolated from the family and that sends a powerful but not harmful message. A big hug and a kiss at the end of the timeout wipes the slate clear.

Some critics believe that timeout should be condemned because it is a punishment. Here again, it’s a case of semantics. Punishments in my mind are inhumane, “a pound of flesh” or “an eye for an eye” response. A well-done timeout is a harmless consequence and one that particularly makes sense when the misbehavior has been or is creating an unpleasant atmosphere in the family.

Other critics will claim that timeouts aren’t an effective deterrent. Correct! They aren’t meant to be a deterrent. A detailed discussion, more likely a lecture, about the misbehavior before and even immediately after a timeout is a waste of time. If timeouts are a deterrent it is because of their safety. Parents will be more likely to use them as a consequence, and most importantly to follow up on their threats. A parent whose words can be believed is his or her own best deterrent.

Finally, many parents who have tried timeouts will claim that they don’t work. This is true if they were talking about deterrent value. Maybe the timeouts have been too long or too short. About 30-60 seconds after the child stops crying may be enough. However, if the parents mean that the child wouldn’t stay in timeout in his room, then they have not taken the difficult final step. If the parent doesn’t have the stamina to keep walking the child back into his room, then it is time to put a latch on the door. Whoops. ... I may have lost some of you who up to this point have been nodding agreement along with my rationale. I know, I know it smacks of prison. It may be used only once or twice, but it will remain as a tangible reminder that sometimes enough is enough. Frequent trips into the room to help the child self-calm make it clear he hasn’t been abandoned.

It’s hard to provide a fully nuanced argument for including timeout in the consequence arsenal in 500 words. I’m eager to hear how you feel on the subject. I can take the heat.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

msullivan@mdedge.com

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

msullivan@mdedge.com

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

msullivan@mdedge.com

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

ORLANDO – When you extend your hand to a new patient, and he reflexively wipes his palm before shaking hands, be alert. It’s possible you’re seeing primary hyperhidrosis, a condition that’s both more common and more disabling than once thought.

Koldunov/iStock/Getty Images

“Looking at the biology of sweating, normally, it’s a good thing – we need it to survive. However, hyperhidrosis is too much of a good thing – it’s an excess of what is needed for normal biology,” said Adam Friedman, MD, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.

Recent data, he pointed out, show that hyperhidrosis is more prevalent than previously thought – about 4.8% of individuals may have the condition, with about half having axillary hyperhidrosis. Symptoms peak in early adulthood, with adults aged 18-54 most affected. “These are the prime working years,” he said.

About 2% of teens are affected, and many adults report that symptoms began before they were 12 years old. Hand hyperhidrosis is a factor for computer and electronic device work, sports, and even handling paper and pencils, noted Dr. Friedman, professor of dermatology at George Washington University, Washington.

“Does it affect quality of life? Yes. We have data to support the impact. The adverse impact is actually greater than that of eczema and psoriasis,” he said, adding that patients won’t always bring up their concerns about sweating. “Often, it’s the patient who apologizes for having sweaty palms or who sticks to the paper on the exam table. It’s worth asking these patients if they are bothered by excessive sweating.”
 

Is it hyperhidrosis?

A 2016 paper defined hyperhidrosis as “a condition that involves chronic excessive sweating of the underarms, hands, feet, face, groin, or other bodily areas, which is much more than what is normal, and occurs regardless of temperature, exercise, or situation, and may have an impact on quality of life” (Arch Dermatol Res. 2016 Dec;308[10]:743-9). The amount of sweating can be four to five times that seen in healthy controls.

Other clues that excess sweating might be hyperhidrosis? General hyperhidrosis is a secondary syndrome that can be caused by a variety of conditions including endocrine and metabolic disorders and malignancies. Drugs and toxins can also cause generalized excessive sweating.

Focal hyperhidrosis can be primary idiopathic disease; some neuropathies and certain spinal diseases and spinal cord injury can also cause focal hyperhidrosis, though not usually in the axillary/palmar/plantar distribution seen in primary hyperhidrosis.

Before settling on primary hyperhidrosis, the history and exam should also account for other possibilities in the differential: social anxiety disorder, eccrine nevus, gustatory sweating, Frey syndrome, and impaired evaporation could all account for excess sweating, which is also a postsurgical phenomenon for some patients.

Diagnostic criteria call for “focal, visible, excessive sweating” persisting for at least 6 months with no apparent cause. Additionally, patients must have at least two of the additional following criteria: sweating that is bilateral and symmetric, occurs at least once weekly, impairs daily activities, and starts before age 25 years, as well as a positive family history of hyperhidrosis and cessation of sweating during sleep.

The last point is critical, Dr. Friedman said. “If you sweat a lot at night, it’s not hyperhidrosis!”

Though gravimetric evaluation is used in hyperhidrosis research, the history and exam are really where the diagnosis is made in practice, he noted. The Hyperhidrosis Disease Severity Scale is a brief, useful clinical tool that asks patients to peg the extent to which their sweating interferes with daily life.
 

Topical treatments to try

Topical antiperspirants and other topical agents are a logical place to start and may be required as part of step therapy by insurers. Many patients will already have tried clinical strength over-the-counter antiperspirants containing aluminum zirconium trichlorohydrex, but these products rate low in patient satisfaction among those with primary hyperhidrosis.

Prescription aluminum salts can be compounded to various strengths, with 10%-20% concentration appropriate for axillae and 30%-40% a good strength for palms and soles, according to Dr. Friedman. All of these agents work by precipitating out solids that form a shallow plug in sweat ducts, slowing the flow of perspiration.

Pearls for topical treatment include the need for the product to be on the skin for 6-8 hours overnight. “Remember hyperhidrosis patients do not sweat at night,” so this is the time when the occlusive plugs can form. Then residue can be washed off in the morning, and patients can apply a deodorant. “I remind my patients that antiperspirants are for sweating, and deodorants are for odor,” said Dr. Friedman. These products can damage fabric, and they can be irritating, a problem addressed with low-potency topical steroids.

Topical regimens don’t need to be adjusted for pediatric patients, said Dr. Friedman.

Iontophoresis has been around since the 1950s, is effective, has few side effects, and is considered first-line treatment for severe palmar and plantar hyperhidrosis. But he said there’s one big rub: time. To be effective, patients need 20-30 minutes of application of 15-20 milliamperes of current 3-4 times weekly, not a schedule that works for most patients or practitioners, Dr. Friedman noted.

A treatment recently approved by the Food and Drug Administration for primary axillary hyperhidrosis is a topical anticholinergic, glycopyrronium tosylate, applied with wipes impregnated with glycopyrronium solution. This product significantly outperformed placebo in two clinical trials, with up to 64% of users meeting the primary endpoint of improving by at least 4 points on the Axillary Sweating Daily Diary (ASDD) scale. This product significantly outperformed placebo in two clinical trials, with 53% and 66% of users meeting the primary endpoint, improvement of at least 4 points from baseline in the weekly mean ASDD Item #2. It was approved in those aged 9 years and older.

“You can use this in kids, but you need to educate the kid and the parent or adult,” he said. “This is the last thing you do before bed, after brushing your teeth and after washing your face.”

Patients should apply one swipe to the clean skin of each underarm, and then wash their hands thoroughly. Clinical trials saw a greater proportion of off-target effects such as dry eyes and mouth and mydriasis in the active arm; unilateral mydriasis was more common than bilateral, underscoring the importance of hand washing as this was probably secondary transfer from hands to face during sleep, said Dr. Friedman. Patients can expect results in 2-3 weeks, and doses can be held as needed for anticholinergic side effects.

Systemic choices are limited

There are no FDA-approved systemic agents for hyperhidrosis, and the literature holds only case reports or small series, Dr. Friedman pointed out.

Though systemic treatment may be more effective in generalized hyperhidrosis and for patients with dysautonomia-associated hyperhidrosis, glycopyrrolate is a logical choice if a systemic anticholinergic is desired. A starting dose of 1 mg twice daily can be titrated for effect to about 6 mg daily. Though off-target effects may be a dose-limiting factor, glycopyrrolate is not very lipid soluble, so it penetrates the blood-brain barrier relatively poorly, he said.

Oxybutynin is available in many forms, including a slow-release tablet that permits once-daily dosing. Starting at 5-10 mg daily is a good idea, but dosing may need to be increased to as high as 20 mg daily to be effective. However, patients will often experience “major side effects” with oxybutynin, including significant xerostomia, constipation, blurred vision, and difficulty urinating.

For children, small studies have seen improvement with glycopyrrolate at an average dose of about 2 mg/day. Oxybutynin, which has been extensively studied in the pediatric population, was also effective, but central nervous system adverse events were common.

For some, beta-adrenergic blockade can be an extremely valuable tool, said Dr. Friedman. When sweating is linked to social phobia or performance anxiety, 10-20 mg of atenolol about an hour before the performance or public appearance can make a big difference. Bradycardia, atrioventricular block, and asthma are all contraindications, and the usual precautions should be taken with a host of other comorbidities, he noted.

It’s a good idea to check resting blood pressure and heart rate and take body mass into consideration, and adjust the dose downward appropriately. A key pearl: “Have them do a test run at home, to make sure they don’t keel over on the podium!” said Dr. Friedman.
 

Botulinum toxin tips and tricks

Botulinum toxin can be very effective and works directly by blocking acetylcholine release at the junction of the sympathetic sudomotor neuron and the sweat gland.

Before treatment, make sure the patient prepares correctly by abstaining from over-the-counter deodorants or antiperspirants, and resting without exertion or drinking hot beverages for about 30 minutes before the procedure.

To ascertain the follicular outline of the area to be injected, the iodine starch test can be used: Paint the axilla with iodine, allow it to dry, and then dust corn starch over the area. The follicular outline is mapped by the purple-blue reaction of the starch and iodine in the presence of moisture from perspiration, Dr. Friedman said.

Applying topical analgesia 30 minutes prior to the procedure helps with patient discomfort with axillary injections. When it comes time to inject, a shallow approach with the bevel side up works well, with a goal of blanketing the field identified by the iodine starch test with small aliquots of toxin placed 1-2 centimeters apart, said Dr. Friedman. However, for patients who might have tattoos that extend to the axillary area, “Avoid the ink!”

Patients will start to see improvement within 2-4 days, and although the literature says a toxin treatment can last 6-9 months, Dr. Friedman said he sees patients coming back in 4-5 months.

Obtaining botulinum toxin can be done in one of two ways: the “buy and bill” approach has the dermatologist purchasing the medication, using CPT 64650 and J code J0585 – “Remember the units!” said Dr. Friedman, because reimbursement will be based on the volume of toxin purchased.. This route may be cheaper for the patient because it avoids a medication copay. The physician obtains preauthorization for both the medication and procedure with this strategy.

The other route is to have the provider prescribe botulinum toxin and the patient purchase it at a regular or specialty pharmacy. In this case, the pharmacist obtains precertification for the medication, but the physician still needs to be precertified – and bill – for the injection procedure itself. This scenario is less risky for the physician but may trigger two separate copays for the patient.

Botulinum toxin can be effective for up to 90% of patients, but at a cost: Without insurance reimbursement, treatments can cost in the neighborhood of $1,500.

A good resource for patients and clinicians is the International Hyperhidrosis Society’s website (sweathelp.org), said Dr. Friedman.

Dr. Friedman disclosed relationships with multiple pharmaceutical and cosmetic companies, including Dermira, which markets topical glycopyrronium tosylate as Qbrexza.

koakes@mdedge.com

ORLANDO – When you extend your hand to a new patient, and he reflexively wipes his palm before shaking hands, be alert. It’s possible you’re seeing primary hyperhidrosis, a condition that’s both more common and more disabling than once thought.

Koldunov/iStock/Getty Images

“Looking at the biology of sweating, normally, it’s a good thing – we need it to survive. However, hyperhidrosis is too much of a good thing – it’s an excess of what is needed for normal biology,” said Adam Friedman, MD, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.

Recent data, he pointed out, show that hyperhidrosis is more prevalent than previously thought – about 4.8% of individuals may have the condition, with about half having axillary hyperhidrosis. Symptoms peak in early adulthood, with adults aged 18-54 most affected. “These are the prime working years,” he said.

About 2% of teens are affected, and many adults report that symptoms began before they were 12 years old. Hand hyperhidrosis is a factor for computer and electronic device work, sports, and even handling paper and pencils, noted Dr. Friedman, professor of dermatology at George Washington University, Washington.

“Does it affect quality of life? Yes. We have data to support the impact. The adverse impact is actually greater than that of eczema and psoriasis,” he said, adding that patients won’t always bring up their concerns about sweating. “Often, it’s the patient who apologizes for having sweaty palms or who sticks to the paper on the exam table. It’s worth asking these patients if they are bothered by excessive sweating.”
 

Is it hyperhidrosis?

A 2016 paper defined hyperhidrosis as “a condition that involves chronic excessive sweating of the underarms, hands, feet, face, groin, or other bodily areas, which is much more than what is normal, and occurs regardless of temperature, exercise, or situation, and may have an impact on quality of life” (Arch Dermatol Res. 2016 Dec;308[10]:743-9). The amount of sweating can be four to five times that seen in healthy controls.

Other clues that excess sweating might be hyperhidrosis? General hyperhidrosis is a secondary syndrome that can be caused by a variety of conditions including endocrine and metabolic disorders and malignancies. Drugs and toxins can also cause generalized excessive sweating.

Focal hyperhidrosis can be primary idiopathic disease; some neuropathies and certain spinal diseases and spinal cord injury can also cause focal hyperhidrosis, though not usually in the axillary/palmar/plantar distribution seen in primary hyperhidrosis.

Before settling on primary hyperhidrosis, the history and exam should also account for other possibilities in the differential: social anxiety disorder, eccrine nevus, gustatory sweating, Frey syndrome, and impaired evaporation could all account for excess sweating, which is also a postsurgical phenomenon for some patients.

Diagnostic criteria call for “focal, visible, excessive sweating” persisting for at least 6 months with no apparent cause. Additionally, patients must have at least two of the additional following criteria: sweating that is bilateral and symmetric, occurs at least once weekly, impairs daily activities, and starts before age 25 years, as well as a positive family history of hyperhidrosis and cessation of sweating during sleep.

The last point is critical, Dr. Friedman said. “If you sweat a lot at night, it’s not hyperhidrosis!”

Though gravimetric evaluation is used in hyperhidrosis research, the history and exam are really where the diagnosis is made in practice, he noted. The Hyperhidrosis Disease Severity Scale is a brief, useful clinical tool that asks patients to peg the extent to which their sweating interferes with daily life.
 

Topical treatments to try

Topical antiperspirants and other topical agents are a logical place to start and may be required as part of step therapy by insurers. Many patients will already have tried clinical strength over-the-counter antiperspirants containing aluminum zirconium trichlorohydrex, but these products rate low in patient satisfaction among those with primary hyperhidrosis.

Prescription aluminum salts can be compounded to various strengths, with 10%-20% concentration appropriate for axillae and 30%-40% a good strength for palms and soles, according to Dr. Friedman. All of these agents work by precipitating out solids that form a shallow plug in sweat ducts, slowing the flow of perspiration.

Pearls for topical treatment include the need for the product to be on the skin for 6-8 hours overnight. “Remember hyperhidrosis patients do not sweat at night,” so this is the time when the occlusive plugs can form. Then residue can be washed off in the morning, and patients can apply a deodorant. “I remind my patients that antiperspirants are for sweating, and deodorants are for odor,” said Dr. Friedman. These products can damage fabric, and they can be irritating, a problem addressed with low-potency topical steroids.

Topical regimens don’t need to be adjusted for pediatric patients, said Dr. Friedman.

Iontophoresis has been around since the 1950s, is effective, has few side effects, and is considered first-line treatment for severe palmar and plantar hyperhidrosis. But he said there’s one big rub: time. To be effective, patients need 20-30 minutes of application of 15-20 milliamperes of current 3-4 times weekly, not a schedule that works for most patients or practitioners, Dr. Friedman noted.

A treatment recently approved by the Food and Drug Administration for primary axillary hyperhidrosis is a topical anticholinergic, glycopyrronium tosylate, applied with wipes impregnated with glycopyrronium solution. This product significantly outperformed placebo in two clinical trials, with up to 64% of users meeting the primary endpoint of improving by at least 4 points on the Axillary Sweating Daily Diary (ASDD) scale. This product significantly outperformed placebo in two clinical trials, with 53% and 66% of users meeting the primary endpoint, improvement of at least 4 points from baseline in the weekly mean ASDD Item #2. It was approved in those aged 9 years and older.

“You can use this in kids, but you need to educate the kid and the parent or adult,” he said. “This is the last thing you do before bed, after brushing your teeth and after washing your face.”

Patients should apply one swipe to the clean skin of each underarm, and then wash their hands thoroughly. Clinical trials saw a greater proportion of off-target effects such as dry eyes and mouth and mydriasis in the active arm; unilateral mydriasis was more common than bilateral, underscoring the importance of hand washing as this was probably secondary transfer from hands to face during sleep, said Dr. Friedman. Patients can expect results in 2-3 weeks, and doses can be held as needed for anticholinergic side effects.

Systemic choices are limited

There are no FDA-approved systemic agents for hyperhidrosis, and the literature holds only case reports or small series, Dr. Friedman pointed out.

Though systemic treatment may be more effective in generalized hyperhidrosis and for patients with dysautonomia-associated hyperhidrosis, glycopyrrolate is a logical choice if a systemic anticholinergic is desired. A starting dose of 1 mg twice daily can be titrated for effect to about 6 mg daily. Though off-target effects may be a dose-limiting factor, glycopyrrolate is not very lipid soluble, so it penetrates the blood-brain barrier relatively poorly, he said.

Oxybutynin is available in many forms, including a slow-release tablet that permits once-daily dosing. Starting at 5-10 mg daily is a good idea, but dosing may need to be increased to as high as 20 mg daily to be effective. However, patients will often experience “major side effects” with oxybutynin, including significant xerostomia, constipation, blurred vision, and difficulty urinating.

For children, small studies have seen improvement with glycopyrrolate at an average dose of about 2 mg/day. Oxybutynin, which has been extensively studied in the pediatric population, was also effective, but central nervous system adverse events were common.

For some, beta-adrenergic blockade can be an extremely valuable tool, said Dr. Friedman. When sweating is linked to social phobia or performance anxiety, 10-20 mg of atenolol about an hour before the performance or public appearance can make a big difference. Bradycardia, atrioventricular block, and asthma are all contraindications, and the usual precautions should be taken with a host of other comorbidities, he noted.

It’s a good idea to check resting blood pressure and heart rate and take body mass into consideration, and adjust the dose downward appropriately. A key pearl: “Have them do a test run at home, to make sure they don’t keel over on the podium!” said Dr. Friedman.
 

Botulinum toxin tips and tricks

Botulinum toxin can be very effective and works directly by blocking acetylcholine release at the junction of the sympathetic sudomotor neuron and the sweat gland.

Before treatment, make sure the patient prepares correctly by abstaining from over-the-counter deodorants or antiperspirants, and resting without exertion or drinking hot beverages for about 30 minutes before the procedure.

To ascertain the follicular outline of the area to be injected, the iodine starch test can be used: Paint the axilla with iodine, allow it to dry, and then dust corn starch over the area. The follicular outline is mapped by the purple-blue reaction of the starch and iodine in the presence of moisture from perspiration, Dr. Friedman said.

Applying topical analgesia 30 minutes prior to the procedure helps with patient discomfort with axillary injections. When it comes time to inject, a shallow approach with the bevel side up works well, with a goal of blanketing the field identified by the iodine starch test with small aliquots of toxin placed 1-2 centimeters apart, said Dr. Friedman. However, for patients who might have tattoos that extend to the axillary area, “Avoid the ink!”

Patients will start to see improvement within 2-4 days, and although the literature says a toxin treatment can last 6-9 months, Dr. Friedman said he sees patients coming back in 4-5 months.

Obtaining botulinum toxin can be done in one of two ways: the “buy and bill” approach has the dermatologist purchasing the medication, using CPT 64650 and J code J0585 – “Remember the units!” said Dr. Friedman, because reimbursement will be based on the volume of toxin purchased.. This route may be cheaper for the patient because it avoids a medication copay. The physician obtains preauthorization for both the medication and procedure with this strategy.

The other route is to have the provider prescribe botulinum toxin and the patient purchase it at a regular or specialty pharmacy. In this case, the pharmacist obtains precertification for the medication, but the physician still needs to be precertified – and bill – for the injection procedure itself. This scenario is less risky for the physician but may trigger two separate copays for the patient.

Botulinum toxin can be effective for up to 90% of patients, but at a cost: Without insurance reimbursement, treatments can cost in the neighborhood of $1,500.

A good resource for patients and clinicians is the International Hyperhidrosis Society’s website (sweathelp.org), said Dr. Friedman.

Dr. Friedman disclosed relationships with multiple pharmaceutical and cosmetic companies, including Dermira, which markets topical glycopyrronium tosylate as Qbrexza.

koakes@mdedge.com

ORLANDO – When you extend your hand to a new patient, and he reflexively wipes his palm before shaking hands, be alert. It’s possible you’re seeing primary hyperhidrosis, a condition that’s both more common and more disabling than once thought.

Koldunov/iStock/Getty Images

“Looking at the biology of sweating, normally, it’s a good thing – we need it to survive. However, hyperhidrosis is too much of a good thing – it’s an excess of what is needed for normal biology,” said Adam Friedman, MD, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.

Recent data, he pointed out, show that hyperhidrosis is more prevalent than previously thought – about 4.8% of individuals may have the condition, with about half having axillary hyperhidrosis. Symptoms peak in early adulthood, with adults aged 18-54 most affected. “These are the prime working years,” he said.

About 2% of teens are affected, and many adults report that symptoms began before they were 12 years old. Hand hyperhidrosis is a factor for computer and electronic device work, sports, and even handling paper and pencils, noted Dr. Friedman, professor of dermatology at George Washington University, Washington.

“Does it affect quality of life? Yes. We have data to support the impact. The adverse impact is actually greater than that of eczema and psoriasis,” he said, adding that patients won’t always bring up their concerns about sweating. “Often, it’s the patient who apologizes for having sweaty palms or who sticks to the paper on the exam table. It’s worth asking these patients if they are bothered by excessive sweating.”
 

Is it hyperhidrosis?

A 2016 paper defined hyperhidrosis as “a condition that involves chronic excessive sweating of the underarms, hands, feet, face, groin, or other bodily areas, which is much more than what is normal, and occurs regardless of temperature, exercise, or situation, and may have an impact on quality of life” (Arch Dermatol Res. 2016 Dec;308[10]:743-9). The amount of sweating can be four to five times that seen in healthy controls.

Other clues that excess sweating might be hyperhidrosis? General hyperhidrosis is a secondary syndrome that can be caused by a variety of conditions including endocrine and metabolic disorders and malignancies. Drugs and toxins can also cause generalized excessive sweating.

Focal hyperhidrosis can be primary idiopathic disease; some neuropathies and certain spinal diseases and spinal cord injury can also cause focal hyperhidrosis, though not usually in the axillary/palmar/plantar distribution seen in primary hyperhidrosis.

Before settling on primary hyperhidrosis, the history and exam should also account for other possibilities in the differential: social anxiety disorder, eccrine nevus, gustatory sweating, Frey syndrome, and impaired evaporation could all account for excess sweating, which is also a postsurgical phenomenon for some patients.

Diagnostic criteria call for “focal, visible, excessive sweating” persisting for at least 6 months with no apparent cause. Additionally, patients must have at least two of the additional following criteria: sweating that is bilateral and symmetric, occurs at least once weekly, impairs daily activities, and starts before age 25 years, as well as a positive family history of hyperhidrosis and cessation of sweating during sleep.

The last point is critical, Dr. Friedman said. “If you sweat a lot at night, it’s not hyperhidrosis!”

Though gravimetric evaluation is used in hyperhidrosis research, the history and exam are really where the diagnosis is made in practice, he noted. The Hyperhidrosis Disease Severity Scale is a brief, useful clinical tool that asks patients to peg the extent to which their sweating interferes with daily life.
 

Topical treatments to try

Topical antiperspirants and other topical agents are a logical place to start and may be required as part of step therapy by insurers. Many patients will already have tried clinical strength over-the-counter antiperspirants containing aluminum zirconium trichlorohydrex, but these products rate low in patient satisfaction among those with primary hyperhidrosis.

Prescription aluminum salts can be compounded to various strengths, with 10%-20% concentration appropriate for axillae and 30%-40% a good strength for palms and soles, according to Dr. Friedman. All of these agents work by precipitating out solids that form a shallow plug in sweat ducts, slowing the flow of perspiration.

Pearls for topical treatment include the need for the product to be on the skin for 6-8 hours overnight. “Remember hyperhidrosis patients do not sweat at night,” so this is the time when the occlusive plugs can form. Then residue can be washed off in the morning, and patients can apply a deodorant. “I remind my patients that antiperspirants are for sweating, and deodorants are for odor,” said Dr. Friedman. These products can damage fabric, and they can be irritating, a problem addressed with low-potency topical steroids.

Topical regimens don’t need to be adjusted for pediatric patients, said Dr. Friedman.

Iontophoresis has been around since the 1950s, is effective, has few side effects, and is considered first-line treatment for severe palmar and plantar hyperhidrosis. But he said there’s one big rub: time. To be effective, patients need 20-30 minutes of application of 15-20 milliamperes of current 3-4 times weekly, not a schedule that works for most patients or practitioners, Dr. Friedman noted.

A treatment recently approved by the Food and Drug Administration for primary axillary hyperhidrosis is a topical anticholinergic, glycopyrronium tosylate, applied with wipes impregnated with glycopyrronium solution. This product significantly outperformed placebo in two clinical trials, with up to 64% of users meeting the primary endpoint of improving by at least 4 points on the Axillary Sweating Daily Diary (ASDD) scale. This product significantly outperformed placebo in two clinical trials, with 53% and 66% of users meeting the primary endpoint, improvement of at least 4 points from baseline in the weekly mean ASDD Item #2. It was approved in those aged 9 years and older.

“You can use this in kids, but you need to educate the kid and the parent or adult,” he said. “This is the last thing you do before bed, after brushing your teeth and after washing your face.”

Patients should apply one swipe to the clean skin of each underarm, and then wash their hands thoroughly. Clinical trials saw a greater proportion of off-target effects such as dry eyes and mouth and mydriasis in the active arm; unilateral mydriasis was more common than bilateral, underscoring the importance of hand washing as this was probably secondary transfer from hands to face during sleep, said Dr. Friedman. Patients can expect results in 2-3 weeks, and doses can be held as needed for anticholinergic side effects.

Systemic choices are limited

There are no FDA-approved systemic agents for hyperhidrosis, and the literature holds only case reports or small series, Dr. Friedman pointed out.

Though systemic treatment may be more effective in generalized hyperhidrosis and for patients with dysautonomia-associated hyperhidrosis, glycopyrrolate is a logical choice if a systemic anticholinergic is desired. A starting dose of 1 mg twice daily can be titrated for effect to about 6 mg daily. Though off-target effects may be a dose-limiting factor, glycopyrrolate is not very lipid soluble, so it penetrates the blood-brain barrier relatively poorly, he said.

Oxybutynin is available in many forms, including a slow-release tablet that permits once-daily dosing. Starting at 5-10 mg daily is a good idea, but dosing may need to be increased to as high as 20 mg daily to be effective. However, patients will often experience “major side effects” with oxybutynin, including significant xerostomia, constipation, blurred vision, and difficulty urinating.

For children, small studies have seen improvement with glycopyrrolate at an average dose of about 2 mg/day. Oxybutynin, which has been extensively studied in the pediatric population, was also effective, but central nervous system adverse events were common.

For some, beta-adrenergic blockade can be an extremely valuable tool, said Dr. Friedman. When sweating is linked to social phobia or performance anxiety, 10-20 mg of atenolol about an hour before the performance or public appearance can make a big difference. Bradycardia, atrioventricular block, and asthma are all contraindications, and the usual precautions should be taken with a host of other comorbidities, he noted.

It’s a good idea to check resting blood pressure and heart rate and take body mass into consideration, and adjust the dose downward appropriately. A key pearl: “Have them do a test run at home, to make sure they don’t keel over on the podium!” said Dr. Friedman.
 

Botulinum toxin tips and tricks

Botulinum toxin can be very effective and works directly by blocking acetylcholine release at the junction of the sympathetic sudomotor neuron and the sweat gland.

Before treatment, make sure the patient prepares correctly by abstaining from over-the-counter deodorants or antiperspirants, and resting without exertion or drinking hot beverages for about 30 minutes before the procedure.

To ascertain the follicular outline of the area to be injected, the iodine starch test can be used: Paint the axilla with iodine, allow it to dry, and then dust corn starch over the area. The follicular outline is mapped by the purple-blue reaction of the starch and iodine in the presence of moisture from perspiration, Dr. Friedman said.

Applying topical analgesia 30 minutes prior to the procedure helps with patient discomfort with axillary injections. When it comes time to inject, a shallow approach with the bevel side up works well, with a goal of blanketing the field identified by the iodine starch test with small aliquots of toxin placed 1-2 centimeters apart, said Dr. Friedman. However, for patients who might have tattoos that extend to the axillary area, “Avoid the ink!”

Patients will start to see improvement within 2-4 days, and although the literature says a toxin treatment can last 6-9 months, Dr. Friedman said he sees patients coming back in 4-5 months.

Obtaining botulinum toxin can be done in one of two ways: the “buy and bill” approach has the dermatologist purchasing the medication, using CPT 64650 and J code J0585 – “Remember the units!” said Dr. Friedman, because reimbursement will be based on the volume of toxin purchased.. This route may be cheaper for the patient because it avoids a medication copay. The physician obtains preauthorization for both the medication and procedure with this strategy.

The other route is to have the provider prescribe botulinum toxin and the patient purchase it at a regular or specialty pharmacy. In this case, the pharmacist obtains precertification for the medication, but the physician still needs to be precertified – and bill – for the injection procedure itself. This scenario is less risky for the physician but may trigger two separate copays for the patient.

Botulinum toxin can be effective for up to 90% of patients, but at a cost: Without insurance reimbursement, treatments can cost in the neighborhood of $1,500.

A good resource for patients and clinicians is the International Hyperhidrosis Society’s website (sweathelp.org), said Dr. Friedman.

Dr. Friedman disclosed relationships with multiple pharmaceutical and cosmetic companies, including Dermira, which markets topical glycopyrronium tosylate as Qbrexza.

koakes@mdedge.com

You have run your experiments, analyzed your data, and finished your manuscript, but now you are asked to write a cover letter for journal submission. How do you effectively convey your message in a cover letter? To understand how to gain the editors’ support for your paper, let us first discuss the role of this letter.

The cover letter is your first communication with the editors. As this serves as your first impression, you want to send a clear and concise message that highlights the novelty, validity, and significance of your manuscript. You also want to state why your manuscript would be a good fit for the journal. Keeping this letter concise and ideally to one page allows the editors to quickly review the highlights of your manuscript. Here are 10 steps we believe are important to follow when writing an effective cover letter (Table 1). We have listed examples to accompany each step; note that our examples are for illustrative purposes only.
 

1) Address the editor(s) formally by name in your cover letter

This information is found on the journal’s website and in the journal. Common mistakes we have seen is reporting the wrong editor(s) for submission or omitting an introduction. Though this cover letter is not published, it reflects poorly on the authors if there are incorrect editors listed or misspelled words.

Example:
Richard M. Peek, Jr., MD, and Douglas A. Corley, MD, PhD, MPH
Editors in Chief, Gastroenterology

Dear Drs. Peek and Corley:

2) Manuscript title and authors

Bolding your manuscript and listing the authors are essential parts of the cover letter.

3) Methods

We recommend dedicating one sentence to your methods. Take this time to highlight key features if appropriate, such as novel techniques, prospective enrollment, and randomized, controlled studies, which are all generally viewed as stronger study designs than retrospective studies. Make sure you are truthful in your claims. Mistakes we have seen include making claims the group is the “first” or the “largest,” but our review of the literature disproves these statements. These are false claims and raise flags regarding the integrity of the science.

4) Results and key findings

We recommend dedicating a sentence to the key finding of this study. This allows the editors in chief to identify which associate editor should handle the manuscript and highlights the importance of the study, which will determine whether the associate editor will send your paper for external review.

Example:
We found that combined endoscopic dilation and oral steroid therapy at index food impaction improved quality of life and need for repeat dilation measured at 1-year follow-up, compared with sham dilation and placebo.
 

5) Novelty

The editors want to know the degree to which your paper is unique among other publications in the field. We recommend emphasizing the novelty of your study as compared with other published work. The focus of this should be how your manuscript adds to the literature and serves to advance the science in this field.

Example:
Our study is unique because we enrolled patients in a pragmatic fashion at time of admission for food impaction to the emergency department. This design allows implementation of our intervention in most clinical settings, where we expect our findings to translate broadly into reduced hospital admissions and repeat endoscopic interventions, as well as improved quality of life as documented by patient-reported outcomes.

6) Submission to other journals

Certain manuscripts are only part of the entire study, which can be because of interim results or prespecified secondary endpoints. It is important to state whether this manuscript or any part has been published elsewhere or parts of the study are in submission elsewhere.

Example:
Neither the entire paper nor any part of its content has been published or has been accepted elsewhere. This work has not been submitted to any other journal, and in case of acceptance of the manuscript, the copyright is transferred to Gastroenterology.

7) Journal fit

Not all journals have the same readership or focus. When submitting to the journals, please highlight why this manuscript fits this journal and its readership. When able, also recommend what section of the journal this manuscript should go to for review. This allows for expedited review process and shows you understand the journal’s readership and categories.

Example:
We believe our study will be of great interest to readers of Gastroenterology and suggest the manuscript section: “Clinical: Alimentary Tract.”

8) Influence of sponsors and conflicts of interest

Given the concern for potential conflict of interests in study design, data collection, or analysis, we recommend listing any important conflicts of interest or study sponsors. The entire list of conflicts of interest is typically included elsewhere, but a sponsored study or direct conflict should be listed to prevent any perceived influence from sponsors that may limit data integrity.

Example:
The study was supported by RDN-Gastro, a nonprofit private organization aimed to promote clinical and translational research in eosinophilic esophagitis. The RDN-Gastro organization receives support from the National Institutes of Health and the Emergency Department Eosinophilic Esophagitis Association.

9) Suggestions for editors and reviewers

It is helpful to suggest potential associate editors to handle your manuscript. Similarly, suggesting potential reviewers (and providing their email addresses) who are experts in the field and understand your research topic can enhance the quality of reviews. Soliciting reviewers who you know may seem like a recipe for friendly reviews; however, this is a flawed assumption because sometimes these reviewers are more rigorous in their comments.

Example:
Preferred Associate Editor: John M. Inadomi.
Preferred Reviewer: Rishi Naik (Rishi.D.Naik@vumc.org); expertise in esophageal motility.

10) Do Not Review list (optional)

Unfortunately, not all review processes for all journals are created equal. For particular topics, you may wish to ensure your data are not compromised through the review process. Some journals will have the option for selecting reviewers who you prefer not review your manuscript and this request should be respected in the review process.

Example:
Nonpreferred reviewers: Rishi D. Naik (Nashville, TN).

In summary, the cover letter should be viewed as an opportunity to highlight the significance of your manuscript and reasons why your manuscript should be published in the journal. Highlighting the innovation, validity, and importance of your manuscript using this systematic approach will allow the editors and reviewers to more effectively evaluate your paper. Being truthful about potential conflicts of interest and sponsorships will also be appreciated by the editors. Good luck with your future submissions!
 

Dr. Naik is a gastroenterology fellow, department of gastroenterology, Vanderbilt University, Nashville, Tenn., as well as fellow editor of Gastroenterology. Dr. Inadomi is the Cyrus E. Rubin Chair, professor of medicine and head, division of gastroenterology, University of Washington, Seattle, as well as associate editor of Gastroenterology. Dr. Naik and Dr. Inadomi have no conflicts of interest to disclose.
 

You have run your experiments, analyzed your data, and finished your manuscript, but now you are asked to write a cover letter for journal submission. How do you effectively convey your message in a cover letter? To understand how to gain the editors’ support for your paper, let us first discuss the role of this letter.

The cover letter is your first communication with the editors. As this serves as your first impression, you want to send a clear and concise message that highlights the novelty, validity, and significance of your manuscript. You also want to state why your manuscript would be a good fit for the journal. Keeping this letter concise and ideally to one page allows the editors to quickly review the highlights of your manuscript. Here are 10 steps we believe are important to follow when writing an effective cover letter (Table 1). We have listed examples to accompany each step; note that our examples are for illustrative purposes only.
 

1) Address the editor(s) formally by name in your cover letter

This information is found on the journal’s website and in the journal. Common mistakes we have seen is reporting the wrong editor(s) for submission or omitting an introduction. Though this cover letter is not published, it reflects poorly on the authors if there are incorrect editors listed or misspelled words.

Example:
Richard M. Peek, Jr., MD, and Douglas A. Corley, MD, PhD, MPH
Editors in Chief, Gastroenterology

Dear Drs. Peek and Corley:

2) Manuscript title and authors

Bolding your manuscript and listing the authors are essential parts of the cover letter.

3) Methods

We recommend dedicating one sentence to your methods. Take this time to highlight key features if appropriate, such as novel techniques, prospective enrollment, and randomized, controlled studies, which are all generally viewed as stronger study designs than retrospective studies. Make sure you are truthful in your claims. Mistakes we have seen include making claims the group is the “first” or the “largest,” but our review of the literature disproves these statements. These are false claims and raise flags regarding the integrity of the science.

4) Results and key findings

We recommend dedicating a sentence to the key finding of this study. This allows the editors in chief to identify which associate editor should handle the manuscript and highlights the importance of the study, which will determine whether the associate editor will send your paper for external review.

Example:
We found that combined endoscopic dilation and oral steroid therapy at index food impaction improved quality of life and need for repeat dilation measured at 1-year follow-up, compared with sham dilation and placebo.
 

5) Novelty

The editors want to know the degree to which your paper is unique among other publications in the field. We recommend emphasizing the novelty of your study as compared with other published work. The focus of this should be how your manuscript adds to the literature and serves to advance the science in this field.

Example:
Our study is unique because we enrolled patients in a pragmatic fashion at time of admission for food impaction to the emergency department. This design allows implementation of our intervention in most clinical settings, where we expect our findings to translate broadly into reduced hospital admissions and repeat endoscopic interventions, as well as improved quality of life as documented by patient-reported outcomes.

6) Submission to other journals

Certain manuscripts are only part of the entire study, which can be because of interim results or prespecified secondary endpoints. It is important to state whether this manuscript or any part has been published elsewhere or parts of the study are in submission elsewhere.

Example:
Neither the entire paper nor any part of its content has been published or has been accepted elsewhere. This work has not been submitted to any other journal, and in case of acceptance of the manuscript, the copyright is transferred to Gastroenterology.

7) Journal fit

Not all journals have the same readership or focus. When submitting to the journals, please highlight why this manuscript fits this journal and its readership. When able, also recommend what section of the journal this manuscript should go to for review. This allows for expedited review process and shows you understand the journal’s readership and categories.

Example:
We believe our study will be of great interest to readers of Gastroenterology and suggest the manuscript section: “Clinical: Alimentary Tract.”

8) Influence of sponsors and conflicts of interest

Given the concern for potential conflict of interests in study design, data collection, or analysis, we recommend listing any important conflicts of interest or study sponsors. The entire list of conflicts of interest is typically included elsewhere, but a sponsored study or direct conflict should be listed to prevent any perceived influence from sponsors that may limit data integrity.

Example:
The study was supported by RDN-Gastro, a nonprofit private organization aimed to promote clinical and translational research in eosinophilic esophagitis. The RDN-Gastro organization receives support from the National Institutes of Health and the Emergency Department Eosinophilic Esophagitis Association.

9) Suggestions for editors and reviewers

It is helpful to suggest potential associate editors to handle your manuscript. Similarly, suggesting potential reviewers (and providing their email addresses) who are experts in the field and understand your research topic can enhance the quality of reviews. Soliciting reviewers who you know may seem like a recipe for friendly reviews; however, this is a flawed assumption because sometimes these reviewers are more rigorous in their comments.

Example:
Preferred Associate Editor: John M. Inadomi.
Preferred Reviewer: Rishi Naik (Rishi.D.Naik@vumc.org); expertise in esophageal motility.

10) Do Not Review list (optional)

Unfortunately, not all review processes for all journals are created equal. For particular topics, you may wish to ensure your data are not compromised through the review process. Some journals will have the option for selecting reviewers who you prefer not review your manuscript and this request should be respected in the review process.

Example:
Nonpreferred reviewers: Rishi D. Naik (Nashville, TN).

In summary, the cover letter should be viewed as an opportunity to highlight the significance of your manuscript and reasons why your manuscript should be published in the journal. Highlighting the innovation, validity, and importance of your manuscript using this systematic approach will allow the editors and reviewers to more effectively evaluate your paper. Being truthful about potential conflicts of interest and sponsorships will also be appreciated by the editors. Good luck with your future submissions!
 

Dr. Naik is a gastroenterology fellow, department of gastroenterology, Vanderbilt University, Nashville, Tenn., as well as fellow editor of Gastroenterology. Dr. Inadomi is the Cyrus E. Rubin Chair, professor of medicine and head, division of gastroenterology, University of Washington, Seattle, as well as associate editor of Gastroenterology. Dr. Naik and Dr. Inadomi have no conflicts of interest to disclose.
 

You have run your experiments, analyzed your data, and finished your manuscript, but now you are asked to write a cover letter for journal submission. How do you effectively convey your message in a cover letter? To understand how to gain the editors’ support for your paper, let us first discuss the role of this letter.

The cover letter is your first communication with the editors. As this serves as your first impression, you want to send a clear and concise message that highlights the novelty, validity, and significance of your manuscript. You also want to state why your manuscript would be a good fit for the journal. Keeping this letter concise and ideally to one page allows the editors to quickly review the highlights of your manuscript. Here are 10 steps we believe are important to follow when writing an effective cover letter (Table 1). We have listed examples to accompany each step; note that our examples are for illustrative purposes only.
 

1) Address the editor(s) formally by name in your cover letter

This information is found on the journal’s website and in the journal. Common mistakes we have seen is reporting the wrong editor(s) for submission or omitting an introduction. Though this cover letter is not published, it reflects poorly on the authors if there are incorrect editors listed or misspelled words.

Example:
Richard M. Peek, Jr., MD, and Douglas A. Corley, MD, PhD, MPH
Editors in Chief, Gastroenterology

Dear Drs. Peek and Corley:

2) Manuscript title and authors

Bolding your manuscript and listing the authors are essential parts of the cover letter.

3) Methods

We recommend dedicating one sentence to your methods. Take this time to highlight key features if appropriate, such as novel techniques, prospective enrollment, and randomized, controlled studies, which are all generally viewed as stronger study designs than retrospective studies. Make sure you are truthful in your claims. Mistakes we have seen include making claims the group is the “first” or the “largest,” but our review of the literature disproves these statements. These are false claims and raise flags regarding the integrity of the science.

4) Results and key findings

We recommend dedicating a sentence to the key finding of this study. This allows the editors in chief to identify which associate editor should handle the manuscript and highlights the importance of the study, which will determine whether the associate editor will send your paper for external review.

Example:
We found that combined endoscopic dilation and oral steroid therapy at index food impaction improved quality of life and need for repeat dilation measured at 1-year follow-up, compared with sham dilation and placebo.
 

5) Novelty

The editors want to know the degree to which your paper is unique among other publications in the field. We recommend emphasizing the novelty of your study as compared with other published work. The focus of this should be how your manuscript adds to the literature and serves to advance the science in this field.

Example:
Our study is unique because we enrolled patients in a pragmatic fashion at time of admission for food impaction to the emergency department. This design allows implementation of our intervention in most clinical settings, where we expect our findings to translate broadly into reduced hospital admissions and repeat endoscopic interventions, as well as improved quality of life as documented by patient-reported outcomes.

6) Submission to other journals

Certain manuscripts are only part of the entire study, which can be because of interim results or prespecified secondary endpoints. It is important to state whether this manuscript or any part has been published elsewhere or parts of the study are in submission elsewhere.

Example:
Neither the entire paper nor any part of its content has been published or has been accepted elsewhere. This work has not been submitted to any other journal, and in case of acceptance of the manuscript, the copyright is transferred to Gastroenterology.

7) Journal fit

Not all journals have the same readership or focus. When submitting to the journals, please highlight why this manuscript fits this journal and its readership. When able, also recommend what section of the journal this manuscript should go to for review. This allows for expedited review process and shows you understand the journal’s readership and categories.

Example:
We believe our study will be of great interest to readers of Gastroenterology and suggest the manuscript section: “Clinical: Alimentary Tract.”

8) Influence of sponsors and conflicts of interest

Given the concern for potential conflict of interests in study design, data collection, or analysis, we recommend listing any important conflicts of interest or study sponsors. The entire list of conflicts of interest is typically included elsewhere, but a sponsored study or direct conflict should be listed to prevent any perceived influence from sponsors that may limit data integrity.

Example:
The study was supported by RDN-Gastro, a nonprofit private organization aimed to promote clinical and translational research in eosinophilic esophagitis. The RDN-Gastro organization receives support from the National Institutes of Health and the Emergency Department Eosinophilic Esophagitis Association.

9) Suggestions for editors and reviewers

It is helpful to suggest potential associate editors to handle your manuscript. Similarly, suggesting potential reviewers (and providing their email addresses) who are experts in the field and understand your research topic can enhance the quality of reviews. Soliciting reviewers who you know may seem like a recipe for friendly reviews; however, this is a flawed assumption because sometimes these reviewers are more rigorous in their comments.

Example:
Preferred Associate Editor: John M. Inadomi.
Preferred Reviewer: Rishi Naik (Rishi.D.Naik@vumc.org); expertise in esophageal motility.

10) Do Not Review list (optional)

Unfortunately, not all review processes for all journals are created equal. For particular topics, you may wish to ensure your data are not compromised through the review process. Some journals will have the option for selecting reviewers who you prefer not review your manuscript and this request should be respected in the review process.

Example:
Nonpreferred reviewers: Rishi D. Naik (Nashville, TN).

In summary, the cover letter should be viewed as an opportunity to highlight the significance of your manuscript and reasons why your manuscript should be published in the journal. Highlighting the innovation, validity, and importance of your manuscript using this systematic approach will allow the editors and reviewers to more effectively evaluate your paper. Being truthful about potential conflicts of interest and sponsorships will also be appreciated by the editors. Good luck with your future submissions!
 

Dr. Naik is a gastroenterology fellow, department of gastroenterology, Vanderbilt University, Nashville, Tenn., as well as fellow editor of Gastroenterology. Dr. Inadomi is the Cyrus E. Rubin Chair, professor of medicine and head, division of gastroenterology, University of Washington, Seattle, as well as associate editor of Gastroenterology. Dr. Naik and Dr. Inadomi have no conflicts of interest to disclose.
 

LAS VEGAS – In patients with essential tremor, peripheral nerve stimulation significantly improves hand tremor and activities of daily living, compared with sham treatment. In addition, sensors worn on the wrist can provide objective measures of tremor in the home environment, said the investigators, who presented their research at the annual meeting of the North American Neuromodulation Society.

The current hypothesis is that tremulous activity within a central tremor network causes essential tremor, but the specific mechanisms are unknown. Research suggests that invasive neuromodulation of deep brain structures within this tremor network provides clinical benefit. The question of whether noninvasive neuromodulation of the peripheral nerve inputs connected to this network is beneficial has received comparatively little attention, however.

Rajesh Pahwa, MD, movement disorders division chief at the University of Kansas Medical Center in Kansas City, and his colleagues examined the safety and efficacy of noninvasive neuromodulation for hand tremor in patients with essential tremor. To provide treatment, they used a wristband with three electrodes that targeted the median and radial nerves. The stimulation pattern was adjusted to interrupt each patient’s tremulous signal in the clinical setting and at home. Participants were asked to hold a certain posture for 20 seconds while the device recorded tremor frequency. After determining the peak tremor frequency, the device was able to adapt stimulation parameters to each patient.

Dr. Pahwa and his colleagues conducted an acute in-office study and an at-home study. In the in-office study, 77 participants were randomized to peripheral nerve treatment or sham stimulation of the tremor-dominant hand. The researchers evaluated tremor before and after one stimulation session using the Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Tremor Scale and the TETRAS Archimedes Spiral Rating Scale. In the at-home study, 61 participants were randomized to stimulation, sham, or standard of care for 2 weeks. After that point, all participants underwent two to five 40-minute stimulation sessions daily for 2 weeks. Patients in the treatment and sham groups had at least two sessions per day.

In the in-office study, the researchers randomized 40 patients to stimulation and 37 patients to sham. Dr. Pahwa and his colleagues determined that participants had been blinded successfully. The investigators observed a mean improvement in forward posture of approximately 0.75 points among treated patients, compared with a mean improvement of 0.3 points in the sham group. The difference between groups was statistically significant. Treated patients had significant improvements in upper limb tremor score and total performance score, compared with the sham group. The investigators also observed greater mean improvements in spiral drawing, lateral posture, and movement among treated patients, compared with the sham group, but the differences were not statistically significant.

Participants in the in-office study rated their improvement on activities of daily living. Average improvement across tasks was significantly greater for the treated group, compared to the sham group. Improvement on each individual task also was greater for the treated group than the sham group. The differences in improvement were significant for holding a cup of tea, dialing a telephone, picking up change, and unlocking a door with a key.

In the at-home study, the decrease in tremor amplitude, as measured by the wrist-worn device, was significantly greater among participants who received stimulation than in the sham group. “These randomized, controlled studies suggest that noninvasive peripheral neuromodulation may offer meaningful symptomatic relief from hand tremor in essential tremor with a favorable safety profile, compared to other available therapies,” noted Dr. Pahwa and his colleagues. “At-home monitoring may provide key insights into evaluating and treating tremor,” they added.

The studies were supported by Cala Health.

egreb@mdedge.com

LAS VEGAS – In patients with essential tremor, peripheral nerve stimulation significantly improves hand tremor and activities of daily living, compared with sham treatment. In addition, sensors worn on the wrist can provide objective measures of tremor in the home environment, said the investigators, who presented their research at the annual meeting of the North American Neuromodulation Society.

The current hypothesis is that tremulous activity within a central tremor network causes essential tremor, but the specific mechanisms are unknown. Research suggests that invasive neuromodulation of deep brain structures within this tremor network provides clinical benefit. The question of whether noninvasive neuromodulation of the peripheral nerve inputs connected to this network is beneficial has received comparatively little attention, however.

Rajesh Pahwa, MD, movement disorders division chief at the University of Kansas Medical Center in Kansas City, and his colleagues examined the safety and efficacy of noninvasive neuromodulation for hand tremor in patients with essential tremor. To provide treatment, they used a wristband with three electrodes that targeted the median and radial nerves. The stimulation pattern was adjusted to interrupt each patient’s tremulous signal in the clinical setting and at home. Participants were asked to hold a certain posture for 20 seconds while the device recorded tremor frequency. After determining the peak tremor frequency, the device was able to adapt stimulation parameters to each patient.

Dr. Pahwa and his colleagues conducted an acute in-office study and an at-home study. In the in-office study, 77 participants were randomized to peripheral nerve treatment or sham stimulation of the tremor-dominant hand. The researchers evaluated tremor before and after one stimulation session using the Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Tremor Scale and the TETRAS Archimedes Spiral Rating Scale. In the at-home study, 61 participants were randomized to stimulation, sham, or standard of care for 2 weeks. After that point, all participants underwent two to five 40-minute stimulation sessions daily for 2 weeks. Patients in the treatment and sham groups had at least two sessions per day.

In the in-office study, the researchers randomized 40 patients to stimulation and 37 patients to sham. Dr. Pahwa and his colleagues determined that participants had been blinded successfully. The investigators observed a mean improvement in forward posture of approximately 0.75 points among treated patients, compared with a mean improvement of 0.3 points in the sham group. The difference between groups was statistically significant. Treated patients had significant improvements in upper limb tremor score and total performance score, compared with the sham group. The investigators also observed greater mean improvements in spiral drawing, lateral posture, and movement among treated patients, compared with the sham group, but the differences were not statistically significant.

Participants in the in-office study rated their improvement on activities of daily living. Average improvement across tasks was significantly greater for the treated group, compared to the sham group. Improvement on each individual task also was greater for the treated group than the sham group. The differences in improvement were significant for holding a cup of tea, dialing a telephone, picking up change, and unlocking a door with a key.

In the at-home study, the decrease in tremor amplitude, as measured by the wrist-worn device, was significantly greater among participants who received stimulation than in the sham group. “These randomized, controlled studies suggest that noninvasive peripheral neuromodulation may offer meaningful symptomatic relief from hand tremor in essential tremor with a favorable safety profile, compared to other available therapies,” noted Dr. Pahwa and his colleagues. “At-home monitoring may provide key insights into evaluating and treating tremor,” they added.

The studies were supported by Cala Health.

egreb@mdedge.com

LAS VEGAS – In patients with essential tremor, peripheral nerve stimulation significantly improves hand tremor and activities of daily living, compared with sham treatment. In addition, sensors worn on the wrist can provide objective measures of tremor in the home environment, said the investigators, who presented their research at the annual meeting of the North American Neuromodulation Society.

The current hypothesis is that tremulous activity within a central tremor network causes essential tremor, but the specific mechanisms are unknown. Research suggests that invasive neuromodulation of deep brain structures within this tremor network provides clinical benefit. The question of whether noninvasive neuromodulation of the peripheral nerve inputs connected to this network is beneficial has received comparatively little attention, however.

Rajesh Pahwa, MD, movement disorders division chief at the University of Kansas Medical Center in Kansas City, and his colleagues examined the safety and efficacy of noninvasive neuromodulation for hand tremor in patients with essential tremor. To provide treatment, they used a wristband with three electrodes that targeted the median and radial nerves. The stimulation pattern was adjusted to interrupt each patient’s tremulous signal in the clinical setting and at home. Participants were asked to hold a certain posture for 20 seconds while the device recorded tremor frequency. After determining the peak tremor frequency, the device was able to adapt stimulation parameters to each patient.

Dr. Pahwa and his colleagues conducted an acute in-office study and an at-home study. In the in-office study, 77 participants were randomized to peripheral nerve treatment or sham stimulation of the tremor-dominant hand. The researchers evaluated tremor before and after one stimulation session using the Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb Tremor Scale and the TETRAS Archimedes Spiral Rating Scale. In the at-home study, 61 participants were randomized to stimulation, sham, or standard of care for 2 weeks. After that point, all participants underwent two to five 40-minute stimulation sessions daily for 2 weeks. Patients in the treatment and sham groups had at least two sessions per day.

In the in-office study, the researchers randomized 40 patients to stimulation and 37 patients to sham. Dr. Pahwa and his colleagues determined that participants had been blinded successfully. The investigators observed a mean improvement in forward posture of approximately 0.75 points among treated patients, compared with a mean improvement of 0.3 points in the sham group. The difference between groups was statistically significant. Treated patients had significant improvements in upper limb tremor score and total performance score, compared with the sham group. The investigators also observed greater mean improvements in spiral drawing, lateral posture, and movement among treated patients, compared with the sham group, but the differences were not statistically significant.

Participants in the in-office study rated their improvement on activities of daily living. Average improvement across tasks was significantly greater for the treated group, compared to the sham group. Improvement on each individual task also was greater for the treated group than the sham group. The differences in improvement were significant for holding a cup of tea, dialing a telephone, picking up change, and unlocking a door with a key.

In the at-home study, the decrease in tremor amplitude, as measured by the wrist-worn device, was significantly greater among participants who received stimulation than in the sham group. “These randomized, controlled studies suggest that noninvasive peripheral neuromodulation may offer meaningful symptomatic relief from hand tremor in essential tremor with a favorable safety profile, compared to other available therapies,” noted Dr. Pahwa and his colleagues. “At-home monitoring may provide key insights into evaluating and treating tremor,” they added.

The studies were supported by Cala Health.

egreb@mdedge.com

Pap tests have the reputation of being a simple, noninvasive, low-cost test to offer patients, and, therefore, it is understandable to believe there is no harm in offering it in all situations. However, if inappropriately applied in isolation, performing the Pap test may do more harm than good.

monkeybusinessimages/iStock/Getty Images

I recently saw a patient in consultation for cervical cancer. Her story was similar to one I’ve seen many times before. She was a 30-year-old non–English-speaking Hispanic woman who received regular care from the health department clinics.

In April of the prior year, she had noticed abnormal bleeding symptoms including intermenstrual and postcoital bleeding. She visited the health department and reported these symptoms to the provider who performed an examination. According to the provider’s notes, the cervix appeared “abnormal” and a Pap test was done. The result of this Pap test was high-grade dysplasia. The patient was promptly notified of the result and an appointment was arranged with the local ob.gyn. for a consultation, presumably for colposcopy and subsequent appropriate excisional procedure. Unfortunately, the patient did not attend that scheduled appointment. She later recounted to me that it was because she had not understood that it was important. She had a long history of abnormal Pap tests which, in the past, had only required repeat testing or minor interventions such as “freezing.”

Her bleeding symptoms became worse, and she developed abnormal discharge and pain. In November, she presented again for evaluation to the same provider. Now her cervix appeared very abnormal and was described as a “crater.” Again a Pap test was done. This time the Pap test showed “carcinoma,” and the patient was informed that she had cancer and was referred to gynecologic oncology. When I examined this unfortunate young woman, I discovered a 10 cm, stage IIB very locally advanced tumor. She is currently receiving primary chemotherapy/radiation with an approximately 60% probability of cure, and a high likelihood of lifelong sequelae of this toxic therapy.

This case highlights that, even when patients are engaged within our health care system, we can miss the opportunity to diagnose early-stage cancers if we are not utilizing screening versus diagnostic tests appropriately.

The purpose of a Pap test is as a screening test, which are designed to detect disease in asymptomatic individuals. The accuracy of these tests is determined in low-risk (asymptomatic) populations, which influences the pretest probability of disease. In asymptomatic patients with a normal screening test, it is safe to wait out the interval of time for the repeat screening test, because the combination of a low pretest probability and a high sensitivity of the test in finding disease means that there is a very low chance of missing disease.

Dysplasia rarely causes bleeding. However, invasive cervical cancer does. If a patient has a symptom such as abnormal bleeding, they no longer fit into the population with a low pretest probability for having cervical cancer. This same sensitivity of the Pap test in finding disease, combined with the now-higher pretest probability can raise the level of false-negative results to unacceptably high levels.

Patients with symptoms of cervical cancer should not receive screening tests exclusively; they should receive diagnostic tests. For example, Pap tests should not be used in isolation to diagnose pathology in patients with abnormal bleeding or discharge, just as screening mammograms should not be ordered in patients with symptomatic breast lumps, nipple discharge, retraction, etc. (these women should be referred for diagnostic mammography and ultrasound). It is not unusual for gynecologic oncologists to see patients with visible invasive cervical cancer who have only cervical intraepithelial neoplasia grade 3 on the preceding Pap test. There is a 34% positive predictive value that a cervical cancer will be found with a high-grade dysplastic Pap test.¹ Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. It analyzes individual cells rather than a piece of tissue with intercellular relationships.

The take-home message for this column is that, if a provider sees an abnormal lesion on a cervix, they should biopsy the visible lesion to obtain a histologic diagnosis. Simply performing a Pap test alone may result in false reassurance and in underestimating the severity of disease.

Some providers will tell me that they have concerns about performing a biopsy on a grossly abnormal cervix for fear that the subsequent bleeding will be difficult to manage in the outpatient setting. This is understandable, although it is unlikely that an office equipped with the ability to perform colposcopy or excisional procedures would not have the necessary equipment to manage this. Prolonged pressure applied to the cervix with topical hemostatic agents or – in extreme cases – vaginal packing with gauze always has been effective for me in these circumstances.

The additional benefit of establishing histologic confirmation prior to referral is expediting care, including additional imaging and referrals to treating providers. If the diagnosis is inadequately established prior to their appointment with a gynecologic oncologist, it can add further delays before definitive surgical or nonsurgical management can be initiated, which is particularly problematic if the patient is experiencing severe bleeding. If the provider feels uncomfortable with proceeding with biopsy, they should inform the patient very clearly that they suspect that there is a cancer of the cervix, and it needs attention from a cancer specialist to confirm the diagnosis. This clear communication will minimize the likelihood that the patient may not show up for the subsequent appointments before her diagnosis is definitively established.

Another common scenario in which Pap tests are inappropriately applied is in the surveillance of endometrial cancer. In 2013, the Society of Gynecologic Oncology released its five “Choosing Wisely” recommendations. This included the recommendation to not perform Pap tests in the surveillance of endometrial cancer. This recommendation was based on a body of evidence that demonstrates screening for endometrial cancer recurrence with Pap smears does not detect vaginal mucosal recurrences any sooner than visualization of lesions on speculum examination.^2,3 These Pap-positive recurrences almost always are visible on exam. Additionally, false positives are common in this population, particularly among women who have had radiation or have atrophic tissues.

Using Pap tests for the surveillance of cervical cancer is somewhat more complicated. Similarly, they do not detect cervical cancer recurrence any sooner than comprehensive examination does. However, this population may suffer from chronic human papillomavirus (HPV) infection, and there remains a role of the Pap test in screening for future, new HPV-related preinvasive vaginal disease. Therefore, Pap tests, and/or HPV testing can be offered to cervical cancer survivors in accordance with the American Society for Colposcopy and Cervical Pathology guidelines for noncervical cancer patients, with the caveat that, if radiation has been given, false positives are more likely.²

Pap tests clearly have an important role as a screening test in asymptomatic individuals. However, when the patient has a symptom that might be cervical cancer or a visibly suspicious lesion, she should receive a diagnostic test, and Pap tests are not designed for that purpose.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.

References

1. Cytopathology. 2016 Jun;27(3):201-9.

2. Gynecol Oncol. 2017 Jul;146(1):3-10.

3. Gynecol Oncol. 2011 Nov;123(2):205-7.

Pap tests have the reputation of being a simple, noninvasive, low-cost test to offer patients, and, therefore, it is understandable to believe there is no harm in offering it in all situations. However, if inappropriately applied in isolation, performing the Pap test may do more harm than good.

monkeybusinessimages/iStock/Getty Images

I recently saw a patient in consultation for cervical cancer. Her story was similar to one I’ve seen many times before. She was a 30-year-old non–English-speaking Hispanic woman who received regular care from the health department clinics.

In April of the prior year, she had noticed abnormal bleeding symptoms including intermenstrual and postcoital bleeding. She visited the health department and reported these symptoms to the provider who performed an examination. According to the provider’s notes, the cervix appeared “abnormal” and a Pap test was done. The result of this Pap test was high-grade dysplasia. The patient was promptly notified of the result and an appointment was arranged with the local ob.gyn. for a consultation, presumably for colposcopy and subsequent appropriate excisional procedure. Unfortunately, the patient did not attend that scheduled appointment. She later recounted to me that it was because she had not understood that it was important. She had a long history of abnormal Pap tests which, in the past, had only required repeat testing or minor interventions such as “freezing.”

Her bleeding symptoms became worse, and she developed abnormal discharge and pain. In November, she presented again for evaluation to the same provider. Now her cervix appeared very abnormal and was described as a “crater.” Again a Pap test was done. This time the Pap test showed “carcinoma,” and the patient was informed that she had cancer and was referred to gynecologic oncology. When I examined this unfortunate young woman, I discovered a 10 cm, stage IIB very locally advanced tumor. She is currently receiving primary chemotherapy/radiation with an approximately 60% probability of cure, and a high likelihood of lifelong sequelae of this toxic therapy.

This case highlights that, even when patients are engaged within our health care system, we can miss the opportunity to diagnose early-stage cancers if we are not utilizing screening versus diagnostic tests appropriately.

The purpose of a Pap test is as a screening test, which are designed to detect disease in asymptomatic individuals. The accuracy of these tests is determined in low-risk (asymptomatic) populations, which influences the pretest probability of disease. In asymptomatic patients with a normal screening test, it is safe to wait out the interval of time for the repeat screening test, because the combination of a low pretest probability and a high sensitivity of the test in finding disease means that there is a very low chance of missing disease.

Dysplasia rarely causes bleeding. However, invasive cervical cancer does. If a patient has a symptom such as abnormal bleeding, they no longer fit into the population with a low pretest probability for having cervical cancer. This same sensitivity of the Pap test in finding disease, combined with the now-higher pretest probability can raise the level of false-negative results to unacceptably high levels.

Patients with symptoms of cervical cancer should not receive screening tests exclusively; they should receive diagnostic tests. For example, Pap tests should not be used in isolation to diagnose pathology in patients with abnormal bleeding or discharge, just as screening mammograms should not be ordered in patients with symptomatic breast lumps, nipple discharge, retraction, etc. (these women should be referred for diagnostic mammography and ultrasound). It is not unusual for gynecologic oncologists to see patients with visible invasive cervical cancer who have only cervical intraepithelial neoplasia grade 3 on the preceding Pap test. There is a 34% positive predictive value that a cervical cancer will be found with a high-grade dysplastic Pap test.¹ Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. It analyzes individual cells rather than a piece of tissue with intercellular relationships.

The take-home message for this column is that, if a provider sees an abnormal lesion on a cervix, they should biopsy the visible lesion to obtain a histologic diagnosis. Simply performing a Pap test alone may result in false reassurance and in underestimating the severity of disease.

Some providers will tell me that they have concerns about performing a biopsy on a grossly abnormal cervix for fear that the subsequent bleeding will be difficult to manage in the outpatient setting. This is understandable, although it is unlikely that an office equipped with the ability to perform colposcopy or excisional procedures would not have the necessary equipment to manage this. Prolonged pressure applied to the cervix with topical hemostatic agents or – in extreme cases – vaginal packing with gauze always has been effective for me in these circumstances.

The additional benefit of establishing histologic confirmation prior to referral is expediting care, including additional imaging and referrals to treating providers. If the diagnosis is inadequately established prior to their appointment with a gynecologic oncologist, it can add further delays before definitive surgical or nonsurgical management can be initiated, which is particularly problematic if the patient is experiencing severe bleeding. If the provider feels uncomfortable with proceeding with biopsy, they should inform the patient very clearly that they suspect that there is a cancer of the cervix, and it needs attention from a cancer specialist to confirm the diagnosis. This clear communication will minimize the likelihood that the patient may not show up for the subsequent appointments before her diagnosis is definitively established.

Another common scenario in which Pap tests are inappropriately applied is in the surveillance of endometrial cancer. In 2013, the Society of Gynecologic Oncology released its five “Choosing Wisely” recommendations. This included the recommendation to not perform Pap tests in the surveillance of endometrial cancer. This recommendation was based on a body of evidence that demonstrates screening for endometrial cancer recurrence with Pap smears does not detect vaginal mucosal recurrences any sooner than visualization of lesions on speculum examination.^2,3 These Pap-positive recurrences almost always are visible on exam. Additionally, false positives are common in this population, particularly among women who have had radiation or have atrophic tissues.

Using Pap tests for the surveillance of cervical cancer is somewhat more complicated. Similarly, they do not detect cervical cancer recurrence any sooner than comprehensive examination does. However, this population may suffer from chronic human papillomavirus (HPV) infection, and there remains a role of the Pap test in screening for future, new HPV-related preinvasive vaginal disease. Therefore, Pap tests, and/or HPV testing can be offered to cervical cancer survivors in accordance with the American Society for Colposcopy and Cervical Pathology guidelines for noncervical cancer patients, with the caveat that, if radiation has been given, false positives are more likely.²

Pap tests clearly have an important role as a screening test in asymptomatic individuals. However, when the patient has a symptom that might be cervical cancer or a visibly suspicious lesion, she should receive a diagnostic test, and Pap tests are not designed for that purpose.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.

References

1. Cytopathology. 2016 Jun;27(3):201-9.

2. Gynecol Oncol. 2017 Jul;146(1):3-10.

3. Gynecol Oncol. 2011 Nov;123(2):205-7.

Pap tests have the reputation of being a simple, noninvasive, low-cost test to offer patients, and, therefore, it is understandable to believe there is no harm in offering it in all situations. However, if inappropriately applied in isolation, performing the Pap test may do more harm than good.

monkeybusinessimages/iStock/Getty Images

I recently saw a patient in consultation for cervical cancer. Her story was similar to one I’ve seen many times before. She was a 30-year-old non–English-speaking Hispanic woman who received regular care from the health department clinics.

In April of the prior year, she had noticed abnormal bleeding symptoms including intermenstrual and postcoital bleeding. She visited the health department and reported these symptoms to the provider who performed an examination. According to the provider’s notes, the cervix appeared “abnormal” and a Pap test was done. The result of this Pap test was high-grade dysplasia. The patient was promptly notified of the result and an appointment was arranged with the local ob.gyn. for a consultation, presumably for colposcopy and subsequent appropriate excisional procedure. Unfortunately, the patient did not attend that scheduled appointment. She later recounted to me that it was because she had not understood that it was important. She had a long history of abnormal Pap tests which, in the past, had only required repeat testing or minor interventions such as “freezing.”

Her bleeding symptoms became worse, and she developed abnormal discharge and pain. In November, she presented again for evaluation to the same provider. Now her cervix appeared very abnormal and was described as a “crater.” Again a Pap test was done. This time the Pap test showed “carcinoma,” and the patient was informed that she had cancer and was referred to gynecologic oncology. When I examined this unfortunate young woman, I discovered a 10 cm, stage IIB very locally advanced tumor. She is currently receiving primary chemotherapy/radiation with an approximately 60% probability of cure, and a high likelihood of lifelong sequelae of this toxic therapy.

This case highlights that, even when patients are engaged within our health care system, we can miss the opportunity to diagnose early-stage cancers if we are not utilizing screening versus diagnostic tests appropriately.

The purpose of a Pap test is as a screening test, which are designed to detect disease in asymptomatic individuals. The accuracy of these tests is determined in low-risk (asymptomatic) populations, which influences the pretest probability of disease. In asymptomatic patients with a normal screening test, it is safe to wait out the interval of time for the repeat screening test, because the combination of a low pretest probability and a high sensitivity of the test in finding disease means that there is a very low chance of missing disease.

Dysplasia rarely causes bleeding. However, invasive cervical cancer does. If a patient has a symptom such as abnormal bleeding, they no longer fit into the population with a low pretest probability for having cervical cancer. This same sensitivity of the Pap test in finding disease, combined with the now-higher pretest probability can raise the level of false-negative results to unacceptably high levels.

Patients with symptoms of cervical cancer should not receive screening tests exclusively; they should receive diagnostic tests. For example, Pap tests should not be used in isolation to diagnose pathology in patients with abnormal bleeding or discharge, just as screening mammograms should not be ordered in patients with symptomatic breast lumps, nipple discharge, retraction, etc. (these women should be referred for diagnostic mammography and ultrasound). It is not unusual for gynecologic oncologists to see patients with visible invasive cervical cancer who have only cervical intraepithelial neoplasia grade 3 on the preceding Pap test. There is a 34% positive predictive value that a cervical cancer will be found with a high-grade dysplastic Pap test.¹ Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. Cytology is an inferior diagnostic tool, compared with histology, in determining invasive cancer from preinvasive lesions. It analyzes individual cells rather than a piece of tissue with intercellular relationships.

The take-home message for this column is that, if a provider sees an abnormal lesion on a cervix, they should biopsy the visible lesion to obtain a histologic diagnosis. Simply performing a Pap test alone may result in false reassurance and in underestimating the severity of disease.

Some providers will tell me that they have concerns about performing a biopsy on a grossly abnormal cervix for fear that the subsequent bleeding will be difficult to manage in the outpatient setting. This is understandable, although it is unlikely that an office equipped with the ability to perform colposcopy or excisional procedures would not have the necessary equipment to manage this. Prolonged pressure applied to the cervix with topical hemostatic agents or – in extreme cases – vaginal packing with gauze always has been effective for me in these circumstances.

The additional benefit of establishing histologic confirmation prior to referral is expediting care, including additional imaging and referrals to treating providers. If the diagnosis is inadequately established prior to their appointment with a gynecologic oncologist, it can add further delays before definitive surgical or nonsurgical management can be initiated, which is particularly problematic if the patient is experiencing severe bleeding. If the provider feels uncomfortable with proceeding with biopsy, they should inform the patient very clearly that they suspect that there is a cancer of the cervix, and it needs attention from a cancer specialist to confirm the diagnosis. This clear communication will minimize the likelihood that the patient may not show up for the subsequent appointments before her diagnosis is definitively established.

Another common scenario in which Pap tests are inappropriately applied is in the surveillance of endometrial cancer. In 2013, the Society of Gynecologic Oncology released its five “Choosing Wisely” recommendations. This included the recommendation to not perform Pap tests in the surveillance of endometrial cancer. This recommendation was based on a body of evidence that demonstrates screening for endometrial cancer recurrence with Pap smears does not detect vaginal mucosal recurrences any sooner than visualization of lesions on speculum examination.^2,3 These Pap-positive recurrences almost always are visible on exam. Additionally, false positives are common in this population, particularly among women who have had radiation or have atrophic tissues.

Using Pap tests for the surveillance of cervical cancer is somewhat more complicated. Similarly, they do not detect cervical cancer recurrence any sooner than comprehensive examination does. However, this population may suffer from chronic human papillomavirus (HPV) infection, and there remains a role of the Pap test in screening for future, new HPV-related preinvasive vaginal disease. Therefore, Pap tests, and/or HPV testing can be offered to cervical cancer survivors in accordance with the American Society for Colposcopy and Cervical Pathology guidelines for noncervical cancer patients, with the caveat that, if radiation has been given, false positives are more likely.²

Pap tests clearly have an important role as a screening test in asymptomatic individuals. However, when the patient has a symptom that might be cervical cancer or a visibly suspicious lesion, she should receive a diagnostic test, and Pap tests are not designed for that purpose.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no conflicts of interest. Email Dr. Rossi at obnews@mdedge.com.

References

1. Cytopathology. 2016 Jun;27(3):201-9.

2. Gynecol Oncol. 2017 Jul;146(1):3-10.

3. Gynecol Oncol. 2011 Nov;123(2):205-7.

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with obinutuzumab to treat adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This is the tenth FDA approval for ibrutinib, a Bruton tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Biotech.

The approval is supported by the phase 3 iLLUMINATE trial (NCT02264574).

Results from this study were recently presented at the annual meeting of the American Society of Hematology (Blood. 2018;132:691) and published in the Lancet Oncology (2019 Jan;20[1]:43-56).

The iLLUMINATE trial enrolled newly diagnosed CLL patients who were randomized to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The median follow-up was 31.3 months. The overall response rate was 88% in the ibrutinib arm and 73% in the chlorambucil arm. The complete response rate, including complete response with incomplete marrow recovery, was 19% and 8%, respectively.

The median progression-free survival was not reached in the ibrutinib arm and was 19.0 months in the chlorambucil arm (hazard ratio, 0.23; 95% confidence interval, 0.15-0.37; P less than .0001). The estimated 30-month progression-free survival was 79% and 31%, respectively.

The most common grade 3/4 adverse events in both arms were neutropenia (36% in the ibrutinib arm and 46% in the chlorambucil arm) and thrombocytopenia (19% and 10%, respectively).

There were 10 deaths caused by adverse events in the ibrutinib arm and 3 in the chlorambucil arm. One death was considered possibly related to ibrutinib (sudden death), and another was considered possibly related to chlorambucil (neuroendocrine carcinoma of the skin).

jensmith@mdedge.com

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with obinutuzumab to treat adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This is the tenth FDA approval for ibrutinib, a Bruton tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Biotech.

The approval is supported by the phase 3 iLLUMINATE trial (NCT02264574).

Results from this study were recently presented at the annual meeting of the American Society of Hematology (Blood. 2018;132:691) and published in the Lancet Oncology (2019 Jan;20[1]:43-56).

The iLLUMINATE trial enrolled newly diagnosed CLL patients who were randomized to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The median follow-up was 31.3 months. The overall response rate was 88% in the ibrutinib arm and 73% in the chlorambucil arm. The complete response rate, including complete response with incomplete marrow recovery, was 19% and 8%, respectively.

The median progression-free survival was not reached in the ibrutinib arm and was 19.0 months in the chlorambucil arm (hazard ratio, 0.23; 95% confidence interval, 0.15-0.37; P less than .0001). The estimated 30-month progression-free survival was 79% and 31%, respectively.

The most common grade 3/4 adverse events in both arms were neutropenia (36% in the ibrutinib arm and 46% in the chlorambucil arm) and thrombocytopenia (19% and 10%, respectively).

There were 10 deaths caused by adverse events in the ibrutinib arm and 3 in the chlorambucil arm. One death was considered possibly related to ibrutinib (sudden death), and another was considered possibly related to chlorambucil (neuroendocrine carcinoma of the skin).

jensmith@mdedge.com

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with obinutuzumab to treat adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

This is the tenth FDA approval for ibrutinib, a Bruton tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Biotech.

The approval is supported by the phase 3 iLLUMINATE trial (NCT02264574).

Results from this study were recently presented at the annual meeting of the American Society of Hematology (Blood. 2018;132:691) and published in the Lancet Oncology (2019 Jan;20[1]:43-56).

The iLLUMINATE trial enrolled newly diagnosed CLL patients who were randomized to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116).

The median follow-up was 31.3 months. The overall response rate was 88% in the ibrutinib arm and 73% in the chlorambucil arm. The complete response rate, including complete response with incomplete marrow recovery, was 19% and 8%, respectively.

The median progression-free survival was not reached in the ibrutinib arm and was 19.0 months in the chlorambucil arm (hazard ratio, 0.23; 95% confidence interval, 0.15-0.37; P less than .0001). The estimated 30-month progression-free survival was 79% and 31%, respectively.

The most common grade 3/4 adverse events in both arms were neutropenia (36% in the ibrutinib arm and 46% in the chlorambucil arm) and thrombocytopenia (19% and 10%, respectively).

There were 10 deaths caused by adverse events in the ibrutinib arm and 3 in the chlorambucil arm. One death was considered possibly related to ibrutinib (sudden death), and another was considered possibly related to chlorambucil (neuroendocrine carcinoma of the skin).

jensmith@mdedge.com

Age, symptom severity, and serum glucose do not influence the benefit of endovascular thrombectomy for patients with stroke, according to research published online ahead of print Jan. 28 in JAMA Neurology. The location of the arterial occlusive lesion and the imaging technique used to select patients for the procedure also do not influence the therapy’s benefits, the researchers said. Although the proportional benefit of thrombectomy plus medical management is uniform across subgroups, compared with medical management alone, patients may have different amounts of absolute benefit.

The results of the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial, which were published in 2018, indicated that endovascular thrombectomy provided clinical benefits for patients with acute ischemic stroke if administered at 6-16 hours after stroke onset. As part of the trial’s prespecified analyses, Maarten G. Lansberg, MD, PhD, associate professor of neurology and neurological sciences at Stanford (Calif.) University Medical Center in California, and his colleagues sought to determine whether thrombectomy had uniform benefit among various patient subgroups (e.g., elderly people, patients with mild symptoms, and those who present late after onset).

A total of 296 patients were enrolled in the randomized, open-label, blinded-endpoint DEFUSE 3 trial at 38 sites in the United States. Eligible participants had acute ischemic stroke resulting from an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion CT or MRI. In all, 182 patients met these criteria and were randomized and included in the intention-to-treat analysis. The researchers stopped DEFUSE 3 early because of efficacy.

The study’s primary endpoint was functional outcome at day 90, as measured with the modified Rankin Scale. Dr. Lansberg and his colleagues performed multivariate ordinal logistic regression to calculate the adjusted proportional association between endovascular treatment and clinical outcome among participants of various ages, baseline stroke severities, periods between onset and treatment, locations of the arterial occlusion, and imaging modalities, such as CT or MRI, used to identify salvageable tissue.

The population’s median age was 70 years, and 51% of participants were women. The median National Institutes of Health Stroke Scale score was 16. When the researchers considered the whole sample, they found that younger age, lower baseline NIHSS score, and lower serum glucose level independently predicted better functional outcome. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1. Age, NIHSS score, time to randomization, imaging modality, and location of the arterial occlusion did not interact significantly with treatment effect.

“Our results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy, provided that the patient is fully independent prior to stroke onset,” said the researchers. “Although age did not modify the treatment effect, it was a strong independent predictor of 90-day disability, which is consistent with prior studies of both tissue plasminogen activator and endovascular therapy.”

The trial’s small sample size may have allowed small differences between groups to pass unnoticed, said the reseachers. Other trials of late-window thrombectomy will be required to validate these results, they concluded.

The National Institute for Neurological Disorders and Stroke supported the study through grants. Several investigators received consulting fees from and hold shares in iSchemaView, which manufactures the software that the investigators used for postprocessing of CT and MRI perfusion studies. Other authors received consulting fees from various pharmaceutical and medical device companies, including Genentech, Medtronic, Pfizer, and Stryker Neurovascular.

egreb@mdedge.com

SOURCE: Lansberg MG et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4587.

Age, symptom severity, and serum glucose do not influence the benefit of endovascular thrombectomy for patients with stroke, according to research published online ahead of print Jan. 28 in JAMA Neurology. The location of the arterial occlusive lesion and the imaging technique used to select patients for the procedure also do not influence the therapy’s benefits, the researchers said. Although the proportional benefit of thrombectomy plus medical management is uniform across subgroups, compared with medical management alone, patients may have different amounts of absolute benefit.

The results of the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial, which were published in 2018, indicated that endovascular thrombectomy provided clinical benefits for patients with acute ischemic stroke if administered at 6-16 hours after stroke onset. As part of the trial’s prespecified analyses, Maarten G. Lansberg, MD, PhD, associate professor of neurology and neurological sciences at Stanford (Calif.) University Medical Center in California, and his colleagues sought to determine whether thrombectomy had uniform benefit among various patient subgroups (e.g., elderly people, patients with mild symptoms, and those who present late after onset).

A total of 296 patients were enrolled in the randomized, open-label, blinded-endpoint DEFUSE 3 trial at 38 sites in the United States. Eligible participants had acute ischemic stroke resulting from an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion CT or MRI. In all, 182 patients met these criteria and were randomized and included in the intention-to-treat analysis. The researchers stopped DEFUSE 3 early because of efficacy.

The study’s primary endpoint was functional outcome at day 90, as measured with the modified Rankin Scale. Dr. Lansberg and his colleagues performed multivariate ordinal logistic regression to calculate the adjusted proportional association between endovascular treatment and clinical outcome among participants of various ages, baseline stroke severities, periods between onset and treatment, locations of the arterial occlusion, and imaging modalities, such as CT or MRI, used to identify salvageable tissue.

The population’s median age was 70 years, and 51% of participants were women. The median National Institutes of Health Stroke Scale score was 16. When the researchers considered the whole sample, they found that younger age, lower baseline NIHSS score, and lower serum glucose level independently predicted better functional outcome. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1. Age, NIHSS score, time to randomization, imaging modality, and location of the arterial occlusion did not interact significantly with treatment effect.

“Our results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy, provided that the patient is fully independent prior to stroke onset,” said the researchers. “Although age did not modify the treatment effect, it was a strong independent predictor of 90-day disability, which is consistent with prior studies of both tissue plasminogen activator and endovascular therapy.”

The trial’s small sample size may have allowed small differences between groups to pass unnoticed, said the reseachers. Other trials of late-window thrombectomy will be required to validate these results, they concluded.

The National Institute for Neurological Disorders and Stroke supported the study through grants. Several investigators received consulting fees from and hold shares in iSchemaView, which manufactures the software that the investigators used for postprocessing of CT and MRI perfusion studies. Other authors received consulting fees from various pharmaceutical and medical device companies, including Genentech, Medtronic, Pfizer, and Stryker Neurovascular.

egreb@mdedge.com

SOURCE: Lansberg MG et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4587.

Age, symptom severity, and serum glucose do not influence the benefit of endovascular thrombectomy for patients with stroke, according to research published online ahead of print Jan. 28 in JAMA Neurology. The location of the arterial occlusive lesion and the imaging technique used to select patients for the procedure also do not influence the therapy’s benefits, the researchers said. Although the proportional benefit of thrombectomy plus medical management is uniform across subgroups, compared with medical management alone, patients may have different amounts of absolute benefit.

The results of the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial, which were published in 2018, indicated that endovascular thrombectomy provided clinical benefits for patients with acute ischemic stroke if administered at 6-16 hours after stroke onset. As part of the trial’s prespecified analyses, Maarten G. Lansberg, MD, PhD, associate professor of neurology and neurological sciences at Stanford (Calif.) University Medical Center in California, and his colleagues sought to determine whether thrombectomy had uniform benefit among various patient subgroups (e.g., elderly people, patients with mild symptoms, and those who present late after onset).

A total of 296 patients were enrolled in the randomized, open-label, blinded-endpoint DEFUSE 3 trial at 38 sites in the United States. Eligible participants had acute ischemic stroke resulting from an occlusion of the internal carotid artery or middle cerebral artery and evidence of salvageable tissue on perfusion CT or MRI. In all, 182 patients met these criteria and were randomized and included in the intention-to-treat analysis. The researchers stopped DEFUSE 3 early because of efficacy.

The study’s primary endpoint was functional outcome at day 90, as measured with the modified Rankin Scale. Dr. Lansberg and his colleagues performed multivariate ordinal logistic regression to calculate the adjusted proportional association between endovascular treatment and clinical outcome among participants of various ages, baseline stroke severities, periods between onset and treatment, locations of the arterial occlusion, and imaging modalities, such as CT or MRI, used to identify salvageable tissue.

The population’s median age was 70 years, and 51% of participants were women. The median National Institutes of Health Stroke Scale score was 16. When the researchers considered the whole sample, they found that younger age, lower baseline NIHSS score, and lower serum glucose level independently predicted better functional outcome. The common odds ratio for improved functional outcome with endovascular therapy, adjusted for these variables, was 3.1. Age, NIHSS score, time to randomization, imaging modality, and location of the arterial occlusion did not interact significantly with treatment effect.

“Our results indicate that advanced age, up to 90 years, should not be considered a contraindication to thrombectomy, provided that the patient is fully independent prior to stroke onset,” said the researchers. “Although age did not modify the treatment effect, it was a strong independent predictor of 90-day disability, which is consistent with prior studies of both tissue plasminogen activator and endovascular therapy.”

The trial’s small sample size may have allowed small differences between groups to pass unnoticed, said the reseachers. Other trials of late-window thrombectomy will be required to validate these results, they concluded.

The National Institute for Neurological Disorders and Stroke supported the study through grants. Several investigators received consulting fees from and hold shares in iSchemaView, which manufactures the software that the investigators used for postprocessing of CT and MRI perfusion studies. Other authors received consulting fees from various pharmaceutical and medical device companies, including Genentech, Medtronic, Pfizer, and Stryker Neurovascular.

egreb@mdedge.com

SOURCE: Lansberg MG et al. JAMA Neurol. 2019 Jan 28. doi: 10.1001/jamaneurol.2018.4587.