In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

REFERENCES

1. Weng MK. Universal adult hepatitis B vaccinations: work group considerations. Presented to the Advisory Committee on Immunization Practices on November 3, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf
2. Kovayashi M. Considerations for age-based and risk-based use of PCV15 and PCV20 among US adults and proposed policy options. Presented to the Advisory Committee on Immunization Practices on October 20, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-10-20-21/02-Pneumococcal-Kobayashi-508.pdf
3. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67:1-31.
4. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep. 2019;68:1069-1075.

REFERENCES

1. Weng MK. Universal adult hepatitis B vaccinations: work group considerations. Presented to the Advisory Committee on Immunization Practices on November 3, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf
2. Kovayashi M. Considerations for age-based and risk-based use of PCV15 and PCV20 among US adults and proposed policy options. Presented to the Advisory Committee on Immunization Practices on October 20, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-10-20-21/02-Pneumococcal-Kobayashi-508.pdf
3. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67:1-31.
4. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep. 2019;68:1069-1075.

REFERENCES

1. Weng MK. Universal adult hepatitis B vaccinations: work group considerations. Presented to the Advisory Committee on Immunization Practices on November 3, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/02-HepWG-weng-508.pdf
2. Kovayashi M. Considerations for age-based and risk-based use of PCV15 and PCV20 among US adults and proposed policy options. Presented to the Advisory Committee on Immunization Practices on October 20, 2021. Accessed November 17, 2021. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-10-20-21/02-Pneumococcal-Kobayashi-508.pdf
3. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67:1-31.
4. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morbid Mortal Wkly Rep. 2019;68:1069-1075.

An analysis of open-access skin image datasets available to train machine-learning algorithms to identify skin cancer has revealed that darker skin types are markedly underrepresented in the databases, researchers in the United Kingdom report.

Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”

In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”

The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”

Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).

The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.

“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”

There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”

While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.

“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.

Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”

“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.

‘We need more images of everybody’

Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.

“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.

He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.

A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”

“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”

While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.

“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.

A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.

“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.

Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.

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

An analysis of open-access skin image datasets available to train machine-learning algorithms to identify skin cancer has revealed that darker skin types are markedly underrepresented in the databases, researchers in the United Kingdom report.

Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”

In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”

The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”

Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).

The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.

“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”

There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”

While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.

“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.

Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”

“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.

‘We need more images of everybody’

Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.

“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.

He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.

A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”

“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”

While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.

“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.

A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.

“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.

Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.

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

An analysis of open-access skin image datasets available to train machine-learning algorithms to identify skin cancer has revealed that darker skin types are markedly underrepresented in the databases, researchers in the United Kingdom report.

Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”

In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”

The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”

Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).

The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.

“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”

There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”

While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.

“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.

Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”

“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.

‘We need more images of everybody’

Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.

“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.

He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.

A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.

Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”

“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”

While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.

“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.

A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.

“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.

Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.

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

Background: Though most PEs do not have significant complications, 15% may be associated with risk of death or hemodynamic compromise. Retrospectively derived risk scores are used to risk-stratify patients and guide acute treatment strategies. It is unclear how well existing risk scores estimate mortality outcomes in patients with acute PE. 

Dr. Korovaichuk is a hospitalist at Northwestern Memorial Hospital and assistant professor of medicine, Feinberg School of Medicine, both in Chicago.

Background: Though most PEs do not have significant complications, 15% may be associated with risk of death or hemodynamic compromise. Retrospectively derived risk scores are used to risk-stratify patients and guide acute treatment strategies. It is unclear how well existing risk scores estimate mortality outcomes in patients with acute PE. 

Dr. Korovaichuk is a hospitalist at Northwestern Memorial Hospital and assistant professor of medicine, Feinberg School of Medicine, both in Chicago.

Background: Though most PEs do not have significant complications, 15% may be associated with risk of death or hemodynamic compromise. Retrospectively derived risk scores are used to risk-stratify patients and guide acute treatment strategies. It is unclear how well existing risk scores estimate mortality outcomes in patients with acute PE. 

Dr. Korovaichuk is a hospitalist at Northwestern Memorial Hospital and assistant professor of medicine, Feinberg School of Medicine, both in Chicago.

Sea buckthorn oil continues to show up in skin care products and in skin care blogs. To avoid jumping on the bandwagon of another ingredient trend, we sought to examine the scientific background and properties of sea buckthorn oil and it’s utility for the skin.

Indre Brazauskaite/EyeEm/Getty Images

Sea buckthorn (Hippophae rhamnoides) – also known as a Siberian pineapple tree, and as sandthorn, sallowthorn, or seaberry – is a thorny, dioecious shrub (or tree) in the oleaster family. It can grow up to 23 feet high and is found in coastal sea cliff areas and on mountain slopes of Western Europe, and in dry sandy areas of Asia Minor and Central Asia, Siberia, China, and Tibet. Common sea buckthorn flowers in late April and early May, producing a large number of small, green and brown flowers, turning into edible, usually yellow or orange round berries. The berries have a bitter, sour taste and have a mild aroma, resembling that of a pineapple. The fruit contains a small stone that covers an oily seed.

The berries are a source of antioxidant vitamins, flavonoids, and organic acids, and when pressed, produce a juice that separates into three layers: a thick cream (upper layer), a combination of saturated and unsaturated fatty acids (middle layer), and juice that is a source of fat (lower layer). The berries contain mainly vitamin C, but also vitamin A (alpha- and beta-carotene) and a mixture of other carotenoids, as well as varying concentrations of tocopherols (vitamin E), folic acid, and vitamin B complex–group vitamins.

In addition to flavonoids, the berries contain catechins and procyanidins, cyclitols, phospholipids, tannins, sugars (galactose, fructose, xylose), organic acids (maleic acid, oxalic acid, malic acid, tartaric acid), phenolic acids (such as ferulic acid), and fatty oil. The amount of vitamin C content varies with the variety of the plant and where it is found. The oil of sea buckthorn may be extracted from two parts of the plant, with mechanical cold pressing of seeds (up to 12.5% weight as oil content) and fruit pulp (8%-12% oil content).

Among vegetable oils, sea buckthorn fruit oil has the highest content of palmitoleic acid (omega-7).

Fruit and seed oils contain tocotrienols and plant sterols. Pulp sea buckthorn oil has a high carotenoid content, as opposed to seed oil, and in Mongolia, Russia, and China, is used as a topical therapy for skin burns.

Other significant fatty acids found in sea buckthorn oil are saturated fatty acids (palmitic acid and stearic acid) and polyunsaturated fatty acids, which include alpha-linolenic acid (omega-3), gamma-linolenic acid (omega-6), linolic acid (omega-6), oleic acid (omega-9), and eicosanoic acid (omega-9). Gamma-linoleic acid in particular is reduced in dry skin conditions, such as aging and atopic dermatitis. The human body can produce some gamma-linolenic acid, oleic acid, and palmitoleic acid, but not linolic acid and alpha-linolenic acid. The addition of these substances to diet or skin care has been found to be beneficial in improving dryness and the skin barrier.

In addition, linolic acid, a natural component of human sebum, has been noted to be decreased in the sebum of people with acne-prone skin. Preliminary evidence indicates that dietary supplements containing fatty acids such as docosahexaenoic acid, sea buckthorn oil, and hemp seed oil may decrease the severity of atopic dermatitis.

Besides use in topical skin care and cosmetic preparations, sea buckthorn has also been used successfully in the treatment of chronic gastric ulcer disease, inflammation of the vagina and cervix, and cervical erosion. The bark and leaves of sea buckthorn used to be applied to treat diarrhea and dermatologic conditions, while berry oil has been applied topically or taken orally to soften the skin.

In traditional Indian, Chinese, and Tibetan medicines, sea buckthorn berries are used for medicinal purposes, as their ingredients were thought to have a beneficial effect on the function of the alimentary, respiratory, and circulatory systems. Current studies and uses are now confirming their utility experienced over hundreds of years.

Harvesting sea buckthorn fruit is difficult because of dense thorn arrangement among the berries. Therefore, sometimes the only way to obtain fruit is to remove the entire branch of the shrub, which reduces future crops. For this reason berries can only be harvested once every 2 years.

Sea buckthorn has interesting properties and could be of benefit in topical skin care, as long as it is not overharvested or harvested in a way that has a detrimental impact on the environment.

Dr. Wesley and Lily Talakoub, MD, are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at dermnews@mdedge.com. They had no relevant disclosures.
 

References

United States Department of Agriculture. PLANTS Profile for Hippophae rhamnoides (seaberry). 2007.

Zielińska A and Nowak I. Lipids Health Dis. 2017 May 19;16(1):95.

Reynolds KA et al. Int J Dermatol. 2019 Dec;58(12):1371-6.

Sea buckthorn oil continues to show up in skin care products and in skin care blogs. To avoid jumping on the bandwagon of another ingredient trend, we sought to examine the scientific background and properties of sea buckthorn oil and it’s utility for the skin.

Indre Brazauskaite/EyeEm/Getty Images

Sea buckthorn (Hippophae rhamnoides) – also known as a Siberian pineapple tree, and as sandthorn, sallowthorn, or seaberry – is a thorny, dioecious shrub (or tree) in the oleaster family. It can grow up to 23 feet high and is found in coastal sea cliff areas and on mountain slopes of Western Europe, and in dry sandy areas of Asia Minor and Central Asia, Siberia, China, and Tibet. Common sea buckthorn flowers in late April and early May, producing a large number of small, green and brown flowers, turning into edible, usually yellow or orange round berries. The berries have a bitter, sour taste and have a mild aroma, resembling that of a pineapple. The fruit contains a small stone that covers an oily seed.

The berries are a source of antioxidant vitamins, flavonoids, and organic acids, and when pressed, produce a juice that separates into three layers: a thick cream (upper layer), a combination of saturated and unsaturated fatty acids (middle layer), and juice that is a source of fat (lower layer). The berries contain mainly vitamin C, but also vitamin A (alpha- and beta-carotene) and a mixture of other carotenoids, as well as varying concentrations of tocopherols (vitamin E), folic acid, and vitamin B complex–group vitamins.

In addition to flavonoids, the berries contain catechins and procyanidins, cyclitols, phospholipids, tannins, sugars (galactose, fructose, xylose), organic acids (maleic acid, oxalic acid, malic acid, tartaric acid), phenolic acids (such as ferulic acid), and fatty oil. The amount of vitamin C content varies with the variety of the plant and where it is found. The oil of sea buckthorn may be extracted from two parts of the plant, with mechanical cold pressing of seeds (up to 12.5% weight as oil content) and fruit pulp (8%-12% oil content).

Among vegetable oils, sea buckthorn fruit oil has the highest content of palmitoleic acid (omega-7).

Fruit and seed oils contain tocotrienols and plant sterols. Pulp sea buckthorn oil has a high carotenoid content, as opposed to seed oil, and in Mongolia, Russia, and China, is used as a topical therapy for skin burns.

Other significant fatty acids found in sea buckthorn oil are saturated fatty acids (palmitic acid and stearic acid) and polyunsaturated fatty acids, which include alpha-linolenic acid (omega-3), gamma-linolenic acid (omega-6), linolic acid (omega-6), oleic acid (omega-9), and eicosanoic acid (omega-9). Gamma-linoleic acid in particular is reduced in dry skin conditions, such as aging and atopic dermatitis. The human body can produce some gamma-linolenic acid, oleic acid, and palmitoleic acid, but not linolic acid and alpha-linolenic acid. The addition of these substances to diet or skin care has been found to be beneficial in improving dryness and the skin barrier.

In addition, linolic acid, a natural component of human sebum, has been noted to be decreased in the sebum of people with acne-prone skin. Preliminary evidence indicates that dietary supplements containing fatty acids such as docosahexaenoic acid, sea buckthorn oil, and hemp seed oil may decrease the severity of atopic dermatitis.

Besides use in topical skin care and cosmetic preparations, sea buckthorn has also been used successfully in the treatment of chronic gastric ulcer disease, inflammation of the vagina and cervix, and cervical erosion. The bark and leaves of sea buckthorn used to be applied to treat diarrhea and dermatologic conditions, while berry oil has been applied topically or taken orally to soften the skin.

In traditional Indian, Chinese, and Tibetan medicines, sea buckthorn berries are used for medicinal purposes, as their ingredients were thought to have a beneficial effect on the function of the alimentary, respiratory, and circulatory systems. Current studies and uses are now confirming their utility experienced over hundreds of years.

Harvesting sea buckthorn fruit is difficult because of dense thorn arrangement among the berries. Therefore, sometimes the only way to obtain fruit is to remove the entire branch of the shrub, which reduces future crops. For this reason berries can only be harvested once every 2 years.

Sea buckthorn has interesting properties and could be of benefit in topical skin care, as long as it is not overharvested or harvested in a way that has a detrimental impact on the environment.

Dr. Wesley and Lily Talakoub, MD, are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at dermnews@mdedge.com. They had no relevant disclosures.
 

References

United States Department of Agriculture. PLANTS Profile for Hippophae rhamnoides (seaberry). 2007.

Zielińska A and Nowak I. Lipids Health Dis. 2017 May 19;16(1):95.

Reynolds KA et al. Int J Dermatol. 2019 Dec;58(12):1371-6.

Sea buckthorn oil continues to show up in skin care products and in skin care blogs. To avoid jumping on the bandwagon of another ingredient trend, we sought to examine the scientific background and properties of sea buckthorn oil and it’s utility for the skin.

Indre Brazauskaite/EyeEm/Getty Images

Sea buckthorn (Hippophae rhamnoides) – also known as a Siberian pineapple tree, and as sandthorn, sallowthorn, or seaberry – is a thorny, dioecious shrub (or tree) in the oleaster family. It can grow up to 23 feet high and is found in coastal sea cliff areas and on mountain slopes of Western Europe, and in dry sandy areas of Asia Minor and Central Asia, Siberia, China, and Tibet. Common sea buckthorn flowers in late April and early May, producing a large number of small, green and brown flowers, turning into edible, usually yellow or orange round berries. The berries have a bitter, sour taste and have a mild aroma, resembling that of a pineapple. The fruit contains a small stone that covers an oily seed.

The berries are a source of antioxidant vitamins, flavonoids, and organic acids, and when pressed, produce a juice that separates into three layers: a thick cream (upper layer), a combination of saturated and unsaturated fatty acids (middle layer), and juice that is a source of fat (lower layer). The berries contain mainly vitamin C, but also vitamin A (alpha- and beta-carotene) and a mixture of other carotenoids, as well as varying concentrations of tocopherols (vitamin E), folic acid, and vitamin B complex–group vitamins.

In addition to flavonoids, the berries contain catechins and procyanidins, cyclitols, phospholipids, tannins, sugars (galactose, fructose, xylose), organic acids (maleic acid, oxalic acid, malic acid, tartaric acid), phenolic acids (such as ferulic acid), and fatty oil. The amount of vitamin C content varies with the variety of the plant and where it is found. The oil of sea buckthorn may be extracted from two parts of the plant, with mechanical cold pressing of seeds (up to 12.5% weight as oil content) and fruit pulp (8%-12% oil content).

Among vegetable oils, sea buckthorn fruit oil has the highest content of palmitoleic acid (omega-7).

Fruit and seed oils contain tocotrienols and plant sterols. Pulp sea buckthorn oil has a high carotenoid content, as opposed to seed oil, and in Mongolia, Russia, and China, is used as a topical therapy for skin burns.

Other significant fatty acids found in sea buckthorn oil are saturated fatty acids (palmitic acid and stearic acid) and polyunsaturated fatty acids, which include alpha-linolenic acid (omega-3), gamma-linolenic acid (omega-6), linolic acid (omega-6), oleic acid (omega-9), and eicosanoic acid (omega-9). Gamma-linoleic acid in particular is reduced in dry skin conditions, such as aging and atopic dermatitis. The human body can produce some gamma-linolenic acid, oleic acid, and palmitoleic acid, but not linolic acid and alpha-linolenic acid. The addition of these substances to diet or skin care has been found to be beneficial in improving dryness and the skin barrier.

In addition, linolic acid, a natural component of human sebum, has been noted to be decreased in the sebum of people with acne-prone skin. Preliminary evidence indicates that dietary supplements containing fatty acids such as docosahexaenoic acid, sea buckthorn oil, and hemp seed oil may decrease the severity of atopic dermatitis.

Besides use in topical skin care and cosmetic preparations, sea buckthorn has also been used successfully in the treatment of chronic gastric ulcer disease, inflammation of the vagina and cervix, and cervical erosion. The bark and leaves of sea buckthorn used to be applied to treat diarrhea and dermatologic conditions, while berry oil has been applied topically or taken orally to soften the skin.

In traditional Indian, Chinese, and Tibetan medicines, sea buckthorn berries are used for medicinal purposes, as their ingredients were thought to have a beneficial effect on the function of the alimentary, respiratory, and circulatory systems. Current studies and uses are now confirming their utility experienced over hundreds of years.

Harvesting sea buckthorn fruit is difficult because of dense thorn arrangement among the berries. Therefore, sometimes the only way to obtain fruit is to remove the entire branch of the shrub, which reduces future crops. For this reason berries can only be harvested once every 2 years.

Sea buckthorn has interesting properties and could be of benefit in topical skin care, as long as it is not overharvested or harvested in a way that has a detrimental impact on the environment.

Dr. Wesley and Lily Talakoub, MD, are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at dermnews@mdedge.com. They had no relevant disclosures.
 

References

United States Department of Agriculture. PLANTS Profile for Hippophae rhamnoides (seaberry). 2007.

Zielińska A and Nowak I. Lipids Health Dis. 2017 May 19;16(1):95.

Reynolds KA et al. Int J Dermatol. 2019 Dec;58(12):1371-6.

Surgery offers the best chance of a cure for patients with early cancer and is fundamental to cancer management, but it does not receive enough political and financial recognition, warns a European expert.

In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.

Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.

These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.

The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.

The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.

However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.

The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
 

Best chance of cure

“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.

In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.

There is thus a substantial and steadily growing demand for surgical oncology.

It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.

Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.

It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.

The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.

At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.

Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.

Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”

At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.

Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.

Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.

D’Ugo has disclosed no relevant financial relationships.

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

Surgery offers the best chance of a cure for patients with early cancer and is fundamental to cancer management, but it does not receive enough political and financial recognition, warns a European expert.

In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.

Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.

These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.

The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.

The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.

However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.

The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
 

Best chance of cure

“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.

In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.

There is thus a substantial and steadily growing demand for surgical oncology.

It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.

Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.

It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.

The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.

At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.

Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.

Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”

At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.

Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.

Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.

D’Ugo has disclosed no relevant financial relationships.

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

Surgery offers the best chance of a cure for patients with early cancer and is fundamental to cancer management, but it does not receive enough political and financial recognition, warns a European expert.

In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.

Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.

These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.

The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.

The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.

However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.

The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
 

Best chance of cure

“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.

In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.

There is thus a substantial and steadily growing demand for surgical oncology.

It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.

Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.

It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.

The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.

At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.

Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.

Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”

At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.

Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.

Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.

D’Ugo has disclosed no relevant financial relationships.

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

The first drug to target a KRAS mutation in non-small cell lung cancer (NSCLC) has been recommended for approval in Europe.

At its November meeting, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) endorsed the novel oral therapy sotorasib (Lumykras). The indication is use in the treatment of adults with advanced NSCLC with a KRAS G12C mutation who have progressed after at least one prior line of systemic therapy.

Sotorasib is an inhibitor of KRAS G12C, an oncogenic driver of tumorigenesis. The drug blocks tumor cell signaling and survival, inhibits cell growth, and selectively promotes apoptosis in tumors harboring KRAS G12C, according to the CHMP.

KRAS mutations are the most common mutations in NSCLC tumors, but for a long time appeared to be resistant to drug therapy.  

The KRAS G12C mutation occurs in about 13% of NSCLC mutations.

When clinical data on sotorasib were presented at the 2020 World Conference on Lung Cancer, lung cancer experts greeted the results enthusiastically.

“This is a historic milestone in lung cancer therapy. After four decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” Bob Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York City, said at the time.

The drug was approved by the U.S. Food and Drug Administration in May based on a study of 124 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.

The FDA approval was based on an overall response rate of 36%, the study’s primary outcome. Of the patients who responded, 58% had a duration of response of 6 months or longer.

The EMA says its recommendation for approval is based on objective response rate and response duration data.

The most common side effects of sotorasib are diarrhea, nausea, fatigue, increased aspartate aminotransferase, and arthralgia said the CHMP.

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

The first drug to target a KRAS mutation in non-small cell lung cancer (NSCLC) has been recommended for approval in Europe.

At its November meeting, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) endorsed the novel oral therapy sotorasib (Lumykras). The indication is use in the treatment of adults with advanced NSCLC with a KRAS G12C mutation who have progressed after at least one prior line of systemic therapy.

Sotorasib is an inhibitor of KRAS G12C, an oncogenic driver of tumorigenesis. The drug blocks tumor cell signaling and survival, inhibits cell growth, and selectively promotes apoptosis in tumors harboring KRAS G12C, according to the CHMP.

KRAS mutations are the most common mutations in NSCLC tumors, but for a long time appeared to be resistant to drug therapy.  

The KRAS G12C mutation occurs in about 13% of NSCLC mutations.

When clinical data on sotorasib were presented at the 2020 World Conference on Lung Cancer, lung cancer experts greeted the results enthusiastically.

“This is a historic milestone in lung cancer therapy. After four decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” Bob Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York City, said at the time.

The drug was approved by the U.S. Food and Drug Administration in May based on a study of 124 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.

The FDA approval was based on an overall response rate of 36%, the study’s primary outcome. Of the patients who responded, 58% had a duration of response of 6 months or longer.

The EMA says its recommendation for approval is based on objective response rate and response duration data.

The most common side effects of sotorasib are diarrhea, nausea, fatigue, increased aspartate aminotransferase, and arthralgia said the CHMP.

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

The first drug to target a KRAS mutation in non-small cell lung cancer (NSCLC) has been recommended for approval in Europe.

At its November meeting, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) endorsed the novel oral therapy sotorasib (Lumykras). The indication is use in the treatment of adults with advanced NSCLC with a KRAS G12C mutation who have progressed after at least one prior line of systemic therapy.

Sotorasib is an inhibitor of KRAS G12C, an oncogenic driver of tumorigenesis. The drug blocks tumor cell signaling and survival, inhibits cell growth, and selectively promotes apoptosis in tumors harboring KRAS G12C, according to the CHMP.

KRAS mutations are the most common mutations in NSCLC tumors, but for a long time appeared to be resistant to drug therapy.  

The KRAS G12C mutation occurs in about 13% of NSCLC mutations.

When clinical data on sotorasib were presented at the 2020 World Conference on Lung Cancer, lung cancer experts greeted the results enthusiastically.

“This is a historic milestone in lung cancer therapy. After four decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” Bob Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York City, said at the time.

The drug was approved by the U.S. Food and Drug Administration in May based on a study of 124 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.

The FDA approval was based on an overall response rate of 36%, the study’s primary outcome. Of the patients who responded, 58% had a duration of response of 6 months or longer.

The EMA says its recommendation for approval is based on objective response rate and response duration data.

The most common side effects of sotorasib are diarrhea, nausea, fatigue, increased aspartate aminotransferase, and arthralgia said the CHMP.

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

A large, multicenter, sham-controlled trial in heart failure showed no benefit at all from stem cell delivery on the primary outcome of recurrent nonfatal decompensated HF events, but the results were still promising, according to the DREAM-HF study’s principal investigator.

When added to guideline-directed medical therapy in patients with HF, a single dose of mesenchymal progenitor cells (MPC) significantly reduced major adverse cardiovascular events (MACE) – a composite of cardiac death, nonfatal MI, and nonfatal stroke – and all-cause death in New York Heart Association (NYHA) class II (but not class III patients), reported Emerson C. Perin, MD, PhD, at the American Heart Association scientific sessions.

The problem is that none of these outcomes were included in the primary endpoint, which was recurrent events because of nonfatal decompensated heart failure. On this endpoint, the hazard ratio for events by the end of follow-up was nonsignificantly but slightly increased among those randomized to MPCs rather than sham control (HR, 1.2; P = .406).

“We learned a lot in this trial,” said Dr. Perin, who is medical director of the Texas Heart Institute in Houston, acknowledging that the expectation of benefit on the primary endpoint now appears to have been misplaced, but the positive result on other outcomes opens a new research direction.

With a negative result on the primary endpoint, a benefit on secondary endpoints is considered hypothesis generating. But Dr. Perin defended his sense of overall optimism about the results, because all of the endpoints on which benefit was demonstrated were prespecified. The positive findings “are not from a post hoc analyses,” he emphasized.
 

DREAM-HF

In the trial, 537 patients with chronic ischemic or nonischemic heart failure with NYHA class II or III symptoms and a left ventricular ejection fraction of 40% or lower were randomized at 51 sites in the United States and Canada. Patients were required to have elevated N-terminal of the prohormone brain natriuretic peptide levels, at least one prior hospitalization for heart failure, and have been on positive inotropic therapy for more than 1 month (but less than 9 months).

The intracardiac administration of MPCs, which are derived from adult human bone marrow, were delivered by injection guided with the NOGA left ventricular electromechanical mapping system. Multiple transendocardial injections were delivered, all in a single session.

There were no differences in baseline characteristics between those receiving MPCs and those who underwent a sham procedure. In both groups, more than half of patients had a previous MI and a coronary revascularization. Nearly 85% had an implanted defibrillator. Roughly two-thirds were in NYHA class III HF and the remaining were in class II.

Over the follow-up, the lines on a graph documenting nonfatal decompensated heart failure events were largely superimposed for the MPC-treated and sham-treated patients, with no significant differences seen over time.

However, the differences on the secondary events were sizable. For the composite outcome of nonfatal MI and nonfatal stroke over a mean follow-up of about 30 months, the rate of events was less than half as great in those randomized to MPCs (4.6% vs. 13.0%). This translated into about 65% reduction in risk (HR, 0.346; P = .001) overall, and the reduction was about the same in class II or III patients.

For a composite endpoint of MACE, events in the group treated with MPCs were about one-third lower than in the sham procedure group (20.3% vs. 30.1%), a difference that also reached significance (HR, 0.667; P = .021).

For this MACE endpoint, response was evaluated by systemic inflammation. For those with a high-sensitivity C-reactive protein (hsCRP) level of less than 2 mg/L, the risk reduction was small and not significant (HR, 0.843; P = .519). Conversely, there was a large risk reduction in those with hsCRP of at least 2 mg/L that did reach statistical significance (HR, 0.551; P = .012).

Inflammation was also found to be a discriminator for time to cardiac death among the patients with NYHA class II HF. Again, there was no benefit among those with hsCRP below 2 mg/L (HR, 1.355; P = .672), but an 80% risk reduction for those with hsCRP of at least 2 mg/L (HR, 0.204; P = .005).

In class II patients with hsCRP at least 2 mg/L, there was also a 60% reduction in all-cause death (HR, 0.401; P = .027). Neither the reduction in cardiac death nor all-cause death was observed in class III HF patients whether or not they had elevated hsCRP.

These signals of benefit provide a direction for a new set of studies, but Dr. Perin said that safety analyses from the DREAM-HF trial are reassuring for further clinical development.

In addition to the fact that “treatment-emergent adverse events and serious adverse events were similar in the MPC-treated and control patients,” Dr. Perin said that MPC administration was not associated with any clinically meaningful immune responses.

MPCs were first injected into a human 15 years ago, according to Dr. Perin. While a phase 2 trial published several years ago did show an association of MPC administration with a reduction in HF-associated events as well as a reduction in adverse ventricular remodeling, the ischemic benefits observed in this trial, particularly in those with elevated hsCRP, provide a new direction for future trials.

“This turns the page in heart failure research. We now have a new mechanism to consider,” Dr. Perin said.
 

Not so fast, expert says

This might be a reasonable conclusion, but the AHA-invited discussant, Larry Allen, MD, believes there is essentially no clinical message from this trial. He reiterated multiple times that this trial was neutral with no trend for benefit on the primary outcome.

“There was benefit on the secondary outcomes of nonfatal MI or stroke, but these are not the outcomes we follow in heart failure patients,” he said, noting that benefit from regenerative therapy on ischemic events has not been a major focus of the trials that preceded DREAM-HF.

Despite these intriguing results, “patients should understand that stem cells remain experimental,” he said. For the patient, it is “more important to double down on the importance of guideline directed medical therapy,” which is still being administered at levels that are suboptimal, according to Dr. Allen, medical director of advanced heart failure at the University of Colorado at Denver, Aurora.

“Keep up the investment” in the promise of stem cell therapy, he said, but he cautioned that some of the secondary benefits observed in DREAM-HF, such as the greater response in patients with elevated hsCRP, appear to be new observations that will require a great deal more study to validate.

Dr. Perin has a financial relationship with Mesoblast, which provided funding for the DREAM-HF trial. Dr. Allen reported no relevant conflicts of interest.

A large, multicenter, sham-controlled trial in heart failure showed no benefit at all from stem cell delivery on the primary outcome of recurrent nonfatal decompensated HF events, but the results were still promising, according to the DREAM-HF study’s principal investigator.

When added to guideline-directed medical therapy in patients with HF, a single dose of mesenchymal progenitor cells (MPC) significantly reduced major adverse cardiovascular events (MACE) – a composite of cardiac death, nonfatal MI, and nonfatal stroke – and all-cause death in New York Heart Association (NYHA) class II (but not class III patients), reported Emerson C. Perin, MD, PhD, at the American Heart Association scientific sessions.

The problem is that none of these outcomes were included in the primary endpoint, which was recurrent events because of nonfatal decompensated heart failure. On this endpoint, the hazard ratio for events by the end of follow-up was nonsignificantly but slightly increased among those randomized to MPCs rather than sham control (HR, 1.2; P = .406).

“We learned a lot in this trial,” said Dr. Perin, who is medical director of the Texas Heart Institute in Houston, acknowledging that the expectation of benefit on the primary endpoint now appears to have been misplaced, but the positive result on other outcomes opens a new research direction.

With a negative result on the primary endpoint, a benefit on secondary endpoints is considered hypothesis generating. But Dr. Perin defended his sense of overall optimism about the results, because all of the endpoints on which benefit was demonstrated were prespecified. The positive findings “are not from a post hoc analyses,” he emphasized.
 

DREAM-HF

In the trial, 537 patients with chronic ischemic or nonischemic heart failure with NYHA class II or III symptoms and a left ventricular ejection fraction of 40% or lower were randomized at 51 sites in the United States and Canada. Patients were required to have elevated N-terminal of the prohormone brain natriuretic peptide levels, at least one prior hospitalization for heart failure, and have been on positive inotropic therapy for more than 1 month (but less than 9 months).

The intracardiac administration of MPCs, which are derived from adult human bone marrow, were delivered by injection guided with the NOGA left ventricular electromechanical mapping system. Multiple transendocardial injections were delivered, all in a single session.

There were no differences in baseline characteristics between those receiving MPCs and those who underwent a sham procedure. In both groups, more than half of patients had a previous MI and a coronary revascularization. Nearly 85% had an implanted defibrillator. Roughly two-thirds were in NYHA class III HF and the remaining were in class II.

Over the follow-up, the lines on a graph documenting nonfatal decompensated heart failure events were largely superimposed for the MPC-treated and sham-treated patients, with no significant differences seen over time.

However, the differences on the secondary events were sizable. For the composite outcome of nonfatal MI and nonfatal stroke over a mean follow-up of about 30 months, the rate of events was less than half as great in those randomized to MPCs (4.6% vs. 13.0%). This translated into about 65% reduction in risk (HR, 0.346; P = .001) overall, and the reduction was about the same in class II or III patients.

For a composite endpoint of MACE, events in the group treated with MPCs were about one-third lower than in the sham procedure group (20.3% vs. 30.1%), a difference that also reached significance (HR, 0.667; P = .021).

For this MACE endpoint, response was evaluated by systemic inflammation. For those with a high-sensitivity C-reactive protein (hsCRP) level of less than 2 mg/L, the risk reduction was small and not significant (HR, 0.843; P = .519). Conversely, there was a large risk reduction in those with hsCRP of at least 2 mg/L that did reach statistical significance (HR, 0.551; P = .012).

Inflammation was also found to be a discriminator for time to cardiac death among the patients with NYHA class II HF. Again, there was no benefit among those with hsCRP below 2 mg/L (HR, 1.355; P = .672), but an 80% risk reduction for those with hsCRP of at least 2 mg/L (HR, 0.204; P = .005).

In class II patients with hsCRP at least 2 mg/L, there was also a 60% reduction in all-cause death (HR, 0.401; P = .027). Neither the reduction in cardiac death nor all-cause death was observed in class III HF patients whether or not they had elevated hsCRP.

These signals of benefit provide a direction for a new set of studies, but Dr. Perin said that safety analyses from the DREAM-HF trial are reassuring for further clinical development.

In addition to the fact that “treatment-emergent adverse events and serious adverse events were similar in the MPC-treated and control patients,” Dr. Perin said that MPC administration was not associated with any clinically meaningful immune responses.

MPCs were first injected into a human 15 years ago, according to Dr. Perin. While a phase 2 trial published several years ago did show an association of MPC administration with a reduction in HF-associated events as well as a reduction in adverse ventricular remodeling, the ischemic benefits observed in this trial, particularly in those with elevated hsCRP, provide a new direction for future trials.

“This turns the page in heart failure research. We now have a new mechanism to consider,” Dr. Perin said.
 

Not so fast, expert says

This might be a reasonable conclusion, but the AHA-invited discussant, Larry Allen, MD, believes there is essentially no clinical message from this trial. He reiterated multiple times that this trial was neutral with no trend for benefit on the primary outcome.

“There was benefit on the secondary outcomes of nonfatal MI or stroke, but these are not the outcomes we follow in heart failure patients,” he said, noting that benefit from regenerative therapy on ischemic events has not been a major focus of the trials that preceded DREAM-HF.

Despite these intriguing results, “patients should understand that stem cells remain experimental,” he said. For the patient, it is “more important to double down on the importance of guideline directed medical therapy,” which is still being administered at levels that are suboptimal, according to Dr. Allen, medical director of advanced heart failure at the University of Colorado at Denver, Aurora.

“Keep up the investment” in the promise of stem cell therapy, he said, but he cautioned that some of the secondary benefits observed in DREAM-HF, such as the greater response in patients with elevated hsCRP, appear to be new observations that will require a great deal more study to validate.

Dr. Perin has a financial relationship with Mesoblast, which provided funding for the DREAM-HF trial. Dr. Allen reported no relevant conflicts of interest.

A large, multicenter, sham-controlled trial in heart failure showed no benefit at all from stem cell delivery on the primary outcome of recurrent nonfatal decompensated HF events, but the results were still promising, according to the DREAM-HF study’s principal investigator.

When added to guideline-directed medical therapy in patients with HF, a single dose of mesenchymal progenitor cells (MPC) significantly reduced major adverse cardiovascular events (MACE) – a composite of cardiac death, nonfatal MI, and nonfatal stroke – and all-cause death in New York Heart Association (NYHA) class II (but not class III patients), reported Emerson C. Perin, MD, PhD, at the American Heart Association scientific sessions.

The problem is that none of these outcomes were included in the primary endpoint, which was recurrent events because of nonfatal decompensated heart failure. On this endpoint, the hazard ratio for events by the end of follow-up was nonsignificantly but slightly increased among those randomized to MPCs rather than sham control (HR, 1.2; P = .406).

“We learned a lot in this trial,” said Dr. Perin, who is medical director of the Texas Heart Institute in Houston, acknowledging that the expectation of benefit on the primary endpoint now appears to have been misplaced, but the positive result on other outcomes opens a new research direction.

With a negative result on the primary endpoint, a benefit on secondary endpoints is considered hypothesis generating. But Dr. Perin defended his sense of overall optimism about the results, because all of the endpoints on which benefit was demonstrated were prespecified. The positive findings “are not from a post hoc analyses,” he emphasized.
 

DREAM-HF

In the trial, 537 patients with chronic ischemic or nonischemic heart failure with NYHA class II or III symptoms and a left ventricular ejection fraction of 40% or lower were randomized at 51 sites in the United States and Canada. Patients were required to have elevated N-terminal of the prohormone brain natriuretic peptide levels, at least one prior hospitalization for heart failure, and have been on positive inotropic therapy for more than 1 month (but less than 9 months).

The intracardiac administration of MPCs, which are derived from adult human bone marrow, were delivered by injection guided with the NOGA left ventricular electromechanical mapping system. Multiple transendocardial injections were delivered, all in a single session.

There were no differences in baseline characteristics between those receiving MPCs and those who underwent a sham procedure. In both groups, more than half of patients had a previous MI and a coronary revascularization. Nearly 85% had an implanted defibrillator. Roughly two-thirds were in NYHA class III HF and the remaining were in class II.

Over the follow-up, the lines on a graph documenting nonfatal decompensated heart failure events were largely superimposed for the MPC-treated and sham-treated patients, with no significant differences seen over time.

However, the differences on the secondary events were sizable. For the composite outcome of nonfatal MI and nonfatal stroke over a mean follow-up of about 30 months, the rate of events was less than half as great in those randomized to MPCs (4.6% vs. 13.0%). This translated into about 65% reduction in risk (HR, 0.346; P = .001) overall, and the reduction was about the same in class II or III patients.

For a composite endpoint of MACE, events in the group treated with MPCs were about one-third lower than in the sham procedure group (20.3% vs. 30.1%), a difference that also reached significance (HR, 0.667; P = .021).

For this MACE endpoint, response was evaluated by systemic inflammation. For those with a high-sensitivity C-reactive protein (hsCRP) level of less than 2 mg/L, the risk reduction was small and not significant (HR, 0.843; P = .519). Conversely, there was a large risk reduction in those with hsCRP of at least 2 mg/L that did reach statistical significance (HR, 0.551; P = .012).

Inflammation was also found to be a discriminator for time to cardiac death among the patients with NYHA class II HF. Again, there was no benefit among those with hsCRP below 2 mg/L (HR, 1.355; P = .672), but an 80% risk reduction for those with hsCRP of at least 2 mg/L (HR, 0.204; P = .005).

In class II patients with hsCRP at least 2 mg/L, there was also a 60% reduction in all-cause death (HR, 0.401; P = .027). Neither the reduction in cardiac death nor all-cause death was observed in class III HF patients whether or not they had elevated hsCRP.

These signals of benefit provide a direction for a new set of studies, but Dr. Perin said that safety analyses from the DREAM-HF trial are reassuring for further clinical development.

In addition to the fact that “treatment-emergent adverse events and serious adverse events were similar in the MPC-treated and control patients,” Dr. Perin said that MPC administration was not associated with any clinically meaningful immune responses.

MPCs were first injected into a human 15 years ago, according to Dr. Perin. While a phase 2 trial published several years ago did show an association of MPC administration with a reduction in HF-associated events as well as a reduction in adverse ventricular remodeling, the ischemic benefits observed in this trial, particularly in those with elevated hsCRP, provide a new direction for future trials.

“This turns the page in heart failure research. We now have a new mechanism to consider,” Dr. Perin said.
 

Not so fast, expert says

This might be a reasonable conclusion, but the AHA-invited discussant, Larry Allen, MD, believes there is essentially no clinical message from this trial. He reiterated multiple times that this trial was neutral with no trend for benefit on the primary outcome.

“There was benefit on the secondary outcomes of nonfatal MI or stroke, but these are not the outcomes we follow in heart failure patients,” he said, noting that benefit from regenerative therapy on ischemic events has not been a major focus of the trials that preceded DREAM-HF.

Despite these intriguing results, “patients should understand that stem cells remain experimental,” he said. For the patient, it is “more important to double down on the importance of guideline directed medical therapy,” which is still being administered at levels that are suboptimal, according to Dr. Allen, medical director of advanced heart failure at the University of Colorado at Denver, Aurora.

“Keep up the investment” in the promise of stem cell therapy, he said, but he cautioned that some of the secondary benefits observed in DREAM-HF, such as the greater response in patients with elevated hsCRP, appear to be new observations that will require a great deal more study to validate.

Dr. Perin has a financial relationship with Mesoblast, which provided funding for the DREAM-HF trial. Dr. Allen reported no relevant conflicts of interest.