LAS VEGAS – Additional findings from the landmark PARADIGM-HF trial presented at the annual meeting of the Heart Failure Society of America provided what many observers deemed a persuasive case for the novel angiotensin receptor neprilysin inhibitor known for now as LCZ696 as deserving of a level I indication in the next update of the major heart failure management guidelines.

At a special session added late to the meeting program in the wake of the spectacularly positive top-line results of PARADIGM-HF presented just a few weeks earlier at the European Society of Cardiology meeting in Barcelona, an international panel of heart failure heavyweights tackled questions about the study’s implications, including whether the results need replication in a second randomized controlled trial before LCZ696 can win regulatory approval. And once approved, should guidelines committees give it a level I, must-use indication? How applicable are the PARADIGM-HF results to the broader population of heart failure patients, and in particular black patients and older individuals with class III/IV heart failure? And what about patients with heart failure with preserved ejection fraction (HFpEF) ?

In other words, does PARADIGM-HF, with more than 8,400 randomized subjects, represent a true paradigm shift in heart failure management?

For coprincipal investigator Dr. Milton Packer, the answer is a resounding yes.

“For the past 25 years, the magnitude of the effect of ACE inhibitors on cardiovascular mortality – about an 18% reduction – has created an ethical mandate for their use in all patients with chronic heart failure who could tolerate treatment with these drugs. The finding that LCZ696 has a 20% greater effect on cardiovascular mortality than ACE inhibitors strongly supports the conclusion that LCZ696 should replace the current use of ACE inhibitors and angiotensin receptor blockers in the management of chronic heart failure,” said Dr. Packer, professor and chair of the department of clinical sciences at University of Texas Southwestern Medical Center, Dallas.

Naseem S. Miller/Frontline Medical News

His coprincipal investigator, Dr. John J.V. McMurray, cited the statistical strength of the PARADIGM-HF results for the primary composite outcome of cardiovascular death or heart failure hospitalization, which had an extraordinary P value of .0000004, in making the case that the trial findings are sufficient to win regulatory approval without a confirmatory study.

He noted that the regulatory standard in the United States and Europe is that a positive clinical trial having a P value of less than .05 requires replication in a second study that also yields outcomes with a P value of less than .05.

“If, however, you have a large single trial, you can win approval by meeting a standard of P less than .00125. The strength of the result of PARADIGM-HF, with a P of .0000004, is equivalent to between four and five single trials replicated at P less than .05. And for the endpoint of cardiovascular mortality, where the PARADIGM-HF result was significant at a P of .00008, that’s equivalent to between two and three trials replicated at P less than .05. So in my view PARADIGM-HF easily meets the criteria for a level IA indication,” said Dr. McMurray, professor of cardiology at the University of Glasgow.

He presented for the first time a new analysis with a major wow factor. This was an imputed placebo analysis providing the answer to a question many cardiologists have asked him since the presentation of the top-line PARADIGM-HF results in Barcelona: namely, how would LCZ696 have stacked up in a placebo-controlled trial?

Such a study wouldn’t be ethical now, of course, but it’s possible to make inferences by comparing LCZ696’s superiority to enalapril at 10 mg b.i.d. in PARADIGM-HF to enalapril’s performance at the same dose relative to placebo in the earlier 2,569-patient SOLVD-Treatment trial, which featured the same composite primary endpoint (N. Engl. J. Med. 1991;325:293-302).

In SOLVD-Treatment, enalapril resulted in a 28% relative risk reduction in the composite endpoint, compared with placebo. Through indirect comparison, LCZ696 would have an imputed 43% relative risk reduction, compared with placebo. For the endpoint of cardiovascular mortality, enalapril showed a 17% risk reduction relative to placebo; when the PARADIGM-HF results are factored in, this translates to an inferred 34% relative risk reduction for LCZ696 versus placebo.

Similarly, in the CHARM-Alternative trial (Lancet 2003;362:772-6), which featured 2,028 patients on more contemporary guideline–recommended background therapy than in SOLVD-Treatment, patients on the angiotensin receptor blocker candesartan showed a 23% relative risk reduction in the composite endpoint, compared with placebo, along with a 15% reduction in cardiovascular mortality. In the imputed placebo analysis, this translated to relative risk reductions of 49% and 34%, respectively, for LCZ696 versus placebo.

“We see a doubling in the reduction in cardiovascular mortality with this new therapy over and above that obtained with an ACE inhibitor or ARB [angiotensin receptor blocker],” Dr. McMurray emphasized.

Panelist Dr. Lynne W. Stevenson wasn’t convinced.

“I don’t believe it is time to replace ACE inhibitors and ARBs. I don’t think LCZ696 is ready for a level I [treatment should be performed] indication; that is a higher bar. ... I think we could see a level IIa [treatment is reasonable to perform] indication based on the strong results that we’ve seen,” said Dr. Stevenson, director of the heart failure and cardiomyopathy program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

She estimated that fewer than 10% of U.S. heart failure patients fit the description of PARADIGM-HF participants, with mild to moderate heart failure with reduced ejection fraction. Importantly, the run-in process employed in the study ensured that only patients with a demonstrated ability to tolerate enalapril in therapeutic doses were enrolled. And even in that filtered population, there was a substantial dropout rate in the LCZ696 arm due to hypotension during follow-up.

“I certainly don’t think we have any information about patients newly diagnosed with heart failure. I don’t think if you put new heart failure patients on LCZ696, they’d necessarily be able to stand up, and if they could stand up I’m not sure we could get them on the appropriate dose of beta blockers,” Dr. Stevenson added.

Noting that only 5% of PARADIGM-HF participants were black, she said that “clearly this is something we will need to watch as we get more experience with this drug, but there was no signal of concern.”

Dr. Marvin A. Konstam, professor of medicine at Tufts University, Boston, shared one of Dr. Stevenson’s concerns: “How do we know what will happen with ACE inhibitor virgins in the real world where you don’t get a run-in period?”

Panelist Dr. John G.F. Cleland said, “I don’t want to second-guess the guideline committees, but surely this must be a IA [data derived from multiple clinical trials or meta-analyses] indication. What intrigues me is what will the indication for ACE inhibitors look like in future guidelines? Is it also going to be IA in the same group of patients? That’s something the guidelines committees are going to have to sort out.”

“A lot of these questions and people’s concerns will either be increased or reduced once we start to get the medicine into clinical practice. What I find quite distressing is that we might be sitting here at this time next year and still not be in a position to prescribe this agent because it may still be going through the regulatory process,” said Dr. Cleland, professor of cardiology at the University of Hull (England).

[email protected]

LAS VEGAS – Additional findings from the landmark PARADIGM-HF trial presented at the annual meeting of the Heart Failure Society of America provided what many observers deemed a persuasive case for the novel angiotensin receptor neprilysin inhibitor known for now as LCZ696 as deserving of a level I indication in the next update of the major heart failure management guidelines.

At a special session added late to the meeting program in the wake of the spectacularly positive top-line results of PARADIGM-HF presented just a few weeks earlier at the European Society of Cardiology meeting in Barcelona, an international panel of heart failure heavyweights tackled questions about the study’s implications, including whether the results need replication in a second randomized controlled trial before LCZ696 can win regulatory approval. And once approved, should guidelines committees give it a level I, must-use indication? How applicable are the PARADIGM-HF results to the broader population of heart failure patients, and in particular black patients and older individuals with class III/IV heart failure? And what about patients with heart failure with preserved ejection fraction (HFpEF) ?

In other words, does PARADIGM-HF, with more than 8,400 randomized subjects, represent a true paradigm shift in heart failure management?

For coprincipal investigator Dr. Milton Packer, the answer is a resounding yes.

“For the past 25 years, the magnitude of the effect of ACE inhibitors on cardiovascular mortality – about an 18% reduction – has created an ethical mandate for their use in all patients with chronic heart failure who could tolerate treatment with these drugs. The finding that LCZ696 has a 20% greater effect on cardiovascular mortality than ACE inhibitors strongly supports the conclusion that LCZ696 should replace the current use of ACE inhibitors and angiotensin receptor blockers in the management of chronic heart failure,” said Dr. Packer, professor and chair of the department of clinical sciences at University of Texas Southwestern Medical Center, Dallas.

Naseem S. Miller/Frontline Medical News

His coprincipal investigator, Dr. John J.V. McMurray, cited the statistical strength of the PARADIGM-HF results for the primary composite outcome of cardiovascular death or heart failure hospitalization, which had an extraordinary P value of .0000004, in making the case that the trial findings are sufficient to win regulatory approval without a confirmatory study.

He noted that the regulatory standard in the United States and Europe is that a positive clinical trial having a P value of less than .05 requires replication in a second study that also yields outcomes with a P value of less than .05.

“If, however, you have a large single trial, you can win approval by meeting a standard of P less than .00125. The strength of the result of PARADIGM-HF, with a P of .0000004, is equivalent to between four and five single trials replicated at P less than .05. And for the endpoint of cardiovascular mortality, where the PARADIGM-HF result was significant at a P of .00008, that’s equivalent to between two and three trials replicated at P less than .05. So in my view PARADIGM-HF easily meets the criteria for a level IA indication,” said Dr. McMurray, professor of cardiology at the University of Glasgow.

He presented for the first time a new analysis with a major wow factor. This was an imputed placebo analysis providing the answer to a question many cardiologists have asked him since the presentation of the top-line PARADIGM-HF results in Barcelona: namely, how would LCZ696 have stacked up in a placebo-controlled trial?

Such a study wouldn’t be ethical now, of course, but it’s possible to make inferences by comparing LCZ696’s superiority to enalapril at 10 mg b.i.d. in PARADIGM-HF to enalapril’s performance at the same dose relative to placebo in the earlier 2,569-patient SOLVD-Treatment trial, which featured the same composite primary endpoint (N. Engl. J. Med. 1991;325:293-302).

In SOLVD-Treatment, enalapril resulted in a 28% relative risk reduction in the composite endpoint, compared with placebo. Through indirect comparison, LCZ696 would have an imputed 43% relative risk reduction, compared with placebo. For the endpoint of cardiovascular mortality, enalapril showed a 17% risk reduction relative to placebo; when the PARADIGM-HF results are factored in, this translates to an inferred 34% relative risk reduction for LCZ696 versus placebo.

Similarly, in the CHARM-Alternative trial (Lancet 2003;362:772-6), which featured 2,028 patients on more contemporary guideline–recommended background therapy than in SOLVD-Treatment, patients on the angiotensin receptor blocker candesartan showed a 23% relative risk reduction in the composite endpoint, compared with placebo, along with a 15% reduction in cardiovascular mortality. In the imputed placebo analysis, this translated to relative risk reductions of 49% and 34%, respectively, for LCZ696 versus placebo.

“We see a doubling in the reduction in cardiovascular mortality with this new therapy over and above that obtained with an ACE inhibitor or ARB [angiotensin receptor blocker],” Dr. McMurray emphasized.

Panelist Dr. Lynne W. Stevenson wasn’t convinced.

“I don’t believe it is time to replace ACE inhibitors and ARBs. I don’t think LCZ696 is ready for a level I [treatment should be performed] indication; that is a higher bar. ... I think we could see a level IIa [treatment is reasonable to perform] indication based on the strong results that we’ve seen,” said Dr. Stevenson, director of the heart failure and cardiomyopathy program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

She estimated that fewer than 10% of U.S. heart failure patients fit the description of PARADIGM-HF participants, with mild to moderate heart failure with reduced ejection fraction. Importantly, the run-in process employed in the study ensured that only patients with a demonstrated ability to tolerate enalapril in therapeutic doses were enrolled. And even in that filtered population, there was a substantial dropout rate in the LCZ696 arm due to hypotension during follow-up.

“I certainly don’t think we have any information about patients newly diagnosed with heart failure. I don’t think if you put new heart failure patients on LCZ696, they’d necessarily be able to stand up, and if they could stand up I’m not sure we could get them on the appropriate dose of beta blockers,” Dr. Stevenson added.

Noting that only 5% of PARADIGM-HF participants were black, she said that “clearly this is something we will need to watch as we get more experience with this drug, but there was no signal of concern.”

Dr. Marvin A. Konstam, professor of medicine at Tufts University, Boston, shared one of Dr. Stevenson’s concerns: “How do we know what will happen with ACE inhibitor virgins in the real world where you don’t get a run-in period?”

Panelist Dr. John G.F. Cleland said, “I don’t want to second-guess the guideline committees, but surely this must be a IA [data derived from multiple clinical trials or meta-analyses] indication. What intrigues me is what will the indication for ACE inhibitors look like in future guidelines? Is it also going to be IA in the same group of patients? That’s something the guidelines committees are going to have to sort out.”

“A lot of these questions and people’s concerns will either be increased or reduced once we start to get the medicine into clinical practice. What I find quite distressing is that we might be sitting here at this time next year and still not be in a position to prescribe this agent because it may still be going through the regulatory process,” said Dr. Cleland, professor of cardiology at the University of Hull (England).

[email protected]

LAS VEGAS – Additional findings from the landmark PARADIGM-HF trial presented at the annual meeting of the Heart Failure Society of America provided what many observers deemed a persuasive case for the novel angiotensin receptor neprilysin inhibitor known for now as LCZ696 as deserving of a level I indication in the next update of the major heart failure management guidelines.

At a special session added late to the meeting program in the wake of the spectacularly positive top-line results of PARADIGM-HF presented just a few weeks earlier at the European Society of Cardiology meeting in Barcelona, an international panel of heart failure heavyweights tackled questions about the study’s implications, including whether the results need replication in a second randomized controlled trial before LCZ696 can win regulatory approval. And once approved, should guidelines committees give it a level I, must-use indication? How applicable are the PARADIGM-HF results to the broader population of heart failure patients, and in particular black patients and older individuals with class III/IV heart failure? And what about patients with heart failure with preserved ejection fraction (HFpEF) ?

In other words, does PARADIGM-HF, with more than 8,400 randomized subjects, represent a true paradigm shift in heart failure management?

For coprincipal investigator Dr. Milton Packer, the answer is a resounding yes.

“For the past 25 years, the magnitude of the effect of ACE inhibitors on cardiovascular mortality – about an 18% reduction – has created an ethical mandate for their use in all patients with chronic heart failure who could tolerate treatment with these drugs. The finding that LCZ696 has a 20% greater effect on cardiovascular mortality than ACE inhibitors strongly supports the conclusion that LCZ696 should replace the current use of ACE inhibitors and angiotensin receptor blockers in the management of chronic heart failure,” said Dr. Packer, professor and chair of the department of clinical sciences at University of Texas Southwestern Medical Center, Dallas.

Naseem S. Miller/Frontline Medical News

His coprincipal investigator, Dr. John J.V. McMurray, cited the statistical strength of the PARADIGM-HF results for the primary composite outcome of cardiovascular death or heart failure hospitalization, which had an extraordinary P value of .0000004, in making the case that the trial findings are sufficient to win regulatory approval without a confirmatory study.

He noted that the regulatory standard in the United States and Europe is that a positive clinical trial having a P value of less than .05 requires replication in a second study that also yields outcomes with a P value of less than .05.

“If, however, you have a large single trial, you can win approval by meeting a standard of P less than .00125. The strength of the result of PARADIGM-HF, with a P of .0000004, is equivalent to between four and five single trials replicated at P less than .05. And for the endpoint of cardiovascular mortality, where the PARADIGM-HF result was significant at a P of .00008, that’s equivalent to between two and three trials replicated at P less than .05. So in my view PARADIGM-HF easily meets the criteria for a level IA indication,” said Dr. McMurray, professor of cardiology at the University of Glasgow.

He presented for the first time a new analysis with a major wow factor. This was an imputed placebo analysis providing the answer to a question many cardiologists have asked him since the presentation of the top-line PARADIGM-HF results in Barcelona: namely, how would LCZ696 have stacked up in a placebo-controlled trial?

Such a study wouldn’t be ethical now, of course, but it’s possible to make inferences by comparing LCZ696’s superiority to enalapril at 10 mg b.i.d. in PARADIGM-HF to enalapril’s performance at the same dose relative to placebo in the earlier 2,569-patient SOLVD-Treatment trial, which featured the same composite primary endpoint (N. Engl. J. Med. 1991;325:293-302).

In SOLVD-Treatment, enalapril resulted in a 28% relative risk reduction in the composite endpoint, compared with placebo. Through indirect comparison, LCZ696 would have an imputed 43% relative risk reduction, compared with placebo. For the endpoint of cardiovascular mortality, enalapril showed a 17% risk reduction relative to placebo; when the PARADIGM-HF results are factored in, this translates to an inferred 34% relative risk reduction for LCZ696 versus placebo.

Similarly, in the CHARM-Alternative trial (Lancet 2003;362:772-6), which featured 2,028 patients on more contemporary guideline–recommended background therapy than in SOLVD-Treatment, patients on the angiotensin receptor blocker candesartan showed a 23% relative risk reduction in the composite endpoint, compared with placebo, along with a 15% reduction in cardiovascular mortality. In the imputed placebo analysis, this translated to relative risk reductions of 49% and 34%, respectively, for LCZ696 versus placebo.

“We see a doubling in the reduction in cardiovascular mortality with this new therapy over and above that obtained with an ACE inhibitor or ARB [angiotensin receptor blocker],” Dr. McMurray emphasized.

Panelist Dr. Lynne W. Stevenson wasn’t convinced.

“I don’t believe it is time to replace ACE inhibitors and ARBs. I don’t think LCZ696 is ready for a level I [treatment should be performed] indication; that is a higher bar. ... I think we could see a level IIa [treatment is reasonable to perform] indication based on the strong results that we’ve seen,” said Dr. Stevenson, director of the heart failure and cardiomyopathy program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

She estimated that fewer than 10% of U.S. heart failure patients fit the description of PARADIGM-HF participants, with mild to moderate heart failure with reduced ejection fraction. Importantly, the run-in process employed in the study ensured that only patients with a demonstrated ability to tolerate enalapril in therapeutic doses were enrolled. And even in that filtered population, there was a substantial dropout rate in the LCZ696 arm due to hypotension during follow-up.

“I certainly don’t think we have any information about patients newly diagnosed with heart failure. I don’t think if you put new heart failure patients on LCZ696, they’d necessarily be able to stand up, and if they could stand up I’m not sure we could get them on the appropriate dose of beta blockers,” Dr. Stevenson added.

Noting that only 5% of PARADIGM-HF participants were black, she said that “clearly this is something we will need to watch as we get more experience with this drug, but there was no signal of concern.”

Dr. Marvin A. Konstam, professor of medicine at Tufts University, Boston, shared one of Dr. Stevenson’s concerns: “How do we know what will happen with ACE inhibitor virgins in the real world where you don’t get a run-in period?”

Panelist Dr. John G.F. Cleland said, “I don’t want to second-guess the guideline committees, but surely this must be a IA [data derived from multiple clinical trials or meta-analyses] indication. What intrigues me is what will the indication for ACE inhibitors look like in future guidelines? Is it also going to be IA in the same group of patients? That’s something the guidelines committees are going to have to sort out.”

“A lot of these questions and people’s concerns will either be increased or reduced once we start to get the medicine into clinical practice. What I find quite distressing is that we might be sitting here at this time next year and still not be in a position to prescribe this agent because it may still be going through the regulatory process,” said Dr. Cleland, professor of cardiology at the University of Hull (England).

[email protected]

We can learn a lot from a car rentals. Like medicine, they are a service industry. And all service industries have the same problem: Service is delivered in real time, and the quality of that service depends on variables that may or may not be in the company’s control.

Even so, one bad experience can result in termination of a life-long customer, or in our case, patient. Worse, the patient can now go online and write a scathing review, criticizing everything from your bedside manner to the artwork in your waiting room.

What can you do when a visit goes wrong? Employ service-recovery techniques. Service recovery is the act of trying to resuscitate an encounter once things have gone badly. It happens to physicians and to restaurants and to car rentals.

While on vacation with my wife in Salt Lake City, we rented a car from a company (let’s call them “Discount Cars”). We don’t usually book with them; however, we got double airline points for choosing them, so we bit.

At the airport rental terminal, we waited for 15 minutes before being helped. When we reached the counter, we were told that our reserved car was not ready yet. (I immediately thought of the Seinfeld episode when Jerry says: “So you can take a reservation, but you can’t keep a reservation?!”) We were advised that our car was being washed and would be ready in 15 minutes “tops.” Thirty minutes later, my miffed wife pushed through the line to the counter. “It’s still being washed,” she was told. So she asked for another car and was offered a full-size pickup truck. My wife, who drives a teeny Honda Fit at home, said no thanks. Another 30 minutes passed and my incensed wife returned to the counter. “It’s been over an hour! This is unacceptable!” A different representative replied it was our fault for declining the pickup truck. There would be more cars soon, so they promised.

We were too far to walk to any airport bars, and the situation was rapidly deteriorating. I decided to take action. I fired up Twitter and let her rip:

“Closing in on 1 hr for a car promised in 15 min. Which we reserved ahead. This isn’t the first time, @DiscountCars #operations #fail.”

Within minutes, they replied by Twitter:

Them: @Dermdoc We are so sorry for the wait! What location are you at?

My wife, along with five other equally incensed wives, continued to wait for a response (and a car) from the live representatives at the counter.

Nearly 1 hour and 20 minutes later, we got a car. It was much larger than we wanted, but we were done waiting. After signing the papers, we got inside – it reeked of smoke. Oh, this is no bueno, I thought. We requested a different car. Twenty more minutes passed before our smoke-free vehicle arrived. The gas tank was 7/8’s full. And the carpets were littered with twigs and leaves.

Now I’m thinking, this is so bad, I should write an article about it. From the front seat of our faulty but moving vehicle, I fired again: “Dear @DiscountCars we waited 1+ hrs. Not the car we wanted. Then tank not full. Yet, not a single apology from anyone. Really?”

Them: @Dermdoc, we are sorry.

Them: @Dermdoc Please e-mail us the details and your RA# to [email protected] so we can look into this for you!

Me: @Discount Thank you! Will do.

I sent a list of grievances to the e-mail as they requested. Within an hour they offered us a $50 credit on a future rental.

What’s remarkable about this story is that not a single live person was able to assuage us, but their digital team managed to apologize and save us as customers. There might have been legitimate reasons for their service failure, but it didn’t matter. What mattered was that they responded to me personally, apologized, and made amends. This is an important lesson for us physicians. Patients will expect that your digital channels are legitimate ways to express their level of satisfaction with your practice. The stakes are higher for us in health care in particular because of the risks of violating patients’ privacy. However, as you can see from the rental car example, it can effectively be done without revealing any information about the customer or the experience. The goal is to recover the service publicly and take all of the information offline and manage it in a secure, private fashion.

The formula is simple: Believe the customer. Listen. Apologize for not satisfying the customer. Even if you’ve done nothing wrong, you have in some way failed to satisfy the customer’s needs. Ask for more information in a secure, private manner, never on a public platform. Do what you can reasonably do to remedy the problem and remediate the situation.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

We can learn a lot from a car rentals. Like medicine, they are a service industry. And all service industries have the same problem: Service is delivered in real time, and the quality of that service depends on variables that may or may not be in the company’s control.

Even so, one bad experience can result in termination of a life-long customer, or in our case, patient. Worse, the patient can now go online and write a scathing review, criticizing everything from your bedside manner to the artwork in your waiting room.

What can you do when a visit goes wrong? Employ service-recovery techniques. Service recovery is the act of trying to resuscitate an encounter once things have gone badly. It happens to physicians and to restaurants and to car rentals.

While on vacation with my wife in Salt Lake City, we rented a car from a company (let’s call them “Discount Cars”). We don’t usually book with them; however, we got double airline points for choosing them, so we bit.

At the airport rental terminal, we waited for 15 minutes before being helped. When we reached the counter, we were told that our reserved car was not ready yet. (I immediately thought of the Seinfeld episode when Jerry says: “So you can take a reservation, but you can’t keep a reservation?!”) We were advised that our car was being washed and would be ready in 15 minutes “tops.” Thirty minutes later, my miffed wife pushed through the line to the counter. “It’s still being washed,” she was told. So she asked for another car and was offered a full-size pickup truck. My wife, who drives a teeny Honda Fit at home, said no thanks. Another 30 minutes passed and my incensed wife returned to the counter. “It’s been over an hour! This is unacceptable!” A different representative replied it was our fault for declining the pickup truck. There would be more cars soon, so they promised.

We were too far to walk to any airport bars, and the situation was rapidly deteriorating. I decided to take action. I fired up Twitter and let her rip:

“Closing in on 1 hr for a car promised in 15 min. Which we reserved ahead. This isn’t the first time, @DiscountCars #operations #fail.”

Within minutes, they replied by Twitter:

Them: @Dermdoc We are so sorry for the wait! What location are you at?

My wife, along with five other equally incensed wives, continued to wait for a response (and a car) from the live representatives at the counter.

Nearly 1 hour and 20 minutes later, we got a car. It was much larger than we wanted, but we were done waiting. After signing the papers, we got inside – it reeked of smoke. Oh, this is no bueno, I thought. We requested a different car. Twenty more minutes passed before our smoke-free vehicle arrived. The gas tank was 7/8’s full. And the carpets were littered with twigs and leaves.

Now I’m thinking, this is so bad, I should write an article about it. From the front seat of our faulty but moving vehicle, I fired again: “Dear @DiscountCars we waited 1+ hrs. Not the car we wanted. Then tank not full. Yet, not a single apology from anyone. Really?”

Them: @Dermdoc, we are sorry.

Them: @Dermdoc Please e-mail us the details and your RA# to [email protected] so we can look into this for you!

Me: @Discount Thank you! Will do.

I sent a list of grievances to the e-mail as they requested. Within an hour they offered us a $50 credit on a future rental.

What’s remarkable about this story is that not a single live person was able to assuage us, but their digital team managed to apologize and save us as customers. There might have been legitimate reasons for their service failure, but it didn’t matter. What mattered was that they responded to me personally, apologized, and made amends. This is an important lesson for us physicians. Patients will expect that your digital channels are legitimate ways to express their level of satisfaction with your practice. The stakes are higher for us in health care in particular because of the risks of violating patients’ privacy. However, as you can see from the rental car example, it can effectively be done without revealing any information about the customer or the experience. The goal is to recover the service publicly and take all of the information offline and manage it in a secure, private fashion.

The formula is simple: Believe the customer. Listen. Apologize for not satisfying the customer. Even if you’ve done nothing wrong, you have in some way failed to satisfy the customer’s needs. Ask for more information in a secure, private manner, never on a public platform. Do what you can reasonably do to remedy the problem and remediate the situation.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

We can learn a lot from a car rentals. Like medicine, they are a service industry. And all service industries have the same problem: Service is delivered in real time, and the quality of that service depends on variables that may or may not be in the company’s control.

Even so, one bad experience can result in termination of a life-long customer, or in our case, patient. Worse, the patient can now go online and write a scathing review, criticizing everything from your bedside manner to the artwork in your waiting room.

What can you do when a visit goes wrong? Employ service-recovery techniques. Service recovery is the act of trying to resuscitate an encounter once things have gone badly. It happens to physicians and to restaurants and to car rentals.

While on vacation with my wife in Salt Lake City, we rented a car from a company (let’s call them “Discount Cars”). We don’t usually book with them; however, we got double airline points for choosing them, so we bit.

At the airport rental terminal, we waited for 15 minutes before being helped. When we reached the counter, we were told that our reserved car was not ready yet. (I immediately thought of the Seinfeld episode when Jerry says: “So you can take a reservation, but you can’t keep a reservation?!”) We were advised that our car was being washed and would be ready in 15 minutes “tops.” Thirty minutes later, my miffed wife pushed through the line to the counter. “It’s still being washed,” she was told. So she asked for another car and was offered a full-size pickup truck. My wife, who drives a teeny Honda Fit at home, said no thanks. Another 30 minutes passed and my incensed wife returned to the counter. “It’s been over an hour! This is unacceptable!” A different representative replied it was our fault for declining the pickup truck. There would be more cars soon, so they promised.

We were too far to walk to any airport bars, and the situation was rapidly deteriorating. I decided to take action. I fired up Twitter and let her rip:

“Closing in on 1 hr for a car promised in 15 min. Which we reserved ahead. This isn’t the first time, @DiscountCars #operations #fail.”

Within minutes, they replied by Twitter:

Them: @Dermdoc We are so sorry for the wait! What location are you at?

My wife, along with five other equally incensed wives, continued to wait for a response (and a car) from the live representatives at the counter.

Nearly 1 hour and 20 minutes later, we got a car. It was much larger than we wanted, but we were done waiting. After signing the papers, we got inside – it reeked of smoke. Oh, this is no bueno, I thought. We requested a different car. Twenty more minutes passed before our smoke-free vehicle arrived. The gas tank was 7/8’s full. And the carpets were littered with twigs and leaves.

Now I’m thinking, this is so bad, I should write an article about it. From the front seat of our faulty but moving vehicle, I fired again: “Dear @DiscountCars we waited 1+ hrs. Not the car we wanted. Then tank not full. Yet, not a single apology from anyone. Really?”

Them: @Dermdoc, we are sorry.

Them: @Dermdoc Please e-mail us the details and your RA# to [email protected] so we can look into this for you!

Me: @Discount Thank you! Will do.

I sent a list of grievances to the e-mail as they requested. Within an hour they offered us a $50 credit on a future rental.

What’s remarkable about this story is that not a single live person was able to assuage us, but their digital team managed to apologize and save us as customers. There might have been legitimate reasons for their service failure, but it didn’t matter. What mattered was that they responded to me personally, apologized, and made amends. This is an important lesson for us physicians. Patients will expect that your digital channels are legitimate ways to express their level of satisfaction with your practice. The stakes are higher for us in health care in particular because of the risks of violating patients’ privacy. However, as you can see from the rental car example, it can effectively be done without revealing any information about the customer or the experience. The goal is to recover the service publicly and take all of the information offline and manage it in a secure, private fashion.

The formula is simple: Believe the customer. Listen. Apologize for not satisfying the customer. Even if you’ve done nothing wrong, you have in some way failed to satisfy the customer’s needs. Ask for more information in a secure, private manner, never on a public platform. Do what you can reasonably do to remedy the problem and remediate the situation.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

African Americans have higher rates of high blood pressure and lower levels of 25-hydroxyvitamin D, compared with those of whites, and may be prescribed both thiazide diuretics and vitamin D supplements concurrently. But with thiazide diuretics, the kidneys excrete less calcium, and with vitamin D, the intestines absorb more calcium. Is there a risk of hypercalcemia for these patients?

To find out, researchers from Brigham and Women’s Hospital, Harvard Medical School and School of Public Health, Massachusetts General Hospital, and Dana-Farber Cancer Institute, all in Boston, Massachusetts; Michigan State University in East Lansing; Washington University School of Medicine in St. Louis, Missouri; Duke University in Durham, North Carolina; and Medical University of South Carolina in Charleston assigned 328 healthy African American volunteers to receive 1,000 IU, 2,000 IU, or 4,000 IU of vitamin D or placebo once a day for 3 months during the winters from 2007 to 2010. Of the participants, 84 were taking hydrochlorothiazide (HCTZ) and had serum calcium levels assessed. A comparison group of 44 participants who were not taking HCTZ had serum calcium measurements at 3 months but not at baseline. Participants were assessed for adverse events in person at the beginning of each month and by telephone during the second week of each month.

Five of the participants taking HCTZ had a serum calcium level above the upper limit of normal. The 4 participants who had hypercalcemia during month 1 were asked to stop taking the study medication and were withdrawn from the study.

Only 5.9% of the participants taking concurrent HCTZ and vitamin D developed hypercalcemia. At 1 month, 3 of the HCTZ participants in the 1,000 IU group and 1 in the 2,000 IU group had hypercalcemia. After 1 month of the vitamin D supplementation, 4 participants taking HCTZ had modestly elevated serum calcium levels, ranging from 10.7 mg/dL to 11.0 mg/dL. At 3 months, only 1 HCTZ participant had elevated calcium. The late appearance of 1 case of hypercalcemia may mean hypercalcemia can occur later in therapy, or it may have been a random event, the researchers say.

This is the first analysis to directly assess the effect of concurrent use of vitamin D and HCTZ in otherwise healthy adults with hypertension. Although the optimal plasma levels of vitamin D have yet to be established, their study is critical, the researchers say, because lower doses of vitamin D may not be enough to correct the vitamin D deficiency common in African Americans.

Source
Chandler PD, Scott JB, Drake BF, et al. Am J Med. 2014;127(8):772-778.
doi: 10.1016/j.amjmed.2014.02.044.

African Americans have higher rates of high blood pressure and lower levels of 25-hydroxyvitamin D, compared with those of whites, and may be prescribed both thiazide diuretics and vitamin D supplements concurrently. But with thiazide diuretics, the kidneys excrete less calcium, and with vitamin D, the intestines absorb more calcium. Is there a risk of hypercalcemia for these patients?

To find out, researchers from Brigham and Women’s Hospital, Harvard Medical School and School of Public Health, Massachusetts General Hospital, and Dana-Farber Cancer Institute, all in Boston, Massachusetts; Michigan State University in East Lansing; Washington University School of Medicine in St. Louis, Missouri; Duke University in Durham, North Carolina; and Medical University of South Carolina in Charleston assigned 328 healthy African American volunteers to receive 1,000 IU, 2,000 IU, or 4,000 IU of vitamin D or placebo once a day for 3 months during the winters from 2007 to 2010. Of the participants, 84 were taking hydrochlorothiazide (HCTZ) and had serum calcium levels assessed. A comparison group of 44 participants who were not taking HCTZ had serum calcium measurements at 3 months but not at baseline. Participants were assessed for adverse events in person at the beginning of each month and by telephone during the second week of each month.

Five of the participants taking HCTZ had a serum calcium level above the upper limit of normal. The 4 participants who had hypercalcemia during month 1 were asked to stop taking the study medication and were withdrawn from the study.

Only 5.9% of the participants taking concurrent HCTZ and vitamin D developed hypercalcemia. At 1 month, 3 of the HCTZ participants in the 1,000 IU group and 1 in the 2,000 IU group had hypercalcemia. After 1 month of the vitamin D supplementation, 4 participants taking HCTZ had modestly elevated serum calcium levels, ranging from 10.7 mg/dL to 11.0 mg/dL. At 3 months, only 1 HCTZ participant had elevated calcium. The late appearance of 1 case of hypercalcemia may mean hypercalcemia can occur later in therapy, or it may have been a random event, the researchers say.

This is the first analysis to directly assess the effect of concurrent use of vitamin D and HCTZ in otherwise healthy adults with hypertension. Although the optimal plasma levels of vitamin D have yet to be established, their study is critical, the researchers say, because lower doses of vitamin D may not be enough to correct the vitamin D deficiency common in African Americans.

Source
Chandler PD, Scott JB, Drake BF, et al. Am J Med. 2014;127(8):772-778.
doi: 10.1016/j.amjmed.2014.02.044.

African Americans have higher rates of high blood pressure and lower levels of 25-hydroxyvitamin D, compared with those of whites, and may be prescribed both thiazide diuretics and vitamin D supplements concurrently. But with thiazide diuretics, the kidneys excrete less calcium, and with vitamin D, the intestines absorb more calcium. Is there a risk of hypercalcemia for these patients?

To find out, researchers from Brigham and Women’s Hospital, Harvard Medical School and School of Public Health, Massachusetts General Hospital, and Dana-Farber Cancer Institute, all in Boston, Massachusetts; Michigan State University in East Lansing; Washington University School of Medicine in St. Louis, Missouri; Duke University in Durham, North Carolina; and Medical University of South Carolina in Charleston assigned 328 healthy African American volunteers to receive 1,000 IU, 2,000 IU, or 4,000 IU of vitamin D or placebo once a day for 3 months during the winters from 2007 to 2010. Of the participants, 84 were taking hydrochlorothiazide (HCTZ) and had serum calcium levels assessed. A comparison group of 44 participants who were not taking HCTZ had serum calcium measurements at 3 months but not at baseline. Participants were assessed for adverse events in person at the beginning of each month and by telephone during the second week of each month.

Five of the participants taking HCTZ had a serum calcium level above the upper limit of normal. The 4 participants who had hypercalcemia during month 1 were asked to stop taking the study medication and were withdrawn from the study.

Only 5.9% of the participants taking concurrent HCTZ and vitamin D developed hypercalcemia. At 1 month, 3 of the HCTZ participants in the 1,000 IU group and 1 in the 2,000 IU group had hypercalcemia. After 1 month of the vitamin D supplementation, 4 participants taking HCTZ had modestly elevated serum calcium levels, ranging from 10.7 mg/dL to 11.0 mg/dL. At 3 months, only 1 HCTZ participant had elevated calcium. The late appearance of 1 case of hypercalcemia may mean hypercalcemia can occur later in therapy, or it may have been a random event, the researchers say.

This is the first analysis to directly assess the effect of concurrent use of vitamin D and HCTZ in otherwise healthy adults with hypertension. Although the optimal plasma levels of vitamin D have yet to be established, their study is critical, the researchers say, because lower doses of vitamin D may not be enough to correct the vitamin D deficiency common in African Americans.

Source
Chandler PD, Scott JB, Drake BF, et al. Am J Med. 2014;127(8):772-778.
doi: 10.1016/j.amjmed.2014.02.044.

Lab mice

Credit: Aaron Logan

Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.

The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.

A subset of the mice developed MPNs, which also bore the JAK2 mutation.

The researchers described this work in The Journal of Experimental Medicine.

Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.

In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).

The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.

Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.

To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.

Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.

Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.

The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.

Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.

Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.

Lab mice

Credit: Aaron Logan

Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.

The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.

A subset of the mice developed MPNs, which also bore the JAK2 mutation.

The researchers described this work in The Journal of Experimental Medicine.

Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.

In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).

The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.

Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.

To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.

Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.

Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.

The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.

Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.

Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.

Lab mice

Credit: Aaron Logan

Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.

The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.

A subset of the mice developed MPNs, which also bore the JAK2 mutation.

The researchers described this work in The Journal of Experimental Medicine.

Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.

In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).

The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.

Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.

To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.

Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.

Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.

The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.

Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.

Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.

Chemotherapy drugs

Credit: Bill Branson

Healthcare professionals do not consistently follow the recommended safe handling practices for antineoplastic drugs, according to a survey published in the Journal of Occupational and Environmental Hygiene.

Researchers surveyed more than 2000 healthcare workers and found that a majority do not always use the recommended personal protective equipment when they are administering antineoplastic drugs.

Furthermore, some respondents reported spills or leaks of a drug during administration, and a small percentage said they had experienced skin

contact with an antineoplastic drug.

“Chemotherapy drugs save lives of cancer patients but also can result in adverse health outcomes in workers who are exposed to these drugs, including cancer, reproductive problems, and organ damage when recommended safe handling guidelines are not followed,” said John Howard, MD, director of the National Institute for Occupational Safety and Health (NIOSH).

NIOSH researchers conducted this study, which included 2069 healthcare personnel who completed the 2011 Health and Safety Practices Survey of Healthcare Workers.

Results showed that, despite the longstanding availability of authoritative safe handling guidelines (ASHP, NIOSH, ONS, OSHA), recommended exposure controls were not always used.

For example, 80% of respondents said they do not always wear 2 pairs of chemotherapy gloves, and 15% said they don’t always wear a single pair.

Forty-two percent of respondents said they don’t always wear a nonabsorbent gown with a closed front and tight-fitting cuffs, and 12% had taken home potentially contaminated clothing.

Twelve percent of respondents reported a spill or leak of an antineoplastic drug during administration, and 4% reported skin contact with an antineoplastic drug.

Six percent of respondents said they primed intravenous tubing with an antineoplastic drug instead of a non-drug containing liquid, and 12% said the pharmacy department followed this practice.

Taking these and other findings into account, the researchers concluded that better risk communication is needed to ensure that employers and employees are fully aware of the hazards and the availability of precautionary measures to minimize exposure to antineoplastic drugs.

Chemotherapy drugs

Credit: Bill Branson

Healthcare professionals do not consistently follow the recommended safe handling practices for antineoplastic drugs, according to a survey published in the Journal of Occupational and Environmental Hygiene.

Researchers surveyed more than 2000 healthcare workers and found that a majority do not always use the recommended personal protective equipment when they are administering antineoplastic drugs.

Furthermore, some respondents reported spills or leaks of a drug during administration, and a small percentage said they had experienced skin

contact with an antineoplastic drug.

“Chemotherapy drugs save lives of cancer patients but also can result in adverse health outcomes in workers who are exposed to these drugs, including cancer, reproductive problems, and organ damage when recommended safe handling guidelines are not followed,” said John Howard, MD, director of the National Institute for Occupational Safety and Health (NIOSH).

NIOSH researchers conducted this study, which included 2069 healthcare personnel who completed the 2011 Health and Safety Practices Survey of Healthcare Workers.

Results showed that, despite the longstanding availability of authoritative safe handling guidelines (ASHP, NIOSH, ONS, OSHA), recommended exposure controls were not always used.

For example, 80% of respondents said they do not always wear 2 pairs of chemotherapy gloves, and 15% said they don’t always wear a single pair.

Forty-two percent of respondents said they don’t always wear a nonabsorbent gown with a closed front and tight-fitting cuffs, and 12% had taken home potentially contaminated clothing.

Twelve percent of respondents reported a spill or leak of an antineoplastic drug during administration, and 4% reported skin contact with an antineoplastic drug.

Six percent of respondents said they primed intravenous tubing with an antineoplastic drug instead of a non-drug containing liquid, and 12% said the pharmacy department followed this practice.

Taking these and other findings into account, the researchers concluded that better risk communication is needed to ensure that employers and employees are fully aware of the hazards and the availability of precautionary measures to minimize exposure to antineoplastic drugs.

Chemotherapy drugs

Credit: Bill Branson

Healthcare professionals do not consistently follow the recommended safe handling practices for antineoplastic drugs, according to a survey published in the Journal of Occupational and Environmental Hygiene.

Researchers surveyed more than 2000 healthcare workers and found that a majority do not always use the recommended personal protective equipment when they are administering antineoplastic drugs.

Furthermore, some respondents reported spills or leaks of a drug during administration, and a small percentage said they had experienced skin

contact with an antineoplastic drug.

“Chemotherapy drugs save lives of cancer patients but also can result in adverse health outcomes in workers who are exposed to these drugs, including cancer, reproductive problems, and organ damage when recommended safe handling guidelines are not followed,” said John Howard, MD, director of the National Institute for Occupational Safety and Health (NIOSH).

NIOSH researchers conducted this study, which included 2069 healthcare personnel who completed the 2011 Health and Safety Practices Survey of Healthcare Workers.

Results showed that, despite the longstanding availability of authoritative safe handling guidelines (ASHP, NIOSH, ONS, OSHA), recommended exposure controls were not always used.

For example, 80% of respondents said they do not always wear 2 pairs of chemotherapy gloves, and 15% said they don’t always wear a single pair.

Forty-two percent of respondents said they don’t always wear a nonabsorbent gown with a closed front and tight-fitting cuffs, and 12% had taken home potentially contaminated clothing.

Twelve percent of respondents reported a spill or leak of an antineoplastic drug during administration, and 4% reported skin contact with an antineoplastic drug.

Six percent of respondents said they primed intravenous tubing with an antineoplastic drug instead of a non-drug containing liquid, and 12% said the pharmacy department followed this practice.

Taking these and other findings into account, the researchers concluded that better risk communication is needed to ensure that employers and employees are fully aware of the hazards and the availability of precautionary measures to minimize exposure to antineoplastic drugs.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

The sea mollusk Aplysia

californica

releasing ink

after being disturbed

Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.

Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.

This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.

“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.

He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.

Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.

The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.

To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.

Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.

The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term

synaptic depression.

They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.

However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.

Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.

The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

 Do you remember the discussion of the ethical dilemma of Huntington’s disease you probably participated in during medical school? The question was whether you would want to know that you were at risk for a chronic debilitating condition that would develop at some later age if there was nothing that could be done about it. In that discussion, you also may have heard about individuals who, after hearing about their risk status, become depressed or suicidal, depending on the story line.

Some pediatricians seem to have taken this example too far in arguing that there is no point in screening for issues of development, autism, maternal depression, or child mental health because “there are no services” available to treat them.

Despair is understandable. Physicians’ lack of knowledge about resources in the community is often a sore point among local agencies, parents, and even pediatricians themselves. In spite of United Way, state 3-1-1 programs ,and the occasionally available social worker, the resources with which we are familiar sometimes come from hard-working parents telling us about a program they found on their own. It also seems that, just when we hit upon a valuable resource, it runs out of funding, changes eligibility requirements, or loses key staff. Worse yet, we may rely on resources we know about because of our own children’s problems, activities, or friends. While the Internet is an increasingly valuable method of finding resources, there is no filter of the evidence-basis of the care provided, and the process of searching, vetting, and informing your patients is extremely time consuming, and often the patient is not eligible or has a long waiting period after all that.

There are important reasons not to succumb to throwing up one’s hands about service availability. And more important reasons to still screen even if you do not know where to refer.

Screening using validated tools is recommended by the American Academy of Pediatrics because parent concern and even clinical observation are not adequately sensitive to detect significant problems of development and mental health, even when done by experienced physicians who know families well. The process of screening sends an important message to the parents – that you care about the child’s progress and are using proven methods to ensure that it is going well and consider it part of complete medical care.

And families often already think that their child may have a problem, even when they don’t bring it up. Perhaps deep down they are afraid that somehow raising the question of autism will make it true. They may be in denial, are feeling guilty, or are under pressure from their spouse, relatives, or friends not to worry, that “he will grow out” of it, that better discipline will fix the problem, etc. They may even care so much about your positive regard that they do not want to seem overly anxious, obsessive, or be regarded as a failure for having a “defective” child. They, like you, also may be in despair about finding effective help.

But there can be serious consequences to not screening, even when you are not sure what you will do with the results. The family may push the child with delays or mental health problems beyond his abilities, and even become negative and punitive in trying to make him succeed, in the process promoting unnecessary behavior problems, discouragement, and even defiance in the child. Failure to detect also means failure to list the child on a registry for follow-up to determine progress or refer when resources become available. Some problems of development or mental health that are detected by screening may have medical causes that you can treat, even though counseling or therapy interventions are not available. Examples include hearing or vision deficits causing delays or anemia, sleep apnea, or hypothyroidism or maternal depression or attention-deficit/hyperactivity disorder (ADHD). For issues with a genetic basis, siblings may be born with same problem during the period of delay in making a diagnosis, a prime example being Fragile X. In untold cases, the family loses trust in you and in the medical system for not acknowledging a problem.

In many cases, your acknowledgment, explanation, sympathy, and advice can help enormously. Families can cope better, garner support from family or friends, deal with the child’s behavior better, and find steps to take to help their child in their own ways, even without formal services, once told that their child has a specific problem.

On a system level, it is important to realize that how services are established and maintained is far less rational than might be imagined. State programs, schools, hospitals, and insurers all have legal requirements to provide services within a certain time frame once referred. Even if the services are not there to help a your child or family right now, the referral itself adds to the data used to determine if services are adequate and to plan for additional service types or capacity. The Autism Waiver is one such example where waits are years long, but getting on the list is crucial to the future of the program.

Until you screen and give parents information – especially middle-class parents – we will never have the resources. As it was for lead paint, until we identified prevalence of elevated lead levels and the harm associated, we got no action on lead paint removal policies. Another example where complaints about access made a difference, is the relatively new Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 that requires health insurers and health plans to guarantee that financial requirements on benefits for mental health, such as copays, deductibles, and limitations on treatment benefits, are not more restrictive than those that are for medical benefits. This does not guarantee that services will be available or of high quality, but is a step toward accessibility.

You may be one of the many pediatricians who consider advocacy a basic component of your professional responsibilities. If you cannot advocate for services that you see your patients in need of, you can pass your concerns onto a group that does. Many American Academy of Pediatrics state chapters have so-called Pediatric Councils that receive ideas about system problems and put group pressure on leaders in the state to address them.

As in the historic painting of the physician leaning over the ill child whom he could not cure, after detection through screening our thoughtful evaluation, explanations, shared concern, and our patients’ advocacy have great value even when specific services are not yet available.

Dr. Howard is an assistant professor of pediatrics at the Johns Hopkins University, Baltimore, and creator of CHADIS (www.chadis.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. E-mail her at [email protected].

 Do you remember the discussion of the ethical dilemma of Huntington’s disease you probably participated in during medical school? The question was whether you would want to know that you were at risk for a chronic debilitating condition that would develop at some later age if there was nothing that could be done about it. In that discussion, you also may have heard about individuals who, after hearing about their risk status, become depressed or suicidal, depending on the story line.

Some pediatricians seem to have taken this example too far in arguing that there is no point in screening for issues of development, autism, maternal depression, or child mental health because “there are no services” available to treat them.

Despair is understandable. Physicians’ lack of knowledge about resources in the community is often a sore point among local agencies, parents, and even pediatricians themselves. In spite of United Way, state 3-1-1 programs ,and the occasionally available social worker, the resources with which we are familiar sometimes come from hard-working parents telling us about a program they found on their own. It also seems that, just when we hit upon a valuable resource, it runs out of funding, changes eligibility requirements, or loses key staff. Worse yet, we may rely on resources we know about because of our own children’s problems, activities, or friends. While the Internet is an increasingly valuable method of finding resources, there is no filter of the evidence-basis of the care provided, and the process of searching, vetting, and informing your patients is extremely time consuming, and often the patient is not eligible or has a long waiting period after all that.

There are important reasons not to succumb to throwing up one’s hands about service availability. And more important reasons to still screen even if you do not know where to refer.

Screening using validated tools is recommended by the American Academy of Pediatrics because parent concern and even clinical observation are not adequately sensitive to detect significant problems of development and mental health, even when done by experienced physicians who know families well. The process of screening sends an important message to the parents – that you care about the child’s progress and are using proven methods to ensure that it is going well and consider it part of complete medical care.

And families often already think that their child may have a problem, even when they don’t bring it up. Perhaps deep down they are afraid that somehow raising the question of autism will make it true. They may be in denial, are feeling guilty, or are under pressure from their spouse, relatives, or friends not to worry, that “he will grow out” of it, that better discipline will fix the problem, etc. They may even care so much about your positive regard that they do not want to seem overly anxious, obsessive, or be regarded as a failure for having a “defective” child. They, like you, also may be in despair about finding effective help.

But there can be serious consequences to not screening, even when you are not sure what you will do with the results. The family may push the child with delays or mental health problems beyond his abilities, and even become negative and punitive in trying to make him succeed, in the process promoting unnecessary behavior problems, discouragement, and even defiance in the child. Failure to detect also means failure to list the child on a registry for follow-up to determine progress or refer when resources become available. Some problems of development or mental health that are detected by screening may have medical causes that you can treat, even though counseling or therapy interventions are not available. Examples include hearing or vision deficits causing delays or anemia, sleep apnea, or hypothyroidism or maternal depression or attention-deficit/hyperactivity disorder (ADHD). For issues with a genetic basis, siblings may be born with same problem during the period of delay in making a diagnosis, a prime example being Fragile X. In untold cases, the family loses trust in you and in the medical system for not acknowledging a problem.

In many cases, your acknowledgment, explanation, sympathy, and advice can help enormously. Families can cope better, garner support from family or friends, deal with the child’s behavior better, and find steps to take to help their child in their own ways, even without formal services, once told that their child has a specific problem.

On a system level, it is important to realize that how services are established and maintained is far less rational than might be imagined. State programs, schools, hospitals, and insurers all have legal requirements to provide services within a certain time frame once referred. Even if the services are not there to help a your child or family right now, the referral itself adds to the data used to determine if services are adequate and to plan for additional service types or capacity. The Autism Waiver is one such example where waits are years long, but getting on the list is crucial to the future of the program.

Until you screen and give parents information – especially middle-class parents – we will never have the resources. As it was for lead paint, until we identified prevalence of elevated lead levels and the harm associated, we got no action on lead paint removal policies. Another example where complaints about access made a difference, is the relatively new Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 that requires health insurers and health plans to guarantee that financial requirements on benefits for mental health, such as copays, deductibles, and limitations on treatment benefits, are not more restrictive than those that are for medical benefits. This does not guarantee that services will be available or of high quality, but is a step toward accessibility.

You may be one of the many pediatricians who consider advocacy a basic component of your professional responsibilities. If you cannot advocate for services that you see your patients in need of, you can pass your concerns onto a group that does. Many American Academy of Pediatrics state chapters have so-called Pediatric Councils that receive ideas about system problems and put group pressure on leaders in the state to address them.

As in the historic painting of the physician leaning over the ill child whom he could not cure, after detection through screening our thoughtful evaluation, explanations, shared concern, and our patients’ advocacy have great value even when specific services are not yet available.

Dr. Howard is an assistant professor of pediatrics at the Johns Hopkins University, Baltimore, and creator of CHADIS (www.chadis.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. E-mail her at [email protected].

 Do you remember the discussion of the ethical dilemma of Huntington’s disease you probably participated in during medical school? The question was whether you would want to know that you were at risk for a chronic debilitating condition that would develop at some later age if there was nothing that could be done about it. In that discussion, you also may have heard about individuals who, after hearing about their risk status, become depressed or suicidal, depending on the story line.

Some pediatricians seem to have taken this example too far in arguing that there is no point in screening for issues of development, autism, maternal depression, or child mental health because “there are no services” available to treat them.

Despair is understandable. Physicians’ lack of knowledge about resources in the community is often a sore point among local agencies, parents, and even pediatricians themselves. In spite of United Way, state 3-1-1 programs ,and the occasionally available social worker, the resources with which we are familiar sometimes come from hard-working parents telling us about a program they found on their own. It also seems that, just when we hit upon a valuable resource, it runs out of funding, changes eligibility requirements, or loses key staff. Worse yet, we may rely on resources we know about because of our own children’s problems, activities, or friends. While the Internet is an increasingly valuable method of finding resources, there is no filter of the evidence-basis of the care provided, and the process of searching, vetting, and informing your patients is extremely time consuming, and often the patient is not eligible or has a long waiting period after all that.

There are important reasons not to succumb to throwing up one’s hands about service availability. And more important reasons to still screen even if you do not know where to refer.

Screening using validated tools is recommended by the American Academy of Pediatrics because parent concern and even clinical observation are not adequately sensitive to detect significant problems of development and mental health, even when done by experienced physicians who know families well. The process of screening sends an important message to the parents – that you care about the child’s progress and are using proven methods to ensure that it is going well and consider it part of complete medical care.

And families often already think that their child may have a problem, even when they don’t bring it up. Perhaps deep down they are afraid that somehow raising the question of autism will make it true. They may be in denial, are feeling guilty, or are under pressure from their spouse, relatives, or friends not to worry, that “he will grow out” of it, that better discipline will fix the problem, etc. They may even care so much about your positive regard that they do not want to seem overly anxious, obsessive, or be regarded as a failure for having a “defective” child. They, like you, also may be in despair about finding effective help.

But there can be serious consequences to not screening, even when you are not sure what you will do with the results. The family may push the child with delays or mental health problems beyond his abilities, and even become negative and punitive in trying to make him succeed, in the process promoting unnecessary behavior problems, discouragement, and even defiance in the child. Failure to detect also means failure to list the child on a registry for follow-up to determine progress or refer when resources become available. Some problems of development or mental health that are detected by screening may have medical causes that you can treat, even though counseling or therapy interventions are not available. Examples include hearing or vision deficits causing delays or anemia, sleep apnea, or hypothyroidism or maternal depression or attention-deficit/hyperactivity disorder (ADHD). For issues with a genetic basis, siblings may be born with same problem during the period of delay in making a diagnosis, a prime example being Fragile X. In untold cases, the family loses trust in you and in the medical system for not acknowledging a problem.

In many cases, your acknowledgment, explanation, sympathy, and advice can help enormously. Families can cope better, garner support from family or friends, deal with the child’s behavior better, and find steps to take to help their child in their own ways, even without formal services, once told that their child has a specific problem.

On a system level, it is important to realize that how services are established and maintained is far less rational than might be imagined. State programs, schools, hospitals, and insurers all have legal requirements to provide services within a certain time frame once referred. Even if the services are not there to help a your child or family right now, the referral itself adds to the data used to determine if services are adequate and to plan for additional service types or capacity. The Autism Waiver is one such example where waits are years long, but getting on the list is crucial to the future of the program.

Until you screen and give parents information – especially middle-class parents – we will never have the resources. As it was for lead paint, until we identified prevalence of elevated lead levels and the harm associated, we got no action on lead paint removal policies. Another example where complaints about access made a difference, is the relatively new Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 that requires health insurers and health plans to guarantee that financial requirements on benefits for mental health, such as copays, deductibles, and limitations on treatment benefits, are not more restrictive than those that are for medical benefits. This does not guarantee that services will be available or of high quality, but is a step toward accessibility.

You may be one of the many pediatricians who consider advocacy a basic component of your professional responsibilities. If you cannot advocate for services that you see your patients in need of, you can pass your concerns onto a group that does. Many American Academy of Pediatrics state chapters have so-called Pediatric Councils that receive ideas about system problems and put group pressure on leaders in the state to address them.

As in the historic painting of the physician leaning over the ill child whom he could not cure, after detection through screening our thoughtful evaluation, explanations, shared concern, and our patients’ advocacy have great value even when specific services are not yet available.

Dr. Howard is an assistant professor of pediatrics at the Johns Hopkins University, Baltimore, and creator of CHADIS (www.chadis.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. E-mail her at [email protected].

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

To the Editor:
Flurbiprofen, a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat fever, inflammation, and pain of arthritis.¹ The exact prevalence of allergic reactions to NSAIDs in the general population is not known. Rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and anaphylaxis can occur as an allergic reaction to NSAIDs. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth.² These patients may develop urticaria and/or angioedema only after NSAID ingestion, but they do not have underlying chronic urticaria. We report a rare case of isolated unilateral eyelid angioedema with flurbiprofen.

A 39-year-old man presented with the onset of unilateral angioedema of the left upper eyelid that had developed approximately 30 minutes after taking flurbiprofen (100 mg). He reported frequent use of flurbiprofen for headaches. The patient also had a history of taking aspirin, ibuprofen, diclofenac, etodolac, and naproxen sodium as needed for migraines with no prior angioedema. He had no history of chronic urticaria or allergic disease. The patient was treated with oral pheniramine hydrogen maleate and angioedema resolved after 12 hours. Three days later, the patient used flurbiprofen again for a headache. He was readmitted to our clinic with unilateral angioedema of the left upper eyelid (Figure). The symptoms started approximately 30 minutes after taking flurbiprofen. Angioedema resolved within 1 day with oral pheniramine.

Unilateral angioedema of the left upper eyelid following use of flurbiprofen for headaches.

Nonsteroidal anti-inflammatory drugs are the most commonly prescribed class of drugs in the world and are the most common cause of all adverse drug reactions.³ Urticaria, angioedema, and anaphylaxis are common adverse reactions to NSAIDs. The prevalence of urticaria and angioedema to NSAIDs has been reported to be 0.1% to 3% worldwide.⁴

Angioedema is an abrupt localized swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities, and genitalia. Angioedema generally develops over minutes to hours and resolves in 24 to 48 hours.⁵ Angioedema without urticaria is the clinical syndrome that can be caused by an adverse drug reaction. In an Italian review of 2137 reactions, NSAIDs were causative agents in 33.6% of patients with drug-induced angioedema.⁶ In another study, Leeyaphan et al⁵ reported that 50% of patients with drug-induced angioedema resulted from NSAIDs, commonly with ibuprofen and diclofenac. Although angioedema is due to inhibition of cyclooxygenase 1, overproduction of leukotrienes, and possibly IgE-mediated reactions to single drugs,⁷ localized unilateral eyelid angioedema with NSAIDs is rare. The exact mechanism of localized eyelid edema is not known.⁸ We believe that the unilateral eyelid angioedema in our patient was caused by flurbiprofen use because the reaction recurred when the drug was used again.

To the Editor:
Flurbiprofen, a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat fever, inflammation, and pain of arthritis.¹ The exact prevalence of allergic reactions to NSAIDs in the general population is not known. Rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and anaphylaxis can occur as an allergic reaction to NSAIDs. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth.² These patients may develop urticaria and/or angioedema only after NSAID ingestion, but they do not have underlying chronic urticaria. We report a rare case of isolated unilateral eyelid angioedema with flurbiprofen.

A 39-year-old man presented with the onset of unilateral angioedema of the left upper eyelid that had developed approximately 30 minutes after taking flurbiprofen (100 mg). He reported frequent use of flurbiprofen for headaches. The patient also had a history of taking aspirin, ibuprofen, diclofenac, etodolac, and naproxen sodium as needed for migraines with no prior angioedema. He had no history of chronic urticaria or allergic disease. The patient was treated with oral pheniramine hydrogen maleate and angioedema resolved after 12 hours. Three days later, the patient used flurbiprofen again for a headache. He was readmitted to our clinic with unilateral angioedema of the left upper eyelid (Figure). The symptoms started approximately 30 minutes after taking flurbiprofen. Angioedema resolved within 1 day with oral pheniramine.

Unilateral angioedema of the left upper eyelid following use of flurbiprofen for headaches.

Nonsteroidal anti-inflammatory drugs are the most commonly prescribed class of drugs in the world and are the most common cause of all adverse drug reactions.³ Urticaria, angioedema, and anaphylaxis are common adverse reactions to NSAIDs. The prevalence of urticaria and angioedema to NSAIDs has been reported to be 0.1% to 3% worldwide.⁴

Angioedema is an abrupt localized swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities, and genitalia. Angioedema generally develops over minutes to hours and resolves in 24 to 48 hours.⁵ Angioedema without urticaria is the clinical syndrome that can be caused by an adverse drug reaction. In an Italian review of 2137 reactions, NSAIDs were causative agents in 33.6% of patients with drug-induced angioedema.⁶ In another study, Leeyaphan et al⁵ reported that 50% of patients with drug-induced angioedema resulted from NSAIDs, commonly with ibuprofen and diclofenac. Although angioedema is due to inhibition of cyclooxygenase 1, overproduction of leukotrienes, and possibly IgE-mediated reactions to single drugs,⁷ localized unilateral eyelid angioedema with NSAIDs is rare. The exact mechanism of localized eyelid edema is not known.⁸ We believe that the unilateral eyelid angioedema in our patient was caused by flurbiprofen use because the reaction recurred when the drug was used again.

To the Editor:
Flurbiprofen, a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat fever, inflammation, and pain of arthritis.¹ The exact prevalence of allergic reactions to NSAIDs in the general population is not known. Rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and anaphylaxis can occur as an allergic reaction to NSAIDs. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth.² These patients may develop urticaria and/or angioedema only after NSAID ingestion, but they do not have underlying chronic urticaria. We report a rare case of isolated unilateral eyelid angioedema with flurbiprofen.

A 39-year-old man presented with the onset of unilateral angioedema of the left upper eyelid that had developed approximately 30 minutes after taking flurbiprofen (100 mg). He reported frequent use of flurbiprofen for headaches. The patient also had a history of taking aspirin, ibuprofen, diclofenac, etodolac, and naproxen sodium as needed for migraines with no prior angioedema. He had no history of chronic urticaria or allergic disease. The patient was treated with oral pheniramine hydrogen maleate and angioedema resolved after 12 hours. Three days later, the patient used flurbiprofen again for a headache. He was readmitted to our clinic with unilateral angioedema of the left upper eyelid (Figure). The symptoms started approximately 30 minutes after taking flurbiprofen. Angioedema resolved within 1 day with oral pheniramine.

Unilateral angioedema of the left upper eyelid following use of flurbiprofen for headaches.

Nonsteroidal anti-inflammatory drugs are the most commonly prescribed class of drugs in the world and are the most common cause of all adverse drug reactions.³ Urticaria, angioedema, and anaphylaxis are common adverse reactions to NSAIDs. The prevalence of urticaria and angioedema to NSAIDs has been reported to be 0.1% to 3% worldwide.⁴

Angioedema is an abrupt localized swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities, and genitalia. Angioedema generally develops over minutes to hours and resolves in 24 to 48 hours.⁵ Angioedema without urticaria is the clinical syndrome that can be caused by an adverse drug reaction. In an Italian review of 2137 reactions, NSAIDs were causative agents in 33.6% of patients with drug-induced angioedema.⁶ In another study, Leeyaphan et al⁵ reported that 50% of patients with drug-induced angioedema resulted from NSAIDs, commonly with ibuprofen and diclofenac. Although angioedema is due to inhibition of cyclooxygenase 1, overproduction of leukotrienes, and possibly IgE-mediated reactions to single drugs,⁷ localized unilateral eyelid angioedema with NSAIDs is rare. The exact mechanism of localized eyelid edema is not known.⁸ We believe that the unilateral eyelid angioedema in our patient was caused by flurbiprofen use because the reaction recurred when the drug was used again.