I recently returned from the DASS (Dermatology and Allied Specialties Summit) in New Delhi. It was interesting and thought provoking. New Delhi, and India in general, are modern and ancient, growing like Topsy, crushed into one another, in a hyperkinetic mix, something like Mexico on amphetamines.

I generally find conferences far afield introduce novel ideas. It helps greatly that these conferences almost always use English as the official language.

The underlying concept for DASS is multidisciplinary, which is unusual in dermatology. It was rewarding to discuss skin cancer treatment with surgical oncologists, plastic and general surgeons, and medical oncologists. There were also discussions on polycystic ovary disease, rosacea and the “red face,” current treatment of Hansen disease, man-eating psoriasis and urticaria, and of course, botulinum toxin, fillers, lasers, and chemical peels. Of great interest were new “old” treatments for skin disease, since biologics are generally not affordable.

I also got into lively discussions at the World Congress of Dermatology in Vancouver a few weeks earlier. The problem in many countries is funding of dermatologic treatments (particularly Mohs) within a fixed dermatology budget. We in the United States can vote with our feet, and generally seek out treatment we decide is best. Over the past 30 years, 70% of skin cancer has migrated from hospital-based surgical specialties to office-based dermatology, at great cost savings to the health care system.

In most of the world, the government allocates money, and tells hospitals and doctors to make do. This results in a static, change-resistant budget process, where patients have even fewer choices than in the U.S. Hospitals always win in these budget battles, to the detriment of office-based medicine and patient choice, and innovation.

Internationally, correcting this may require dermatologists going to politicians and not saying, “we need more money,” but rather saying, “we can save you money.” For example, if 99% of skin cancer treatment moves out of the hospital to the office setting, where it should be, the budgeteers should be delighted to pay your office costs, which are a fraction of those for an operating room. The budget should reflect that X number of new operating rooms do not need to be built, X number of scrub nurses do not need to trained or can be reassigned, X number of support staff are not needed, or that wait times, a chronic complaint around the world, can shrink.

There will be resistance to this approach from hospital-dependent specialists, and the hospitals. They will argue it isn’t safe, and that the costs aren’t defined. However, these issues have been worked out in detail and the data published.

The same argument can be made for the use of biologics. How many erythrodermic hospitalizations will be avoided? How many missed days of work will not be missed?

It is far easier to budge a bureaucracy by emphasizing cost savings rather than quality, though these are opportunities for dermatologists to improve both.

Dr. Coldiron is in private practice, but maintains a clinical assistant professorship of dermatology at the University of Cincinnati. Email him at dermnews@frontlinemedcom.com.

I recently returned from the DASS (Dermatology and Allied Specialties Summit) in New Delhi. It was interesting and thought provoking. New Delhi, and India in general, are modern and ancient, growing like Topsy, crushed into one another, in a hyperkinetic mix, something like Mexico on amphetamines.

I generally find conferences far afield introduce novel ideas. It helps greatly that these conferences almost always use English as the official language.

The underlying concept for DASS is multidisciplinary, which is unusual in dermatology. It was rewarding to discuss skin cancer treatment with surgical oncologists, plastic and general surgeons, and medical oncologists. There were also discussions on polycystic ovary disease, rosacea and the “red face,” current treatment of Hansen disease, man-eating psoriasis and urticaria, and of course, botulinum toxin, fillers, lasers, and chemical peels. Of great interest were new “old” treatments for skin disease, since biologics are generally not affordable.

I also got into lively discussions at the World Congress of Dermatology in Vancouver a few weeks earlier. The problem in many countries is funding of dermatologic treatments (particularly Mohs) within a fixed dermatology budget. We in the United States can vote with our feet, and generally seek out treatment we decide is best. Over the past 30 years, 70% of skin cancer has migrated from hospital-based surgical specialties to office-based dermatology, at great cost savings to the health care system.

In most of the world, the government allocates money, and tells hospitals and doctors to make do. This results in a static, change-resistant budget process, where patients have even fewer choices than in the U.S. Hospitals always win in these budget battles, to the detriment of office-based medicine and patient choice, and innovation.

Internationally, correcting this may require dermatologists going to politicians and not saying, “we need more money,” but rather saying, “we can save you money.” For example, if 99% of skin cancer treatment moves out of the hospital to the office setting, where it should be, the budgeteers should be delighted to pay your office costs, which are a fraction of those for an operating room. The budget should reflect that X number of new operating rooms do not need to be built, X number of scrub nurses do not need to trained or can be reassigned, X number of support staff are not needed, or that wait times, a chronic complaint around the world, can shrink.

There will be resistance to this approach from hospital-dependent specialists, and the hospitals. They will argue it isn’t safe, and that the costs aren’t defined. However, these issues have been worked out in detail and the data published.

The same argument can be made for the use of biologics. How many erythrodermic hospitalizations will be avoided? How many missed days of work will not be missed?

It is far easier to budge a bureaucracy by emphasizing cost savings rather than quality, though these are opportunities for dermatologists to improve both.

Dr. Coldiron is in private practice, but maintains a clinical assistant professorship of dermatology at the University of Cincinnati. Email him at dermnews@frontlinemedcom.com.

I recently returned from the DASS (Dermatology and Allied Specialties Summit) in New Delhi. It was interesting and thought provoking. New Delhi, and India in general, are modern and ancient, growing like Topsy, crushed into one another, in a hyperkinetic mix, something like Mexico on amphetamines.

I generally find conferences far afield introduce novel ideas. It helps greatly that these conferences almost always use English as the official language.

The underlying concept for DASS is multidisciplinary, which is unusual in dermatology. It was rewarding to discuss skin cancer treatment with surgical oncologists, plastic and general surgeons, and medical oncologists. There were also discussions on polycystic ovary disease, rosacea and the “red face,” current treatment of Hansen disease, man-eating psoriasis and urticaria, and of course, botulinum toxin, fillers, lasers, and chemical peels. Of great interest were new “old” treatments for skin disease, since biologics are generally not affordable.

I also got into lively discussions at the World Congress of Dermatology in Vancouver a few weeks earlier. The problem in many countries is funding of dermatologic treatments (particularly Mohs) within a fixed dermatology budget. We in the United States can vote with our feet, and generally seek out treatment we decide is best. Over the past 30 years, 70% of skin cancer has migrated from hospital-based surgical specialties to office-based dermatology, at great cost savings to the health care system.

In most of the world, the government allocates money, and tells hospitals and doctors to make do. This results in a static, change-resistant budget process, where patients have even fewer choices than in the U.S. Hospitals always win in these budget battles, to the detriment of office-based medicine and patient choice, and innovation.

Internationally, correcting this may require dermatologists going to politicians and not saying, “we need more money,” but rather saying, “we can save you money.” For example, if 99% of skin cancer treatment moves out of the hospital to the office setting, where it should be, the budgeteers should be delighted to pay your office costs, which are a fraction of those for an operating room. The budget should reflect that X number of new operating rooms do not need to be built, X number of scrub nurses do not need to trained or can be reassigned, X number of support staff are not needed, or that wait times, a chronic complaint around the world, can shrink.

There will be resistance to this approach from hospital-dependent specialists, and the hospitals. They will argue it isn’t safe, and that the costs aren’t defined. However, these issues have been worked out in detail and the data published.

The same argument can be made for the use of biologics. How many erythrodermic hospitalizations will be avoided? How many missed days of work will not be missed?

It is far easier to budge a bureaucracy by emphasizing cost savings rather than quality, though these are opportunities for dermatologists to improve both.

Dr. Coldiron is in private practice, but maintains a clinical assistant professorship of dermatology at the University of Cincinnati. Email him at dermnews@frontlinemedcom.com.

NEW YORK - Compared with dual antiplatelet therapy (DAPT), triple therapy increases the risk of major bleeding without altering the rates of myocardial infarction (MI), stroke, or death in older patients with acute MI and atrial fibrillation (AF), according to a registry study.

"These data suggest that the risk-benefit ratio of triple therapy in older patients with myocardial infarction and atrial fibrillation should be carefully considered," Dr. Connie N. Hess, from Duke Clinical Research Institute, Duke University, Durham, North Carolina, told Reuters Health by email. "However, these results need to be confirmed with prospective studies; a number of ongoing randomized clinical trials may help to provide insight."

Therapeutic decisions for older patients with acute MI and AF are challenging, not least because they have been excluded from or underrepresented in clinical trials.

Dr. Hess's team linked data from the ACTION Registry Get With The Guidelines and Medicare administrative claims to compare outcomes with DAPT or triple therapy (DAPT plus warfarin) in 4959 patients age 65 and older with acute MI and AF who underwent coronary stenting.

More patients were discharged on DAPT (72.4%) than on triple therapy (27.6%), the researchers report in the August 11 issue of the Journal of the American College of Cardiology (JACC), available online now.

The primary effectiveness outcome, major adverse cardiac events (MACE, including death or readmission for MI or stroke) at two years, did not differ in incidence between triple therapy (32.6%) and DAPT (32.7%), and there were no significant differences in the incidences of the individual MACE components.

In contrast, the cumulative incidence of bleeding requiring hospitalization within two years of discharge was significantly higher for patients on triple therapy (17.6%) than for patients on DAPT (11.0%; p<0.0001), and this difference persisted after adjustment for case-mix, treatment, and hospital features.

Triple therapy was also associated with a 2.04-fold higher risk of intracranial hemorrhage, compared with DAPT.

The association of triple therapy with MACE and bleeding outcomes was similar for patients older and younger than 75, for men and women, for patients with low and high predicted stroke risk, for patients with shorter versus longer duration of AF, for patients treated with drug-eluting versus bare-metal stents, and for patients presenting with non-ST-segment elevation MI versus ST-segment elevation MI.

"Until we have data from prospective studies to define optimal antithrombotic use in older patients with myocardial infarction and atrial fibrillation, providers should be especially mindful of an individual's bleeding risk when deciding to prescribe triple therapy," Dr. Hess concluded.

Dr. John C. Messenger, from the University of Colorado School of Medicine, Aurora, cowrote an editorial related to this report. He told Reuters Health by email, "We should ideally look to minimize duration of triple therapy, keeping it as short as possible. We also need to enroll patients in trials designed to evaluate double therapy without the use of aspirin."

"With the change in guidelines recommending oral anticoagulation for patients with atrial fibrillation at lower risk for ischemic stroke, the negative impact of bleeding related to the use of triple therapy may far outweigh the benefit of reduction of ischemic stroke," Dr. Messenger said. "We obviously need further study on this topic."

Dr. Andrea Rubboli, from Ospedale Maggiore, Bologna, Italy, has researched how best to treat these patients. He told Reuters Health by email, "Given that I practice in Europe, where current guidelines recommend triple therapy for these patients, what I found most surprising is the relatively small proportion of AF patients treated with (percutaneous coronary intervention) PCI who were discharged on triple therapy. Conversely, it was not surprising that DAPT was comparable to triple therapy in terms of MACE and superior in terms of bleeding because this has been previously reported and the several limitations of this kind of analysis (especially the lack of information on the therapy really ongoing at the time of event) may account for that."

"Triple therapy confirmed to be the best treatment for these patients," Dr. Rubboli concluded. "While not reducing MACE versus DAPT, it is indeed significantly more effective in reducing the most feared and devastating complication of AF, that is, stroke. Given the increased risk of bleeding, however, great care should be put in monitoring such therapy."

Dr. Nikolaus Sarafoff, from Ludwig-Maximilians University, Munich, Germany, told Reuters Health by email, "In my opinion, one major limitation of the study is that only 7.7% of patients in the DAPT group were on oral anticoagulation (OAC) at randomization as compared to 62.1% in the triple arm. This shows clearly that physicians felt that patients in the DAPT arm had no real indication for OAC (even before the myocardial infarction with PCI occurred) and this makes the comparison of the two groups very difficult."

"The indication for triple therapy and the optimal antithrombotic treatment should be taken carefully, weighing the bleeding and the ischemic risk of the patient," Dr. Sarafoff concluded. "Several options to reduce bleeding complications in this high-risk population exist, such as omitting aspirin, shortening the duration of therapy. The results of the present study cannot supplant current guidelines that state clearly that patients with atrial fibrillation and a CHA2DS2-VASc Score 2 are in need of OAC no matter whether concomitant antiplatelet therapy is needed."

The American College of Cardiology Foundation's National Cardiovascular Data Registry supported this study. Three coauthors reported relevant relationships.

NEW YORK - Compared with dual antiplatelet therapy (DAPT), triple therapy increases the risk of major bleeding without altering the rates of myocardial infarction (MI), stroke, or death in older patients with acute MI and atrial fibrillation (AF), according to a registry study.

"These data suggest that the risk-benefit ratio of triple therapy in older patients with myocardial infarction and atrial fibrillation should be carefully considered," Dr. Connie N. Hess, from Duke Clinical Research Institute, Duke University, Durham, North Carolina, told Reuters Health by email. "However, these results need to be confirmed with prospective studies; a number of ongoing randomized clinical trials may help to provide insight."

Therapeutic decisions for older patients with acute MI and AF are challenging, not least because they have been excluded from or underrepresented in clinical trials.

Dr. Hess's team linked data from the ACTION Registry Get With The Guidelines and Medicare administrative claims to compare outcomes with DAPT or triple therapy (DAPT plus warfarin) in 4959 patients age 65 and older with acute MI and AF who underwent coronary stenting.

More patients were discharged on DAPT (72.4%) than on triple therapy (27.6%), the researchers report in the August 11 issue of the Journal of the American College of Cardiology (JACC), available online now.

The primary effectiveness outcome, major adverse cardiac events (MACE, including death or readmission for MI or stroke) at two years, did not differ in incidence between triple therapy (32.6%) and DAPT (32.7%), and there were no significant differences in the incidences of the individual MACE components.

In contrast, the cumulative incidence of bleeding requiring hospitalization within two years of discharge was significantly higher for patients on triple therapy (17.6%) than for patients on DAPT (11.0%; p<0.0001), and this difference persisted after adjustment for case-mix, treatment, and hospital features.

Triple therapy was also associated with a 2.04-fold higher risk of intracranial hemorrhage, compared with DAPT.

The association of triple therapy with MACE and bleeding outcomes was similar for patients older and younger than 75, for men and women, for patients with low and high predicted stroke risk, for patients with shorter versus longer duration of AF, for patients treated with drug-eluting versus bare-metal stents, and for patients presenting with non-ST-segment elevation MI versus ST-segment elevation MI.

"Until we have data from prospective studies to define optimal antithrombotic use in older patients with myocardial infarction and atrial fibrillation, providers should be especially mindful of an individual's bleeding risk when deciding to prescribe triple therapy," Dr. Hess concluded.

Dr. John C. Messenger, from the University of Colorado School of Medicine, Aurora, cowrote an editorial related to this report. He told Reuters Health by email, "We should ideally look to minimize duration of triple therapy, keeping it as short as possible. We also need to enroll patients in trials designed to evaluate double therapy without the use of aspirin."

"With the change in guidelines recommending oral anticoagulation for patients with atrial fibrillation at lower risk for ischemic stroke, the negative impact of bleeding related to the use of triple therapy may far outweigh the benefit of reduction of ischemic stroke," Dr. Messenger said. "We obviously need further study on this topic."

Dr. Andrea Rubboli, from Ospedale Maggiore, Bologna, Italy, has researched how best to treat these patients. He told Reuters Health by email, "Given that I practice in Europe, where current guidelines recommend triple therapy for these patients, what I found most surprising is the relatively small proportion of AF patients treated with (percutaneous coronary intervention) PCI who were discharged on triple therapy. Conversely, it was not surprising that DAPT was comparable to triple therapy in terms of MACE and superior in terms of bleeding because this has been previously reported and the several limitations of this kind of analysis (especially the lack of information on the therapy really ongoing at the time of event) may account for that."

"Triple therapy confirmed to be the best treatment for these patients," Dr. Rubboli concluded. "While not reducing MACE versus DAPT, it is indeed significantly more effective in reducing the most feared and devastating complication of AF, that is, stroke. Given the increased risk of bleeding, however, great care should be put in monitoring such therapy."

Dr. Nikolaus Sarafoff, from Ludwig-Maximilians University, Munich, Germany, told Reuters Health by email, "In my opinion, one major limitation of the study is that only 7.7% of patients in the DAPT group were on oral anticoagulation (OAC) at randomization as compared to 62.1% in the triple arm. This shows clearly that physicians felt that patients in the DAPT arm had no real indication for OAC (even before the myocardial infarction with PCI occurred) and this makes the comparison of the two groups very difficult."

"The indication for triple therapy and the optimal antithrombotic treatment should be taken carefully, weighing the bleeding and the ischemic risk of the patient," Dr. Sarafoff concluded. "Several options to reduce bleeding complications in this high-risk population exist, such as omitting aspirin, shortening the duration of therapy. The results of the present study cannot supplant current guidelines that state clearly that patients with atrial fibrillation and a CHA2DS2-VASc Score 2 are in need of OAC no matter whether concomitant antiplatelet therapy is needed."

The American College of Cardiology Foundation's National Cardiovascular Data Registry supported this study. Three coauthors reported relevant relationships.

NEW YORK - Compared with dual antiplatelet therapy (DAPT), triple therapy increases the risk of major bleeding without altering the rates of myocardial infarction (MI), stroke, or death in older patients with acute MI and atrial fibrillation (AF), according to a registry study.

"These data suggest that the risk-benefit ratio of triple therapy in older patients with myocardial infarction and atrial fibrillation should be carefully considered," Dr. Connie N. Hess, from Duke Clinical Research Institute, Duke University, Durham, North Carolina, told Reuters Health by email. "However, these results need to be confirmed with prospective studies; a number of ongoing randomized clinical trials may help to provide insight."

Therapeutic decisions for older patients with acute MI and AF are challenging, not least because they have been excluded from or underrepresented in clinical trials.

Dr. Hess's team linked data from the ACTION Registry Get With The Guidelines and Medicare administrative claims to compare outcomes with DAPT or triple therapy (DAPT plus warfarin) in 4959 patients age 65 and older with acute MI and AF who underwent coronary stenting.

More patients were discharged on DAPT (72.4%) than on triple therapy (27.6%), the researchers report in the August 11 issue of the Journal of the American College of Cardiology (JACC), available online now.

The primary effectiveness outcome, major adverse cardiac events (MACE, including death or readmission for MI or stroke) at two years, did not differ in incidence between triple therapy (32.6%) and DAPT (32.7%), and there were no significant differences in the incidences of the individual MACE components.

In contrast, the cumulative incidence of bleeding requiring hospitalization within two years of discharge was significantly higher for patients on triple therapy (17.6%) than for patients on DAPT (11.0%; p<0.0001), and this difference persisted after adjustment for case-mix, treatment, and hospital features.

Triple therapy was also associated with a 2.04-fold higher risk of intracranial hemorrhage, compared with DAPT.

The association of triple therapy with MACE and bleeding outcomes was similar for patients older and younger than 75, for men and women, for patients with low and high predicted stroke risk, for patients with shorter versus longer duration of AF, for patients treated with drug-eluting versus bare-metal stents, and for patients presenting with non-ST-segment elevation MI versus ST-segment elevation MI.

"Until we have data from prospective studies to define optimal antithrombotic use in older patients with myocardial infarction and atrial fibrillation, providers should be especially mindful of an individual's bleeding risk when deciding to prescribe triple therapy," Dr. Hess concluded.

Dr. John C. Messenger, from the University of Colorado School of Medicine, Aurora, cowrote an editorial related to this report. He told Reuters Health by email, "We should ideally look to minimize duration of triple therapy, keeping it as short as possible. We also need to enroll patients in trials designed to evaluate double therapy without the use of aspirin."

"With the change in guidelines recommending oral anticoagulation for patients with atrial fibrillation at lower risk for ischemic stroke, the negative impact of bleeding related to the use of triple therapy may far outweigh the benefit of reduction of ischemic stroke," Dr. Messenger said. "We obviously need further study on this topic."

Dr. Andrea Rubboli, from Ospedale Maggiore, Bologna, Italy, has researched how best to treat these patients. He told Reuters Health by email, "Given that I practice in Europe, where current guidelines recommend triple therapy for these patients, what I found most surprising is the relatively small proportion of AF patients treated with (percutaneous coronary intervention) PCI who were discharged on triple therapy. Conversely, it was not surprising that DAPT was comparable to triple therapy in terms of MACE and superior in terms of bleeding because this has been previously reported and the several limitations of this kind of analysis (especially the lack of information on the therapy really ongoing at the time of event) may account for that."

"Triple therapy confirmed to be the best treatment for these patients," Dr. Rubboli concluded. "While not reducing MACE versus DAPT, it is indeed significantly more effective in reducing the most feared and devastating complication of AF, that is, stroke. Given the increased risk of bleeding, however, great care should be put in monitoring such therapy."

Dr. Nikolaus Sarafoff, from Ludwig-Maximilians University, Munich, Germany, told Reuters Health by email, "In my opinion, one major limitation of the study is that only 7.7% of patients in the DAPT group were on oral anticoagulation (OAC) at randomization as compared to 62.1% in the triple arm. This shows clearly that physicians felt that patients in the DAPT arm had no real indication for OAC (even before the myocardial infarction with PCI occurred) and this makes the comparison of the two groups very difficult."

"The indication for triple therapy and the optimal antithrombotic treatment should be taken carefully, weighing the bleeding and the ischemic risk of the patient," Dr. Sarafoff concluded. "Several options to reduce bleeding complications in this high-risk population exist, such as omitting aspirin, shortening the duration of therapy. The results of the present study cannot supplant current guidelines that state clearly that patients with atrial fibrillation and a CHA2DS2-VASc Score 2 are in need of OAC no matter whether concomitant antiplatelet therapy is needed."

The American College of Cardiology Foundation's National Cardiovascular Data Registry supported this study. Three coauthors reported relevant relationships.

Burkitt lymphoma cells

Image by Ed Uthman

A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.

Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.

Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.

The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.

“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.

As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.

But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.

“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”

To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.

And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.

“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.

Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.

“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with

chronic B lymphocyte activation and an increased risk of lymphoma.

Therefore,

strategies aimed at reducing unintended DNA damage caused by AID might

also help reduce the risk of lymphoma in patients with these conditions.

“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”

Burkitt lymphoma cells

Image by Ed Uthman

A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.

Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.

Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.

The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.

“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.

As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.

But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.

“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”

To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.

And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.

“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.

Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.

“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with

chronic B lymphocyte activation and an increased risk of lymphoma.

Therefore,

strategies aimed at reducing unintended DNA damage caused by AID might

also help reduce the risk of lymphoma in patients with these conditions.

“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”

Burkitt lymphoma cells

Image by Ed Uthman

A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.

Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.

Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.

The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.

“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.

As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.

But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.

“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”

To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.

And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.

“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.

Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.

“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with

chronic B lymphocyte activation and an increased risk of lymphoma.

Therefore,

strategies aimed at reducing unintended DNA damage caused by AID might

also help reduce the risk of lymphoma in patients with these conditions.

“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”

ESTES PARK, COLO. – Clopidogrel is vastly underutilized in real-world medical management of patients with unstable angina or non–ST-segment elevation MI who don’t undergo coronary revascularization, Dr. Mel L. Anderson said at a conference on internal medicine sponsored by the University of Colorado.

Such patients fall under the umbrella of the so-called CURE indication for clopidogrel, named for the landmark Clopidogrel in Unstable Angina to Prevent Recurrent Events trial. CURE showed that adding clopidogrel to aspirin for an average of 9 months in patients with acute coronary syndrome without ST-segment elevation reduced the major adverse cardiovascular event rate from 11.4% to 9.3% (N Engl J Med. 2001;345[7]:494-502).

Bruce Jancin/Frontline Medical News

Clinical practice has changed enormously since CURE was published in 2001, so a group of investigators decided to see if discharging medically managed ACS patients on clopidogrel is still beneficial in the contemporary setting. They conducted a retrospective observational cohort study of 16,345 Kaiser Permanente Northern California patients with unstable angina or NSTEMI managed medically without percutaneous coronary intervention or coronary artery bypass graft, of whom only 36% were discharged on clopidogrel.

“It’s disappointing that fully two-thirds of patients did not get clopidogrel when they had an indication for it,” commented Dr. Anderson, chief of the hospital medicine section at the Denver VA Medical Center and an internist at the university.

Two-year all-cause mortality was 8.3% in the clopidogrel users, compared with 13% in propensity-matched controls not on clopidogrel, for an adjusted 37% relative risk reduction in favor of the antiplatelet agent (J Am Coll Cardiol. 2014 Jun 3;63[21]:2249-57).

“That’s a number-needed-to-treat of 20. It’s really quite a robust benefit for a drug that’s now generic and has a well-established safety profile,” Dr. Anderson continued.

The 2-year composite outcome of death or MI occurred in 13.5% of the clopidogrel group and 17.4% of controls, for a number-needed-to-treat of about 25. Clopidogrel’s benefit in terms of this composite endpoint achieved significance only among the 65% of participants with NSTEMI, not those with unstable angina.

“Don’t forget the CURE indication for clopidogrel,” the hospitalist concluded.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – Clopidogrel is vastly underutilized in real-world medical management of patients with unstable angina or non–ST-segment elevation MI who don’t undergo coronary revascularization, Dr. Mel L. Anderson said at a conference on internal medicine sponsored by the University of Colorado.

Such patients fall under the umbrella of the so-called CURE indication for clopidogrel, named for the landmark Clopidogrel in Unstable Angina to Prevent Recurrent Events trial. CURE showed that adding clopidogrel to aspirin for an average of 9 months in patients with acute coronary syndrome without ST-segment elevation reduced the major adverse cardiovascular event rate from 11.4% to 9.3% (N Engl J Med. 2001;345[7]:494-502).

Bruce Jancin/Frontline Medical News

Clinical practice has changed enormously since CURE was published in 2001, so a group of investigators decided to see if discharging medically managed ACS patients on clopidogrel is still beneficial in the contemporary setting. They conducted a retrospective observational cohort study of 16,345 Kaiser Permanente Northern California patients with unstable angina or NSTEMI managed medically without percutaneous coronary intervention or coronary artery bypass graft, of whom only 36% were discharged on clopidogrel.

“It’s disappointing that fully two-thirds of patients did not get clopidogrel when they had an indication for it,” commented Dr. Anderson, chief of the hospital medicine section at the Denver VA Medical Center and an internist at the university.

Two-year all-cause mortality was 8.3% in the clopidogrel users, compared with 13% in propensity-matched controls not on clopidogrel, for an adjusted 37% relative risk reduction in favor of the antiplatelet agent (J Am Coll Cardiol. 2014 Jun 3;63[21]:2249-57).

“That’s a number-needed-to-treat of 20. It’s really quite a robust benefit for a drug that’s now generic and has a well-established safety profile,” Dr. Anderson continued.

The 2-year composite outcome of death or MI occurred in 13.5% of the clopidogrel group and 17.4% of controls, for a number-needed-to-treat of about 25. Clopidogrel’s benefit in terms of this composite endpoint achieved significance only among the 65% of participants with NSTEMI, not those with unstable angina.

“Don’t forget the CURE indication for clopidogrel,” the hospitalist concluded.

bjancin@frontlinemedcom.com

ESTES PARK, COLO. – Clopidogrel is vastly underutilized in real-world medical management of patients with unstable angina or non–ST-segment elevation MI who don’t undergo coronary revascularization, Dr. Mel L. Anderson said at a conference on internal medicine sponsored by the University of Colorado.

Such patients fall under the umbrella of the so-called CURE indication for clopidogrel, named for the landmark Clopidogrel in Unstable Angina to Prevent Recurrent Events trial. CURE showed that adding clopidogrel to aspirin for an average of 9 months in patients with acute coronary syndrome without ST-segment elevation reduced the major adverse cardiovascular event rate from 11.4% to 9.3% (N Engl J Med. 2001;345[7]:494-502).

Bruce Jancin/Frontline Medical News

Clinical practice has changed enormously since CURE was published in 2001, so a group of investigators decided to see if discharging medically managed ACS patients on clopidogrel is still beneficial in the contemporary setting. They conducted a retrospective observational cohort study of 16,345 Kaiser Permanente Northern California patients with unstable angina or NSTEMI managed medically without percutaneous coronary intervention or coronary artery bypass graft, of whom only 36% were discharged on clopidogrel.

“It’s disappointing that fully two-thirds of patients did not get clopidogrel when they had an indication for it,” commented Dr. Anderson, chief of the hospital medicine section at the Denver VA Medical Center and an internist at the university.

Two-year all-cause mortality was 8.3% in the clopidogrel users, compared with 13% in propensity-matched controls not on clopidogrel, for an adjusted 37% relative risk reduction in favor of the antiplatelet agent (J Am Coll Cardiol. 2014 Jun 3;63[21]:2249-57).

“That’s a number-needed-to-treat of 20. It’s really quite a robust benefit for a drug that’s now generic and has a well-established safety profile,” Dr. Anderson continued.

The 2-year composite outcome of death or MI occurred in 13.5% of the clopidogrel group and 17.4% of controls, for a number-needed-to-treat of about 25. Clopidogrel’s benefit in terms of this composite endpoint achieved significance only among the 65% of participants with NSTEMI, not those with unstable angina.

“Don’t forget the CURE indication for clopidogrel,” the hospitalist concluded.

bjancin@frontlinemedcom.com

Study author

Chenyue Wendy Hu

Photo courtesy of Jeff Fitlow

and Rice University

A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.

The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.

And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.

Details on progeny clustering have been published in Scientific Reports.

The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.

“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”

The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.

“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”

Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.

These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.

By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.

Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.

And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.

Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.

The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.

“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”

Dr Qutub added that the algorithm could apply to any data set.

“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”

Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.

Study author

Chenyue Wendy Hu

Photo courtesy of Jeff Fitlow

and Rice University

A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.

The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.

And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.

Details on progeny clustering have been published in Scientific Reports.

The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.

“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”

The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.

“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”

Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.

These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.

By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.

Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.

And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.

Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.

The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.

“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”

Dr Qutub added that the algorithm could apply to any data set.

“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”

Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.

Study author

Chenyue Wendy Hu

Photo courtesy of Jeff Fitlow

and Rice University

A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.

The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.

And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.

Details on progeny clustering have been published in Scientific Reports.

The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.

“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”

The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.

“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”

Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.

These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.

By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.

Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.

And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.

Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.

The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.

“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”

Dr Qutub added that the algorithm could apply to any data set.

“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”

Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.

Cynomolgus macaque

Photo by Sakura Midori

Researchers say they have developed a nanoparticle-based vaccine against Epstein-Barr virus (EBV) that can induce potent neutralizing antibodies in mice and monkeys.

These results suggest that using a structure-based vaccine design and self-assembling nanoparticles to deliver a viral protein that prompts an immune response could be a promising approach for developing an EBV vaccine for humans.

Most efforts to develop a preventive EBV vaccine have focused on glycoprotein 350 (gp350), a molecule on the surface of EBV that helps the virus attach to B cells. EBV gp350 is thought to be a key target for antibodies capable of preventing viral infection.

Previously, researchers showed that vaccinating monkeys with gp350 protected the animals from developing lymphomas after exposure to a high dose of EBV.

However, in the only large human trial of an experimental EBV vaccine conducted to date, the EBV gp350 vaccine did not prevent EBV infection, although it did reduce the rate of infectious mononucleosis by 78%.

With this in mind, Masaru Kanekiyo, DVM, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to create a better vaccine.

They described their work in a paper published in Cell.

The team designed a nanoparticle-based vaccine that expressed the cell-binding portion of gp350. In tests, the experimental vaccine induced potent neutralizing antibodies in both mice and cynomolgus macaques (Macaca fascicularis).

In fact, compared with soluble gp350, the nanoparticle-based vaccine induced 10- to 100-fold higher levels of neutralizing antibodies in mice.

The researchers believe the nanoparticle vaccine design could be used to create or redesign vaccines against other pathogens as well.

Cynomolgus macaque

Photo by Sakura Midori

Researchers say they have developed a nanoparticle-based vaccine against Epstein-Barr virus (EBV) that can induce potent neutralizing antibodies in mice and monkeys.

These results suggest that using a structure-based vaccine design and self-assembling nanoparticles to deliver a viral protein that prompts an immune response could be a promising approach for developing an EBV vaccine for humans.

Most efforts to develop a preventive EBV vaccine have focused on glycoprotein 350 (gp350), a molecule on the surface of EBV that helps the virus attach to B cells. EBV gp350 is thought to be a key target for antibodies capable of preventing viral infection.

Previously, researchers showed that vaccinating monkeys with gp350 protected the animals from developing lymphomas after exposure to a high dose of EBV.

However, in the only large human trial of an experimental EBV vaccine conducted to date, the EBV gp350 vaccine did not prevent EBV infection, although it did reduce the rate of infectious mononucleosis by 78%.

With this in mind, Masaru Kanekiyo, DVM, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to create a better vaccine.

They described their work in a paper published in Cell.

The team designed a nanoparticle-based vaccine that expressed the cell-binding portion of gp350. In tests, the experimental vaccine induced potent neutralizing antibodies in both mice and cynomolgus macaques (Macaca fascicularis).

In fact, compared with soluble gp350, the nanoparticle-based vaccine induced 10- to 100-fold higher levels of neutralizing antibodies in mice.

The researchers believe the nanoparticle vaccine design could be used to create or redesign vaccines against other pathogens as well.

Cynomolgus macaque

Photo by Sakura Midori

Researchers say they have developed a nanoparticle-based vaccine against Epstein-Barr virus (EBV) that can induce potent neutralizing antibodies in mice and monkeys.

These results suggest that using a structure-based vaccine design and self-assembling nanoparticles to deliver a viral protein that prompts an immune response could be a promising approach for developing an EBV vaccine for humans.

Most efforts to develop a preventive EBV vaccine have focused on glycoprotein 350 (gp350), a molecule on the surface of EBV that helps the virus attach to B cells. EBV gp350 is thought to be a key target for antibodies capable of preventing viral infection.

Previously, researchers showed that vaccinating monkeys with gp350 protected the animals from developing lymphomas after exposure to a high dose of EBV.

However, in the only large human trial of an experimental EBV vaccine conducted to date, the EBV gp350 vaccine did not prevent EBV infection, although it did reduce the rate of infectious mononucleosis by 78%.

With this in mind, Masaru Kanekiyo, DVM, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to create a better vaccine.

They described their work in a paper published in Cell.

The team designed a nanoparticle-based vaccine that expressed the cell-binding portion of gp350. In tests, the experimental vaccine induced potent neutralizing antibodies in both mice and cynomolgus macaques (Macaca fascicularis).

In fact, compared with soluble gp350, the nanoparticle-based vaccine induced 10- to 100-fold higher levels of neutralizing antibodies in mice.

The researchers believe the nanoparticle vaccine design could be used to create or redesign vaccines against other pathogens as well.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.

The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.

The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.

This research was published in JAMA Oncology.

“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.

“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”

To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.

The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.

The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).

A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).

Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.

To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.

Construct validity

The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.

Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.

When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).

Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).

Test-retest reliability and responsiveness

The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.

Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).

The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.

Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).

“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.

The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.

The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.

This research was published in JAMA Oncology.

“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.

“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”

To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.

The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.

The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).

A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).

Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.

To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.

Construct validity

The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.

Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.

When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).

Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).

Test-retest reliability and responsiveness

The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.

Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).

The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.

Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).

“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.

The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.

The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.

This research was published in JAMA Oncology.

“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.

“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”

To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.

The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.

The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).

A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).

Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.

To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.

Construct validity

The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.

Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.

When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).

Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).

Test-retest reliability and responsiveness

The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.

Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).

The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.

Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).

“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.

A 12-year-old girl is brought to dermatology by her mother for evaluation of a lesion on her arm. It’s been there for two years without causing symptoms—but lately it has grown, as has the mother’s concern.

The child is otherwise healthy. The mother reports that the child has neither a personal nor a family history of seizures.

EXAMINATION
A solitary, firm, subcutaneous nodule measuring 2 cm is located on the lateral aspect of the child’s left triceps. It is bluish pink, nontender, and firm on palpation. No other overlying skin changes are seen.

Lateral digital traction toward the center of the lesion produces no dimpling, while lateral traction toward its periphery accentuates the lesion’s central raised portion. The lesion is moderately mobile. No lymph nodes are felt on palpation of nodal sites in the area, and no other such lesions are found elsewhere on the child’s skin.

What is the diagnosis?

DISCUSSION
At this point, the differential included items such as pilomatricoma, dermatofibroma, calcinosis cutis, or epidermal cyst. The firm feel, bluish color, and shallow subcutaneous location of the lesion lent themselves to a provisional diagnosis of pilomatricoma, as did the patient’s age. But the fact that the lesion was changing was of sufficient concern to prompt removal.

Excision revealed a cystic lesion with cottage-cheese­­–like contents and a poorly defined wall, extending more than a centimeter into the subcutaneous tissue. It was removed in one piece and submitted to pathology. Primary closure completed the procedure.

The pathology report showed sheets of anucleate squamous cells (called ghost cells), benign viable nucleated squamous cells, and a center filled with multiple soft calcified granules. A positive von Kossa stain confirmed the expected diagnosis of pilomatricoma (PMC; also spelled pilomatrixoma).

PMCs, also known by their eponymous designation of calcifying epithelioma of Malherbe, are common, benign appendageal tumors derived from hair matrix. They usually manifest (as in this case) as a solitary subcutaneous firm mass, often with bluish discoloration, on the face, neck, or upper extremities. While they average around 2 cm, they can be as large as 15 cm in diameter. They are more common in children and occur slightly more often in girls.

There is some evidence that the tendency to develop PMCs is associated with increased levels of beta-catenin, which encourages cell growth by diminishing apoptosis. This mechanism is thought to promote malignant transformation of PMCs—a  rare event.

As is often the case, the main concern about this patient’s lesion related to its unknown source and recent alteration. Aside from scarring, the patient was no worse off for its removal—and her mother was much relieved.

TAKE-HOME LEARNING POINTS
• PMCs are benign cystic lesions of appendageal origin, commonly found on the necks, faces, and upper extremities of children.

• Diagnostic clues for PMC include firm feel, subcutaneous location, bluish discoloration, and patient age.

• PMCs have poorly defined cyst walls and granular calcified contents.

• Except when occurring in multiples, PMCs have no pathologic implications.

• The term calcifying epithelioma of Malherbe is still in use, as is the alternate spelling of pilomatrixoma. 

A 12-year-old girl is brought to dermatology by her mother for evaluation of a lesion on her arm. It’s been there for two years without causing symptoms—but lately it has grown, as has the mother’s concern.

The child is otherwise healthy. The mother reports that the child has neither a personal nor a family history of seizures.

EXAMINATION
A solitary, firm, subcutaneous nodule measuring 2 cm is located on the lateral aspect of the child’s left triceps. It is bluish pink, nontender, and firm on palpation. No other overlying skin changes are seen.

Lateral digital traction toward the center of the lesion produces no dimpling, while lateral traction toward its periphery accentuates the lesion’s central raised portion. The lesion is moderately mobile. No lymph nodes are felt on palpation of nodal sites in the area, and no other such lesions are found elsewhere on the child’s skin.

What is the diagnosis?

DISCUSSION
At this point, the differential included items such as pilomatricoma, dermatofibroma, calcinosis cutis, or epidermal cyst. The firm feel, bluish color, and shallow subcutaneous location of the lesion lent themselves to a provisional diagnosis of pilomatricoma, as did the patient’s age. But the fact that the lesion was changing was of sufficient concern to prompt removal.

Excision revealed a cystic lesion with cottage-cheese­­–like contents and a poorly defined wall, extending more than a centimeter into the subcutaneous tissue. It was removed in one piece and submitted to pathology. Primary closure completed the procedure.

The pathology report showed sheets of anucleate squamous cells (called ghost cells), benign viable nucleated squamous cells, and a center filled with multiple soft calcified granules. A positive von Kossa stain confirmed the expected diagnosis of pilomatricoma (PMC; also spelled pilomatrixoma).

PMCs, also known by their eponymous designation of calcifying epithelioma of Malherbe, are common, benign appendageal tumors derived from hair matrix. They usually manifest (as in this case) as a solitary subcutaneous firm mass, often with bluish discoloration, on the face, neck, or upper extremities. While they average around 2 cm, they can be as large as 15 cm in diameter. They are more common in children and occur slightly more often in girls.

There is some evidence that the tendency to develop PMCs is associated with increased levels of beta-catenin, which encourages cell growth by diminishing apoptosis. This mechanism is thought to promote malignant transformation of PMCs—a  rare event.

As is often the case, the main concern about this patient’s lesion related to its unknown source and recent alteration. Aside from scarring, the patient was no worse off for its removal—and her mother was much relieved.

TAKE-HOME LEARNING POINTS
• PMCs are benign cystic lesions of appendageal origin, commonly found on the necks, faces, and upper extremities of children.

• Diagnostic clues for PMC include firm feel, subcutaneous location, bluish discoloration, and patient age.

• PMCs have poorly defined cyst walls and granular calcified contents.

• Except when occurring in multiples, PMCs have no pathologic implications.

• The term calcifying epithelioma of Malherbe is still in use, as is the alternate spelling of pilomatrixoma. 

A 12-year-old girl is brought to dermatology by her mother for evaluation of a lesion on her arm. It’s been there for two years without causing symptoms—but lately it has grown, as has the mother’s concern.

The child is otherwise healthy. The mother reports that the child has neither a personal nor a family history of seizures.

EXAMINATION
A solitary, firm, subcutaneous nodule measuring 2 cm is located on the lateral aspect of the child’s left triceps. It is bluish pink, nontender, and firm on palpation. No other overlying skin changes are seen.

Lateral digital traction toward the center of the lesion produces no dimpling, while lateral traction toward its periphery accentuates the lesion’s central raised portion. The lesion is moderately mobile. No lymph nodes are felt on palpation of nodal sites in the area, and no other such lesions are found elsewhere on the child’s skin.

What is the diagnosis?

DISCUSSION
At this point, the differential included items such as pilomatricoma, dermatofibroma, calcinosis cutis, or epidermal cyst. The firm feel, bluish color, and shallow subcutaneous location of the lesion lent themselves to a provisional diagnosis of pilomatricoma, as did the patient’s age. But the fact that the lesion was changing was of sufficient concern to prompt removal.

Excision revealed a cystic lesion with cottage-cheese­­–like contents and a poorly defined wall, extending more than a centimeter into the subcutaneous tissue. It was removed in one piece and submitted to pathology. Primary closure completed the procedure.

The pathology report showed sheets of anucleate squamous cells (called ghost cells), benign viable nucleated squamous cells, and a center filled with multiple soft calcified granules. A positive von Kossa stain confirmed the expected diagnosis of pilomatricoma (PMC; also spelled pilomatrixoma).

PMCs, also known by their eponymous designation of calcifying epithelioma of Malherbe, are common, benign appendageal tumors derived from hair matrix. They usually manifest (as in this case) as a solitary subcutaneous firm mass, often with bluish discoloration, on the face, neck, or upper extremities. While they average around 2 cm, they can be as large as 15 cm in diameter. They are more common in children and occur slightly more often in girls.

There is some evidence that the tendency to develop PMCs is associated with increased levels of beta-catenin, which encourages cell growth by diminishing apoptosis. This mechanism is thought to promote malignant transformation of PMCs—a  rare event.

As is often the case, the main concern about this patient’s lesion related to its unknown source and recent alteration. Aside from scarring, the patient was no worse off for its removal—and her mother was much relieved.

TAKE-HOME LEARNING POINTS
• PMCs are benign cystic lesions of appendageal origin, commonly found on the necks, faces, and upper extremities of children.

• Diagnostic clues for PMC include firm feel, subcutaneous location, bluish discoloration, and patient age.

• PMCs have poorly defined cyst walls and granular calcified contents.

• Except when occurring in multiples, PMCs have no pathologic implications.

• The term calcifying epithelioma of Malherbe is still in use, as is the alternate spelling of pilomatrixoma. 

The active ingredient of any pharmaceutical product is responsible for the agent’s efficacy and safety profile. This ingredient is extensively studied in clinical trials and evaluated by the US Food and Drug Administration before the product is commercially available. In dermatologic products, especially those for treating dermatoses, the vehicle in which the active ingredient is formulated also plays a role in drug delivery and indirectly impacts therapeutic outcomes, unlike excipients in oral medications. Topical vehicles must be stable, provide a suitable environment that will not degrade the active ingredient or affect its efficacy, and be cosmetically acceptable.¹

Topical vehicles are formulated to maintain the stability of the active ingredient and allow it to readily penetrate the skin and reach its target area with minimal absorption into the bloodstream, thus avoiding systemic adverse events. A variety of vehicles can exist for a single active ingredient to accommodate different phases of disease and different anatomical sites where the disease may occur.² For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation of the vehicle is beneficial to prevent greasiness of the hair, while ointments may be preferred due to their occlusive nature for areas with xerotic or thick skin from dermatoses.

Cosmetic acceptability of the vehicle may influence patient adherence to therapy. Housman et al³ assessed a variety of products formulated in different vehicles (ie, solutions, foams, emollients, gels, creams, ointments) for the treatment of psoriasis. Patients with psoriasis applied each test product to a quarter-sized area of normal skin on the forearm using a cotton swab and completed a preference questionnaire. By far, respondents significantly preferred solutions and foams over creams, gels, and ointments (P<.01). Side effects were rated to be the most important characteristics of topical therapy, followed by time needed for application, ease of application, and messiness.³ Presumably, if patients are frustrated with the topical product that they are using, adherence to the prescribed dosage and application instructions will diminish over time, leading to suboptimal steady-state levels of the product. If appropriate levels of the drug are not present at the target site, treatment will not be successful.

Steady-state levels of a topical drug at the site of action also are maintained via appropriate application frequency, most commonly once to 4 times daily for dermatologic products. Fluocinonide and halcinonide are class II (potent) corticosteroids indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and usually are administered at least twice daily. In double-blind clinical studies comparing both products in the treatment of psoriasis, halcinonide resulted in more improved outcomes than fluocinonide.^4-6 Sudilovsky and Clewe⁴ studied 140 patients with moderate to severe psoriasis. After 3 weeks of treatment, 44% showed superior results with halcinonide, 27% showed superior results with fluocinonide, 26% showed equal results with both products, and 3% showed no relief.⁴ Similarly, Close⁵ reported that 61% of patients showed superior results with halcinonide, 25% showed superior results with fluocinonide, 10% showed equal results with both products, and 4% showed no relief (N=50). Lynfield and Watsky⁶ reported that 56% of patients with severe psoriasis who were treated with halcinonide for 2 weeks showed improvement to normal or slight inflammation compared to 44% of patients treated with fluocinonide (N=59). All 3 studies used cream formulations of halcinonide and fluocinonide.

Recently, halcinonide cream was shown to have an immediate release into the stratum corneum that peaked within 1 hour of application and remained elevated for 6 hours before beginning to decline.⁷ These results support a biphasic release of halcinonide, which is in agreement with its formulation—that halcinonide exists in both a solution phase for immediate release into the skin and in a suspension phase that allows a sustained release after equilibrium is reached between the solution and suspension phases.⁸ Fluocinonide is not known to be formulated in a similar way. Its vehicle composition and penetration into the skin could explain the superior efficacy of halcinonide versus fluocinonide.

The current pilot study was conducted to compare the release pattern of fluocinonide cream versus halcinonide cream into the stratum corneum using an in vivo, noninvasive method. Results for halcin-onide have been previously published.⁷

Methods

Participants were sequestered in a controlled environment for the entire day to allow the skin to equilibrate prior to product application. The methodology for the application and quantification of halcinonide cream 0.1% into the stratum corneum of 5 participants using a tape-stripping protocol has been described elsewhere.⁷ Concordia Clinical Research institutional review board (Cedar Knolls, New Jersey) approved this study, which was conducted at Dermatology Consulting Services (High Point, North Carolina).

A 0.1-g dose of generic fluocinonide cream 0.05% was applied to four 2.5-cm circular sites on the forearm in 5 participants with normal skin until completely absorbed. Circular tape strips were subsequently placed on the application site at 1, 3, 6, and 9 hours posttreatment and were held for 10 seconds with a controlled pressure plunger to ensure adequate and consistent contact between the tape strip and the skin. The tape strip was removed with forceps, rolled with the skin scale inside, and placed in a glass vial. This procedure was repeated 6 times at 1 of 4 sites with a new tape strip at each time point to obtain samples from deeper skin layers. A total of 24 tape strips were collected from each participant.

All vials were frozen at -20°C and were shipped overnight to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University (Flagstaff, Arizona) for mass spectroscopy evaluation. Once received at the outside facility, the vials were stored at -20°C until analysis. Each sample was spiked with a known quantity of an appropriate reference standard and extracted with 1 mL acetonitrile at room temperature for 1 minute with agitation. New unused tape strips were spiked with a small amount of fluocinonide reference standard for extraction efficiency.

Extracts were evaporated to dryness under nitrogen gas, resuspended in 200 µL chromatography solvent, and quantified using liquid chromatography–mass spectrometry. To remove the skin scale from the tape strips, 10 mL of a solvent solution of 0.1 mg/mL fludrocortisone acetate in acetonitrile was dispensed into a 4 dram vial containing the tape strip. The vials were ultrasonicated and shaken for 10 to 15 minutes, and the samples were further diluted to 100-fold and were inverted several times to ensure complete dissolution of fluocinonide before liquid chromatography–mass spectrometry.

A standard curve ranging from the lower limit of quantification to the upper limit of quantification for the fluocinonide reference was used to determine the quantity of fluocinonide in each of the tape strips. Once the lower limit of quantification was reached in a given set of tape strip samples (1-, 3-, 6-, and 9-hour samples), the next 2 sequential tape strips in that set were analyzed to confirm fluocinonide was not detectable in deeper layers. Standard quality controls were analyzed to ensure run-to-run and sample-to-sample accuracy.

Each sample was analyzed in duplicate; 10 mg fluocinonide was used as a reference standard. The minimum detectable concentration of fluocinonide was 1 ng/mL.

Results

As expected, tape strip 1 from each participant contained the highest concentration of fluocinonide. This strip corresponded to the most superficial layer of skin. Concentrations decreased in deeper skin layers, as detected in strips 2 to 6.

In general, the average concentration of fluocin-onide in strip 1 for all 5 participants was highest at hour 1, with a subsequent decline at hours 3, 6, and 9; however, participant 1 showed a second peak in fluocinonide concentration at hour 6 (Figure 1). When the fluocinonide concentration in strips 1 to 6 was averaged for each participant at each time point, similar results were obtained: a general decline after hour 1, but a second prominent peak at hour 6 in participant 1 only. In participant 1, the average fluocinonide concentration for strips 1 to 6 was 393 ng/mL at hour 1 and declined to 208 ng/mL at hour 3; it increased to 451 ng/mL at hour 6 before declining again to 202 ng/mL at hour 9.

Figure 1. Fluocinonide concentration in tape strip 1 for all participants (N=5).

Because participant 1 was the only one to exhibit a second peak of fluocinonide concentration, it appears that measurements obtained from this participant may be outliers. When removing partici-pant 1 from the analysis of fluocinonide concentration in strip 1 at each time point, a clear decline is evident from hour 1 to hour 9 (Figure 2A, red line [partici-pants 2–5] vs blue line [participants 1–5]).

When the average concentration of fluocinonide was calculated in strips 1 to 6 from all participants, there was a general steady decline after hour 1 with a slight increase of 25 ng/mL at hour 6 (Figure 2B, blue line). This increase is due to the measurements obtained from participant 1; however, if partici-pant 1 is removed from the analysis, a constant decline is observed from hour 1 to hour 9 (Figure 2B, red line).

Figure 2. Average fluocinonide concentration in tape strip 1 only (A) and strips 1 to 6 (B)(N=5). Error bars indicate standard deviation.

A prior study evaluated the penetration and absorption of halcinonide in the stratum corneum.⁷ In summary, halcinonide concentration peaked at hour 1 following application and remained elevated to hour 6, before beginning a slow decline. The average concentration of halcinonide from all participants in strips 1 to 6 reached 1350 ng/mL at hour 1, remained within 93% to 97% of this level (1253–1303 ng/mL) for the next 5 hours, and declined only 29% from the peak at hour 1 to hour 9 (958 ng/mL)(Figure 3, blue line).⁷ In contrast, the fluocinonide concentration in participants 2 to 5 from the current study reached 190 ng/mL at hour 1 and steadily declined 53% to 89 ng/mL by hour 9 (Figure 3, red line).

Figure 3. Average halcinonide and fluocinonide concentrations in tape strips 1 to 6 (N=5 for both). Adapted from Draelos.7 7

Two participants from the prior halcinonide study also were enrolled in the current fluocinonide study (referred to as participant A and B). In general, halcinonide levels in both participants remained elevated for 6 hours after application and declined 27.5% and 35.5%, respectively, by hour 9 (Figure 4). Participant A experienced a 20.5% dip in halcinonide concentration at hour 3 followed by an increase at hour 6; however, the halcinonide concentration at hour 9 was similar to hour 3.⁷ In contrast, fluocin-onide concentrations for these participants peaked at 1 hour and clearly declined approximately 60% over the next 8 hours.

Figure 4. Fluocinonide and halcin-onide concentrations in tape strips 1 to 6 for 2 participants who received both corticosteroids during different study periods (referred to as participant A and B).

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.

The active ingredient of any pharmaceutical product is responsible for the agent’s efficacy and safety profile. This ingredient is extensively studied in clinical trials and evaluated by the US Food and Drug Administration before the product is commercially available. In dermatologic products, especially those for treating dermatoses, the vehicle in which the active ingredient is formulated also plays a role in drug delivery and indirectly impacts therapeutic outcomes, unlike excipients in oral medications. Topical vehicles must be stable, provide a suitable environment that will not degrade the active ingredient or affect its efficacy, and be cosmetically acceptable.¹

Topical vehicles are formulated to maintain the stability of the active ingredient and allow it to readily penetrate the skin and reach its target area with minimal absorption into the bloodstream, thus avoiding systemic adverse events. A variety of vehicles can exist for a single active ingredient to accommodate different phases of disease and different anatomical sites where the disease may occur.² For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation of the vehicle is beneficial to prevent greasiness of the hair, while ointments may be preferred due to their occlusive nature for areas with xerotic or thick skin from dermatoses.

Cosmetic acceptability of the vehicle may influence patient adherence to therapy. Housman et al³ assessed a variety of products formulated in different vehicles (ie, solutions, foams, emollients, gels, creams, ointments) for the treatment of psoriasis. Patients with psoriasis applied each test product to a quarter-sized area of normal skin on the forearm using a cotton swab and completed a preference questionnaire. By far, respondents significantly preferred solutions and foams over creams, gels, and ointments (P<.01). Side effects were rated to be the most important characteristics of topical therapy, followed by time needed for application, ease of application, and messiness.³ Presumably, if patients are frustrated with the topical product that they are using, adherence to the prescribed dosage and application instructions will diminish over time, leading to suboptimal steady-state levels of the product. If appropriate levels of the drug are not present at the target site, treatment will not be successful.

Steady-state levels of a topical drug at the site of action also are maintained via appropriate application frequency, most commonly once to 4 times daily for dermatologic products. Fluocinonide and halcinonide are class II (potent) corticosteroids indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and usually are administered at least twice daily. In double-blind clinical studies comparing both products in the treatment of psoriasis, halcinonide resulted in more improved outcomes than fluocinonide.^4-6 Sudilovsky and Clewe⁴ studied 140 patients with moderate to severe psoriasis. After 3 weeks of treatment, 44% showed superior results with halcinonide, 27% showed superior results with fluocinonide, 26% showed equal results with both products, and 3% showed no relief.⁴ Similarly, Close⁵ reported that 61% of patients showed superior results with halcinonide, 25% showed superior results with fluocinonide, 10% showed equal results with both products, and 4% showed no relief (N=50). Lynfield and Watsky⁶ reported that 56% of patients with severe psoriasis who were treated with halcinonide for 2 weeks showed improvement to normal or slight inflammation compared to 44% of patients treated with fluocinonide (N=59). All 3 studies used cream formulations of halcinonide and fluocinonide.

Recently, halcinonide cream was shown to have an immediate release into the stratum corneum that peaked within 1 hour of application and remained elevated for 6 hours before beginning to decline.⁷ These results support a biphasic release of halcinonide, which is in agreement with its formulation—that halcinonide exists in both a solution phase for immediate release into the skin and in a suspension phase that allows a sustained release after equilibrium is reached between the solution and suspension phases.⁸ Fluocinonide is not known to be formulated in a similar way. Its vehicle composition and penetration into the skin could explain the superior efficacy of halcinonide versus fluocinonide.

The current pilot study was conducted to compare the release pattern of fluocinonide cream versus halcinonide cream into the stratum corneum using an in vivo, noninvasive method. Results for halcin-onide have been previously published.⁷

Methods

Participants were sequestered in a controlled environment for the entire day to allow the skin to equilibrate prior to product application. The methodology for the application and quantification of halcinonide cream 0.1% into the stratum corneum of 5 participants using a tape-stripping protocol has been described elsewhere.⁷ Concordia Clinical Research institutional review board (Cedar Knolls, New Jersey) approved this study, which was conducted at Dermatology Consulting Services (High Point, North Carolina).

A 0.1-g dose of generic fluocinonide cream 0.05% was applied to four 2.5-cm circular sites on the forearm in 5 participants with normal skin until completely absorbed. Circular tape strips were subsequently placed on the application site at 1, 3, 6, and 9 hours posttreatment and were held for 10 seconds with a controlled pressure plunger to ensure adequate and consistent contact between the tape strip and the skin. The tape strip was removed with forceps, rolled with the skin scale inside, and placed in a glass vial. This procedure was repeated 6 times at 1 of 4 sites with a new tape strip at each time point to obtain samples from deeper skin layers. A total of 24 tape strips were collected from each participant.

All vials were frozen at -20°C and were shipped overnight to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University (Flagstaff, Arizona) for mass spectroscopy evaluation. Once received at the outside facility, the vials were stored at -20°C until analysis. Each sample was spiked with a known quantity of an appropriate reference standard and extracted with 1 mL acetonitrile at room temperature for 1 minute with agitation. New unused tape strips were spiked with a small amount of fluocinonide reference standard for extraction efficiency.

Extracts were evaporated to dryness under nitrogen gas, resuspended in 200 µL chromatography solvent, and quantified using liquid chromatography–mass spectrometry. To remove the skin scale from the tape strips, 10 mL of a solvent solution of 0.1 mg/mL fludrocortisone acetate in acetonitrile was dispensed into a 4 dram vial containing the tape strip. The vials were ultrasonicated and shaken for 10 to 15 minutes, and the samples were further diluted to 100-fold and were inverted several times to ensure complete dissolution of fluocinonide before liquid chromatography–mass spectrometry.

A standard curve ranging from the lower limit of quantification to the upper limit of quantification for the fluocinonide reference was used to determine the quantity of fluocinonide in each of the tape strips. Once the lower limit of quantification was reached in a given set of tape strip samples (1-, 3-, 6-, and 9-hour samples), the next 2 sequential tape strips in that set were analyzed to confirm fluocinonide was not detectable in deeper layers. Standard quality controls were analyzed to ensure run-to-run and sample-to-sample accuracy.

Each sample was analyzed in duplicate; 10 mg fluocinonide was used as a reference standard. The minimum detectable concentration of fluocinonide was 1 ng/mL.

Results

As expected, tape strip 1 from each participant contained the highest concentration of fluocinonide. This strip corresponded to the most superficial layer of skin. Concentrations decreased in deeper skin layers, as detected in strips 2 to 6.

In general, the average concentration of fluocin-onide in strip 1 for all 5 participants was highest at hour 1, with a subsequent decline at hours 3, 6, and 9; however, participant 1 showed a second peak in fluocinonide concentration at hour 6 (Figure 1). When the fluocinonide concentration in strips 1 to 6 was averaged for each participant at each time point, similar results were obtained: a general decline after hour 1, but a second prominent peak at hour 6 in participant 1 only. In participant 1, the average fluocinonide concentration for strips 1 to 6 was 393 ng/mL at hour 1 and declined to 208 ng/mL at hour 3; it increased to 451 ng/mL at hour 6 before declining again to 202 ng/mL at hour 9.

Figure 1. Fluocinonide concentration in tape strip 1 for all participants (N=5).

Because participant 1 was the only one to exhibit a second peak of fluocinonide concentration, it appears that measurements obtained from this participant may be outliers. When removing partici-pant 1 from the analysis of fluocinonide concentration in strip 1 at each time point, a clear decline is evident from hour 1 to hour 9 (Figure 2A, red line [partici-pants 2–5] vs blue line [participants 1–5]).

When the average concentration of fluocinonide was calculated in strips 1 to 6 from all participants, there was a general steady decline after hour 1 with a slight increase of 25 ng/mL at hour 6 (Figure 2B, blue line). This increase is due to the measurements obtained from participant 1; however, if partici-pant 1 is removed from the analysis, a constant decline is observed from hour 1 to hour 9 (Figure 2B, red line).

Figure 2. Average fluocinonide concentration in tape strip 1 only (A) and strips 1 to 6 (B)(N=5). Error bars indicate standard deviation.

A prior study evaluated the penetration and absorption of halcinonide in the stratum corneum.⁷ In summary, halcinonide concentration peaked at hour 1 following application and remained elevated to hour 6, before beginning a slow decline. The average concentration of halcinonide from all participants in strips 1 to 6 reached 1350 ng/mL at hour 1, remained within 93% to 97% of this level (1253–1303 ng/mL) for the next 5 hours, and declined only 29% from the peak at hour 1 to hour 9 (958 ng/mL)(Figure 3, blue line).⁷ In contrast, the fluocinonide concentration in participants 2 to 5 from the current study reached 190 ng/mL at hour 1 and steadily declined 53% to 89 ng/mL by hour 9 (Figure 3, red line).

Figure 3. Average halcinonide and fluocinonide concentrations in tape strips 1 to 6 (N=5 for both). Adapted from Draelos.7 7

Two participants from the prior halcinonide study also were enrolled in the current fluocinonide study (referred to as participant A and B). In general, halcinonide levels in both participants remained elevated for 6 hours after application and declined 27.5% and 35.5%, respectively, by hour 9 (Figure 4). Participant A experienced a 20.5% dip in halcinonide concentration at hour 3 followed by an increase at hour 6; however, the halcinonide concentration at hour 9 was similar to hour 3.⁷ In contrast, fluocin-onide concentrations for these participants peaked at 1 hour and clearly declined approximately 60% over the next 8 hours.

Figure 4. Fluocinonide and halcin-onide concentrations in tape strips 1 to 6 for 2 participants who received both corticosteroids during different study periods (referred to as participant A and B).

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.

The active ingredient of any pharmaceutical product is responsible for the agent’s efficacy and safety profile. This ingredient is extensively studied in clinical trials and evaluated by the US Food and Drug Administration before the product is commercially available. In dermatologic products, especially those for treating dermatoses, the vehicle in which the active ingredient is formulated also plays a role in drug delivery and indirectly impacts therapeutic outcomes, unlike excipients in oral medications. Topical vehicles must be stable, provide a suitable environment that will not degrade the active ingredient or affect its efficacy, and be cosmetically acceptable.¹

Topical vehicles are formulated to maintain the stability of the active ingredient and allow it to readily penetrate the skin and reach its target area with minimal absorption into the bloodstream, thus avoiding systemic adverse events. A variety of vehicles can exist for a single active ingredient to accommodate different phases of disease and different anatomical sites where the disease may occur.² For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation of the vehicle is beneficial to prevent greasiness of the hair, while ointments may be preferred due to their occlusive nature for areas with xerotic or thick skin from dermatoses.

Cosmetic acceptability of the vehicle may influence patient adherence to therapy. Housman et al³ assessed a variety of products formulated in different vehicles (ie, solutions, foams, emollients, gels, creams, ointments) for the treatment of psoriasis. Patients with psoriasis applied each test product to a quarter-sized area of normal skin on the forearm using a cotton swab and completed a preference questionnaire. By far, respondents significantly preferred solutions and foams over creams, gels, and ointments (P<.01). Side effects were rated to be the most important characteristics of topical therapy, followed by time needed for application, ease of application, and messiness.³ Presumably, if patients are frustrated with the topical product that they are using, adherence to the prescribed dosage and application instructions will diminish over time, leading to suboptimal steady-state levels of the product. If appropriate levels of the drug are not present at the target site, treatment will not be successful.

Steady-state levels of a topical drug at the site of action also are maintained via appropriate application frequency, most commonly once to 4 times daily for dermatologic products. Fluocinonide and halcinonide are class II (potent) corticosteroids indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and usually are administered at least twice daily. In double-blind clinical studies comparing both products in the treatment of psoriasis, halcinonide resulted in more improved outcomes than fluocinonide.^4-6 Sudilovsky and Clewe⁴ studied 140 patients with moderate to severe psoriasis. After 3 weeks of treatment, 44% showed superior results with halcinonide, 27% showed superior results with fluocinonide, 26% showed equal results with both products, and 3% showed no relief.⁴ Similarly, Close⁵ reported that 61% of patients showed superior results with halcinonide, 25% showed superior results with fluocinonide, 10% showed equal results with both products, and 4% showed no relief (N=50). Lynfield and Watsky⁶ reported that 56% of patients with severe psoriasis who were treated with halcinonide for 2 weeks showed improvement to normal or slight inflammation compared to 44% of patients treated with fluocinonide (N=59). All 3 studies used cream formulations of halcinonide and fluocinonide.

Recently, halcinonide cream was shown to have an immediate release into the stratum corneum that peaked within 1 hour of application and remained elevated for 6 hours before beginning to decline.⁷ These results support a biphasic release of halcinonide, which is in agreement with its formulation—that halcinonide exists in both a solution phase for immediate release into the skin and in a suspension phase that allows a sustained release after equilibrium is reached between the solution and suspension phases.⁸ Fluocinonide is not known to be formulated in a similar way. Its vehicle composition and penetration into the skin could explain the superior efficacy of halcinonide versus fluocinonide.

The current pilot study was conducted to compare the release pattern of fluocinonide cream versus halcinonide cream into the stratum corneum using an in vivo, noninvasive method. Results for halcin-onide have been previously published.⁷

Methods

Participants were sequestered in a controlled environment for the entire day to allow the skin to equilibrate prior to product application. The methodology for the application and quantification of halcinonide cream 0.1% into the stratum corneum of 5 participants using a tape-stripping protocol has been described elsewhere.⁷ Concordia Clinical Research institutional review board (Cedar Knolls, New Jersey) approved this study, which was conducted at Dermatology Consulting Services (High Point, North Carolina).

A 0.1-g dose of generic fluocinonide cream 0.05% was applied to four 2.5-cm circular sites on the forearm in 5 participants with normal skin until completely absorbed. Circular tape strips were subsequently placed on the application site at 1, 3, 6, and 9 hours posttreatment and were held for 10 seconds with a controlled pressure plunger to ensure adequate and consistent contact between the tape strip and the skin. The tape strip was removed with forceps, rolled with the skin scale inside, and placed in a glass vial. This procedure was repeated 6 times at 1 of 4 sites with a new tape strip at each time point to obtain samples from deeper skin layers. A total of 24 tape strips were collected from each participant.

All vials were frozen at -20°C and were shipped overnight to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University (Flagstaff, Arizona) for mass spectroscopy evaluation. Once received at the outside facility, the vials were stored at -20°C until analysis. Each sample was spiked with a known quantity of an appropriate reference standard and extracted with 1 mL acetonitrile at room temperature for 1 minute with agitation. New unused tape strips were spiked with a small amount of fluocinonide reference standard for extraction efficiency.

Extracts were evaporated to dryness under nitrogen gas, resuspended in 200 µL chromatography solvent, and quantified using liquid chromatography–mass spectrometry. To remove the skin scale from the tape strips, 10 mL of a solvent solution of 0.1 mg/mL fludrocortisone acetate in acetonitrile was dispensed into a 4 dram vial containing the tape strip. The vials were ultrasonicated and shaken for 10 to 15 minutes, and the samples were further diluted to 100-fold and were inverted several times to ensure complete dissolution of fluocinonide before liquid chromatography–mass spectrometry.

A standard curve ranging from the lower limit of quantification to the upper limit of quantification for the fluocinonide reference was used to determine the quantity of fluocinonide in each of the tape strips. Once the lower limit of quantification was reached in a given set of tape strip samples (1-, 3-, 6-, and 9-hour samples), the next 2 sequential tape strips in that set were analyzed to confirm fluocinonide was not detectable in deeper layers. Standard quality controls were analyzed to ensure run-to-run and sample-to-sample accuracy.

Each sample was analyzed in duplicate; 10 mg fluocinonide was used as a reference standard. The minimum detectable concentration of fluocinonide was 1 ng/mL.

Results

As expected, tape strip 1 from each participant contained the highest concentration of fluocinonide. This strip corresponded to the most superficial layer of skin. Concentrations decreased in deeper skin layers, as detected in strips 2 to 6.

In general, the average concentration of fluocin-onide in strip 1 for all 5 participants was highest at hour 1, with a subsequent decline at hours 3, 6, and 9; however, participant 1 showed a second peak in fluocinonide concentration at hour 6 (Figure 1). When the fluocinonide concentration in strips 1 to 6 was averaged for each participant at each time point, similar results were obtained: a general decline after hour 1, but a second prominent peak at hour 6 in participant 1 only. In participant 1, the average fluocinonide concentration for strips 1 to 6 was 393 ng/mL at hour 1 and declined to 208 ng/mL at hour 3; it increased to 451 ng/mL at hour 6 before declining again to 202 ng/mL at hour 9.

Figure 1. Fluocinonide concentration in tape strip 1 for all participants (N=5).

Because participant 1 was the only one to exhibit a second peak of fluocinonide concentration, it appears that measurements obtained from this participant may be outliers. When removing partici-pant 1 from the analysis of fluocinonide concentration in strip 1 at each time point, a clear decline is evident from hour 1 to hour 9 (Figure 2A, red line [partici-pants 2–5] vs blue line [participants 1–5]).

When the average concentration of fluocinonide was calculated in strips 1 to 6 from all participants, there was a general steady decline after hour 1 with a slight increase of 25 ng/mL at hour 6 (Figure 2B, blue line). This increase is due to the measurements obtained from participant 1; however, if partici-pant 1 is removed from the analysis, a constant decline is observed from hour 1 to hour 9 (Figure 2B, red line).

Figure 2. Average fluocinonide concentration in tape strip 1 only (A) and strips 1 to 6 (B)(N=5). Error bars indicate standard deviation.

A prior study evaluated the penetration and absorption of halcinonide in the stratum corneum.⁷ In summary, halcinonide concentration peaked at hour 1 following application and remained elevated to hour 6, before beginning a slow decline. The average concentration of halcinonide from all participants in strips 1 to 6 reached 1350 ng/mL at hour 1, remained within 93% to 97% of this level (1253–1303 ng/mL) for the next 5 hours, and declined only 29% from the peak at hour 1 to hour 9 (958 ng/mL)(Figure 3, blue line).⁷ In contrast, the fluocinonide concentration in participants 2 to 5 from the current study reached 190 ng/mL at hour 1 and steadily declined 53% to 89 ng/mL by hour 9 (Figure 3, red line).

Figure 3. Average halcinonide and fluocinonide concentrations in tape strips 1 to 6 (N=5 for both). Adapted from Draelos.7 7

Two participants from the prior halcinonide study also were enrolled in the current fluocinonide study (referred to as participant A and B). In general, halcinonide levels in both participants remained elevated for 6 hours after application and declined 27.5% and 35.5%, respectively, by hour 9 (Figure 4). Participant A experienced a 20.5% dip in halcinonide concentration at hour 3 followed by an increase at hour 6; however, the halcinonide concentration at hour 9 was similar to hour 3.⁷ In contrast, fluocin-onide concentrations for these participants peaked at 1 hour and clearly declined approximately 60% over the next 8 hours.

Figure 4. Fluocinonide and halcin-onide concentrations in tape strips 1 to 6 for 2 participants who received both corticosteroids during different study periods (referred to as participant A and B).

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.