Melanoma

Durga Udayakumar, PhD; Bisundev Mahato, Michele Gabree, MGC and
Hensin Tsao, MD, PhD

In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing.

*For a PDF of the full article, click on the link to the left of this introduction.

Durga Udayakumar, PhD; Bisundev Mahato, Michele Gabree, MGC and
Hensin Tsao, MD, PhD

In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing.

*For a PDF of the full article, click on the link to the left of this introduction.

Durga Udayakumar, PhD; Bisundev Mahato, Michele Gabree, MGC and
Hensin Tsao, MD, PhD

In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing.

*For a PDF of the full article, click on the link to the left of this introduction.

Igor Puzanov, MD, MSCI, and Keith T. Flaherty, MD

Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.

*For a PDF of the full article, click on the link to the left of this introduction.

Igor Puzanov, MD, MSCI, and Keith T. Flaherty, MD

Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.

*For a PDF of the full article, click on the link to the left of this introduction.

Igor Puzanov, MD, MSCI, and Keith T. Flaherty, MD

Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.

*For a PDF of the full article, click on the link to the left of this introduction.

Many blogs, articles, and tip sheets offer suggestions for keeping skin youthful and breakout free. But often the advice doesn’t apply to all skin types. Below are nine skin care tips modified for darker skin that you can share with your patients.

1. Don’t over wash.

Photo courtesy Michele Hill/Wiki Commons

Washing the face once a day to remove makeup, dirt, and bacteria can be helpful to avoid breakouts, especially in acne prone skin. However, it is important to remind patients to avoid over washing, as this may dry out the skin causing increased irritation, and may even cause wrinkles to look more prominent.

Sebum production decreases with age, especially after menopause in women. It may also be decreased in black patients, compared with white patients, as shown in a recent study (Cutis 2004;73:392-396), although the data were not statistically significant. 

Patients should exercise caution when applying antiaging products after washing because washing allows antiagers to penetrate deeper, leading to faster results in most skin types, but may also lead to increased irritation and then postinflammatory hyperpigmentation in darker skin.

Gentle cleansers are best, unless the skin is especially acne prone. In this case, anti-acne cleansers with ingredients like salicylic acid, benzoyl peroxide, or glycolic acid may be useful. To refresh skin, a splash of lukewarm water should do.

2. Apply products with a lower pH.

Studies have shown pH to be lower in darker skin, compared with lighter skin. For darker skin, products that are slightly acidic, such as those that contain mild glycolic acid, can help maintain the skin’s pH balance and maintain homeostasis and barrier integrity.

3. Be UV obsessed.

Photo courtesy of mark wragg/iStockphoto.com.

While the epidermis of darker skin contains more melanin content and has increased melanosomal dispersion than lighter skin—providing increased protection against UV-induced skin cancers and photoaging—UV damage can still occur.

Many patients with darker skin feel they are immune to skin cancer. Patients with darker skin, while diagnosed less frequently with melanoma, die at an increased frequency from the disease because of later diagnosis. Using a sunscreen that is SPF 30 or higher that blocks both UVA and UVB wavelengths is essential. 

Patients should be reminded that nothing is more important than wearing sunscreen every day to promote younger-looking skin and prevent skin cancer.

Sunscreens, especially those with a higher SPF, often do not rub in well on darker skin. Using a sunscreen with chemical blockers, or micronized physical blockers (zinc and titanium dioxide), may go on less chalky and rub in more smoothly. 

Sun exposure in darker skin also leads to prolonged postinflammatory hyperpigmentation after any skin insult. Even 10 minutes of daily exposure to UVA can cause changes that lead to wrinkles and sunspots in as few as 12 weeks.

Also, advise patients to eat foods that are rich in vitamin D to avoid deficiency.

4. Manage stress.

Emotional upheavals can make a patient’s skin look 5 years older than his or her chronological age.  Constant anxiety increases the stress hormone cortisol, which causes inflammation that breaks down collagen. It also triggers a chain of responses that can lead to facial redness and acne flare-ups. To quell inflammation, advise patients to eat antioxidant-rich foods such as berries, oranges, and asparagus.

5. Use a retinoid.

Vitamin A derivatives, such as topical retinoids, speed cell turnover and collagen growth to smooth fine lines and wrinkles and fade brown spots. Prescription-strength retinoids provide the fastest results—your patient should start to see changes in about a month.

To help skin adjust to any redness or peeling, advise patients to apply a pea-size drop to the face every third night, building up to nightly use. Milder over-the-counter versions are gentler, although it can take up to 3 months for users to see noticeable results.

Redness and peeling should absolutely be avoided in darker skin to avoid postinflammatory hyperpigmentation, so retinoids, while helpful, should be used cautiously.

6. Update your routine.

Advising patients to alter just one thing in their regimen every 6-12 months jump starts more impressive improvements in tone and texture. When products are applied consistently, skin slides into maintenance mode after about a year. To keep skin primed for rejuvenation, tell patients to substitute a cream that contains alpha hydroxy acids in place of a retinoid twice a week to boost benefits. Or, you can bump up the patient’s OTC retinoid to a prescription product.

Photo courtesy Clayton Hansen/iStockphoto.com.

7. Eat omega-3 fats.

These “good fats,”  found in foods such as salmon, flaxseed, and almonds, boost hydration, which keeps skin supple and firm. The same is not true, however, of the saturated fat in dairy products and meats, which increase free-radical damage that makes skin more susceptible to aging. Advise patients to limit their intake of saturated fat to about 17 g per day.

8. Exercise regularly.

Studies find that women who work out regularly have firmer skin than non-exercisers. The reason: Exercise infuses skin with oxygen and nutrients needed for collagen production. Patients who aim to keep skin toned should make time for at least three, 30-minute, heart-pumping workouts per week. 

9. Wash your hair.

Curly hair cannot be washed as often as straight hair because it dries out more readily.  However, decreased hair washing leads to increased scalp sebum production, which can lead to increased breakouts.

If hair cannot be washed, patients should wrap their hair at night so it does not touch the face, and they should change their pillow cases frequently. In addition, many persons of African descent apply oils and pomades to their hair to keep it soft and manageable.  Here, hair wrapping or increased washing is also essential to avoid “pomade acne.”

Many blogs, articles, and tip sheets offer suggestions for keeping skin youthful and breakout free. But often the advice doesn’t apply to all skin types. Below are nine skin care tips modified for darker skin that you can share with your patients.

1. Don’t over wash.

Photo courtesy Michele Hill/Wiki Commons

Washing the face once a day to remove makeup, dirt, and bacteria can be helpful to avoid breakouts, especially in acne prone skin. However, it is important to remind patients to avoid over washing, as this may dry out the skin causing increased irritation, and may even cause wrinkles to look more prominent.

Sebum production decreases with age, especially after menopause in women. It may also be decreased in black patients, compared with white patients, as shown in a recent study (Cutis 2004;73:392-396), although the data were not statistically significant. 

Patients should exercise caution when applying antiaging products after washing because washing allows antiagers to penetrate deeper, leading to faster results in most skin types, but may also lead to increased irritation and then postinflammatory hyperpigmentation in darker skin.

Gentle cleansers are best, unless the skin is especially acne prone. In this case, anti-acne cleansers with ingredients like salicylic acid, benzoyl peroxide, or glycolic acid may be useful. To refresh skin, a splash of lukewarm water should do.

2. Apply products with a lower pH.

Studies have shown pH to be lower in darker skin, compared with lighter skin. For darker skin, products that are slightly acidic, such as those that contain mild glycolic acid, can help maintain the skin’s pH balance and maintain homeostasis and barrier integrity.

3. Be UV obsessed.

Photo courtesy of mark wragg/iStockphoto.com.

While the epidermis of darker skin contains more melanin content and has increased melanosomal dispersion than lighter skin—providing increased protection against UV-induced skin cancers and photoaging—UV damage can still occur.

Many patients with darker skin feel they are immune to skin cancer. Patients with darker skin, while diagnosed less frequently with melanoma, die at an increased frequency from the disease because of later diagnosis. Using a sunscreen that is SPF 30 or higher that blocks both UVA and UVB wavelengths is essential. 

Patients should be reminded that nothing is more important than wearing sunscreen every day to promote younger-looking skin and prevent skin cancer.

Sunscreens, especially those with a higher SPF, often do not rub in well on darker skin. Using a sunscreen with chemical blockers, or micronized physical blockers (zinc and titanium dioxide), may go on less chalky and rub in more smoothly. 

Sun exposure in darker skin also leads to prolonged postinflammatory hyperpigmentation after any skin insult. Even 10 minutes of daily exposure to UVA can cause changes that lead to wrinkles and sunspots in as few as 12 weeks.

Also, advise patients to eat foods that are rich in vitamin D to avoid deficiency.

4. Manage stress.

Emotional upheavals can make a patient’s skin look 5 years older than his or her chronological age.  Constant anxiety increases the stress hormone cortisol, which causes inflammation that breaks down collagen. It also triggers a chain of responses that can lead to facial redness and acne flare-ups. To quell inflammation, advise patients to eat antioxidant-rich foods such as berries, oranges, and asparagus.

5. Use a retinoid.

Vitamin A derivatives, such as topical retinoids, speed cell turnover and collagen growth to smooth fine lines and wrinkles and fade brown spots. Prescription-strength retinoids provide the fastest results—your patient should start to see changes in about a month.

To help skin adjust to any redness or peeling, advise patients to apply a pea-size drop to the face every third night, building up to nightly use. Milder over-the-counter versions are gentler, although it can take up to 3 months for users to see noticeable results.

Redness and peeling should absolutely be avoided in darker skin to avoid postinflammatory hyperpigmentation, so retinoids, while helpful, should be used cautiously.

6. Update your routine.

Advising patients to alter just one thing in their regimen every 6-12 months jump starts more impressive improvements in tone and texture. When products are applied consistently, skin slides into maintenance mode after about a year. To keep skin primed for rejuvenation, tell patients to substitute a cream that contains alpha hydroxy acids in place of a retinoid twice a week to boost benefits. Or, you can bump up the patient’s OTC retinoid to a prescription product.

Photo courtesy Clayton Hansen/iStockphoto.com.

7. Eat omega-3 fats.

These “good fats,”  found in foods such as salmon, flaxseed, and almonds, boost hydration, which keeps skin supple and firm. The same is not true, however, of the saturated fat in dairy products and meats, which increase free-radical damage that makes skin more susceptible to aging. Advise patients to limit their intake of saturated fat to about 17 g per day.

8. Exercise regularly.

Studies find that women who work out regularly have firmer skin than non-exercisers. The reason: Exercise infuses skin with oxygen and nutrients needed for collagen production. Patients who aim to keep skin toned should make time for at least three, 30-minute, heart-pumping workouts per week. 

9. Wash your hair.

Curly hair cannot be washed as often as straight hair because it dries out more readily.  However, decreased hair washing leads to increased scalp sebum production, which can lead to increased breakouts.

If hair cannot be washed, patients should wrap their hair at night so it does not touch the face, and they should change their pillow cases frequently. In addition, many persons of African descent apply oils and pomades to their hair to keep it soft and manageable.  Here, hair wrapping or increased washing is also essential to avoid “pomade acne.”

Many blogs, articles, and tip sheets offer suggestions for keeping skin youthful and breakout free. But often the advice doesn’t apply to all skin types. Below are nine skin care tips modified for darker skin that you can share with your patients.

1. Don’t over wash.

Photo courtesy Michele Hill/Wiki Commons

Washing the face once a day to remove makeup, dirt, and bacteria can be helpful to avoid breakouts, especially in acne prone skin. However, it is important to remind patients to avoid over washing, as this may dry out the skin causing increased irritation, and may even cause wrinkles to look more prominent.

Sebum production decreases with age, especially after menopause in women. It may also be decreased in black patients, compared with white patients, as shown in a recent study (Cutis 2004;73:392-396), although the data were not statistically significant. 

Patients should exercise caution when applying antiaging products after washing because washing allows antiagers to penetrate deeper, leading to faster results in most skin types, but may also lead to increased irritation and then postinflammatory hyperpigmentation in darker skin.

Gentle cleansers are best, unless the skin is especially acne prone. In this case, anti-acne cleansers with ingredients like salicylic acid, benzoyl peroxide, or glycolic acid may be useful. To refresh skin, a splash of lukewarm water should do.

2. Apply products with a lower pH.

Studies have shown pH to be lower in darker skin, compared with lighter skin. For darker skin, products that are slightly acidic, such as those that contain mild glycolic acid, can help maintain the skin’s pH balance and maintain homeostasis and barrier integrity.

3. Be UV obsessed.

Photo courtesy of mark wragg/iStockphoto.com.

While the epidermis of darker skin contains more melanin content and has increased melanosomal dispersion than lighter skin—providing increased protection against UV-induced skin cancers and photoaging—UV damage can still occur.

Many patients with darker skin feel they are immune to skin cancer. Patients with darker skin, while diagnosed less frequently with melanoma, die at an increased frequency from the disease because of later diagnosis. Using a sunscreen that is SPF 30 or higher that blocks both UVA and UVB wavelengths is essential. 

Patients should be reminded that nothing is more important than wearing sunscreen every day to promote younger-looking skin and prevent skin cancer.

Sunscreens, especially those with a higher SPF, often do not rub in well on darker skin. Using a sunscreen with chemical blockers, or micronized physical blockers (zinc and titanium dioxide), may go on less chalky and rub in more smoothly. 

Sun exposure in darker skin also leads to prolonged postinflammatory hyperpigmentation after any skin insult. Even 10 minutes of daily exposure to UVA can cause changes that lead to wrinkles and sunspots in as few as 12 weeks.

Also, advise patients to eat foods that are rich in vitamin D to avoid deficiency.

4. Manage stress.

Emotional upheavals can make a patient’s skin look 5 years older than his or her chronological age.  Constant anxiety increases the stress hormone cortisol, which causes inflammation that breaks down collagen. It also triggers a chain of responses that can lead to facial redness and acne flare-ups. To quell inflammation, advise patients to eat antioxidant-rich foods such as berries, oranges, and asparagus.

5. Use a retinoid.

Vitamin A derivatives, such as topical retinoids, speed cell turnover and collagen growth to smooth fine lines and wrinkles and fade brown spots. Prescription-strength retinoids provide the fastest results—your patient should start to see changes in about a month.

To help skin adjust to any redness or peeling, advise patients to apply a pea-size drop to the face every third night, building up to nightly use. Milder over-the-counter versions are gentler, although it can take up to 3 months for users to see noticeable results.

Redness and peeling should absolutely be avoided in darker skin to avoid postinflammatory hyperpigmentation, so retinoids, while helpful, should be used cautiously.

6. Update your routine.

Advising patients to alter just one thing in their regimen every 6-12 months jump starts more impressive improvements in tone and texture. When products are applied consistently, skin slides into maintenance mode after about a year. To keep skin primed for rejuvenation, tell patients to substitute a cream that contains alpha hydroxy acids in place of a retinoid twice a week to boost benefits. Or, you can bump up the patient’s OTC retinoid to a prescription product.

Photo courtesy Clayton Hansen/iStockphoto.com.

7. Eat omega-3 fats.

These “good fats,”  found in foods such as salmon, flaxseed, and almonds, boost hydration, which keeps skin supple and firm. The same is not true, however, of the saturated fat in dairy products and meats, which increase free-radical damage that makes skin more susceptible to aging. Advise patients to limit their intake of saturated fat to about 17 g per day.

8. Exercise regularly.

Studies find that women who work out regularly have firmer skin than non-exercisers. The reason: Exercise infuses skin with oxygen and nutrients needed for collagen production. Patients who aim to keep skin toned should make time for at least three, 30-minute, heart-pumping workouts per week. 

9. Wash your hair.

Curly hair cannot be washed as often as straight hair because it dries out more readily.  However, decreased hair washing leads to increased scalp sebum production, which can lead to increased breakouts.

If hair cannot be washed, patients should wrap their hair at night so it does not touch the face, and they should change their pillow cases frequently. In addition, many persons of African descent apply oils and pomades to their hair to keep it soft and manageable.  Here, hair wrapping or increased washing is also essential to avoid “pomade acne.”

Another potential Alzheimer's disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer's drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

"Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism," he said in an interview. "IDENTITY had a lot going for it. This was a tough one to swallow."

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

"This is disappointing news for the millions of Alzheimer's patients and their families worldwide who anxiously await a successful treatment for this devastating illness," Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up "will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued."

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. "I would be very cautious on interpreting these data until the full analysis has unfolded."

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. "They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy." Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer's plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

"In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18)," Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

"By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease," he said. "The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?"

It may be time, he said, to think of Alzheimer's as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. "Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage."

Dr. Sabbagh said he wondered if some of the Alzheimer's drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. "My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop."

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. "A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different."

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer's disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer's drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

"Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism," he said in an interview. "IDENTITY had a lot going for it. This was a tough one to swallow."

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

"This is disappointing news for the millions of Alzheimer's patients and their families worldwide who anxiously await a successful treatment for this devastating illness," Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up "will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued."

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. "I would be very cautious on interpreting these data until the full analysis has unfolded."

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. "They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy." Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer's plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

"In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18)," Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

"By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease," he said. "The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?"

It may be time, he said, to think of Alzheimer's as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. "Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage."

Dr. Sabbagh said he wondered if some of the Alzheimer's drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. "My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop."

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. "A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different."

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer's disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer's drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

"Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism," he said in an interview. "IDENTITY had a lot going for it. This was a tough one to swallow."

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

"This is disappointing news for the millions of Alzheimer's patients and their families worldwide who anxiously await a successful treatment for this devastating illness," Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up "will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued."

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. "I would be very cautious on interpreting these data until the full analysis has unfolded."

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. "They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy." Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer's plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

"In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18)," Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

"By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease," he said. "The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?"

It may be time, he said, to think of Alzheimer's as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. "Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage."

Dr. Sabbagh said he wondered if some of the Alzheimer's drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. "My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop."

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. "A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different."

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

CHICAGO - In the not-too distant future, dermatologists may be sending patients off to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.

"In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun," said Dr. Craig Elmets at the American Academy of Dermatology's 2010 meeting. "Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences."

Photo credit: Michele G. Sullivan

Although sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. Theoretically, sunscreens work well, but in reality, their efficacy is less than ideal. "They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount."

Sunscreens also have limited effect, he said. "Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma."

A number of agents are being investigated for the chemoprevention of skin cancers. Some are oral, some are topical, and all have shown promising results in both animal and human studies.

Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body’s DNA repair response by increasing base excision repair, Dr. Elmets said.

A 2001 study allocated 30 patients with xeroderma pigmentosum to either Dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24;926-9).

Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to either the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers.

The second study is a phase III study aiming to recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.

"Another exciting molecule that may have good chemopreventive potential is GDC-0449," Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. "The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults," he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.

A 2009 study involved 33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses. Eighteen achieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).

Twenty-four trials are either in progress or recruiting, studying GDC-0449’s safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.

DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. Dr. Elmets described a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer. After 4-5 years of follow-up (more than 1,200 person/years), there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group. But new basal cell carcinomas were 33% less common in the active group than the placebo group (Cancer Prev. Res. 2010;3:35-47).

There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.

The cyclooxygenase 2 inhibitor celecoxib is even in the skin cancer race. "COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands," Dr. Elmets said. "When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers."

A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34). Celecoxib is also being investigated for use in GI, prostate, and lung cancers.

Finally, Dr. Elmets said, an ancient – and familiar – drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. "When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema," Dr. Elmets said.

Because of its broad antioxidant properties, EGCG is the subject of numerous clinical trials examining its potential in other cancers, Alzheimer’s disease, muscular dystrophy, photoaging, and weight loss.

Disclosures: Dr. Elmets has received research support from Pfizer Inc. and holds an intellectual property right on the use of EGCG as a skin cancer chemopreventive agent.

CHICAGO - In the not-too distant future, dermatologists may be sending patients off to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.

"In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun," said Dr. Craig Elmets at the American Academy of Dermatology's 2010 meeting. "Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences."

Photo credit: Michele G. Sullivan

Although sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. Theoretically, sunscreens work well, but in reality, their efficacy is less than ideal. "They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount."

Sunscreens also have limited effect, he said. "Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma."

A number of agents are being investigated for the chemoprevention of skin cancers. Some are oral, some are topical, and all have shown promising results in both animal and human studies.

Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body’s DNA repair response by increasing base excision repair, Dr. Elmets said.

A 2001 study allocated 30 patients with xeroderma pigmentosum to either Dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24;926-9).

Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to either the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers.

The second study is a phase III study aiming to recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.

"Another exciting molecule that may have good chemopreventive potential is GDC-0449," Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. "The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults," he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.

A 2009 study involved 33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses. Eighteen achieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).

Twenty-four trials are either in progress or recruiting, studying GDC-0449’s safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.

DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. Dr. Elmets described a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer. After 4-5 years of follow-up (more than 1,200 person/years), there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group. But new basal cell carcinomas were 33% less common in the active group than the placebo group (Cancer Prev. Res. 2010;3:35-47).

There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.

The cyclooxygenase 2 inhibitor celecoxib is even in the skin cancer race. "COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands," Dr. Elmets said. "When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers."

A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34). Celecoxib is also being investigated for use in GI, prostate, and lung cancers.

Finally, Dr. Elmets said, an ancient – and familiar – drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. "When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema," Dr. Elmets said.

Because of its broad antioxidant properties, EGCG is the subject of numerous clinical trials examining its potential in other cancers, Alzheimer’s disease, muscular dystrophy, photoaging, and weight loss.

Disclosures: Dr. Elmets has received research support from Pfizer Inc. and holds an intellectual property right on the use of EGCG as a skin cancer chemopreventive agent.

CHICAGO - In the not-too distant future, dermatologists may be sending patients off to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.

"In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun," said Dr. Craig Elmets at the American Academy of Dermatology's 2010 meeting. "Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences."

Photo credit: Michele G. Sullivan

Although sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. Theoretically, sunscreens work well, but in reality, their efficacy is less than ideal. "They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount."

Sunscreens also have limited effect, he said. "Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma."

A number of agents are being investigated for the chemoprevention of skin cancers. Some are oral, some are topical, and all have shown promising results in both animal and human studies.

Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body’s DNA repair response by increasing base excision repair, Dr. Elmets said.

A 2001 study allocated 30 patients with xeroderma pigmentosum to either Dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24;926-9).

Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to either the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers.

The second study is a phase III study aiming to recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.

"Another exciting molecule that may have good chemopreventive potential is GDC-0449," Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. "The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults," he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.

A 2009 study involved 33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses. Eighteen achieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).

Twenty-four trials are either in progress or recruiting, studying GDC-0449’s safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.

DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. Dr. Elmets described a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer. After 4-5 years of follow-up (more than 1,200 person/years), there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group. But new basal cell carcinomas were 33% less common in the active group than the placebo group (Cancer Prev. Res. 2010;3:35-47).

There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.

The cyclooxygenase 2 inhibitor celecoxib is even in the skin cancer race. "COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands," Dr. Elmets said. "When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers."

A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34). Celecoxib is also being investigated for use in GI, prostate, and lung cancers.

Finally, Dr. Elmets said, an ancient – and familiar – drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. "When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema," Dr. Elmets said.

Because of its broad antioxidant properties, EGCG is the subject of numerous clinical trials examining its potential in other cancers, Alzheimer’s disease, muscular dystrophy, photoaging, and weight loss.

Disclosures: Dr. Elmets has received research support from Pfizer Inc. and holds an intellectual property right on the use of EGCG as a skin cancer chemopreventive agent.

Monterey, Calif. - If there is a doppelganger in dermatology, malignant fibrous histiocytoma is it, according to Dr. Henry W. Randle at a meeting of the American Society for Mohs Surgery.

By immunohistochemistry, MFH is a dead ringer for atypical fibroxanthoma (AFX). Compared with rare mortality from AFX, however, approximately 38% of patients with MFH die within 3.5 years, said Dr. Randle.

Photo credit: Dr. Henry W. Randle.

Histologically, we can’t tell them apart. They look the same, but they behave very differently,” and require different treatment approaches, said Dr. Randle of the Mayo Clinic, Jacksonville, Fla.

The two main treatments for AFX are excision with a 1- to 2-cm margin that includes subcutaneous tissue or Mohs surgery.

For MFH, treatment involves tumor staging and wide excision to several centimeters, with consideration of node dissection, radiation, and chemotherapy. Mohs surgery is not the best option. “You’re brave if you do that” for MFH, he said. “This is a different animal.”

The problem lies in telling the two apart. Even the histologic diagnosis of AFX can be challenging, because no specific marker or test exists to identify AFX. Diagnosis requires excluding spindle cell squamous cell carcinomas, melanomas of the spindle cells, and other spindle cell malignancies.

Photo credit: Dr. Henry W. Randle

The only identifiable characteristics that separate the relatively innocuous AFX from the more lethal MFH are the more superficial location of AFX and the fact that AFX typically appears on the head and neck, whereas MFH more typically occurs on the extremities and trunk, but not on the face.

A recent retrospective series of 89 patients with a histologic diagnosis of AFX claimed that no patients developed metastases, but that was because the authors decided not to include three cases with metastases because they acted differently from the other 86, Dr. Randle noted (Derm. Surg. 2009;35:765-772). Had the authors included those three cases, the metastases rate would be 3%.

“It is this small subset that is the problem,” he said.

Dr. Randle reserves the term AFX for small tumors that are less than 1.5 cm in diameter, that are based in the dermis and do not extend into the fat, and that occur in sun-damaged skin with no more than minimal involvement of the subcutis. Any diagnosis of AFX that did not analyze subcutaneous tissue with some fat has the potential for regional or distant spread, and may not be AFX, he said.

Consider the tumor to be MFH or another spindle cell tumor if it extends into the subcutis, shows vascular invasion, or has tumor necrosis, which does not occur with AFX. “I do not do Mohs if it has these features,” Dr. Randle said.

Visually, AFX usually looks like a rapidly growing red nodule, often ulcerated, on the sun-damaged head or neck skin of an elderly patient. It is twice as common in men as in women. Histologically, it’s a nonencapsulated cellular tumor, contiguous with the epidermis, with pleomorphic and atypical cells. It often has spindle-shaped cells with prominent, vesicular nuclei.

Photo credit: Dr. Henry W. Randle

Reported recurrence rates range from 7% to 12% depending on the type of surgical treatment. Rare metastases in the regional node typically come from large, deep, recurrent tumors that are inadequately excised. In Dr. Randle’s personal experience with 56 AFX tumors in the past 20 years, 4 recurred (7%), one with metastasis. For MFH, the reported recurrence rate is 43%, he added.

Patients who have undergone organ transplants have higher prevalences of both AFX and MFH.

Disclosures: Dr. Randle reported having no relevant conflicts of interest.

Monterey, Calif. - If there is a doppelganger in dermatology, malignant fibrous histiocytoma is it, according to Dr. Henry W. Randle at a meeting of the American Society for Mohs Surgery.

By immunohistochemistry, MFH is a dead ringer for atypical fibroxanthoma (AFX). Compared with rare mortality from AFX, however, approximately 38% of patients with MFH die within 3.5 years, said Dr. Randle.

Photo credit: Dr. Henry W. Randle.

Histologically, we can’t tell them apart. They look the same, but they behave very differently,” and require different treatment approaches, said Dr. Randle of the Mayo Clinic, Jacksonville, Fla.

The two main treatments for AFX are excision with a 1- to 2-cm margin that includes subcutaneous tissue or Mohs surgery.

For MFH, treatment involves tumor staging and wide excision to several centimeters, with consideration of node dissection, radiation, and chemotherapy. Mohs surgery is not the best option. “You’re brave if you do that” for MFH, he said. “This is a different animal.”

The problem lies in telling the two apart. Even the histologic diagnosis of AFX can be challenging, because no specific marker or test exists to identify AFX. Diagnosis requires excluding spindle cell squamous cell carcinomas, melanomas of the spindle cells, and other spindle cell malignancies.

Photo credit: Dr. Henry W. Randle

The only identifiable characteristics that separate the relatively innocuous AFX from the more lethal MFH are the more superficial location of AFX and the fact that AFX typically appears on the head and neck, whereas MFH more typically occurs on the extremities and trunk, but not on the face.

A recent retrospective series of 89 patients with a histologic diagnosis of AFX claimed that no patients developed metastases, but that was because the authors decided not to include three cases with metastases because they acted differently from the other 86, Dr. Randle noted (Derm. Surg. 2009;35:765-772). Had the authors included those three cases, the metastases rate would be 3%.

“It is this small subset that is the problem,” he said.

Dr. Randle reserves the term AFX for small tumors that are less than 1.5 cm in diameter, that are based in the dermis and do not extend into the fat, and that occur in sun-damaged skin with no more than minimal involvement of the subcutis. Any diagnosis of AFX that did not analyze subcutaneous tissue with some fat has the potential for regional or distant spread, and may not be AFX, he said.

Consider the tumor to be MFH or another spindle cell tumor if it extends into the subcutis, shows vascular invasion, or has tumor necrosis, which does not occur with AFX. “I do not do Mohs if it has these features,” Dr. Randle said.

Visually, AFX usually looks like a rapidly growing red nodule, often ulcerated, on the sun-damaged head or neck skin of an elderly patient. It is twice as common in men as in women. Histologically, it’s a nonencapsulated cellular tumor, contiguous with the epidermis, with pleomorphic and atypical cells. It often has spindle-shaped cells with prominent, vesicular nuclei.

Photo credit: Dr. Henry W. Randle

Reported recurrence rates range from 7% to 12% depending on the type of surgical treatment. Rare metastases in the regional node typically come from large, deep, recurrent tumors that are inadequately excised. In Dr. Randle’s personal experience with 56 AFX tumors in the past 20 years, 4 recurred (7%), one with metastasis. For MFH, the reported recurrence rate is 43%, he added.

Patients who have undergone organ transplants have higher prevalences of both AFX and MFH.

Disclosures: Dr. Randle reported having no relevant conflicts of interest.

Monterey, Calif. - If there is a doppelganger in dermatology, malignant fibrous histiocytoma is it, according to Dr. Henry W. Randle at a meeting of the American Society for Mohs Surgery.

By immunohistochemistry, MFH is a dead ringer for atypical fibroxanthoma (AFX). Compared with rare mortality from AFX, however, approximately 38% of patients with MFH die within 3.5 years, said Dr. Randle.

Photo credit: Dr. Henry W. Randle.

Histologically, we can’t tell them apart. They look the same, but they behave very differently,” and require different treatment approaches, said Dr. Randle of the Mayo Clinic, Jacksonville, Fla.

The two main treatments for AFX are excision with a 1- to 2-cm margin that includes subcutaneous tissue or Mohs surgery.

For MFH, treatment involves tumor staging and wide excision to several centimeters, with consideration of node dissection, radiation, and chemotherapy. Mohs surgery is not the best option. “You’re brave if you do that” for MFH, he said. “This is a different animal.”

The problem lies in telling the two apart. Even the histologic diagnosis of AFX can be challenging, because no specific marker or test exists to identify AFX. Diagnosis requires excluding spindle cell squamous cell carcinomas, melanomas of the spindle cells, and other spindle cell malignancies.

Photo credit: Dr. Henry W. Randle

The only identifiable characteristics that separate the relatively innocuous AFX from the more lethal MFH are the more superficial location of AFX and the fact that AFX typically appears on the head and neck, whereas MFH more typically occurs on the extremities and trunk, but not on the face.

A recent retrospective series of 89 patients with a histologic diagnosis of AFX claimed that no patients developed metastases, but that was because the authors decided not to include three cases with metastases because they acted differently from the other 86, Dr. Randle noted (Derm. Surg. 2009;35:765-772). Had the authors included those three cases, the metastases rate would be 3%.

“It is this small subset that is the problem,” he said.

Dr. Randle reserves the term AFX for small tumors that are less than 1.5 cm in diameter, that are based in the dermis and do not extend into the fat, and that occur in sun-damaged skin with no more than minimal involvement of the subcutis. Any diagnosis of AFX that did not analyze subcutaneous tissue with some fat has the potential for regional or distant spread, and may not be AFX, he said.

Consider the tumor to be MFH or another spindle cell tumor if it extends into the subcutis, shows vascular invasion, or has tumor necrosis, which does not occur with AFX. “I do not do Mohs if it has these features,” Dr. Randle said.

Visually, AFX usually looks like a rapidly growing red nodule, often ulcerated, on the sun-damaged head or neck skin of an elderly patient. It is twice as common in men as in women. Histologically, it’s a nonencapsulated cellular tumor, contiguous with the epidermis, with pleomorphic and atypical cells. It often has spindle-shaped cells with prominent, vesicular nuclei.

Photo credit: Dr. Henry W. Randle

Reported recurrence rates range from 7% to 12% depending on the type of surgical treatment. Rare metastases in the regional node typically come from large, deep, recurrent tumors that are inadequately excised. In Dr. Randle’s personal experience with 56 AFX tumors in the past 20 years, 4 recurred (7%), one with metastasis. For MFH, the reported recurrence rate is 43%, he added.

Patients who have undergone organ transplants have higher prevalences of both AFX and MFH.

Disclosures: Dr. Randle reported having no relevant conflicts of interest.

PORTLAND, Ore. – Approximately half of 207 patients with mild to moderate atopic dermatitis were clear or almost clear of disease after using EpiCeram skin barrier emulsion for 3 weeks, either alone or in combination with treatment, according to a report of an open-label study.

At the end of 3 weeks, the mean atopic dermatitis (AD) investigator global assessment (IGA) score improved from a baseline of 2.50 on a 5-point scale to 1.47. The mean pruritus score improved from 2.35 to 1.46 on a 5-point scale.

At week 3 after applying the emulsion twice daily to affected sites, 62% of subjects with baseline mild disease (defined as an IGA score of 2) were rated on the IGA scale as clear (a score of 0) or almost clear (a score of 1); 46% of those with moderate disease (an IGA score of 3 at baseline) were rated as clear or almost clear at the end of the study, said Dr. Leon Kircik, a dermatologist at Indiana University Medical Center, Bloomington, and his associates.

When Promius Pharma LLC’s EpiCeram skin barrier emulsion was used alone, 56% of subjects had clear or almost clear IGA scores at the end of week 3; 48% achieved those results when it was used in combination, usually with topical corticosteroids.

The study, not yet published, does not analyze who in the disease severity subgroups improved using EpiCeram alone, and who improved when it was used in combination. The trial had no placebo group.

Results were similar for the 59 pediatric patients in the trial (age range, 1 month–16 years), according to a subgroup analysis presented in poster form by Dr. Kircik at the annual meeting of the Society for Pediatric Dermatology.

At the end of 3 weeks, 62% of EpiCeram monotherapy pediatric patients had clear or almost clear IGA scores; 50% who used EpiCeram in combination with another treatment achieved those results. Pruritus scores were roughly halved among pediatric patients overall, said Dr. Kircik.

The study proved EpiCeram “to be an effective and versatile agent that can be used with or without additional AD therapy to provide good clinical efficacy and high levels of investigator and patient satisfaction,” said Dr. Kircik.

EpiCeram emulsion contains ceramide, cholesterol, and free fatty acids in a molar ratio of 3:1:1. It was cleared for marketing by the Food and Drug Administration in 2006.

Subjects in the trial were recruited from 50 dermatology practices across the country; 49% were assessed by investigators to have mild disease at baseline, 51% moderate disease; 81% reported one or more AD flares per month at baseline.

All subjects were EpiCeram naive. Their mean age was 34 years, and 65% were women, the majority white. The median duration of AD diagnosis was 5 years.

At baseline, current AD medications were stopped and subjects were given EpiCeram along with an add-on prescription, selected at the discretion of their dermatologist-investigator, to use if their AD worsened. Most prescriptions were for topical corticosteroids; three were for Protopic (tacrolimus), and two for an oral antihistamine, according to the report.

Subjects were instructed to apply EpiCeram to affected areas, as well as to antecubital, popliteal, or other predisposed regions, approximately every 12 hours.

At assessment 3 weeks later, 71% of subjects reported using EpiCeram every day, 22% “most every day,” and 7% occasionally; 29% used the additional medication.

The report does not break-down efficacy results by reported usage.

Six subjects reported a total of seven adverse events, including erythema, skin irritation, pruritus, paresthesia, and pain. An additional nine subjects reported worsening AD.

EpiCeram’s effects satisfied 75% of subjects and 77% of investigators; 78% of subjects believed that their AD had improved, at least a little, since baseline, according to the report.

“In this study, it seems that clinical efficacy alone did not contribute to satisfaction, as rates of satisfaction were higher than the rate for clinical success,” the authors noted.

When Dr. Eric Simpson, a dermatologist and AD expert from the Oregon Health and Science University in Portland, was asked to comment on the study, he said, “I think some people with mild to moderate disease can improve with EpiCeram, but it is difficult to draw conclusions without a vehicle control.”

He noted that 20%-25% of AD patients in placebo-controlled trials improve with just vehicle alone. Given the response rates in the EpiCeram trial, “I think these people probably did get better. The question is if they would have gotten better with moisturizer alone.”

Dr. Simpson said he is likely to try EpiCeram when he can’t use the calcineurin inhibitors Protopic or Elidel (pimecrolimus) because these agents burn patients too much on application, if a patient has skin cancer, or for some other reason. Such situations give him “a good opportunity to try it,” he said.

The study was funded by EpiCeram’s distributor, Promius Pharma LLC. Dr. Kircik and his associate Dr. Del Rosso are consultants and speakers for Promius Pharma. Dr. Kircik’s associate Daniel Aversa is a Promius Pharma employee. Dr. Simpson disclosed that he participated in research funded by Ceragenix Pharmaceuticals Inc., the original developer of EpiCeram.

PORTLAND, Ore. – Approximately half of 207 patients with mild to moderate atopic dermatitis were clear or almost clear of disease after using EpiCeram skin barrier emulsion for 3 weeks, either alone or in combination with treatment, according to a report of an open-label study.

At the end of 3 weeks, the mean atopic dermatitis (AD) investigator global assessment (IGA) score improved from a baseline of 2.50 on a 5-point scale to 1.47. The mean pruritus score improved from 2.35 to 1.46 on a 5-point scale.

At week 3 after applying the emulsion twice daily to affected sites, 62% of subjects with baseline mild disease (defined as an IGA score of 2) were rated on the IGA scale as clear (a score of 0) or almost clear (a score of 1); 46% of those with moderate disease (an IGA score of 3 at baseline) were rated as clear or almost clear at the end of the study, said Dr. Leon Kircik, a dermatologist at Indiana University Medical Center, Bloomington, and his associates.

When Promius Pharma LLC’s EpiCeram skin barrier emulsion was used alone, 56% of subjects had clear or almost clear IGA scores at the end of week 3; 48% achieved those results when it was used in combination, usually with topical corticosteroids.

The study, not yet published, does not analyze who in the disease severity subgroups improved using EpiCeram alone, and who improved when it was used in combination. The trial had no placebo group.

Results were similar for the 59 pediatric patients in the trial (age range, 1 month–16 years), according to a subgroup analysis presented in poster form by Dr. Kircik at the annual meeting of the Society for Pediatric Dermatology.

At the end of 3 weeks, 62% of EpiCeram monotherapy pediatric patients had clear or almost clear IGA scores; 50% who used EpiCeram in combination with another treatment achieved those results. Pruritus scores were roughly halved among pediatric patients overall, said Dr. Kircik.

The study proved EpiCeram “to be an effective and versatile agent that can be used with or without additional AD therapy to provide good clinical efficacy and high levels of investigator and patient satisfaction,” said Dr. Kircik.

EpiCeram emulsion contains ceramide, cholesterol, and free fatty acids in a molar ratio of 3:1:1. It was cleared for marketing by the Food and Drug Administration in 2006.

Subjects in the trial were recruited from 50 dermatology practices across the country; 49% were assessed by investigators to have mild disease at baseline, 51% moderate disease; 81% reported one or more AD flares per month at baseline.

All subjects were EpiCeram naive. Their mean age was 34 years, and 65% were women, the majority white. The median duration of AD diagnosis was 5 years.

At baseline, current AD medications were stopped and subjects were given EpiCeram along with an add-on prescription, selected at the discretion of their dermatologist-investigator, to use if their AD worsened. Most prescriptions were for topical corticosteroids; three were for Protopic (tacrolimus), and two for an oral antihistamine, according to the report.

Subjects were instructed to apply EpiCeram to affected areas, as well as to antecubital, popliteal, or other predisposed regions, approximately every 12 hours.

At assessment 3 weeks later, 71% of subjects reported using EpiCeram every day, 22% “most every day,” and 7% occasionally; 29% used the additional medication.

The report does not break-down efficacy results by reported usage.

Six subjects reported a total of seven adverse events, including erythema, skin irritation, pruritus, paresthesia, and pain. An additional nine subjects reported worsening AD.

EpiCeram’s effects satisfied 75% of subjects and 77% of investigators; 78% of subjects believed that their AD had improved, at least a little, since baseline, according to the report.

“In this study, it seems that clinical efficacy alone did not contribute to satisfaction, as rates of satisfaction were higher than the rate for clinical success,” the authors noted.

When Dr. Eric Simpson, a dermatologist and AD expert from the Oregon Health and Science University in Portland, was asked to comment on the study, he said, “I think some people with mild to moderate disease can improve with EpiCeram, but it is difficult to draw conclusions without a vehicle control.”

He noted that 20%-25% of AD patients in placebo-controlled trials improve with just vehicle alone. Given the response rates in the EpiCeram trial, “I think these people probably did get better. The question is if they would have gotten better with moisturizer alone.”

Dr. Simpson said he is likely to try EpiCeram when he can’t use the calcineurin inhibitors Protopic or Elidel (pimecrolimus) because these agents burn patients too much on application, if a patient has skin cancer, or for some other reason. Such situations give him “a good opportunity to try it,” he said.

The study was funded by EpiCeram’s distributor, Promius Pharma LLC. Dr. Kircik and his associate Dr. Del Rosso are consultants and speakers for Promius Pharma. Dr. Kircik’s associate Daniel Aversa is a Promius Pharma employee. Dr. Simpson disclosed that he participated in research funded by Ceragenix Pharmaceuticals Inc., the original developer of EpiCeram.

PORTLAND, Ore. – Approximately half of 207 patients with mild to moderate atopic dermatitis were clear or almost clear of disease after using EpiCeram skin barrier emulsion for 3 weeks, either alone or in combination with treatment, according to a report of an open-label study.

At the end of 3 weeks, the mean atopic dermatitis (AD) investigator global assessment (IGA) score improved from a baseline of 2.50 on a 5-point scale to 1.47. The mean pruritus score improved from 2.35 to 1.46 on a 5-point scale.

At week 3 after applying the emulsion twice daily to affected sites, 62% of subjects with baseline mild disease (defined as an IGA score of 2) were rated on the IGA scale as clear (a score of 0) or almost clear (a score of 1); 46% of those with moderate disease (an IGA score of 3 at baseline) were rated as clear or almost clear at the end of the study, said Dr. Leon Kircik, a dermatologist at Indiana University Medical Center, Bloomington, and his associates.

When Promius Pharma LLC’s EpiCeram skin barrier emulsion was used alone, 56% of subjects had clear or almost clear IGA scores at the end of week 3; 48% achieved those results when it was used in combination, usually with topical corticosteroids.

The study, not yet published, does not analyze who in the disease severity subgroups improved using EpiCeram alone, and who improved when it was used in combination. The trial had no placebo group.

Results were similar for the 59 pediatric patients in the trial (age range, 1 month–16 years), according to a subgroup analysis presented in poster form by Dr. Kircik at the annual meeting of the Society for Pediatric Dermatology.

At the end of 3 weeks, 62% of EpiCeram monotherapy pediatric patients had clear or almost clear IGA scores; 50% who used EpiCeram in combination with another treatment achieved those results. Pruritus scores were roughly halved among pediatric patients overall, said Dr. Kircik.

The study proved EpiCeram “to be an effective and versatile agent that can be used with or without additional AD therapy to provide good clinical efficacy and high levels of investigator and patient satisfaction,” said Dr. Kircik.

EpiCeram emulsion contains ceramide, cholesterol, and free fatty acids in a molar ratio of 3:1:1. It was cleared for marketing by the Food and Drug Administration in 2006.

Subjects in the trial were recruited from 50 dermatology practices across the country; 49% were assessed by investigators to have mild disease at baseline, 51% moderate disease; 81% reported one or more AD flares per month at baseline.

All subjects were EpiCeram naive. Their mean age was 34 years, and 65% were women, the majority white. The median duration of AD diagnosis was 5 years.

At baseline, current AD medications were stopped and subjects were given EpiCeram along with an add-on prescription, selected at the discretion of their dermatologist-investigator, to use if their AD worsened. Most prescriptions were for topical corticosteroids; three were for Protopic (tacrolimus), and two for an oral antihistamine, according to the report.

Subjects were instructed to apply EpiCeram to affected areas, as well as to antecubital, popliteal, or other predisposed regions, approximately every 12 hours.

At assessment 3 weeks later, 71% of subjects reported using EpiCeram every day, 22% “most every day,” and 7% occasionally; 29% used the additional medication.

The report does not break-down efficacy results by reported usage.

Six subjects reported a total of seven adverse events, including erythema, skin irritation, pruritus, paresthesia, and pain. An additional nine subjects reported worsening AD.

EpiCeram’s effects satisfied 75% of subjects and 77% of investigators; 78% of subjects believed that their AD had improved, at least a little, since baseline, according to the report.

“In this study, it seems that clinical efficacy alone did not contribute to satisfaction, as rates of satisfaction were higher than the rate for clinical success,” the authors noted.

When Dr. Eric Simpson, a dermatologist and AD expert from the Oregon Health and Science University in Portland, was asked to comment on the study, he said, “I think some people with mild to moderate disease can improve with EpiCeram, but it is difficult to draw conclusions without a vehicle control.”

He noted that 20%-25% of AD patients in placebo-controlled trials improve with just vehicle alone. Given the response rates in the EpiCeram trial, “I think these people probably did get better. The question is if they would have gotten better with moisturizer alone.”

Dr. Simpson said he is likely to try EpiCeram when he can’t use the calcineurin inhibitors Protopic or Elidel (pimecrolimus) because these agents burn patients too much on application, if a patient has skin cancer, or for some other reason. Such situations give him “a good opportunity to try it,” he said.

The study was funded by EpiCeram’s distributor, Promius Pharma LLC. Dr. Kircik and his associate Dr. Del Rosso are consultants and speakers for Promius Pharma. Dr. Kircik’s associate Daniel Aversa is a Promius Pharma employee. Dr. Simpson disclosed that he participated in research funded by Ceragenix Pharmaceuticals Inc., the original developer of EpiCeram.

CHICAGO — A drug that targets metastatic melanoma with mutations in the BRAF oncogene may be the first step on a path to individualized chemotherapy for patients with these formerly untreatable cancers.

“We are rapidly unraveling the molecular underpinnings of these tumors, and discovering the mechanisms by which they drive melanoma growth. These insights allow us to develop and select drugs on the basis of every patient’s individual genome,” Dr. Hensin Tsao said at the American Academy of Dermatology’s 2010 meeting.

Courtesy Bill Truslow/Massachusetts General Hospital

PLX4032 is the first drug to successfully shrink both cutaneous and internal metastases of BRAF-mutated melanomas, said Dr. Tsao, a dermatologist who is director of the Massachusetts General Hospital Melanoma Genetics Program in Boston.

His colleague, Dr. Keith Flaherty, is about to publish data from the drug’s phase II trial of 87 patients; 81% of those with the BRAF-mutated melanoma responded with a 30% or more shrinkage of the targeted lesions.

After a phase I safety and dose-finding trial, investigators settled on an oral dose of 960 mg twice daily for the phase II study. The effect was little short of remarkable, Dr. Flaherty, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center, said in an interview.

“My first responding patient had cutaneous and internal metastases, and the cutaneous metastases were clearly getting better right in front of our eyes,” he said. “We have seen this in some other areas of cancer, but never in melanoma, which before this was a clinical scenario with an unmet need for therapy.”

PLX4032, first engineered by the Berkeley, Calif., company Plexxikon Inc. and being developed in partnership with Roche, is not a foolproof cure, Dr. Tsao said in an interview. “It’s clearly a huge leap forward for the patients who responded so rapidly, yet most are still progressing despite being on the drug. It’s the best stun we’ve ever seen for melanoma, but it’s not a permanent kill.”

Sustained response in the phase I and II trials has varied from only 2 months to up to 2 years, Dr. Flaherty said. He could find no significant predictors of progression or response among the group except for initial tumor number and size. Typically, he said, the patients with the greatest mass of metastatic disease had the shortest duration of response, while those with a smaller tumor burden had a longer duration of response.

“When you have metastatic melanoma, your days are numbered—and numbered in a way we can’t predict when metastatic disease is diagnosed,” Dr. Flaherty said. “What this therapy does is push out the time until the disease worsens. We are not yet smart enough to understand what it is that allows a tumor to work its way around the drug’s activity.”

Chemotherapy-resistant cancers are nothing new, Dr. Tsao noted. What will be new is the full investigation of melanoma’s genetic pathways, and the development of drugs to block them in multiple ways. “The next frontier will be to understand all the ways that melanoma can outsmart treatment. We may have to use multiple therapies to corner it. So a full discovery of all melanoma’s potential vulnerabilities is very important.”

There is already at least a hint that PLX4032 has a very narrow target—only BRAF tumors with the V600E subtype. “There is some laboratory evidence that if you give this drug to a tumor that may be mutated at another gene you may be worsening things,” Dr. Tsao said. “This has yet to be borne out in clinical studies, but bench-side data suggest that you have to be very precise with this drug, because the wrong choice could be potentially deleterious.”

In vitro and in vivo experiments did suggest that PLX4032 was ineffective against non-BRAF melanomas, Dr. Flaherty said. “In a lab, the drug will kill a cancer cell with a BRAF mutation but not with another mutation. Whether it can facilitate the growth of others is an interesting concept supported by some laboratory data, with the observation that this and drugs like it can transiently stimulate other cancer cells with RAS mutations. In these, the drug basically activates the BRAF pathway instead of blocking it. We don’t know the relevance of this finding to humans. It is interesting, but it may have no real clinical impact.”

Discovering the best targets for molecular therapies is typically a long process, Dr. Tsao said, but the race to treat BRAF metastatic melanoma has so far been a fast one. “In 2002, the first BRAF mutation in melanoma was published, and the first drug is already coming to clinical fruition. This is pretty fast for something we’ve been fooling around with ineffectively for 20 years.”

During the 8 years between the mutation’s discovery and Dr. Flaherty’s trial, drug companies have not been idle. “There is now a pipeline of drugs against BRAF. PLX4032 might not be the best or the least toxic, but it’s the first of a host coming down the pike. This is very significant, because now we have a brand-new way of looking at a previously untreatable cancer.”

Roche Pharmaceuticals and Plexxikon sponsored the PLX4032 studies. Dr. Tsao said he had no financial declarations with regard to the drug. Dr. Flaherty has served as a consultant to Roche regarding further development of PLX4032 in melanoma.

CHICAGO — A drug that targets metastatic melanoma with mutations in the BRAF oncogene may be the first step on a path to individualized chemotherapy for patients with these formerly untreatable cancers.

“We are rapidly unraveling the molecular underpinnings of these tumors, and discovering the mechanisms by which they drive melanoma growth. These insights allow us to develop and select drugs on the basis of every patient’s individual genome,” Dr. Hensin Tsao said at the American Academy of Dermatology’s 2010 meeting.

Courtesy Bill Truslow/Massachusetts General Hospital

PLX4032 is the first drug to successfully shrink both cutaneous and internal metastases of BRAF-mutated melanomas, said Dr. Tsao, a dermatologist who is director of the Massachusetts General Hospital Melanoma Genetics Program in Boston.

His colleague, Dr. Keith Flaherty, is about to publish data from the drug’s phase II trial of 87 patients; 81% of those with the BRAF-mutated melanoma responded with a 30% or more shrinkage of the targeted lesions.

After a phase I safety and dose-finding trial, investigators settled on an oral dose of 960 mg twice daily for the phase II study. The effect was little short of remarkable, Dr. Flaherty, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center, said in an interview.

“My first responding patient had cutaneous and internal metastases, and the cutaneous metastases were clearly getting better right in front of our eyes,” he said. “We have seen this in some other areas of cancer, but never in melanoma, which before this was a clinical scenario with an unmet need for therapy.”

PLX4032, first engineered by the Berkeley, Calif., company Plexxikon Inc. and being developed in partnership with Roche, is not a foolproof cure, Dr. Tsao said in an interview. “It’s clearly a huge leap forward for the patients who responded so rapidly, yet most are still progressing despite being on the drug. It’s the best stun we’ve ever seen for melanoma, but it’s not a permanent kill.”

Sustained response in the phase I and II trials has varied from only 2 months to up to 2 years, Dr. Flaherty said. He could find no significant predictors of progression or response among the group except for initial tumor number and size. Typically, he said, the patients with the greatest mass of metastatic disease had the shortest duration of response, while those with a smaller tumor burden had a longer duration of response.

“When you have metastatic melanoma, your days are numbered—and numbered in a way we can’t predict when metastatic disease is diagnosed,” Dr. Flaherty said. “What this therapy does is push out the time until the disease worsens. We are not yet smart enough to understand what it is that allows a tumor to work its way around the drug’s activity.”

Chemotherapy-resistant cancers are nothing new, Dr. Tsao noted. What will be new is the full investigation of melanoma’s genetic pathways, and the development of drugs to block them in multiple ways. “The next frontier will be to understand all the ways that melanoma can outsmart treatment. We may have to use multiple therapies to corner it. So a full discovery of all melanoma’s potential vulnerabilities is very important.”

There is already at least a hint that PLX4032 has a very narrow target—only BRAF tumors with the V600E subtype. “There is some laboratory evidence that if you give this drug to a tumor that may be mutated at another gene you may be worsening things,” Dr. Tsao said. “This has yet to be borne out in clinical studies, but bench-side data suggest that you have to be very precise with this drug, because the wrong choice could be potentially deleterious.”

In vitro and in vivo experiments did suggest that PLX4032 was ineffective against non-BRAF melanomas, Dr. Flaherty said. “In a lab, the drug will kill a cancer cell with a BRAF mutation but not with another mutation. Whether it can facilitate the growth of others is an interesting concept supported by some laboratory data, with the observation that this and drugs like it can transiently stimulate other cancer cells with RAS mutations. In these, the drug basically activates the BRAF pathway instead of blocking it. We don’t know the relevance of this finding to humans. It is interesting, but it may have no real clinical impact.”

Discovering the best targets for molecular therapies is typically a long process, Dr. Tsao said, but the race to treat BRAF metastatic melanoma has so far been a fast one. “In 2002, the first BRAF mutation in melanoma was published, and the first drug is already coming to clinical fruition. This is pretty fast for something we’ve been fooling around with ineffectively for 20 years.”

During the 8 years between the mutation’s discovery and Dr. Flaherty’s trial, drug companies have not been idle. “There is now a pipeline of drugs against BRAF. PLX4032 might not be the best or the least toxic, but it’s the first of a host coming down the pike. This is very significant, because now we have a brand-new way of looking at a previously untreatable cancer.”

Roche Pharmaceuticals and Plexxikon sponsored the PLX4032 studies. Dr. Tsao said he had no financial declarations with regard to the drug. Dr. Flaherty has served as a consultant to Roche regarding further development of PLX4032 in melanoma.

CHICAGO — A drug that targets metastatic melanoma with mutations in the BRAF oncogene may be the first step on a path to individualized chemotherapy for patients with these formerly untreatable cancers.

“We are rapidly unraveling the molecular underpinnings of these tumors, and discovering the mechanisms by which they drive melanoma growth. These insights allow us to develop and select drugs on the basis of every patient’s individual genome,” Dr. Hensin Tsao said at the American Academy of Dermatology’s 2010 meeting.

Courtesy Bill Truslow/Massachusetts General Hospital

PLX4032 is the first drug to successfully shrink both cutaneous and internal metastases of BRAF-mutated melanomas, said Dr. Tsao, a dermatologist who is director of the Massachusetts General Hospital Melanoma Genetics Program in Boston.

His colleague, Dr. Keith Flaherty, is about to publish data from the drug’s phase II trial of 87 patients; 81% of those with the BRAF-mutated melanoma responded with a 30% or more shrinkage of the targeted lesions.

After a phase I safety and dose-finding trial, investigators settled on an oral dose of 960 mg twice daily for the phase II study. The effect was little short of remarkable, Dr. Flaherty, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center, said in an interview.

“My first responding patient had cutaneous and internal metastases, and the cutaneous metastases were clearly getting better right in front of our eyes,” he said. “We have seen this in some other areas of cancer, but never in melanoma, which before this was a clinical scenario with an unmet need for therapy.”

PLX4032, first engineered by the Berkeley, Calif., company Plexxikon Inc. and being developed in partnership with Roche, is not a foolproof cure, Dr. Tsao said in an interview. “It’s clearly a huge leap forward for the patients who responded so rapidly, yet most are still progressing despite being on the drug. It’s the best stun we’ve ever seen for melanoma, but it’s not a permanent kill.”

Sustained response in the phase I and II trials has varied from only 2 months to up to 2 years, Dr. Flaherty said. He could find no significant predictors of progression or response among the group except for initial tumor number and size. Typically, he said, the patients with the greatest mass of metastatic disease had the shortest duration of response, while those with a smaller tumor burden had a longer duration of response.

“When you have metastatic melanoma, your days are numbered—and numbered in a way we can’t predict when metastatic disease is diagnosed,” Dr. Flaherty said. “What this therapy does is push out the time until the disease worsens. We are not yet smart enough to understand what it is that allows a tumor to work its way around the drug’s activity.”

Chemotherapy-resistant cancers are nothing new, Dr. Tsao noted. What will be new is the full investigation of melanoma’s genetic pathways, and the development of drugs to block them in multiple ways. “The next frontier will be to understand all the ways that melanoma can outsmart treatment. We may have to use multiple therapies to corner it. So a full discovery of all melanoma’s potential vulnerabilities is very important.”

There is already at least a hint that PLX4032 has a very narrow target—only BRAF tumors with the V600E subtype. “There is some laboratory evidence that if you give this drug to a tumor that may be mutated at another gene you may be worsening things,” Dr. Tsao said. “This has yet to be borne out in clinical studies, but bench-side data suggest that you have to be very precise with this drug, because the wrong choice could be potentially deleterious.”

In vitro and in vivo experiments did suggest that PLX4032 was ineffective against non-BRAF melanomas, Dr. Flaherty said. “In a lab, the drug will kill a cancer cell with a BRAF mutation but not with another mutation. Whether it can facilitate the growth of others is an interesting concept supported by some laboratory data, with the observation that this and drugs like it can transiently stimulate other cancer cells with RAS mutations. In these, the drug basically activates the BRAF pathway instead of blocking it. We don’t know the relevance of this finding to humans. It is interesting, but it may have no real clinical impact.”

Discovering the best targets for molecular therapies is typically a long process, Dr. Tsao said, but the race to treat BRAF metastatic melanoma has so far been a fast one. “In 2002, the first BRAF mutation in melanoma was published, and the first drug is already coming to clinical fruition. This is pretty fast for something we’ve been fooling around with ineffectively for 20 years.”

During the 8 years between the mutation’s discovery and Dr. Flaherty’s trial, drug companies have not been idle. “There is now a pipeline of drugs against BRAF. PLX4032 might not be the best or the least toxic, but it’s the first of a host coming down the pike. This is very significant, because now we have a brand-new way of looking at a previously untreatable cancer.”

Roche Pharmaceuticals and Plexxikon sponsored the PLX4032 studies. Dr. Tsao said he had no financial declarations with regard to the drug. Dr. Flaherty has served as a consultant to Roche regarding further development of PLX4032 in melanoma.

The risk profiles for individuals who develop single vs. multiple basal cell carcinoma lesions differ, according to findings from the Rotterdam Study.

Of the 10,820 eligible members of the two cohorts used for the large, Dutch, population-based study, 361 (3%) were diagnosed with a single initial basal cell carcinoma (BCC) lesion, and 163 (1.5%) were diagnosed with subsequent BCC lesions during the study period.

After adjusting for numerous factors such as sex, age, hair and eye color, tendency to develop sunburn, smoking history, body mass index, and educational level, factors found to be significantly associated with developing a first BCC lesion were age (odds ratios of 1.39 and 1.01 for those aged 65-74 years and for those aged 75 years and older, respectively, vs. those younger than age 65 years), and red hair color (OR of 1.98 for red vs. brown or black hair), Dr. Ville Kiiski and colleagues at Erasmus Medical Center, Rotterdam, the Netherlands, reported in the August issue of Archives of Dermatology.

After adjusting for age at index lesion, sex, hair color, eye color, all ultraviolet-related factors, smoking history, and alcohol consumption, the factors found to be associated with a significantly increased risk of developing multiple lesions were lesion location on an upper extremity (hazard ratio 1.49), age younger than 65 years (HRs of 0.58 and 0.65 for those aged 75 years and older and for those aged 65 to 74 years, respectively, vs. those younger than age 65 years), hair color (HR of 1.43 for red vs. brown/black hair), and education level (HR of 1.42 for high vs. low education level), the investigators found (Arch. Dermatol. 2010;146:848-55).

This last finding “may be explained by the probability that people with higher levels of education (which correlates strongly with socioeconomic status) have different lifestyles,” such as more frequent exposure to ultraviolet rays for intermittent periods, they said. Also, people of higher socioeconomic status generally may be expected to live longer and, thus have more time to acquire lesions.

Patients were adults aged 55 years or older from the two Rotterdam Study cohorts, including one studied in 1990, and one studied in 1999. Participants were followed for a mean of 9.5 years.

The findings – particularly regarding increased risk among younger patients and red-heads – largely support those of previous studies, although in the current study men were not shown to be at significantly increased risk of developing a first lesion, which contrasts with findings from some prior studies, the investigators noted.

The differences in risk factor profiles for those who develop single vs. multiple BCC lesions, as seen in the current study, may suggest that phenotypic characteristics of patients are less important for determining risk once “cumulative environmental-genetic interaction has surpassed a certain threshold and resulted in a lesion,” Dr. Ville Kiiski and colleagues wrote.

“The clinical relevance of this finding is that physicians’ risk assessment efforts should differentiate between patients at risk for a first lesion and those who have a history of BCC,” they said, noting that those with the identified risk factors for multiple lesions may require a more stringent follow-up regimen.

That’s not to say, however, that other BCC patients do not require follow-up. In this sample of the general population, more than 30% of the patients with BCC developed subsequent skin cancer, emphasizing the need for annual follow-up for several years,” Dr. Ville Kiiski and colleagues stressed.

Given that more than 1 million people are diagnosed with BCC in the United States each year, and given the strain that is put on limited specialized care by the need for follow-up of the large group of patients with BCCs, additional research is needed to better identify those at risk of developing multiple lesions, they concluded.

The investigators reported no financial disclosures relevant to their study.

The risk profiles for individuals who develop single vs. multiple basal cell carcinoma lesions differ, according to findings from the Rotterdam Study.

Of the 10,820 eligible members of the two cohorts used for the large, Dutch, population-based study, 361 (3%) were diagnosed with a single initial basal cell carcinoma (BCC) lesion, and 163 (1.5%) were diagnosed with subsequent BCC lesions during the study period.

After adjusting for numerous factors such as sex, age, hair and eye color, tendency to develop sunburn, smoking history, body mass index, and educational level, factors found to be significantly associated with developing a first BCC lesion were age (odds ratios of 1.39 and 1.01 for those aged 65-74 years and for those aged 75 years and older, respectively, vs. those younger than age 65 years), and red hair color (OR of 1.98 for red vs. brown or black hair), Dr. Ville Kiiski and colleagues at Erasmus Medical Center, Rotterdam, the Netherlands, reported in the August issue of Archives of Dermatology.

After adjusting for age at index lesion, sex, hair color, eye color, all ultraviolet-related factors, smoking history, and alcohol consumption, the factors found to be associated with a significantly increased risk of developing multiple lesions were lesion location on an upper extremity (hazard ratio 1.49), age younger than 65 years (HRs of 0.58 and 0.65 for those aged 75 years and older and for those aged 65 to 74 years, respectively, vs. those younger than age 65 years), hair color (HR of 1.43 for red vs. brown/black hair), and education level (HR of 1.42 for high vs. low education level), the investigators found (Arch. Dermatol. 2010;146:848-55).

This last finding “may be explained by the probability that people with higher levels of education (which correlates strongly with socioeconomic status) have different lifestyles,” such as more frequent exposure to ultraviolet rays for intermittent periods, they said. Also, people of higher socioeconomic status generally may be expected to live longer and, thus have more time to acquire lesions.

Patients were adults aged 55 years or older from the two Rotterdam Study cohorts, including one studied in 1990, and one studied in 1999. Participants were followed for a mean of 9.5 years.

The findings – particularly regarding increased risk among younger patients and red-heads – largely support those of previous studies, although in the current study men were not shown to be at significantly increased risk of developing a first lesion, which contrasts with findings from some prior studies, the investigators noted.

The differences in risk factor profiles for those who develop single vs. multiple BCC lesions, as seen in the current study, may suggest that phenotypic characteristics of patients are less important for determining risk once “cumulative environmental-genetic interaction has surpassed a certain threshold and resulted in a lesion,” Dr. Ville Kiiski and colleagues wrote.

“The clinical relevance of this finding is that physicians’ risk assessment efforts should differentiate between patients at risk for a first lesion and those who have a history of BCC,” they said, noting that those with the identified risk factors for multiple lesions may require a more stringent follow-up regimen.

That’s not to say, however, that other BCC patients do not require follow-up. In this sample of the general population, more than 30% of the patients with BCC developed subsequent skin cancer, emphasizing the need for annual follow-up for several years,” Dr. Ville Kiiski and colleagues stressed.

Given that more than 1 million people are diagnosed with BCC in the United States each year, and given the strain that is put on limited specialized care by the need for follow-up of the large group of patients with BCCs, additional research is needed to better identify those at risk of developing multiple lesions, they concluded.

The investigators reported no financial disclosures relevant to their study.

The risk profiles for individuals who develop single vs. multiple basal cell carcinoma lesions differ, according to findings from the Rotterdam Study.

Of the 10,820 eligible members of the two cohorts used for the large, Dutch, population-based study, 361 (3%) were diagnosed with a single initial basal cell carcinoma (BCC) lesion, and 163 (1.5%) were diagnosed with subsequent BCC lesions during the study period.

After adjusting for numerous factors such as sex, age, hair and eye color, tendency to develop sunburn, smoking history, body mass index, and educational level, factors found to be significantly associated with developing a first BCC lesion were age (odds ratios of 1.39 and 1.01 for those aged 65-74 years and for those aged 75 years and older, respectively, vs. those younger than age 65 years), and red hair color (OR of 1.98 for red vs. brown or black hair), Dr. Ville Kiiski and colleagues at Erasmus Medical Center, Rotterdam, the Netherlands, reported in the August issue of Archives of Dermatology.

After adjusting for age at index lesion, sex, hair color, eye color, all ultraviolet-related factors, smoking history, and alcohol consumption, the factors found to be associated with a significantly increased risk of developing multiple lesions were lesion location on an upper extremity (hazard ratio 1.49), age younger than 65 years (HRs of 0.58 and 0.65 for those aged 75 years and older and for those aged 65 to 74 years, respectively, vs. those younger than age 65 years), hair color (HR of 1.43 for red vs. brown/black hair), and education level (HR of 1.42 for high vs. low education level), the investigators found (Arch. Dermatol. 2010;146:848-55).

This last finding “may be explained by the probability that people with higher levels of education (which correlates strongly with socioeconomic status) have different lifestyles,” such as more frequent exposure to ultraviolet rays for intermittent periods, they said. Also, people of higher socioeconomic status generally may be expected to live longer and, thus have more time to acquire lesions.

Patients were adults aged 55 years or older from the two Rotterdam Study cohorts, including one studied in 1990, and one studied in 1999. Participants were followed for a mean of 9.5 years.

The findings – particularly regarding increased risk among younger patients and red-heads – largely support those of previous studies, although in the current study men were not shown to be at significantly increased risk of developing a first lesion, which contrasts with findings from some prior studies, the investigators noted.

The differences in risk factor profiles for those who develop single vs. multiple BCC lesions, as seen in the current study, may suggest that phenotypic characteristics of patients are less important for determining risk once “cumulative environmental-genetic interaction has surpassed a certain threshold and resulted in a lesion,” Dr. Ville Kiiski and colleagues wrote.

“The clinical relevance of this finding is that physicians’ risk assessment efforts should differentiate between patients at risk for a first lesion and those who have a history of BCC,” they said, noting that those with the identified risk factors for multiple lesions may require a more stringent follow-up regimen.

That’s not to say, however, that other BCC patients do not require follow-up. In this sample of the general population, more than 30% of the patients with BCC developed subsequent skin cancer, emphasizing the need for annual follow-up for several years,” Dr. Ville Kiiski and colleagues stressed.

Given that more than 1 million people are diagnosed with BCC in the United States each year, and given the strain that is put on limited specialized care by the need for follow-up of the large group of patients with BCCs, additional research is needed to better identify those at risk of developing multiple lesions, they concluded.

The investigators reported no financial disclosures relevant to their study.

In spite of an alarming report earlier this year by the Environmental Working Group, an analysis of human and animal studies found little support for the assertion that sunscreens containing retinyl palmitate cause skin cancer.

In a commentary published online in the Journal of the American Academy of Dermatology, Dr. Steven Q. Wang of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues evaluated the compound from several points of view, and concluded that "there is no convincing evidence" that retinyl palmitate, a form of vitamin A, is carcinogenic in sunscreens (J. Amer. Acad. Dermatol. 2010 [doi:10.1016/j.jaad.2010.07.015]).

In fact, clinical observations spanning over decades suggest that retinoids are helpful in skin cancer chemoprevention, the authors wrote. "Correcting this false impression is an important and necessary step to ensure that the public continues to use sunscreen as a component of photoprotective strategy."

The suggestion by the Environmental Working Group, a nonprofit public health research and advocacy organization, that retinyl palmitate in sunscreens may cause skin cancer garnered widespread media attention, because 41% of sunscreens on the market contain this compound. Retinyl palmitate, an antioxidant, does not directly provide sun protection, but instead is added as a cosmetic ingredient.

Dr. Wang and his colleagues noted that retinyl palmitate and other closely related compounds are natural components of human skin. In 2000, the compound was referred to the National Institutes of Health's National Toxicology Program (NTP) for phototoxicity and photocarcinogenicity testing, along with many other common ingredients such as alpha- and beta-hydroxy acids, aloe vera, and nanoscale titanium dioxide and zinc oxide.

Between 2002 and 2009, the Food and Drug Administration published eight in vitro studies and three animal studies of retinyl palmitate. Several of these studies showed that the combination of retinyl palmitate and UV light induced reactive oxygen species. In addition, an NTP study involving 430 SKH-1 hairless mice examined two concentrations of retinyl palmitate and placebo at three levels of solar radiation.

This study has not been subject to peer review, but some of the data are available online, and Dr. Wang and his colleagues analyzed them. The only statistically significant results were an apparent increase in neoplasms in animals given the higher concentrations (0.5%) of retinyl palmitate at an intermediate level of simulated solar radiation (6.75 mJ/cm²). Higher levels of solar radiation resulted in no significant increase in neoplasms, so the authors concluded that the study failed to provide conclusive evidence indicating that the combination of retinyl palmitate and UV radiation is carcinogenic.

In addition, that study had several limitations, including the fact that the SKH-1 strain of hairless mice is highly susceptible to the development of skin cancer after UV exposure. In fact, at the higher level of solar radiation, 82% of the mice developed malignant skin lesions when given the placebo.

Although no similar studies in humans have been published, Dr. Wang and his colleagues noted that dermatologists have been prescribing various forms of topical retinoids to manage a variety of skin conditions for more than 40 years. While millions of patients have received these compounds, dermatologists have published no evidence suggesting that topical retinoids increase cancer risk.

The authors declared having no conflicts of interest.

In spite of an alarming report earlier this year by the Environmental Working Group, an analysis of human and animal studies found little support for the assertion that sunscreens containing retinyl palmitate cause skin cancer.

In a commentary published online in the Journal of the American Academy of Dermatology, Dr. Steven Q. Wang of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues evaluated the compound from several points of view, and concluded that "there is no convincing evidence" that retinyl palmitate, a form of vitamin A, is carcinogenic in sunscreens (J. Amer. Acad. Dermatol. 2010 [doi:10.1016/j.jaad.2010.07.015]).

In fact, clinical observations spanning over decades suggest that retinoids are helpful in skin cancer chemoprevention, the authors wrote. "Correcting this false impression is an important and necessary step to ensure that the public continues to use sunscreen as a component of photoprotective strategy."

The suggestion by the Environmental Working Group, a nonprofit public health research and advocacy organization, that retinyl palmitate in sunscreens may cause skin cancer garnered widespread media attention, because 41% of sunscreens on the market contain this compound. Retinyl palmitate, an antioxidant, does not directly provide sun protection, but instead is added as a cosmetic ingredient.

Dr. Wang and his colleagues noted that retinyl palmitate and other closely related compounds are natural components of human skin. In 2000, the compound was referred to the National Institutes of Health's National Toxicology Program (NTP) for phototoxicity and photocarcinogenicity testing, along with many other common ingredients such as alpha- and beta-hydroxy acids, aloe vera, and nanoscale titanium dioxide and zinc oxide.

Between 2002 and 2009, the Food and Drug Administration published eight in vitro studies and three animal studies of retinyl palmitate. Several of these studies showed that the combination of retinyl palmitate and UV light induced reactive oxygen species. In addition, an NTP study involving 430 SKH-1 hairless mice examined two concentrations of retinyl palmitate and placebo at three levels of solar radiation.

This study has not been subject to peer review, but some of the data are available online, and Dr. Wang and his colleagues analyzed them. The only statistically significant results were an apparent increase in neoplasms in animals given the higher concentrations (0.5%) of retinyl palmitate at an intermediate level of simulated solar radiation (6.75 mJ/cm²). Higher levels of solar radiation resulted in no significant increase in neoplasms, so the authors concluded that the study failed to provide conclusive evidence indicating that the combination of retinyl palmitate and UV radiation is carcinogenic.

In addition, that study had several limitations, including the fact that the SKH-1 strain of hairless mice is highly susceptible to the development of skin cancer after UV exposure. In fact, at the higher level of solar radiation, 82% of the mice developed malignant skin lesions when given the placebo.

Although no similar studies in humans have been published, Dr. Wang and his colleagues noted that dermatologists have been prescribing various forms of topical retinoids to manage a variety of skin conditions for more than 40 years. While millions of patients have received these compounds, dermatologists have published no evidence suggesting that topical retinoids increase cancer risk.

The authors declared having no conflicts of interest.

In spite of an alarming report earlier this year by the Environmental Working Group, an analysis of human and animal studies found little support for the assertion that sunscreens containing retinyl palmitate cause skin cancer.

In a commentary published online in the Journal of the American Academy of Dermatology, Dr. Steven Q. Wang of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues evaluated the compound from several points of view, and concluded that "there is no convincing evidence" that retinyl palmitate, a form of vitamin A, is carcinogenic in sunscreens (J. Amer. Acad. Dermatol. 2010 [doi:10.1016/j.jaad.2010.07.015]).

In fact, clinical observations spanning over decades suggest that retinoids are helpful in skin cancer chemoprevention, the authors wrote. "Correcting this false impression is an important and necessary step to ensure that the public continues to use sunscreen as a component of photoprotective strategy."

The suggestion by the Environmental Working Group, a nonprofit public health research and advocacy organization, that retinyl palmitate in sunscreens may cause skin cancer garnered widespread media attention, because 41% of sunscreens on the market contain this compound. Retinyl palmitate, an antioxidant, does not directly provide sun protection, but instead is added as a cosmetic ingredient.

Dr. Wang and his colleagues noted that retinyl palmitate and other closely related compounds are natural components of human skin. In 2000, the compound was referred to the National Institutes of Health's National Toxicology Program (NTP) for phototoxicity and photocarcinogenicity testing, along with many other common ingredients such as alpha- and beta-hydroxy acids, aloe vera, and nanoscale titanium dioxide and zinc oxide.

Between 2002 and 2009, the Food and Drug Administration published eight in vitro studies and three animal studies of retinyl palmitate. Several of these studies showed that the combination of retinyl palmitate and UV light induced reactive oxygen species. In addition, an NTP study involving 430 SKH-1 hairless mice examined two concentrations of retinyl palmitate and placebo at three levels of solar radiation.

This study has not been subject to peer review, but some of the data are available online, and Dr. Wang and his colleagues analyzed them. The only statistically significant results were an apparent increase in neoplasms in animals given the higher concentrations (0.5%) of retinyl palmitate at an intermediate level of simulated solar radiation (6.75 mJ/cm²). Higher levels of solar radiation resulted in no significant increase in neoplasms, so the authors concluded that the study failed to provide conclusive evidence indicating that the combination of retinyl palmitate and UV radiation is carcinogenic.

In addition, that study had several limitations, including the fact that the SKH-1 strain of hairless mice is highly susceptible to the development of skin cancer after UV exposure. In fact, at the higher level of solar radiation, 82% of the mice developed malignant skin lesions when given the placebo.

Although no similar studies in humans have been published, Dr. Wang and his colleagues noted that dermatologists have been prescribing various forms of topical retinoids to manage a variety of skin conditions for more than 40 years. While millions of patients have received these compounds, dermatologists have published no evidence suggesting that topical retinoids increase cancer risk.

The authors declared having no conflicts of interest.