Melanoma

Bristol-Myers Squibb reported on Nov. 2 that the Food and Drug Administration would need more time to review ipilimumab, its biologic drug for melanoma.

The agency was due to make an approval decision by Dec. 25, but now will have until March 26, 2011, according to a statement from Bristol-Myers.

The drug maker said that it submitted additional data to the FDA at the agency’s request.

Ipilimumab, to be marketed as Yervoy, was also due to be reviewed by the FDA’s Oncologic Drugs Advisory Committee on Dec. 2. That meeting is now in doubt, said Ira Loss of "Washington Analysis," a research and analysis company, in an interview.

"I've seen this happen enough times in the past where the product is scheduled on a panel, the company submits additional data, the PDUFA [user fee] date gets pushed out, and then they dropped the meeting," said Mr. Loss.

He still expects approval for ipilimumab, in part because he believes the data are strong, and because "there hasn't been any other product approved for melanoma in years," he said.

In its statement, the drug maker said, "Bristol-Myers Squibb continues to be very encouraged by its interactions with the FDA and remains confident in the overall development program for ipilimumab."

The company noted that "ipilimumab is also currently under review with the European Medicines Agency and other health authorities worldwide."

Bristol-Myers Squibb reported on Nov. 2 that the Food and Drug Administration would need more time to review ipilimumab, its biologic drug for melanoma.

The agency was due to make an approval decision by Dec. 25, but now will have until March 26, 2011, according to a statement from Bristol-Myers.

The drug maker said that it submitted additional data to the FDA at the agency’s request.

Ipilimumab, to be marketed as Yervoy, was also due to be reviewed by the FDA’s Oncologic Drugs Advisory Committee on Dec. 2. That meeting is now in doubt, said Ira Loss of "Washington Analysis," a research and analysis company, in an interview.

"I've seen this happen enough times in the past where the product is scheduled on a panel, the company submits additional data, the PDUFA [user fee] date gets pushed out, and then they dropped the meeting," said Mr. Loss.

He still expects approval for ipilimumab, in part because he believes the data are strong, and because "there hasn't been any other product approved for melanoma in years," he said.

In its statement, the drug maker said, "Bristol-Myers Squibb continues to be very encouraged by its interactions with the FDA and remains confident in the overall development program for ipilimumab."

The company noted that "ipilimumab is also currently under review with the European Medicines Agency and other health authorities worldwide."

Bristol-Myers Squibb reported on Nov. 2 that the Food and Drug Administration would need more time to review ipilimumab, its biologic drug for melanoma.

The agency was due to make an approval decision by Dec. 25, but now will have until March 26, 2011, according to a statement from Bristol-Myers.

The drug maker said that it submitted additional data to the FDA at the agency’s request.

Ipilimumab, to be marketed as Yervoy, was also due to be reviewed by the FDA’s Oncologic Drugs Advisory Committee on Dec. 2. That meeting is now in doubt, said Ira Loss of "Washington Analysis," a research and analysis company, in an interview.

"I've seen this happen enough times in the past where the product is scheduled on a panel, the company submits additional data, the PDUFA [user fee] date gets pushed out, and then they dropped the meeting," said Mr. Loss.

He still expects approval for ipilimumab, in part because he believes the data are strong, and because "there hasn't been any other product approved for melanoma in years," he said.

In its statement, the drug maker said, "Bristol-Myers Squibb continues to be very encouraged by its interactions with the FDA and remains confident in the overall development program for ipilimumab."

The company noted that "ipilimumab is also currently under review with the European Medicines Agency and other health authorities worldwide."

Sunscreens are an important part of a dermatologist's tool kit, but they're not a panacea for UV-induced damage, according to Dr. Timothy Berger.

Although sunscreens work well in laboratory testing, almost no one applies them in a way that will provide the advertised UV protection, Dr. Berger noted at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). And for some patients, sunscreens can exacerbate their UV-induced problems.

Sunscreens themselves, not the vehicular preservatives, are usually the culprit when a patient presents with a complaint of being allergic to sunscreens, said Dr. Berger, a professor of dermatology at the University of California, San Francisco.

"You will usually find that the dermatitis only occurs in areas touched by the sun," he said in an interview. "The problem is often an allergy to the PABA or PABA-related substances in the sunscreen they are using."

Photo courtesy Dr. Timothy Berger

For patients like this, the best alternative is a PABA-free sunscreen that contains zinc and titanium oxide – inert compounds that are physical barriers against UV light, rather than chemical barriers.

And although SPF ratings might look great in advertisements, it is almost a sure bet that sun-seeking patients are not getting nearly the protection promised, Dr. Berger noted. "Some interesting recent studies have looked at what SPF you actually get what you put on sunscreen. The amount used in testing is actually about four times more than what people really use."

One study found that most people apply about 0.5 mg/cm2, while the lab tests use a volume of 2 mg/cm2 to achieve the advertised SPF (J. Am. Acad. Dermatol. 2010;62:218-22). "The problem is, efficacy falls off in a very sharp way," Dr. Berger said. "If you apply SPF 30 sun block [at one-quarter the recommended amount], you only end up with an actual SPF of about 3."

"We need to make sure our patients understand this. And while most people are still not going to use the necessary amount, we can stress the importance of reapplying frequently, which can help keep the protective value up somewhat," he said.

Light Therapy for Atopy

UV light therapy is a frequent treatment for eczema and other atopic dermatoses, but for about 3% of patients, it the wrong thing to offer, Dr. Berger said. "For this small population, sun exposure actually makes the condition worse. Put them in the light box and the eczema will flare."

More than a cursory skin exam should be performed on patients with atopic dermatitis, he recommended. "Have them remove their clothing at least from the waist up. Look for eczema that has a photo distribution: It might be worse on the face and side of the neck, but beneath the chin the skin could be spared. If it looks like a photo-distributed rash, and they report a history of flare with sun exposure, then prescribing aggressive sun protection might make a big difference."

A frequently missed diagnosis in young children – particularly infants – is erythropoietic protoporphyria (EPP). "The first time these infants go out into the sun, they will start screaming, because their skin is burning," Dr. Berger said. As quickly as 1 hour after sun exposure, they may develop erythema, edema, urticarial lesions, or purpura on exposed skin.

Europeans are somewhat ahead in drug research for treating EPP, Dr. Berger noted, but the United States is catching up. The University of California is one of six U.S. study sites participating in a phase II placebo-controlled trial of afamelanotide, a synthetically produced analog of human alpha-melanocytic–stimulating hormone (alpha-MSH).

"The hope is that the drug will stimulate the production of melanin, which actually has two benefits," Dr. Berger said. "First, it's a photo protectant, but it's also an antioxidant."

When porphyrins absorb UV rays, they release free radicals that lead to the acute and chronic damage that occurs on EPP patient skin. The porphyrins can accumulate and damage other tissues – including the liver, which causes problems for about 20% of EPP patients. The extra melanin can help neutralize these highly reactive oxygen species and provide protection from the acute symptoms patients suffer when skin is exposed.

While afamelanotide can never cure EPP, Dr. Berger said, it might afford patients the opportunity to live a more normal life. "While they will never be going out looking for a tan, at least they may be able to enjoy being outdoors without having to be completely encased in clothing."

Dr. Berger disclosed serving as a consultant for Prescription Solutions. SDEF and this news organization are owned by Elsevier.

Sunscreens are an important part of a dermatologist's tool kit, but they're not a panacea for UV-induced damage, according to Dr. Timothy Berger.

Although sunscreens work well in laboratory testing, almost no one applies them in a way that will provide the advertised UV protection, Dr. Berger noted at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). And for some patients, sunscreens can exacerbate their UV-induced problems.

Sunscreens themselves, not the vehicular preservatives, are usually the culprit when a patient presents with a complaint of being allergic to sunscreens, said Dr. Berger, a professor of dermatology at the University of California, San Francisco.

"You will usually find that the dermatitis only occurs in areas touched by the sun," he said in an interview. "The problem is often an allergy to the PABA or PABA-related substances in the sunscreen they are using."

Photo courtesy Dr. Timothy Berger

For patients like this, the best alternative is a PABA-free sunscreen that contains zinc and titanium oxide – inert compounds that are physical barriers against UV light, rather than chemical barriers.

And although SPF ratings might look great in advertisements, it is almost a sure bet that sun-seeking patients are not getting nearly the protection promised, Dr. Berger noted. "Some interesting recent studies have looked at what SPF you actually get what you put on sunscreen. The amount used in testing is actually about four times more than what people really use."

One study found that most people apply about 0.5 mg/cm2, while the lab tests use a volume of 2 mg/cm2 to achieve the advertised SPF (J. Am. Acad. Dermatol. 2010;62:218-22). "The problem is, efficacy falls off in a very sharp way," Dr. Berger said. "If you apply SPF 30 sun block [at one-quarter the recommended amount], you only end up with an actual SPF of about 3."

"We need to make sure our patients understand this. And while most people are still not going to use the necessary amount, we can stress the importance of reapplying frequently, which can help keep the protective value up somewhat," he said.

Light Therapy for Atopy

UV light therapy is a frequent treatment for eczema and other atopic dermatoses, but for about 3% of patients, it the wrong thing to offer, Dr. Berger said. "For this small population, sun exposure actually makes the condition worse. Put them in the light box and the eczema will flare."

More than a cursory skin exam should be performed on patients with atopic dermatitis, he recommended. "Have them remove their clothing at least from the waist up. Look for eczema that has a photo distribution: It might be worse on the face and side of the neck, but beneath the chin the skin could be spared. If it looks like a photo-distributed rash, and they report a history of flare with sun exposure, then prescribing aggressive sun protection might make a big difference."

A frequently missed diagnosis in young children – particularly infants – is erythropoietic protoporphyria (EPP). "The first time these infants go out into the sun, they will start screaming, because their skin is burning," Dr. Berger said. As quickly as 1 hour after sun exposure, they may develop erythema, edema, urticarial lesions, or purpura on exposed skin.

Europeans are somewhat ahead in drug research for treating EPP, Dr. Berger noted, but the United States is catching up. The University of California is one of six U.S. study sites participating in a phase II placebo-controlled trial of afamelanotide, a synthetically produced analog of human alpha-melanocytic–stimulating hormone (alpha-MSH).

"The hope is that the drug will stimulate the production of melanin, which actually has two benefits," Dr. Berger said. "First, it's a photo protectant, but it's also an antioxidant."

When porphyrins absorb UV rays, they release free radicals that lead to the acute and chronic damage that occurs on EPP patient skin. The porphyrins can accumulate and damage other tissues – including the liver, which causes problems for about 20% of EPP patients. The extra melanin can help neutralize these highly reactive oxygen species and provide protection from the acute symptoms patients suffer when skin is exposed.

While afamelanotide can never cure EPP, Dr. Berger said, it might afford patients the opportunity to live a more normal life. "While they will never be going out looking for a tan, at least they may be able to enjoy being outdoors without having to be completely encased in clothing."

Dr. Berger disclosed serving as a consultant for Prescription Solutions. SDEF and this news organization are owned by Elsevier.

Sunscreens are an important part of a dermatologist's tool kit, but they're not a panacea for UV-induced damage, according to Dr. Timothy Berger.

Although sunscreens work well in laboratory testing, almost no one applies them in a way that will provide the advertised UV protection, Dr. Berger noted at the Las Vegas Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). And for some patients, sunscreens can exacerbate their UV-induced problems.

Sunscreens themselves, not the vehicular preservatives, are usually the culprit when a patient presents with a complaint of being allergic to sunscreens, said Dr. Berger, a professor of dermatology at the University of California, San Francisco.

"You will usually find that the dermatitis only occurs in areas touched by the sun," he said in an interview. "The problem is often an allergy to the PABA or PABA-related substances in the sunscreen they are using."

Photo courtesy Dr. Timothy Berger

For patients like this, the best alternative is a PABA-free sunscreen that contains zinc and titanium oxide – inert compounds that are physical barriers against UV light, rather than chemical barriers.

And although SPF ratings might look great in advertisements, it is almost a sure bet that sun-seeking patients are not getting nearly the protection promised, Dr. Berger noted. "Some interesting recent studies have looked at what SPF you actually get what you put on sunscreen. The amount used in testing is actually about four times more than what people really use."

One study found that most people apply about 0.5 mg/cm2, while the lab tests use a volume of 2 mg/cm2 to achieve the advertised SPF (J. Am. Acad. Dermatol. 2010;62:218-22). "The problem is, efficacy falls off in a very sharp way," Dr. Berger said. "If you apply SPF 30 sun block [at one-quarter the recommended amount], you only end up with an actual SPF of about 3."

"We need to make sure our patients understand this. And while most people are still not going to use the necessary amount, we can stress the importance of reapplying frequently, which can help keep the protective value up somewhat," he said.

Light Therapy for Atopy

UV light therapy is a frequent treatment for eczema and other atopic dermatoses, but for about 3% of patients, it the wrong thing to offer, Dr. Berger said. "For this small population, sun exposure actually makes the condition worse. Put them in the light box and the eczema will flare."

More than a cursory skin exam should be performed on patients with atopic dermatitis, he recommended. "Have them remove their clothing at least from the waist up. Look for eczema that has a photo distribution: It might be worse on the face and side of the neck, but beneath the chin the skin could be spared. If it looks like a photo-distributed rash, and they report a history of flare with sun exposure, then prescribing aggressive sun protection might make a big difference."

A frequently missed diagnosis in young children – particularly infants – is erythropoietic protoporphyria (EPP). "The first time these infants go out into the sun, they will start screaming, because their skin is burning," Dr. Berger said. As quickly as 1 hour after sun exposure, they may develop erythema, edema, urticarial lesions, or purpura on exposed skin.

Europeans are somewhat ahead in drug research for treating EPP, Dr. Berger noted, but the United States is catching up. The University of California is one of six U.S. study sites participating in a phase II placebo-controlled trial of afamelanotide, a synthetically produced analog of human alpha-melanocytic–stimulating hormone (alpha-MSH).

"The hope is that the drug will stimulate the production of melanin, which actually has two benefits," Dr. Berger said. "First, it's a photo protectant, but it's also an antioxidant."

When porphyrins absorb UV rays, they release free radicals that lead to the acute and chronic damage that occurs on EPP patient skin. The porphyrins can accumulate and damage other tissues – including the liver, which causes problems for about 20% of EPP patients. The extra melanin can help neutralize these highly reactive oxygen species and provide protection from the acute symptoms patients suffer when skin is exposed.

While afamelanotide can never cure EPP, Dr. Berger said, it might afford patients the opportunity to live a more normal life. "While they will never be going out looking for a tan, at least they may be able to enjoy being outdoors without having to be completely encased in clothing."

Dr. Berger disclosed serving as a consultant for Prescription Solutions. SDEF and this news organization are owned by Elsevier.

SANTA BARBARA, CALIF. - Imiquimod should be considered a possible treatment option for most skin cancer patients, according to Dr. Craig Kraffert.

Currently, imiquimod is approved only for the treatment actinic keratoses and basal cell carcinoma (BCC), but its greatest therapeutic benefit may occur with off-label use, Dr. Kraffert said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

"It’s reasonable to consider for all basal cell carcinoma subtypes, but it’s not for aggressive or large squamous cell carcinoma, and it’s certainly not for invasive melanoma," said Dr. Kraffert, who practices dermatology in Redding, Calif.

Advantages to using imiquimod, he said, include the fact it doesn’t require surgery, it has a good cure rate, noncures are identifiable, and it causes minimal scarring "Disadvantages are that it’s time consuming, there’s transient morbidity, and it requires a coherent, compliant patient as well as provider oversight," he said. "And it’s a bit expensive."

In his practice, he uses imiquimod for patients with all types of BCC, for those with in situ and superficially invasive squamous cell carcinoma (SCC), and for those with melanoma in situ. "It’s also good for premalignant epithelial targets such as actinic keratoses, actinic cheilitis, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and oral leukoplakia," he said. "Imiquimod therapeutic considerations for malignant and premalignant processes can be considered essentially equivalent."

Photo courtesy Dr. Craig Kraffert

He presented clinical data from patients in his practice who have been treated with imiquimod to date. Of 50 patients with SCC in situ, 70% had success with combination therapy, 28% had success with monotherapy, and 2% discontinued therapy.

Of 328 patients with BCC, 53% had success with monotherapy, 34% had success with combination therapy, and 13% discontinued therapy.

Photo courtesy Dr. Craig Kraffert

Of 25 patients with melanoma in situ, 20% had success with monotherapy, 56% had success with combination therapy, and 24% discontinued therapy.

The drug’s mechanism of action is not entirely understood, but it appears to activate both innate immunity with a cytokine cascade, as well as adaptive immunity with Langerhans cells. "It also causes a direct apoptotic and antineoplastic effect," he said.

Photo courtesy Dr. Craig Kraffert

In his opinion, high-utility niches include any patient seeking minimized scarring and who doesn’t want surgery, electrodesiccation and curettage (ED & C) failure, partially infiltrative or partially superficial BCC, multifocal temporal BCC, and large and/or ill-defined facial SCC in situ.

He finds that using imiquimod after ED & C in challenging tumors or in tumors with an infiltrative component increases the cure rate and decreases scarring. "I contend that imiquimod after ED & C generally gives you a better scar than ED & C alone," he said. "I don’t know why, but it does. Brisk reaction can be challenging, and close monitoring is required."

Using imiquimod prior to excision "may shrink tumors, leading to a smaller defect, better cosmesis, possible lower recurrence rate, and potential for complete nonsurgical response," he added.

He also finds the drug helpful for infiltrative BCCs in cosmetically vulnerable areas and for edge persistence after Mohs surgery. "Part of this is because imiquimod seems to work better on infiltrative basal cell carcinomas than it does on nodular basal cell carcinomas," he explained. "I think that’s because of access of the immune system to the thin threads of tumor. It’s also useful for melanoma in situ, particularly in cosmetically vulnerable areas. With melanoma in situ, melanin is a visible marker that serves as a clinical treatment site monitor. I don’t know of any reports of amelanotic transformation from imiquimod. Scarring is often minimal or absent, and there is tumor margin auto detection. It does have curative potential for melanoma in situ."

He emphasized that imiquimod monotherapy in patients with melanoma in situ is difficult, with varied response. "That’s where 5-FU [fluorouracil] in addition to imiquimod is often extremely useful," he said.

Dr. Kraffert described imiquimod as "a thinking practitioner’s medication" that requires thought and oversight. "It may provide excellent outcomes when least expected, so it’s important to keep an open mind regarding the clinical utility of this medication with skin cancer," he said.

Patients must be able to follow instructions, comply with treatment, return for monitoring and surveillance, and call or return to the clinic when appropriate. "Believe it or not, these limited requirements exclude many potential candidates," he remarked.

Patients typically use the drug for 6 weeks, beginning with twice daily dosing, "but it’s variable," he said. "For optimal success treatment must be strong enough for long enough."

At the initial consultation Dr. Kraffert educates his patient about the concept of delayed gratification, the reasons why the medication was suggested, and reaffirms that he will be there to oversee treatment.

He instructs them on how to use the medication, explaining they need to rub it into the lesion twice a day very well. "A pinhead amount is all that’s needed," he said, only a small portion of the 0.25 g included in each packet. His patients typically get a few to several applications from each packet.

He also educates patients about possible side effects from imiquimod, including redness, crusting, oozing, and some tenderness. "Nausea, malaise, pain, and secondary infection are rare," he said. "Patients are advised to call the office with any significant treatment related concerns and are generally offered the option of a same day add-on appointment."

At the 2-week follow-up visit he gauges the response as very brisk, brisk, moderate, mild, or none. If the response is very brisk, he halts therapy for 3-7 days, re-initiates treatment once daily for 4 weeks, and schedules a follow-up visit after 2 more weeks of treatment.

If the response is brisk, he halts therapy for 1-3 days, and then continues therapy once daily for 4 weeks.

If the response is moderate he continues therapy once daily for 4 weeks, and if the response is mild he continues therapy twice daily for 4 weeks.

"If there is no response, consider further imiquimod treatment with 2-4-week re-evaluation, or consider application of a small (less than a pea-sized) amount of 5% 5-FU after imiquimod twice daily," Dr. Kraffert said. "Or, you could consider nonimiquimod management of the problem. Sometimes imiquimod just doesn’t work."

After the 2-week follow-up, further visits are discretionary, he said, but some patients require closer follow-up, including nonresponders and patients with severe reactions, systemic complaints, and large or challenging tumors.

"Scheduling a follow-up visit for 3-6 months is best because the reaction takes a month or 2 to diminish," he said. "Taking photos pretherapy and at each visit thereafter improves surveillance."

"There are many approaches to skin cancer," Dr. Kraffert concluded. "Excision or destruction is often the best, but having more options is a plus. Imiquimod doesn’t replace what we have, it just adds to it."

Dr. Kraffert said he had no relevant financial conflicts.

SANTA BARBARA, CALIF. - Imiquimod should be considered a possible treatment option for most skin cancer patients, according to Dr. Craig Kraffert.

Currently, imiquimod is approved only for the treatment actinic keratoses and basal cell carcinoma (BCC), but its greatest therapeutic benefit may occur with off-label use, Dr. Kraffert said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

"It’s reasonable to consider for all basal cell carcinoma subtypes, but it’s not for aggressive or large squamous cell carcinoma, and it’s certainly not for invasive melanoma," said Dr. Kraffert, who practices dermatology in Redding, Calif.

Advantages to using imiquimod, he said, include the fact it doesn’t require surgery, it has a good cure rate, noncures are identifiable, and it causes minimal scarring "Disadvantages are that it’s time consuming, there’s transient morbidity, and it requires a coherent, compliant patient as well as provider oversight," he said. "And it’s a bit expensive."

In his practice, he uses imiquimod for patients with all types of BCC, for those with in situ and superficially invasive squamous cell carcinoma (SCC), and for those with melanoma in situ. "It’s also good for premalignant epithelial targets such as actinic keratoses, actinic cheilitis, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and oral leukoplakia," he said. "Imiquimod therapeutic considerations for malignant and premalignant processes can be considered essentially equivalent."

Photo courtesy Dr. Craig Kraffert

He presented clinical data from patients in his practice who have been treated with imiquimod to date. Of 50 patients with SCC in situ, 70% had success with combination therapy, 28% had success with monotherapy, and 2% discontinued therapy.

Of 328 patients with BCC, 53% had success with monotherapy, 34% had success with combination therapy, and 13% discontinued therapy.

Photo courtesy Dr. Craig Kraffert

Of 25 patients with melanoma in situ, 20% had success with monotherapy, 56% had success with combination therapy, and 24% discontinued therapy.

The drug’s mechanism of action is not entirely understood, but it appears to activate both innate immunity with a cytokine cascade, as well as adaptive immunity with Langerhans cells. "It also causes a direct apoptotic and antineoplastic effect," he said.

Photo courtesy Dr. Craig Kraffert

In his opinion, high-utility niches include any patient seeking minimized scarring and who doesn’t want surgery, electrodesiccation and curettage (ED & C) failure, partially infiltrative or partially superficial BCC, multifocal temporal BCC, and large and/or ill-defined facial SCC in situ.

He finds that using imiquimod after ED & C in challenging tumors or in tumors with an infiltrative component increases the cure rate and decreases scarring. "I contend that imiquimod after ED & C generally gives you a better scar than ED & C alone," he said. "I don’t know why, but it does. Brisk reaction can be challenging, and close monitoring is required."

Using imiquimod prior to excision "may shrink tumors, leading to a smaller defect, better cosmesis, possible lower recurrence rate, and potential for complete nonsurgical response," he added.

He also finds the drug helpful for infiltrative BCCs in cosmetically vulnerable areas and for edge persistence after Mohs surgery. "Part of this is because imiquimod seems to work better on infiltrative basal cell carcinomas than it does on nodular basal cell carcinomas," he explained. "I think that’s because of access of the immune system to the thin threads of tumor. It’s also useful for melanoma in situ, particularly in cosmetically vulnerable areas. With melanoma in situ, melanin is a visible marker that serves as a clinical treatment site monitor. I don’t know of any reports of amelanotic transformation from imiquimod. Scarring is often minimal or absent, and there is tumor margin auto detection. It does have curative potential for melanoma in situ."

He emphasized that imiquimod monotherapy in patients with melanoma in situ is difficult, with varied response. "That’s where 5-FU [fluorouracil] in addition to imiquimod is often extremely useful," he said.

Dr. Kraffert described imiquimod as "a thinking practitioner’s medication" that requires thought and oversight. "It may provide excellent outcomes when least expected, so it’s important to keep an open mind regarding the clinical utility of this medication with skin cancer," he said.

Patients must be able to follow instructions, comply with treatment, return for monitoring and surveillance, and call or return to the clinic when appropriate. "Believe it or not, these limited requirements exclude many potential candidates," he remarked.

Patients typically use the drug for 6 weeks, beginning with twice daily dosing, "but it’s variable," he said. "For optimal success treatment must be strong enough for long enough."

At the initial consultation Dr. Kraffert educates his patient about the concept of delayed gratification, the reasons why the medication was suggested, and reaffirms that he will be there to oversee treatment.

He instructs them on how to use the medication, explaining they need to rub it into the lesion twice a day very well. "A pinhead amount is all that’s needed," he said, only a small portion of the 0.25 g included in each packet. His patients typically get a few to several applications from each packet.

He also educates patients about possible side effects from imiquimod, including redness, crusting, oozing, and some tenderness. "Nausea, malaise, pain, and secondary infection are rare," he said. "Patients are advised to call the office with any significant treatment related concerns and are generally offered the option of a same day add-on appointment."

At the 2-week follow-up visit he gauges the response as very brisk, brisk, moderate, mild, or none. If the response is very brisk, he halts therapy for 3-7 days, re-initiates treatment once daily for 4 weeks, and schedules a follow-up visit after 2 more weeks of treatment.

If the response is brisk, he halts therapy for 1-3 days, and then continues therapy once daily for 4 weeks.

If the response is moderate he continues therapy once daily for 4 weeks, and if the response is mild he continues therapy twice daily for 4 weeks.

"If there is no response, consider further imiquimod treatment with 2-4-week re-evaluation, or consider application of a small (less than a pea-sized) amount of 5% 5-FU after imiquimod twice daily," Dr. Kraffert said. "Or, you could consider nonimiquimod management of the problem. Sometimes imiquimod just doesn’t work."

After the 2-week follow-up, further visits are discretionary, he said, but some patients require closer follow-up, including nonresponders and patients with severe reactions, systemic complaints, and large or challenging tumors.

"Scheduling a follow-up visit for 3-6 months is best because the reaction takes a month or 2 to diminish," he said. "Taking photos pretherapy and at each visit thereafter improves surveillance."

"There are many approaches to skin cancer," Dr. Kraffert concluded. "Excision or destruction is often the best, but having more options is a plus. Imiquimod doesn’t replace what we have, it just adds to it."

Dr. Kraffert said he had no relevant financial conflicts.

SANTA BARBARA, CALIF. - Imiquimod should be considered a possible treatment option for most skin cancer patients, according to Dr. Craig Kraffert.

Currently, imiquimod is approved only for the treatment actinic keratoses and basal cell carcinoma (BCC), but its greatest therapeutic benefit may occur with off-label use, Dr. Kraffert said at the annual meeting of the California Society of Dermatology and Dermatologic Surgery.

"It’s reasonable to consider for all basal cell carcinoma subtypes, but it’s not for aggressive or large squamous cell carcinoma, and it’s certainly not for invasive melanoma," said Dr. Kraffert, who practices dermatology in Redding, Calif.

Advantages to using imiquimod, he said, include the fact it doesn’t require surgery, it has a good cure rate, noncures are identifiable, and it causes minimal scarring "Disadvantages are that it’s time consuming, there’s transient morbidity, and it requires a coherent, compliant patient as well as provider oversight," he said. "And it’s a bit expensive."

In his practice, he uses imiquimod for patients with all types of BCC, for those with in situ and superficially invasive squamous cell carcinoma (SCC), and for those with melanoma in situ. "It’s also good for premalignant epithelial targets such as actinic keratoses, actinic cheilitis, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and oral leukoplakia," he said. "Imiquimod therapeutic considerations for malignant and premalignant processes can be considered essentially equivalent."

Photo courtesy Dr. Craig Kraffert

He presented clinical data from patients in his practice who have been treated with imiquimod to date. Of 50 patients with SCC in situ, 70% had success with combination therapy, 28% had success with monotherapy, and 2% discontinued therapy.

Of 328 patients with BCC, 53% had success with monotherapy, 34% had success with combination therapy, and 13% discontinued therapy.

Photo courtesy Dr. Craig Kraffert

Of 25 patients with melanoma in situ, 20% had success with monotherapy, 56% had success with combination therapy, and 24% discontinued therapy.

The drug’s mechanism of action is not entirely understood, but it appears to activate both innate immunity with a cytokine cascade, as well as adaptive immunity with Langerhans cells. "It also causes a direct apoptotic and antineoplastic effect," he said.

Photo courtesy Dr. Craig Kraffert

In his opinion, high-utility niches include any patient seeking minimized scarring and who doesn’t want surgery, electrodesiccation and curettage (ED & C) failure, partially infiltrative or partially superficial BCC, multifocal temporal BCC, and large and/or ill-defined facial SCC in situ.

He finds that using imiquimod after ED & C in challenging tumors or in tumors with an infiltrative component increases the cure rate and decreases scarring. "I contend that imiquimod after ED & C generally gives you a better scar than ED & C alone," he said. "I don’t know why, but it does. Brisk reaction can be challenging, and close monitoring is required."

Using imiquimod prior to excision "may shrink tumors, leading to a smaller defect, better cosmesis, possible lower recurrence rate, and potential for complete nonsurgical response," he added.

He also finds the drug helpful for infiltrative BCCs in cosmetically vulnerable areas and for edge persistence after Mohs surgery. "Part of this is because imiquimod seems to work better on infiltrative basal cell carcinomas than it does on nodular basal cell carcinomas," he explained. "I think that’s because of access of the immune system to the thin threads of tumor. It’s also useful for melanoma in situ, particularly in cosmetically vulnerable areas. With melanoma in situ, melanin is a visible marker that serves as a clinical treatment site monitor. I don’t know of any reports of amelanotic transformation from imiquimod. Scarring is often minimal or absent, and there is tumor margin auto detection. It does have curative potential for melanoma in situ."

He emphasized that imiquimod monotherapy in patients with melanoma in situ is difficult, with varied response. "That’s where 5-FU [fluorouracil] in addition to imiquimod is often extremely useful," he said.

Dr. Kraffert described imiquimod as "a thinking practitioner’s medication" that requires thought and oversight. "It may provide excellent outcomes when least expected, so it’s important to keep an open mind regarding the clinical utility of this medication with skin cancer," he said.

Patients must be able to follow instructions, comply with treatment, return for monitoring and surveillance, and call or return to the clinic when appropriate. "Believe it or not, these limited requirements exclude many potential candidates," he remarked.

Patients typically use the drug for 6 weeks, beginning with twice daily dosing, "but it’s variable," he said. "For optimal success treatment must be strong enough for long enough."

At the initial consultation Dr. Kraffert educates his patient about the concept of delayed gratification, the reasons why the medication was suggested, and reaffirms that he will be there to oversee treatment.

He instructs them on how to use the medication, explaining they need to rub it into the lesion twice a day very well. "A pinhead amount is all that’s needed," he said, only a small portion of the 0.25 g included in each packet. His patients typically get a few to several applications from each packet.

He also educates patients about possible side effects from imiquimod, including redness, crusting, oozing, and some tenderness. "Nausea, malaise, pain, and secondary infection are rare," he said. "Patients are advised to call the office with any significant treatment related concerns and are generally offered the option of a same day add-on appointment."

At the 2-week follow-up visit he gauges the response as very brisk, brisk, moderate, mild, or none. If the response is very brisk, he halts therapy for 3-7 days, re-initiates treatment once daily for 4 weeks, and schedules a follow-up visit after 2 more weeks of treatment.

If the response is brisk, he halts therapy for 1-3 days, and then continues therapy once daily for 4 weeks.

If the response is moderate he continues therapy once daily for 4 weeks, and if the response is mild he continues therapy twice daily for 4 weeks.

"If there is no response, consider further imiquimod treatment with 2-4-week re-evaluation, or consider application of a small (less than a pea-sized) amount of 5% 5-FU after imiquimod twice daily," Dr. Kraffert said. "Or, you could consider nonimiquimod management of the problem. Sometimes imiquimod just doesn’t work."

After the 2-week follow-up, further visits are discretionary, he said, but some patients require closer follow-up, including nonresponders and patients with severe reactions, systemic complaints, and large or challenging tumors.

"Scheduling a follow-up visit for 3-6 months is best because the reaction takes a month or 2 to diminish," he said. "Taking photos pretherapy and at each visit thereafter improves surveillance."

"There are many approaches to skin cancer," Dr. Kraffert concluded. "Excision or destruction is often the best, but having more options is a plus. Imiquimod doesn’t replace what we have, it just adds to it."

Dr. Kraffert said he had no relevant financial conflicts.

GOTHENBURG, SWEDEN - Legius syndrome, first described only 3 years ago, can be easily misdiagnosed as neurofibromatosis type 1.

The diagnostic confusion has important consequences for the peace of mind of patients and their families. While Legius syndrome and neurofibromatosis type 1 (NF1) share several phenotypic features, Legius syndrome, unlike NF1, does not carry an increased cancer risk. Nor do patients with Legius syndrome develop clusters of benign cutaneous neurofibromas, Dr. Sirkku Peltonen said at the annual congress of the European Academy of Dermatology and Venereology.

Photo copyright 2007, Elsevier

As first described by Dr. Eric Legius and coworkers (Nat. Genet. 2007;39:1120-6) at the Catholic University of Leuven (Belgium), the hallmarks of Legius syndrome include multiple café au lait macules, axillary freckling, and autosomal dominant transmission, all of which are also among the NF1 diagnostic criteria established by the National Institutes of Health (JAMA 1997;278:51-7). But patients with Legius syndrome do not develop any other characteristic findings of NF1, such as bone lesions, plexiform or cutaneous neurofibromas, Lisch nodules in the iris, and nervous system tumors.

Legius syndrome is caused by mutations in the SPRED1 gene, while NF1 is caused by mutations in the gene encoding neurofibromin. Consider the possibility of Legius syndrome, which can be confirmed by molecular genetic analysis, in patients with six or more café au lait macules and axillary freckling but none of the other classic features of NF1, urged Dr. Peltonen of the University of Turku (Finland).

How often is Legius syndrome mistaken for NF1? A report by Dr. Legius and coworkers concluded half a cohort of 40 patients with Legius syndrome confirmed by genetic analysis fulfilled the NIH diagnostic criteria for NF1 based upon the presence of the requisite number of café au lait spots, axillary freckling, and/or a family history compatible with NF1. In the same report, the international group of investigators determined that 1.9% of a series of 1,318 patients with the clinical diagnosis of NF1 based upon the NIH criteria actually had Legius syndrome (JAMA 2009;302:2111-8).

Dr. Peltonen declared having no relevant financial interests.

GOTHENBURG, SWEDEN - Legius syndrome, first described only 3 years ago, can be easily misdiagnosed as neurofibromatosis type 1.

The diagnostic confusion has important consequences for the peace of mind of patients and their families. While Legius syndrome and neurofibromatosis type 1 (NF1) share several phenotypic features, Legius syndrome, unlike NF1, does not carry an increased cancer risk. Nor do patients with Legius syndrome develop clusters of benign cutaneous neurofibromas, Dr. Sirkku Peltonen said at the annual congress of the European Academy of Dermatology and Venereology.

Photo copyright 2007, Elsevier

As first described by Dr. Eric Legius and coworkers (Nat. Genet. 2007;39:1120-6) at the Catholic University of Leuven (Belgium), the hallmarks of Legius syndrome include multiple café au lait macules, axillary freckling, and autosomal dominant transmission, all of which are also among the NF1 diagnostic criteria established by the National Institutes of Health (JAMA 1997;278:51-7). But patients with Legius syndrome do not develop any other characteristic findings of NF1, such as bone lesions, plexiform or cutaneous neurofibromas, Lisch nodules in the iris, and nervous system tumors.

Legius syndrome is caused by mutations in the SPRED1 gene, while NF1 is caused by mutations in the gene encoding neurofibromin. Consider the possibility of Legius syndrome, which can be confirmed by molecular genetic analysis, in patients with six or more café au lait macules and axillary freckling but none of the other classic features of NF1, urged Dr. Peltonen of the University of Turku (Finland).

How often is Legius syndrome mistaken for NF1? A report by Dr. Legius and coworkers concluded half a cohort of 40 patients with Legius syndrome confirmed by genetic analysis fulfilled the NIH diagnostic criteria for NF1 based upon the presence of the requisite number of café au lait spots, axillary freckling, and/or a family history compatible with NF1. In the same report, the international group of investigators determined that 1.9% of a series of 1,318 patients with the clinical diagnosis of NF1 based upon the NIH criteria actually had Legius syndrome (JAMA 2009;302:2111-8).

Dr. Peltonen declared having no relevant financial interests.

GOTHENBURG, SWEDEN - Legius syndrome, first described only 3 years ago, can be easily misdiagnosed as neurofibromatosis type 1.

The diagnostic confusion has important consequences for the peace of mind of patients and their families. While Legius syndrome and neurofibromatosis type 1 (NF1) share several phenotypic features, Legius syndrome, unlike NF1, does not carry an increased cancer risk. Nor do patients with Legius syndrome develop clusters of benign cutaneous neurofibromas, Dr. Sirkku Peltonen said at the annual congress of the European Academy of Dermatology and Venereology.

Photo copyright 2007, Elsevier

As first described by Dr. Eric Legius and coworkers (Nat. Genet. 2007;39:1120-6) at the Catholic University of Leuven (Belgium), the hallmarks of Legius syndrome include multiple café au lait macules, axillary freckling, and autosomal dominant transmission, all of which are also among the NF1 diagnostic criteria established by the National Institutes of Health (JAMA 1997;278:51-7). But patients with Legius syndrome do not develop any other characteristic findings of NF1, such as bone lesions, plexiform or cutaneous neurofibromas, Lisch nodules in the iris, and nervous system tumors.

Legius syndrome is caused by mutations in the SPRED1 gene, while NF1 is caused by mutations in the gene encoding neurofibromin. Consider the possibility of Legius syndrome, which can be confirmed by molecular genetic analysis, in patients with six or more café au lait macules and axillary freckling but none of the other classic features of NF1, urged Dr. Peltonen of the University of Turku (Finland).

How often is Legius syndrome mistaken for NF1? A report by Dr. Legius and coworkers concluded half a cohort of 40 patients with Legius syndrome confirmed by genetic analysis fulfilled the NIH diagnostic criteria for NF1 based upon the presence of the requisite number of café au lait spots, axillary freckling, and/or a family history compatible with NF1. In the same report, the international group of investigators determined that 1.9% of a series of 1,318 patients with the clinical diagnosis of NF1 based upon the NIH criteria actually had Legius syndrome (JAMA 2009;302:2111-8).

Dr. Peltonen declared having no relevant financial interests.

GOTHENBURG, SWEDEN – Topical diclofenac 3% gel proved effective for the treatment of actinic keratoses in organ transplant recipients, according to the results of a new study.

Sixteen weeks of twice-daily therapy with 3% diclofenac in 2.5% hyaluronic acid (Solaraze) not only proved effective and well tolerated for actinic keratoses (AK) clearance in a randomized, placebo-controlled trial, it also prevented invasive squamous cell carcinomas (SCCs) in organ transplant recipients, Dr. Eggert Stockfleth reported at the annual congress of the European Academy of Dermatology and Venereology.

Based upon an earlier favorable but uncontrolled six-patient series (B. J. Dermatol. 2007;156 Suppl. 3:40-2), Dr. Stockfleth and his coworkers conducted a follow-up randomized trial of topical diclofenace 3% gel in 32 organ transplant recipients.

Organ transplant recipients' immunocompromised status renders them highly vulnerable to multiple invasive SCCs, he said. As graft survival has improved over the years, the high incidence of aggressive cutaneous malignancies in organ transplant recipients has come to the fore as a major concern.

In Australia and New Zealand, cancer is now the No. 1 cause of death in organ transplant recipients, not heart disease, graft rejection, or infection. And the risk of aggressive skin cancers in these patients is far higher than the risk of other malignancies, according to Dr. Stockfleth of the director of the skin cancer center at Charité University Hospital, Berlin.

The 32 study participants were randomized 3-to-1 to diclofenac or a vehicle control. Study eligibility required a stable graft during the previous 12 months plus three or more AKs in a 50-cm2 area on the face, hands, or scalp.

Twenty-eight patients (88%) completed the 16-week, twice-daily treatment phase and presented for final evaluation 4 weeks later. Complete clearance of AKs was achieved in 9 of 22 (41%) of the diclofenac group, compared with 0 of 6 controls.

Side effects were limited to mild erythema and mild-to-moderate swelling of treated areas. No laboratory abnormalities or effects on graft function were noted.

With further follow-up, 55% of the patients who had previously cleared developed new AKs in the treated areas an average of 9.3 months after treatment ended. None of these patients developed invasive SCC in the study area within 24 months of follow-up, suggesting that topical diclofenac gel may also prevent invasive SCCs in this high-risk population.

Other treatments that have demonstrated efficacy for treatment of AKs and/or prevention of nonmelanoma skin cancer in high-risk organ transplant recipients include regular use of a sunscreen, imiquimod 5% cream, topical 5-fluorouracil, and photodynamic therapy.

Dr. Stockfleth disclosed serving as a consultant to Graceway, Almirall, Spirig, Intendis, Meda, Abbott, and LEO.

GOTHENBURG, SWEDEN – Topical diclofenac 3% gel proved effective for the treatment of actinic keratoses in organ transplant recipients, according to the results of a new study.

Sixteen weeks of twice-daily therapy with 3% diclofenac in 2.5% hyaluronic acid (Solaraze) not only proved effective and well tolerated for actinic keratoses (AK) clearance in a randomized, placebo-controlled trial, it also prevented invasive squamous cell carcinomas (SCCs) in organ transplant recipients, Dr. Eggert Stockfleth reported at the annual congress of the European Academy of Dermatology and Venereology.

Based upon an earlier favorable but uncontrolled six-patient series (B. J. Dermatol. 2007;156 Suppl. 3:40-2), Dr. Stockfleth and his coworkers conducted a follow-up randomized trial of topical diclofenace 3% gel in 32 organ transplant recipients.

Organ transplant recipients' immunocompromised status renders them highly vulnerable to multiple invasive SCCs, he said. As graft survival has improved over the years, the high incidence of aggressive cutaneous malignancies in organ transplant recipients has come to the fore as a major concern.

In Australia and New Zealand, cancer is now the No. 1 cause of death in organ transplant recipients, not heart disease, graft rejection, or infection. And the risk of aggressive skin cancers in these patients is far higher than the risk of other malignancies, according to Dr. Stockfleth of the director of the skin cancer center at Charité University Hospital, Berlin.

The 32 study participants were randomized 3-to-1 to diclofenac or a vehicle control. Study eligibility required a stable graft during the previous 12 months plus three or more AKs in a 50-cm2 area on the face, hands, or scalp.

Twenty-eight patients (88%) completed the 16-week, twice-daily treatment phase and presented for final evaluation 4 weeks later. Complete clearance of AKs was achieved in 9 of 22 (41%) of the diclofenac group, compared with 0 of 6 controls.

Side effects were limited to mild erythema and mild-to-moderate swelling of treated areas. No laboratory abnormalities or effects on graft function were noted.

With further follow-up, 55% of the patients who had previously cleared developed new AKs in the treated areas an average of 9.3 months after treatment ended. None of these patients developed invasive SCC in the study area within 24 months of follow-up, suggesting that topical diclofenac gel may also prevent invasive SCCs in this high-risk population.

Other treatments that have demonstrated efficacy for treatment of AKs and/or prevention of nonmelanoma skin cancer in high-risk organ transplant recipients include regular use of a sunscreen, imiquimod 5% cream, topical 5-fluorouracil, and photodynamic therapy.

Dr. Stockfleth disclosed serving as a consultant to Graceway, Almirall, Spirig, Intendis, Meda, Abbott, and LEO.

GOTHENBURG, SWEDEN – Topical diclofenac 3% gel proved effective for the treatment of actinic keratoses in organ transplant recipients, according to the results of a new study.

Sixteen weeks of twice-daily therapy with 3% diclofenac in 2.5% hyaluronic acid (Solaraze) not only proved effective and well tolerated for actinic keratoses (AK) clearance in a randomized, placebo-controlled trial, it also prevented invasive squamous cell carcinomas (SCCs) in organ transplant recipients, Dr. Eggert Stockfleth reported at the annual congress of the European Academy of Dermatology and Venereology.

Based upon an earlier favorable but uncontrolled six-patient series (B. J. Dermatol. 2007;156 Suppl. 3:40-2), Dr. Stockfleth and his coworkers conducted a follow-up randomized trial of topical diclofenace 3% gel in 32 organ transplant recipients.

Organ transplant recipients' immunocompromised status renders them highly vulnerable to multiple invasive SCCs, he said. As graft survival has improved over the years, the high incidence of aggressive cutaneous malignancies in organ transplant recipients has come to the fore as a major concern.

In Australia and New Zealand, cancer is now the No. 1 cause of death in organ transplant recipients, not heart disease, graft rejection, or infection. And the risk of aggressive skin cancers in these patients is far higher than the risk of other malignancies, according to Dr. Stockfleth of the director of the skin cancer center at Charité University Hospital, Berlin.

The 32 study participants were randomized 3-to-1 to diclofenac or a vehicle control. Study eligibility required a stable graft during the previous 12 months plus three or more AKs in a 50-cm2 area on the face, hands, or scalp.

Twenty-eight patients (88%) completed the 16-week, twice-daily treatment phase and presented for final evaluation 4 weeks later. Complete clearance of AKs was achieved in 9 of 22 (41%) of the diclofenac group, compared with 0 of 6 controls.

Side effects were limited to mild erythema and mild-to-moderate swelling of treated areas. No laboratory abnormalities or effects on graft function were noted.

With further follow-up, 55% of the patients who had previously cleared developed new AKs in the treated areas an average of 9.3 months after treatment ended. None of these patients developed invasive SCC in the study area within 24 months of follow-up, suggesting that topical diclofenac gel may also prevent invasive SCCs in this high-risk population.

Other treatments that have demonstrated efficacy for treatment of AKs and/or prevention of nonmelanoma skin cancer in high-risk organ transplant recipients include regular use of a sunscreen, imiquimod 5% cream, topical 5-fluorouracil, and photodynamic therapy.

Dr. Stockfleth disclosed serving as a consultant to Graceway, Almirall, Spirig, Intendis, Meda, Abbott, and LEO.

BOSTON – Decreased expression of the PTPN13 gene is associated with improved survival of patients with head and neck squamous cell carcinoma positive for the human papillomavirus, a small retrospective study suggests.

Dr. George F. Harris IV of the University of Iowa, Iowa City, and his colleagues examined the correlation of human papillomavirus (HPV) status; protein tyrosine phosphatase, nonreceptor type 13 (PTPN13) status, and survival over 10 years in 21 patients for whom tissues samples were available for analysis. The patients, identified from University of Iowa Health Care (UIHC) Oncology Registry, were diagnosed with oropharyngeal head and neck squamous cell carcinoma (HNSCC) in 1995.

All 21 patients had HPV-positive cancer – 9 with decreased PTPN13 expression and 12 with unchanged or increased expression of PTPN13. Average survival was approximately 105 months in the low-PTPN13 group vs. 61 months in patients with unchanged or increased PTPN13 expression, Dr. Harris reported at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery.

"An average increase in survival of about 30 months was seen for those patients who had decreased expression of PTPN13 within the tumor," he stated.

Looking at demographics, the investigators found that patients in the "decrease" group were younger at diagnosis but had more advanced disease. Observed Dr. Harris, "These may be confounding variables, but the finding is consistent with other authors' experience with HPV-associated H&N cancer in general."

The investigators employed real-time polymerase chain reaction (RT-PCR) to detect HPV type and activity. Dr. Harris said they used immunohistochemistry to evaluate the status of PTPN13, which has been shown to have a physiologically significant role in regulating mitogen-activated protein (MAP) kinase signaling. The identification and activity of HPV was confirmed by increased p16 immunochemical staining – an accepted marker for HPV activity because, in oropharyngeal HNSCC, HPV integration induces an overexpression of P16, he noted.

The improved survival observed among HPV positive HNSCC patients with decreased PTPN13 expression may be related to the fact that PTPN13 degradation is associated with fewer genetic changes than stable or elevated PTPN13 expression, according to Dr. Harris. It is possible that analyzing PTPN13 status in HPV-positive HNSCC "may identify those patients that will have better survival or, conversely, those patients who may require additional treatment," he said.

Dr. Harris reported having no conflicts of interest with respect to this presentation.

BOSTON – Decreased expression of the PTPN13 gene is associated with improved survival of patients with head and neck squamous cell carcinoma positive for the human papillomavirus, a small retrospective study suggests.

Dr. George F. Harris IV of the University of Iowa, Iowa City, and his colleagues examined the correlation of human papillomavirus (HPV) status; protein tyrosine phosphatase, nonreceptor type 13 (PTPN13) status, and survival over 10 years in 21 patients for whom tissues samples were available for analysis. The patients, identified from University of Iowa Health Care (UIHC) Oncology Registry, were diagnosed with oropharyngeal head and neck squamous cell carcinoma (HNSCC) in 1995.

All 21 patients had HPV-positive cancer – 9 with decreased PTPN13 expression and 12 with unchanged or increased expression of PTPN13. Average survival was approximately 105 months in the low-PTPN13 group vs. 61 months in patients with unchanged or increased PTPN13 expression, Dr. Harris reported at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery.

"An average increase in survival of about 30 months was seen for those patients who had decreased expression of PTPN13 within the tumor," he stated.

Looking at demographics, the investigators found that patients in the "decrease" group were younger at diagnosis but had more advanced disease. Observed Dr. Harris, "These may be confounding variables, but the finding is consistent with other authors' experience with HPV-associated H&N cancer in general."

The investigators employed real-time polymerase chain reaction (RT-PCR) to detect HPV type and activity. Dr. Harris said they used immunohistochemistry to evaluate the status of PTPN13, which has been shown to have a physiologically significant role in regulating mitogen-activated protein (MAP) kinase signaling. The identification and activity of HPV was confirmed by increased p16 immunochemical staining – an accepted marker for HPV activity because, in oropharyngeal HNSCC, HPV integration induces an overexpression of P16, he noted.

The improved survival observed among HPV positive HNSCC patients with decreased PTPN13 expression may be related to the fact that PTPN13 degradation is associated with fewer genetic changes than stable or elevated PTPN13 expression, according to Dr. Harris. It is possible that analyzing PTPN13 status in HPV-positive HNSCC "may identify those patients that will have better survival or, conversely, those patients who may require additional treatment," he said.

Dr. Harris reported having no conflicts of interest with respect to this presentation.

BOSTON – Decreased expression of the PTPN13 gene is associated with improved survival of patients with head and neck squamous cell carcinoma positive for the human papillomavirus, a small retrospective study suggests.

Dr. George F. Harris IV of the University of Iowa, Iowa City, and his colleagues examined the correlation of human papillomavirus (HPV) status; protein tyrosine phosphatase, nonreceptor type 13 (PTPN13) status, and survival over 10 years in 21 patients for whom tissues samples were available for analysis. The patients, identified from University of Iowa Health Care (UIHC) Oncology Registry, were diagnosed with oropharyngeal head and neck squamous cell carcinoma (HNSCC) in 1995.

All 21 patients had HPV-positive cancer – 9 with decreased PTPN13 expression and 12 with unchanged or increased expression of PTPN13. Average survival was approximately 105 months in the low-PTPN13 group vs. 61 months in patients with unchanged or increased PTPN13 expression, Dr. Harris reported at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery.

"An average increase in survival of about 30 months was seen for those patients who had decreased expression of PTPN13 within the tumor," he stated.

Looking at demographics, the investigators found that patients in the "decrease" group were younger at diagnosis but had more advanced disease. Observed Dr. Harris, "These may be confounding variables, but the finding is consistent with other authors' experience with HPV-associated H&N cancer in general."

The investigators employed real-time polymerase chain reaction (RT-PCR) to detect HPV type and activity. Dr. Harris said they used immunohistochemistry to evaluate the status of PTPN13, which has been shown to have a physiologically significant role in regulating mitogen-activated protein (MAP) kinase signaling. The identification and activity of HPV was confirmed by increased p16 immunochemical staining – an accepted marker for HPV activity because, in oropharyngeal HNSCC, HPV integration induces an overexpression of P16, he noted.

The improved survival observed among HPV positive HNSCC patients with decreased PTPN13 expression may be related to the fact that PTPN13 degradation is associated with fewer genetic changes than stable or elevated PTPN13 expression, according to Dr. Harris. It is possible that analyzing PTPN13 status in HPV-positive HNSCC "may identify those patients that will have better survival or, conversely, those patients who may require additional treatment," he said.

Dr. Harris reported having no conflicts of interest with respect to this presentation.

MILAN – Hope for patients with melanoma who develop brain metastases may be on the horizon with the finding that a novel targeted agent reduces the size of multiple brain lesions.

Data from a phase I/II study in 10 patients show that all but one of the participants treated with the oral agent GSK2118436 experienced a partial or complete response, with overall reductions in the size of brain metastases ranging from -20% to -100%.

"These are extremely promising results," said Dr. Caroline Robert of Institut Gustave-Roussy, Villejuif, France, who was asked to comment on the study at the annual congress of the European Society for Medical Oncology.

GSK2118436 inhibits a specific mutation (V600) in the BRAF gene that is present in around 50% of melanomas and "locks BRAF into its active conformation," study investigator Dr. Georgina V. Long explained. The researcher, from Melanoma Institute Australia and Westmead Hospital in Sydney, added that the mutation enhances cancer cells' ability to proliferate, grow, and survive and that GSK2118436 disrupts this unwanted activity.

The positive effect of the novel agent in treating brain metastases was first seen about a year ago, Dr. Long said in an interview: "We had an inkling at the end of 2009, and that's when we really pushed to do a formal, prospective study of the brain cohort."

The melanoma brain cohort consisted of 10 patients with one or more brain lesions of at least 3 mm in size who were asymptomatic and who had not received any prior treatment specifically for their brain lesions. The median age of recruited patients was 59 years, 90% had the V600E mutation in the BRAF gene, and 30% had more than three brain metastases.

Gadolinium-enhanced and T1-weighted magnetic resonance imaging showed that twice-daily oral dosing (150 mg) of GSK2118436 resulted in reductions in brain lesions that correlated to extracranial tumor responses.

The tolerability was very similar to that presented recently at the American Society of Clinical Oncology (J. Clin. Oncol. 2010;28(15s):Abstr 8503). Grade 3/4 adverse events reported in the brain cohort included pyrexia/chills, fatigue, dehydration, nausea, in one patient each, and anemia in two patients.

Patients remained on treatment for a relatively short period of time, however, and it is too early to tell if GSK2118436 is likely to have any effect on the very poor overall survival of patients who develop brain metastases, which is currently around 16 weeks from the time that brain involvement in diagnosed.

"We need to do the phase II study in more patients to get better data," Dr. Long said. A phase II trial has already been started in patients who do not have brain metastases, now it is time to set up a similar trial in those that do, she added.

The phase II brain cohort trial should start recruitment early in 2011 and accruing enough patients should not be an issue. "In melanoma, brain metastases is a major problem; 15%-20% of patients have them at baseline, and nearly three-quarters develop them eventually. It is the cancer where brain metastases are a major problem, more so than any other cancer," commented Dr. Long.

Dr. Long's travel expenses to present the study data were paid for by GlaxoSmithKline, the study's sponsor. She also participated in a phase I advisory board in 2009. Dr. Long's coauthors have received consultancy fees and research report from the company, and three were current employees of GSK with stock ownership. Dr. Robert had no relevant conflicts of interest.

MILAN – Hope for patients with melanoma who develop brain metastases may be on the horizon with the finding that a novel targeted agent reduces the size of multiple brain lesions.

Data from a phase I/II study in 10 patients show that all but one of the participants treated with the oral agent GSK2118436 experienced a partial or complete response, with overall reductions in the size of brain metastases ranging from -20% to -100%.

"These are extremely promising results," said Dr. Caroline Robert of Institut Gustave-Roussy, Villejuif, France, who was asked to comment on the study at the annual congress of the European Society for Medical Oncology.

GSK2118436 inhibits a specific mutation (V600) in the BRAF gene that is present in around 50% of melanomas and "locks BRAF into its active conformation," study investigator Dr. Georgina V. Long explained. The researcher, from Melanoma Institute Australia and Westmead Hospital in Sydney, added that the mutation enhances cancer cells' ability to proliferate, grow, and survive and that GSK2118436 disrupts this unwanted activity.

The positive effect of the novel agent in treating brain metastases was first seen about a year ago, Dr. Long said in an interview: "We had an inkling at the end of 2009, and that's when we really pushed to do a formal, prospective study of the brain cohort."

The melanoma brain cohort consisted of 10 patients with one or more brain lesions of at least 3 mm in size who were asymptomatic and who had not received any prior treatment specifically for their brain lesions. The median age of recruited patients was 59 years, 90% had the V600E mutation in the BRAF gene, and 30% had more than three brain metastases.

Gadolinium-enhanced and T1-weighted magnetic resonance imaging showed that twice-daily oral dosing (150 mg) of GSK2118436 resulted in reductions in brain lesions that correlated to extracranial tumor responses.

The tolerability was very similar to that presented recently at the American Society of Clinical Oncology (J. Clin. Oncol. 2010;28(15s):Abstr 8503). Grade 3/4 adverse events reported in the brain cohort included pyrexia/chills, fatigue, dehydration, nausea, in one patient each, and anemia in two patients.

Patients remained on treatment for a relatively short period of time, however, and it is too early to tell if GSK2118436 is likely to have any effect on the very poor overall survival of patients who develop brain metastases, which is currently around 16 weeks from the time that brain involvement in diagnosed.

"We need to do the phase II study in more patients to get better data," Dr. Long said. A phase II trial has already been started in patients who do not have brain metastases, now it is time to set up a similar trial in those that do, she added.

The phase II brain cohort trial should start recruitment early in 2011 and accruing enough patients should not be an issue. "In melanoma, brain metastases is a major problem; 15%-20% of patients have them at baseline, and nearly three-quarters develop them eventually. It is the cancer where brain metastases are a major problem, more so than any other cancer," commented Dr. Long.

Dr. Long's travel expenses to present the study data were paid for by GlaxoSmithKline, the study's sponsor. She also participated in a phase I advisory board in 2009. Dr. Long's coauthors have received consultancy fees and research report from the company, and three were current employees of GSK with stock ownership. Dr. Robert had no relevant conflicts of interest.

MILAN – Hope for patients with melanoma who develop brain metastases may be on the horizon with the finding that a novel targeted agent reduces the size of multiple brain lesions.

Data from a phase I/II study in 10 patients show that all but one of the participants treated with the oral agent GSK2118436 experienced a partial or complete response, with overall reductions in the size of brain metastases ranging from -20% to -100%.

"These are extremely promising results," said Dr. Caroline Robert of Institut Gustave-Roussy, Villejuif, France, who was asked to comment on the study at the annual congress of the European Society for Medical Oncology.

GSK2118436 inhibits a specific mutation (V600) in the BRAF gene that is present in around 50% of melanomas and "locks BRAF into its active conformation," study investigator Dr. Georgina V. Long explained. The researcher, from Melanoma Institute Australia and Westmead Hospital in Sydney, added that the mutation enhances cancer cells' ability to proliferate, grow, and survive and that GSK2118436 disrupts this unwanted activity.

The positive effect of the novel agent in treating brain metastases was first seen about a year ago, Dr. Long said in an interview: "We had an inkling at the end of 2009, and that's when we really pushed to do a formal, prospective study of the brain cohort."

The melanoma brain cohort consisted of 10 patients with one or more brain lesions of at least 3 mm in size who were asymptomatic and who had not received any prior treatment specifically for their brain lesions. The median age of recruited patients was 59 years, 90% had the V600E mutation in the BRAF gene, and 30% had more than three brain metastases.

Gadolinium-enhanced and T1-weighted magnetic resonance imaging showed that twice-daily oral dosing (150 mg) of GSK2118436 resulted in reductions in brain lesions that correlated to extracranial tumor responses.

The tolerability was very similar to that presented recently at the American Society of Clinical Oncology (J. Clin. Oncol. 2010;28(15s):Abstr 8503). Grade 3/4 adverse events reported in the brain cohort included pyrexia/chills, fatigue, dehydration, nausea, in one patient each, and anemia in two patients.

Patients remained on treatment for a relatively short period of time, however, and it is too early to tell if GSK2118436 is likely to have any effect on the very poor overall survival of patients who develop brain metastases, which is currently around 16 weeks from the time that brain involvement in diagnosed.

"We need to do the phase II study in more patients to get better data," Dr. Long said. A phase II trial has already been started in patients who do not have brain metastases, now it is time to set up a similar trial in those that do, she added.

The phase II brain cohort trial should start recruitment early in 2011 and accruing enough patients should not be an issue. "In melanoma, brain metastases is a major problem; 15%-20% of patients have them at baseline, and nearly three-quarters develop them eventually. It is the cancer where brain metastases are a major problem, more so than any other cancer," commented Dr. Long.

Dr. Long's travel expenses to present the study data were paid for by GlaxoSmithKline, the study's sponsor. She also participated in a phase I advisory board in 2009. Dr. Long's coauthors have received consultancy fees and research report from the company, and three were current employees of GSK with stock ownership. Dr. Robert had no relevant conflicts of interest.

A hand-held, computerized imaging device identified 98% of melanomas in a set of suspicious pigmented skin lesions, according to results published online in the Archives of Dermatology.

The study findings were also published online on Skin & Allergy News Digital Network on May 6, 2010 (AAD: Digital Dermoscopy Device Detects Melanoma).

Results of the automated device – MelaFind from MELA Sciences Inc. – were compared with dermatologists who examined a subset of lesions from the same group, for a 78% identification rate. On lesions that had been previously biopsied to rule out melanoma, MelaFind's average specificity was 10%, significantly better than the 3.7% rate of dermatologists.

The device's 98% sensitivity rating for malignant melanoma was significantly better than that of dermatologists, who showed a wide range of variability about which lesions would have been recommended for biopsy and which relegated to observation, Dr. Gary Monheit and his colleagues reported (Arch. Dermatol. 2010 [doi:10.1001/archdermatol.2010.302]).

The study compared MelaFind's performance on a group of 1,632 lesions with a reading study of 50 lesions randomly extracted from the same set. All of the lesions had been biopsied by the patients’ attending dermatologists.

Lesion data, including the clinical overview and close-up and dermatoscopy images, were provided to 39 dermatologists, who were blinded to the biopsy results. The dermatologists evaluated which lesions they believed should be biopsied as probable melanoma and which should be followed clinically, wrote Dr. Monheit, a dermatologist in private practice in Birmingham, Ala., and his coauthors. The lesion samples came from a group of 1,257 patients whose mean age was 46 years. Most (98%) were white.

The MelaFind study's primary end point was the device’s sensitivity and specificity for lesions classified before biopsy as "melanoma cannot be ruled out" or as "not melanoma." After reviewing each lesion, MelaFind generated one of two conclusions: positive (biopsy) or negative (follow clinically).

Pigmented nevi made up the bulk of the lesion group (77%; 1,258), with 61% being low-grade dysplasia. Another 15% of the lesions were nonmelanocytic. Melanomas accounted for 8% of the group (127), with 57 in situ and 70 invasive; however, the invasive lesions were mostly thin, with a median thickness of 0.36 mm. Only two were relatively thick (1.0 mm and 1.2 mm). "Thus," the investigators noted, "almost all melanomas in this trial were early lesions that are difficult to differentiate from benign simulants."

Other components of the group included keratoses (119), lentigos (76), pigmented basal and squamous cell carcinomas (33), and other lesions (14).

In the reader study, the average biopsy sensitivity of the 39 dermatologists was 78%. However, the authors noted, the inter-reader variability was high. "Only 5 of the 25 melanomas would have been biopsied by all readers, and different readers missed different melanomas." Since all of the lesions had previously been biopsied, the paper did not compare clinician and MelaFind biopsy ratios. However, the authors noted, historical biopsy ratios among dermatologists are about 8:1 for the general population and up to 47:1 for high-risk patients.

The authors concluded that the device could be a valuable tool in accurately assessing pigmented lesions – an area that is largely dependent on clinicians’ individual observations and conclusions.

In a statement from MELA Sciences, coauthor Dr. Kenneth Gross stressed the need for an objective tool in the biopsy decision-making process.

"The pilot reader study found that dermatologists do miss early melanomas," said Dr. Gross, who practices surgical dermatology in San Diego. "Only 20% of the melanomas in the pilot reader study would have been biopsied by all readers and different readers missed different melanomas. Thus, even though all lesions in the clinical trial were biopsied by the examining dermatologists, many of the melanomas would not have been biopsied by other dermatologists, underscoring the need for an objective tool to aid in the decision to biopsy. We believe that the results of the pivotal trial and the pilot reader study underscore the clinical utility of MelaFind as an objective tool to aid clinicians in the detection of early melanoma."

The Food and Drug Administration will consider MelaFind on Nov. 18, during the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee meeting. The committee will make recommendations and vote on data related to the device's premarket approval.

According to the company Web site, MelaFind is a hand-held device that acquires and displays multispectral digital images from blue to near-infrared, for pigmented skin lesions. The computerized device uses automatic image analysis and statistical pattern recognition to help identify lesions that should be considered for biopsy to rule out melanoma. The device consists of an illuminator that produces light in 10 wavelengths, a lens system that creates the images, a light sensor, and an image processor that identifies discrete characteristics of each picture.

MELA Sciences sponsored the study. Dr. Monheit and 7 of the other 15 investigators are on the MELA Sciences Advisory Committee. Dr. Gross did not disclose any financial relationship with the company.

A hand-held, computerized imaging device identified 98% of melanomas in a set of suspicious pigmented skin lesions, according to results published online in the Archives of Dermatology.

The study findings were also published online on Skin & Allergy News Digital Network on May 6, 2010 (AAD: Digital Dermoscopy Device Detects Melanoma).

Results of the automated device – MelaFind from MELA Sciences Inc. – were compared with dermatologists who examined a subset of lesions from the same group, for a 78% identification rate. On lesions that had been previously biopsied to rule out melanoma, MelaFind's average specificity was 10%, significantly better than the 3.7% rate of dermatologists.

The device's 98% sensitivity rating for malignant melanoma was significantly better than that of dermatologists, who showed a wide range of variability about which lesions would have been recommended for biopsy and which relegated to observation, Dr. Gary Monheit and his colleagues reported (Arch. Dermatol. 2010 [doi:10.1001/archdermatol.2010.302]).

The study compared MelaFind's performance on a group of 1,632 lesions with a reading study of 50 lesions randomly extracted from the same set. All of the lesions had been biopsied by the patients’ attending dermatologists.

Lesion data, including the clinical overview and close-up and dermatoscopy images, were provided to 39 dermatologists, who were blinded to the biopsy results. The dermatologists evaluated which lesions they believed should be biopsied as probable melanoma and which should be followed clinically, wrote Dr. Monheit, a dermatologist in private practice in Birmingham, Ala., and his coauthors. The lesion samples came from a group of 1,257 patients whose mean age was 46 years. Most (98%) were white.

The MelaFind study's primary end point was the device’s sensitivity and specificity for lesions classified before biopsy as "melanoma cannot be ruled out" or as "not melanoma." After reviewing each lesion, MelaFind generated one of two conclusions: positive (biopsy) or negative (follow clinically).

Pigmented nevi made up the bulk of the lesion group (77%; 1,258), with 61% being low-grade dysplasia. Another 15% of the lesions were nonmelanocytic. Melanomas accounted for 8% of the group (127), with 57 in situ and 70 invasive; however, the invasive lesions were mostly thin, with a median thickness of 0.36 mm. Only two were relatively thick (1.0 mm and 1.2 mm). "Thus," the investigators noted, "almost all melanomas in this trial were early lesions that are difficult to differentiate from benign simulants."

Other components of the group included keratoses (119), lentigos (76), pigmented basal and squamous cell carcinomas (33), and other lesions (14).

In the reader study, the average biopsy sensitivity of the 39 dermatologists was 78%. However, the authors noted, the inter-reader variability was high. "Only 5 of the 25 melanomas would have been biopsied by all readers, and different readers missed different melanomas." Since all of the lesions had previously been biopsied, the paper did not compare clinician and MelaFind biopsy ratios. However, the authors noted, historical biopsy ratios among dermatologists are about 8:1 for the general population and up to 47:1 for high-risk patients.

The authors concluded that the device could be a valuable tool in accurately assessing pigmented lesions – an area that is largely dependent on clinicians’ individual observations and conclusions.

In a statement from MELA Sciences, coauthor Dr. Kenneth Gross stressed the need for an objective tool in the biopsy decision-making process.

"The pilot reader study found that dermatologists do miss early melanomas," said Dr. Gross, who practices surgical dermatology in San Diego. "Only 20% of the melanomas in the pilot reader study would have been biopsied by all readers and different readers missed different melanomas. Thus, even though all lesions in the clinical trial were biopsied by the examining dermatologists, many of the melanomas would not have been biopsied by other dermatologists, underscoring the need for an objective tool to aid in the decision to biopsy. We believe that the results of the pivotal trial and the pilot reader study underscore the clinical utility of MelaFind as an objective tool to aid clinicians in the detection of early melanoma."

The Food and Drug Administration will consider MelaFind on Nov. 18, during the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee meeting. The committee will make recommendations and vote on data related to the device's premarket approval.

According to the company Web site, MelaFind is a hand-held device that acquires and displays multispectral digital images from blue to near-infrared, for pigmented skin lesions. The computerized device uses automatic image analysis and statistical pattern recognition to help identify lesions that should be considered for biopsy to rule out melanoma. The device consists of an illuminator that produces light in 10 wavelengths, a lens system that creates the images, a light sensor, and an image processor that identifies discrete characteristics of each picture.

MELA Sciences sponsored the study. Dr. Monheit and 7 of the other 15 investigators are on the MELA Sciences Advisory Committee. Dr. Gross did not disclose any financial relationship with the company.

A hand-held, computerized imaging device identified 98% of melanomas in a set of suspicious pigmented skin lesions, according to results published online in the Archives of Dermatology.

The study findings were also published online on Skin & Allergy News Digital Network on May 6, 2010 (AAD: Digital Dermoscopy Device Detects Melanoma).

Results of the automated device – MelaFind from MELA Sciences Inc. – were compared with dermatologists who examined a subset of lesions from the same group, for a 78% identification rate. On lesions that had been previously biopsied to rule out melanoma, MelaFind's average specificity was 10%, significantly better than the 3.7% rate of dermatologists.

The device's 98% sensitivity rating for malignant melanoma was significantly better than that of dermatologists, who showed a wide range of variability about which lesions would have been recommended for biopsy and which relegated to observation, Dr. Gary Monheit and his colleagues reported (Arch. Dermatol. 2010 [doi:10.1001/archdermatol.2010.302]).

The study compared MelaFind's performance on a group of 1,632 lesions with a reading study of 50 lesions randomly extracted from the same set. All of the lesions had been biopsied by the patients’ attending dermatologists.

Lesion data, including the clinical overview and close-up and dermatoscopy images, were provided to 39 dermatologists, who were blinded to the biopsy results. The dermatologists evaluated which lesions they believed should be biopsied as probable melanoma and which should be followed clinically, wrote Dr. Monheit, a dermatologist in private practice in Birmingham, Ala., and his coauthors. The lesion samples came from a group of 1,257 patients whose mean age was 46 years. Most (98%) were white.

The MelaFind study's primary end point was the device’s sensitivity and specificity for lesions classified before biopsy as "melanoma cannot be ruled out" or as "not melanoma." After reviewing each lesion, MelaFind generated one of two conclusions: positive (biopsy) or negative (follow clinically).

Pigmented nevi made up the bulk of the lesion group (77%; 1,258), with 61% being low-grade dysplasia. Another 15% of the lesions were nonmelanocytic. Melanomas accounted for 8% of the group (127), with 57 in situ and 70 invasive; however, the invasive lesions were mostly thin, with a median thickness of 0.36 mm. Only two were relatively thick (1.0 mm and 1.2 mm). "Thus," the investigators noted, "almost all melanomas in this trial were early lesions that are difficult to differentiate from benign simulants."

Other components of the group included keratoses (119), lentigos (76), pigmented basal and squamous cell carcinomas (33), and other lesions (14).

In the reader study, the average biopsy sensitivity of the 39 dermatologists was 78%. However, the authors noted, the inter-reader variability was high. "Only 5 of the 25 melanomas would have been biopsied by all readers, and different readers missed different melanomas." Since all of the lesions had previously been biopsied, the paper did not compare clinician and MelaFind biopsy ratios. However, the authors noted, historical biopsy ratios among dermatologists are about 8:1 for the general population and up to 47:1 for high-risk patients.

The authors concluded that the device could be a valuable tool in accurately assessing pigmented lesions – an area that is largely dependent on clinicians’ individual observations and conclusions.

In a statement from MELA Sciences, coauthor Dr. Kenneth Gross stressed the need for an objective tool in the biopsy decision-making process.

"The pilot reader study found that dermatologists do miss early melanomas," said Dr. Gross, who practices surgical dermatology in San Diego. "Only 20% of the melanomas in the pilot reader study would have been biopsied by all readers and different readers missed different melanomas. Thus, even though all lesions in the clinical trial were biopsied by the examining dermatologists, many of the melanomas would not have been biopsied by other dermatologists, underscoring the need for an objective tool to aid in the decision to biopsy. We believe that the results of the pivotal trial and the pilot reader study underscore the clinical utility of MelaFind as an objective tool to aid clinicians in the detection of early melanoma."

The Food and Drug Administration will consider MelaFind on Nov. 18, during the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee meeting. The committee will make recommendations and vote on data related to the device's premarket approval.

According to the company Web site, MelaFind is a hand-held device that acquires and displays multispectral digital images from blue to near-infrared, for pigmented skin lesions. The computerized device uses automatic image analysis and statistical pattern recognition to help identify lesions that should be considered for biopsy to rule out melanoma. The device consists of an illuminator that produces light in 10 wavelengths, a lens system that creates the images, a light sensor, and an image processor that identifies discrete characteristics of each picture.

MELA Sciences sponsored the study. Dr. Monheit and 7 of the other 15 investigators are on the MELA Sciences Advisory Committee. Dr. Gross did not disclose any financial relationship with the company.

GOTHENBURG, Sweden - Patients with a history of chronic lymphocytic leukemia have an elevated risk of developing malignant melanoma of a particularly aggressive nature.

A new analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry demonstrates that individuals with a history of chronic lymphocytic leukemia (CLL) are at 2.5-fold increased risk of subsequently developing melanoma. And once they do, these patients have an adjusted 2.7-fold greater 10-year all-cause mortality and a 2.8-fold increased mortality caused by melanoma, compared with melanoma patients without prior CLL, Dr. Jerry D. Brewer reported at the annual congress of the European Academy of Dermatology and Venereology .

"Melanoma and CLL is a dangerously common association with bad outcomes," said Dr. Brewer, a dermatologic surgeon at the Mayo Clinic, Rochester, Minn.

The pattern of worse outcomes in melanoma patients with a history of CLL was significant across all categories of Breslow tumor depth and Clark's level, but it was most striking in patients with thicker lesions. For example, melanoma patients with a Breslow depth greater than 4.0 mm had a 2-year overall survival rate of just 36% if they had a history of prior CLL, compared with 71% if they did not. Their 2-year melanoma-specific survival was 50% with prior CLL and 82% without such a history.

These findings have important implications for clinical practice, according to the dermatologist. For example, patients with CLL have to get serious about daily sun protection, and they need to learn how to do regular skin self-examinations.

"We also need to educate our professional colleagues, specifically our hematologists/oncologists, that if their patients with CLL have a lot of moles or a lot of risk factors for melanoma, they should consider referring those patients to a dermatologist sooner, to catch melanomas earlier," he continued.

The population-based study included 212,245 melanoma patients in the SEER database in the years 1990-2006. Among them were 1,246 patients with a prior diagnosis of lymphoma, of which 31% were CLL. Those diagnosed with melanoma after CLL were on average 12 years older than patients diagnosed with melanoma without prior CLL, a difference adjusted for in determining standardized mortality ratios.

The 10-year overall survival in patients diagnosed with melanoma preceded by CLL was 19%, compared with an expected 55% if they had no history of prior CLL. The 10-year melanoma-specific survival rates were 62% with a prior diagnosis of CLL and 84% without.

Other investigators have previously reported higher rates of metastasis and worse survival in patients with squamous cell carcinoma or Merkel cell carcinoma preceded by CLL. "Now we know that’s true for melanoma, too," Dr. Brewer said.

The impetus for the SEER study was an earlier small study he and his coinvestigators conducted involving 69 Mayo Clinic patients with CLL and melanoma. They found worse outcomes in patients who had CLL prior to melanoma than in those diagnosed with melanoma prior to CLL (Dermatol. Surg. 2010;36:368-76).

One case in that series that particularly impressed Dr. Brewer involved a documented metastasis in a patient with a history of CLL prior to diagnosis of melanoma in situ. This was a melanoma in situ without an inflammatory infiltrate, so there was no confusion about the lesion's true depth. It was unmistakably a melanoma in situ, yet after standard therapy it recurred and metastasized.

Like patients with a history of CLL, organ transplant recipients are also at increased risk of aggressive skin cancers. Theories abound as to why immunosuppression, whether caused by lymphoma or organ transplantation, should have this effect. Among the proposed explanations are decreased immune surveillance, direct carcinogenesis caused by chemotherapeutic agents or antitransplant-rejection drugs, and an increased rate of infections with human papillomavirus.

However, Dr. Brewer thinks the most likely explanation involves a shared underlying genetic predisposition. Patients with CLL are rife with genetic aberrations. For example, 7%-10% of patients with CLL have a deletion mutation at 17 p.

"That's where the p53 gene is, which is the strongest predictor of poor survival in patients with CLL, with a median survival of only 32 months. Maybe these patients also have a higher risk of developing aggressive skin cancer; that’s something we just don't know yet," he noted.

Another genetic aberration worthy of further study involves the proto-oncogene B-cell lymphoma 2 (Bcl-2), which suppresses apoptosis. Bcl-2 expression is elevated in 95% of patients with CLL and in 90% of melanoma patients. Intriguingly, the antisense oligonucleotide oblimersen, which is targeted at Bcl-2, has shown encouraging results in combination with dacarbazine in patients with advanced melanoma (Eur. J. Cancer 2009;45:1807-14).

"Maybe that’s something we should consider using in patients with CLL," Dr. Brewer observed.

He argued that a high degree of suspicion is warranted regarding potential tumor recurrence in melanoma patients with a history of CLL. This may warrant more frequent follow-up, a low threshold for biopsy of suspicious lesions, and perhaps a lower bar for adjuvant chemotherapy.

"Perhaps we should consider doing a sentinel lymph node biopsy more often in thinner melanomas in patients with prior CLL. If they have a higher chance of metastasis, then maybe they have a higher chance of sentinel node involvement with thinner melanomas. There is [a lot] of speculation at this point, a lot more questions than answers," he said.

He declared having no financial conflicts, noting that his research on lymphoma-related skin cancer has been funded mainly by the Dermatology Foundation.

GOTHENBURG, Sweden - Patients with a history of chronic lymphocytic leukemia have an elevated risk of developing malignant melanoma of a particularly aggressive nature.

A new analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry demonstrates that individuals with a history of chronic lymphocytic leukemia (CLL) are at 2.5-fold increased risk of subsequently developing melanoma. And once they do, these patients have an adjusted 2.7-fold greater 10-year all-cause mortality and a 2.8-fold increased mortality caused by melanoma, compared with melanoma patients without prior CLL, Dr. Jerry D. Brewer reported at the annual congress of the European Academy of Dermatology and Venereology .

"Melanoma and CLL is a dangerously common association with bad outcomes," said Dr. Brewer, a dermatologic surgeon at the Mayo Clinic, Rochester, Minn.

The pattern of worse outcomes in melanoma patients with a history of CLL was significant across all categories of Breslow tumor depth and Clark's level, but it was most striking in patients with thicker lesions. For example, melanoma patients with a Breslow depth greater than 4.0 mm had a 2-year overall survival rate of just 36% if they had a history of prior CLL, compared with 71% if they did not. Their 2-year melanoma-specific survival was 50% with prior CLL and 82% without such a history.

These findings have important implications for clinical practice, according to the dermatologist. For example, patients with CLL have to get serious about daily sun protection, and they need to learn how to do regular skin self-examinations.

"We also need to educate our professional colleagues, specifically our hematologists/oncologists, that if their patients with CLL have a lot of moles or a lot of risk factors for melanoma, they should consider referring those patients to a dermatologist sooner, to catch melanomas earlier," he continued.

The population-based study included 212,245 melanoma patients in the SEER database in the years 1990-2006. Among them were 1,246 patients with a prior diagnosis of lymphoma, of which 31% were CLL. Those diagnosed with melanoma after CLL were on average 12 years older than patients diagnosed with melanoma without prior CLL, a difference adjusted for in determining standardized mortality ratios.

The 10-year overall survival in patients diagnosed with melanoma preceded by CLL was 19%, compared with an expected 55% if they had no history of prior CLL. The 10-year melanoma-specific survival rates were 62% with a prior diagnosis of CLL and 84% without.

Other investigators have previously reported higher rates of metastasis and worse survival in patients with squamous cell carcinoma or Merkel cell carcinoma preceded by CLL. "Now we know that’s true for melanoma, too," Dr. Brewer said.

The impetus for the SEER study was an earlier small study he and his coinvestigators conducted involving 69 Mayo Clinic patients with CLL and melanoma. They found worse outcomes in patients who had CLL prior to melanoma than in those diagnosed with melanoma prior to CLL (Dermatol. Surg. 2010;36:368-76).

One case in that series that particularly impressed Dr. Brewer involved a documented metastasis in a patient with a history of CLL prior to diagnosis of melanoma in situ. This was a melanoma in situ without an inflammatory infiltrate, so there was no confusion about the lesion's true depth. It was unmistakably a melanoma in situ, yet after standard therapy it recurred and metastasized.

Like patients with a history of CLL, organ transplant recipients are also at increased risk of aggressive skin cancers. Theories abound as to why immunosuppression, whether caused by lymphoma or organ transplantation, should have this effect. Among the proposed explanations are decreased immune surveillance, direct carcinogenesis caused by chemotherapeutic agents or antitransplant-rejection drugs, and an increased rate of infections with human papillomavirus.

However, Dr. Brewer thinks the most likely explanation involves a shared underlying genetic predisposition. Patients with CLL are rife with genetic aberrations. For example, 7%-10% of patients with CLL have a deletion mutation at 17 p.

"That's where the p53 gene is, which is the strongest predictor of poor survival in patients with CLL, with a median survival of only 32 months. Maybe these patients also have a higher risk of developing aggressive skin cancer; that’s something we just don't know yet," he noted.

Another genetic aberration worthy of further study involves the proto-oncogene B-cell lymphoma 2 (Bcl-2), which suppresses apoptosis. Bcl-2 expression is elevated in 95% of patients with CLL and in 90% of melanoma patients. Intriguingly, the antisense oligonucleotide oblimersen, which is targeted at Bcl-2, has shown encouraging results in combination with dacarbazine in patients with advanced melanoma (Eur. J. Cancer 2009;45:1807-14).

"Maybe that’s something we should consider using in patients with CLL," Dr. Brewer observed.

He argued that a high degree of suspicion is warranted regarding potential tumor recurrence in melanoma patients with a history of CLL. This may warrant more frequent follow-up, a low threshold for biopsy of suspicious lesions, and perhaps a lower bar for adjuvant chemotherapy.

"Perhaps we should consider doing a sentinel lymph node biopsy more often in thinner melanomas in patients with prior CLL. If they have a higher chance of metastasis, then maybe they have a higher chance of sentinel node involvement with thinner melanomas. There is [a lot] of speculation at this point, a lot more questions than answers," he said.

He declared having no financial conflicts, noting that his research on lymphoma-related skin cancer has been funded mainly by the Dermatology Foundation.

GOTHENBURG, Sweden - Patients with a history of chronic lymphocytic leukemia have an elevated risk of developing malignant melanoma of a particularly aggressive nature.

A new analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry demonstrates that individuals with a history of chronic lymphocytic leukemia (CLL) are at 2.5-fold increased risk of subsequently developing melanoma. And once they do, these patients have an adjusted 2.7-fold greater 10-year all-cause mortality and a 2.8-fold increased mortality caused by melanoma, compared with melanoma patients without prior CLL, Dr. Jerry D. Brewer reported at the annual congress of the European Academy of Dermatology and Venereology .

"Melanoma and CLL is a dangerously common association with bad outcomes," said Dr. Brewer, a dermatologic surgeon at the Mayo Clinic, Rochester, Minn.

The pattern of worse outcomes in melanoma patients with a history of CLL was significant across all categories of Breslow tumor depth and Clark's level, but it was most striking in patients with thicker lesions. For example, melanoma patients with a Breslow depth greater than 4.0 mm had a 2-year overall survival rate of just 36% if they had a history of prior CLL, compared with 71% if they did not. Their 2-year melanoma-specific survival was 50% with prior CLL and 82% without such a history.

These findings have important implications for clinical practice, according to the dermatologist. For example, patients with CLL have to get serious about daily sun protection, and they need to learn how to do regular skin self-examinations.

"We also need to educate our professional colleagues, specifically our hematologists/oncologists, that if their patients with CLL have a lot of moles or a lot of risk factors for melanoma, they should consider referring those patients to a dermatologist sooner, to catch melanomas earlier," he continued.

The population-based study included 212,245 melanoma patients in the SEER database in the years 1990-2006. Among them were 1,246 patients with a prior diagnosis of lymphoma, of which 31% were CLL. Those diagnosed with melanoma after CLL were on average 12 years older than patients diagnosed with melanoma without prior CLL, a difference adjusted for in determining standardized mortality ratios.

The 10-year overall survival in patients diagnosed with melanoma preceded by CLL was 19%, compared with an expected 55% if they had no history of prior CLL. The 10-year melanoma-specific survival rates were 62% with a prior diagnosis of CLL and 84% without.

Other investigators have previously reported higher rates of metastasis and worse survival in patients with squamous cell carcinoma or Merkel cell carcinoma preceded by CLL. "Now we know that’s true for melanoma, too," Dr. Brewer said.

The impetus for the SEER study was an earlier small study he and his coinvestigators conducted involving 69 Mayo Clinic patients with CLL and melanoma. They found worse outcomes in patients who had CLL prior to melanoma than in those diagnosed with melanoma prior to CLL (Dermatol. Surg. 2010;36:368-76).

One case in that series that particularly impressed Dr. Brewer involved a documented metastasis in a patient with a history of CLL prior to diagnosis of melanoma in situ. This was a melanoma in situ without an inflammatory infiltrate, so there was no confusion about the lesion's true depth. It was unmistakably a melanoma in situ, yet after standard therapy it recurred and metastasized.

Like patients with a history of CLL, organ transplant recipients are also at increased risk of aggressive skin cancers. Theories abound as to why immunosuppression, whether caused by lymphoma or organ transplantation, should have this effect. Among the proposed explanations are decreased immune surveillance, direct carcinogenesis caused by chemotherapeutic agents or antitransplant-rejection drugs, and an increased rate of infections with human papillomavirus.

However, Dr. Brewer thinks the most likely explanation involves a shared underlying genetic predisposition. Patients with CLL are rife with genetic aberrations. For example, 7%-10% of patients with CLL have a deletion mutation at 17 p.

"That's where the p53 gene is, which is the strongest predictor of poor survival in patients with CLL, with a median survival of only 32 months. Maybe these patients also have a higher risk of developing aggressive skin cancer; that’s something we just don't know yet," he noted.

Another genetic aberration worthy of further study involves the proto-oncogene B-cell lymphoma 2 (Bcl-2), which suppresses apoptosis. Bcl-2 expression is elevated in 95% of patients with CLL and in 90% of melanoma patients. Intriguingly, the antisense oligonucleotide oblimersen, which is targeted at Bcl-2, has shown encouraging results in combination with dacarbazine in patients with advanced melanoma (Eur. J. Cancer 2009;45:1807-14).

"Maybe that’s something we should consider using in patients with CLL," Dr. Brewer observed.

He argued that a high degree of suspicion is warranted regarding potential tumor recurrence in melanoma patients with a history of CLL. This may warrant more frequent follow-up, a low threshold for biopsy of suspicious lesions, and perhaps a lower bar for adjuvant chemotherapy.

"Perhaps we should consider doing a sentinel lymph node biopsy more often in thinner melanomas in patients with prior CLL. If they have a higher chance of metastasis, then maybe they have a higher chance of sentinel node involvement with thinner melanomas. There is [a lot] of speculation at this point, a lot more questions than answers," he said.

He declared having no financial conflicts, noting that his research on lymphoma-related skin cancer has been funded mainly by the Dermatology Foundation.