Melanoma

AMSTERDAM — The natural history of actinic keratoses involves high turnover and far greater lability than generally recognized, according to a first-of-its-kind study.

"When you count three or four AKs on a person at time zero and come back and find three or four at time one you may think you're looking at the same AKs, but this study shows you're not. You're probably looking at six or seven different AKs—three have regressed and three others have taken their place," Dr. Adele C. Green said at the 11th World Congress on Cancers of the Skin.

Indeed, she compared AKs to whitecaps arising in a sea of dysplastic skin, then ebbing below the point of detection before reforming.

"It's striking how high the turnover is. This is such a dynamic population. The more frequently you look at patients and count their AKs, the more turnover you see," added Dr. Green, head of the cancer and population studies group at the Queensland Institute of Medical Research, Brisbane, Australia.

The other impressive finding from this AK substudy—conducted within the larger prospective, longitudinal, community-based Nambour Skin Cancer Study—was that a small percentage of individuals carry a disproportionate load of the total AK burden. While the risk that any individual AK will transform into invasive nonmelanoma skin cancer is extremely low, the high total AK count in this heavily burdened subgroup identifies affected individuals as being at high risk.

The AK substudy involved 96 randomly selected adults, equally divided between men and women, who underwent detailed skin examinations every 2–6 months during which every AK was stenciled onto a clear plastic-wrap body map for purposes of lesion comparison over time.

At baseline, 53 of the 96 participants had no prevalent AKs, while the other 43 had a total of 494 lesions. Twelve percent of subjects had 65% of all prevalent AKs.

During the first 12 months of follow-up, 549 new AKs occurred in men and just 65 in women. Meanwhile, 526 prevalent AKs regressed and 53 prevalent AKs regressed and then recurred. The result was a 1-year net 45% increase in the number of AKs in men and a 44% net decrease in women. Seventy-four percent of prevalent AKs regressed, as did 29% of incident AKs.

Participants with baseline AKs were more than sevenfold more likely to develop additional AKs in the next year, Dr. Green noted at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.

The clinical relevance of these findings about the natural history of AKs hinges on the fact that the full 1,621-subject Nambour study showed that regular use of a broad-spectrum sunscreen markedly reduced the incidence of both AKs and invasive squamous cell carcinomas. Since AKs arise and regress so frequently in a field of sun-damaged skin and there is no way to identify which ones will transform into skin cancer, it's illogical to treat individual lesions with cryotherapy, as many dermatologists persist in doing, she continued.

This argument struck a responsive chord with other speakers. "For field cancerization, we need field therapy," agreed Dr. Tobias Forschner of the skin cancer center at Charité University Hospital, Berlin.

"We have lots of treatment options—I would say an armada," Dr. Forschner added, citing the intense commercial interest in field therapy using photodynamic therapy, imiquimod, diclofenac, and 5-fluorouracil.

AMSTERDAM — The natural history of actinic keratoses involves high turnover and far greater lability than generally recognized, according to a first-of-its-kind study.

"When you count three or four AKs on a person at time zero and come back and find three or four at time one you may think you're looking at the same AKs, but this study shows you're not. You're probably looking at six or seven different AKs—three have regressed and three others have taken their place," Dr. Adele C. Green said at the 11th World Congress on Cancers of the Skin.

Indeed, she compared AKs to whitecaps arising in a sea of dysplastic skin, then ebbing below the point of detection before reforming.

"It's striking how high the turnover is. This is such a dynamic population. The more frequently you look at patients and count their AKs, the more turnover you see," added Dr. Green, head of the cancer and population studies group at the Queensland Institute of Medical Research, Brisbane, Australia.

The other impressive finding from this AK substudy—conducted within the larger prospective, longitudinal, community-based Nambour Skin Cancer Study—was that a small percentage of individuals carry a disproportionate load of the total AK burden. While the risk that any individual AK will transform into invasive nonmelanoma skin cancer is extremely low, the high total AK count in this heavily burdened subgroup identifies affected individuals as being at high risk.

The AK substudy involved 96 randomly selected adults, equally divided between men and women, who underwent detailed skin examinations every 2–6 months during which every AK was stenciled onto a clear plastic-wrap body map for purposes of lesion comparison over time.

At baseline, 53 of the 96 participants had no prevalent AKs, while the other 43 had a total of 494 lesions. Twelve percent of subjects had 65% of all prevalent AKs.

During the first 12 months of follow-up, 549 new AKs occurred in men and just 65 in women. Meanwhile, 526 prevalent AKs regressed and 53 prevalent AKs regressed and then recurred. The result was a 1-year net 45% increase in the number of AKs in men and a 44% net decrease in women. Seventy-four percent of prevalent AKs regressed, as did 29% of incident AKs.

Participants with baseline AKs were more than sevenfold more likely to develop additional AKs in the next year, Dr. Green noted at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.

The clinical relevance of these findings about the natural history of AKs hinges on the fact that the full 1,621-subject Nambour study showed that regular use of a broad-spectrum sunscreen markedly reduced the incidence of both AKs and invasive squamous cell carcinomas. Since AKs arise and regress so frequently in a field of sun-damaged skin and there is no way to identify which ones will transform into skin cancer, it's illogical to treat individual lesions with cryotherapy, as many dermatologists persist in doing, she continued.

This argument struck a responsive chord with other speakers. "For field cancerization, we need field therapy," agreed Dr. Tobias Forschner of the skin cancer center at Charité University Hospital, Berlin.

"We have lots of treatment options—I would say an armada," Dr. Forschner added, citing the intense commercial interest in field therapy using photodynamic therapy, imiquimod, diclofenac, and 5-fluorouracil.

AMSTERDAM — The natural history of actinic keratoses involves high turnover and far greater lability than generally recognized, according to a first-of-its-kind study.

"When you count three or four AKs on a person at time zero and come back and find three or four at time one you may think you're looking at the same AKs, but this study shows you're not. You're probably looking at six or seven different AKs—three have regressed and three others have taken their place," Dr. Adele C. Green said at the 11th World Congress on Cancers of the Skin.

Indeed, she compared AKs to whitecaps arising in a sea of dysplastic skin, then ebbing below the point of detection before reforming.

"It's striking how high the turnover is. This is such a dynamic population. The more frequently you look at patients and count their AKs, the more turnover you see," added Dr. Green, head of the cancer and population studies group at the Queensland Institute of Medical Research, Brisbane, Australia.

The other impressive finding from this AK substudy—conducted within the larger prospective, longitudinal, community-based Nambour Skin Cancer Study—was that a small percentage of individuals carry a disproportionate load of the total AK burden. While the risk that any individual AK will transform into invasive nonmelanoma skin cancer is extremely low, the high total AK count in this heavily burdened subgroup identifies affected individuals as being at high risk.

The AK substudy involved 96 randomly selected adults, equally divided between men and women, who underwent detailed skin examinations every 2–6 months during which every AK was stenciled onto a clear plastic-wrap body map for purposes of lesion comparison over time.

At baseline, 53 of the 96 participants had no prevalent AKs, while the other 43 had a total of 494 lesions. Twelve percent of subjects had 65% of all prevalent AKs.

During the first 12 months of follow-up, 549 new AKs occurred in men and just 65 in women. Meanwhile, 526 prevalent AKs regressed and 53 prevalent AKs regressed and then recurred. The result was a 1-year net 45% increase in the number of AKs in men and a 44% net decrease in women. Seventy-four percent of prevalent AKs regressed, as did 29% of incident AKs.

Participants with baseline AKs were more than sevenfold more likely to develop additional AKs in the next year, Dr. Green noted at the congress, cosponsored by the Skin Cancer Foundation and Erasmus University.

The clinical relevance of these findings about the natural history of AKs hinges on the fact that the full 1,621-subject Nambour study showed that regular use of a broad-spectrum sunscreen markedly reduced the incidence of both AKs and invasive squamous cell carcinomas. Since AKs arise and regress so frequently in a field of sun-damaged skin and there is no way to identify which ones will transform into skin cancer, it's illogical to treat individual lesions with cryotherapy, as many dermatologists persist in doing, she continued.

This argument struck a responsive chord with other speakers. "For field cancerization, we need field therapy," agreed Dr. Tobias Forschner of the skin cancer center at Charité University Hospital, Berlin.

"We have lots of treatment options—I would say an armada," Dr. Forschner added, citing the intense commercial interest in field therapy using photodynamic therapy, imiquimod, diclofenac, and 5-fluorouracil.

AMSTERDAM — Recent European guidelines classifying actinic keratoses as in situ squamous cell carcinoma came under fire in a panel discussion at the 11th World Congress on Cancers of the Skin.

"Since our histopathologist started calling AKs carcinoma in situ I've had four patients in my outpatient clinic crying because they were given the diagnosis of cancer. They had to wait 3 weeks for a follow-up appointment to have somebody explain the situation to them, and it was 3 weeks of hell. They were afraid of dying. So I think from the patient's point of view this classification is a big mistake," said Dr. Alexis Sidoroff of the Medical University of Innsbruck (Austria).

Dr. Eggert Stockfleth, lead author of the published guidelines (Eur. J. Dermatol. 2006;16:599–606) developed by the European Dermatology Forum and accepted by the Union of European Medical Specialists, defended the classification scheme on the basis of the histopathologic changes and genetic mutations shared by actinic keratoses (AKs) and squamous cell carcinomas (SCCs).

"Actinic keratosis is an early stage of cancer. It is not a precursor lesion," declared Dr. Stockfleth, director of the skin cancer clinic at Charité University Hospital, Berlin.

With the incidence of nonmelanoma skin cancer climbing worldwide by 7%–10% per year, the guidelines committee felt that routine treatment of AKs is warranted to combat the problem, he said.

Dr. Irene Leigh, however, argued that categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. The chance that any individual AK will transform into invasive SCC is extremely low, so it is better to view AKs as markers of increased risk of SCC. These AKs arise and often regress in a field of sun-damaged, dysplastic skin that is undergoing a process called field cancerization or simply field change, out of which most SCCs arise, she said.

"I don't call these lesions carcinoma in situ. I call them AKs. I don't think every AK is going to progress to squamous cell carcinoma. There's evidence for regression of AKs, and there's not much evidence for anything else," said Dr. Leigh of the University of Dundee (Scotland).

Dr. Hywel Williams expanded on this theme. "We are dealing with a field change. Surely what we see physically is like mushrooms in a mycelium of squamous metaplasia. The mushrooms pop up and others go down. To me, the idea that by freezing or otherwise treating a single lesion of AK we're dealing with the problem seems delusional," said Dr. Williams, professor of dermatology at the University of Nottingham (England).

"We are still in 2007 deluding ourselves about the value of destructive therapies for visible lesions and playing into the agenda of an enormous industry with vested interest in maintaining this ritual that we have," he added at the congress cosponsored by the Skin Cancer Foundation and Erasmus University, Rotterdam, the Netherlands.

Dr. Jean-Jacques Grob agreed that the case for routinely treating AKs to prevent SCC is weak in immunocompetent patients. Nor is there any persuasive evidence as yet that invasive SCCs can be prevented by treating the field cancerization process itself, although clinical trials involving imiquimod, photodynamic therapy, and other treatments are ongoing, noted Dr. Grob, professor of dermatology at the University of Marseille (France).

"Let's face it, aside from a few studies showing regular use of sunscreens prevents AKs, the field is a mess," Dr. Williams agreed. "There's a shocking lack of good-quality evidence to inform the debate. That's especially painful to see in a condition as common as this."

Categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. DR. LEIGH

AMSTERDAM — Recent European guidelines classifying actinic keratoses as in situ squamous cell carcinoma came under fire in a panel discussion at the 11th World Congress on Cancers of the Skin.

"Since our histopathologist started calling AKs carcinoma in situ I've had four patients in my outpatient clinic crying because they were given the diagnosis of cancer. They had to wait 3 weeks for a follow-up appointment to have somebody explain the situation to them, and it was 3 weeks of hell. They were afraid of dying. So I think from the patient's point of view this classification is a big mistake," said Dr. Alexis Sidoroff of the Medical University of Innsbruck (Austria).

Dr. Eggert Stockfleth, lead author of the published guidelines (Eur. J. Dermatol. 2006;16:599–606) developed by the European Dermatology Forum and accepted by the Union of European Medical Specialists, defended the classification scheme on the basis of the histopathologic changes and genetic mutations shared by actinic keratoses (AKs) and squamous cell carcinomas (SCCs).

"Actinic keratosis is an early stage of cancer. It is not a precursor lesion," declared Dr. Stockfleth, director of the skin cancer clinic at Charité University Hospital, Berlin.

With the incidence of nonmelanoma skin cancer climbing worldwide by 7%–10% per year, the guidelines committee felt that routine treatment of AKs is warranted to combat the problem, he said.

Dr. Irene Leigh, however, argued that categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. The chance that any individual AK will transform into invasive SCC is extremely low, so it is better to view AKs as markers of increased risk of SCC. These AKs arise and often regress in a field of sun-damaged, dysplastic skin that is undergoing a process called field cancerization or simply field change, out of which most SCCs arise, she said.

"I don't call these lesions carcinoma in situ. I call them AKs. I don't think every AK is going to progress to squamous cell carcinoma. There's evidence for regression of AKs, and there's not much evidence for anything else," said Dr. Leigh of the University of Dundee (Scotland).

Dr. Hywel Williams expanded on this theme. "We are dealing with a field change. Surely what we see physically is like mushrooms in a mycelium of squamous metaplasia. The mushrooms pop up and others go down. To me, the idea that by freezing or otherwise treating a single lesion of AK we're dealing with the problem seems delusional," said Dr. Williams, professor of dermatology at the University of Nottingham (England).

"We are still in 2007 deluding ourselves about the value of destructive therapies for visible lesions and playing into the agenda of an enormous industry with vested interest in maintaining this ritual that we have," he added at the congress cosponsored by the Skin Cancer Foundation and Erasmus University, Rotterdam, the Netherlands.

Dr. Jean-Jacques Grob agreed that the case for routinely treating AKs to prevent SCC is weak in immunocompetent patients. Nor is there any persuasive evidence as yet that invasive SCCs can be prevented by treating the field cancerization process itself, although clinical trials involving imiquimod, photodynamic therapy, and other treatments are ongoing, noted Dr. Grob, professor of dermatology at the University of Marseille (France).

"Let's face it, aside from a few studies showing regular use of sunscreens prevents AKs, the field is a mess," Dr. Williams agreed. "There's a shocking lack of good-quality evidence to inform the debate. That's especially painful to see in a condition as common as this."

Categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. DR. LEIGH

AMSTERDAM — Recent European guidelines classifying actinic keratoses as in situ squamous cell carcinoma came under fire in a panel discussion at the 11th World Congress on Cancers of the Skin.

"Since our histopathologist started calling AKs carcinoma in situ I've had four patients in my outpatient clinic crying because they were given the diagnosis of cancer. They had to wait 3 weeks for a follow-up appointment to have somebody explain the situation to them, and it was 3 weeks of hell. They were afraid of dying. So I think from the patient's point of view this classification is a big mistake," said Dr. Alexis Sidoroff of the Medical University of Innsbruck (Austria).

Dr. Eggert Stockfleth, lead author of the published guidelines (Eur. J. Dermatol. 2006;16:599–606) developed by the European Dermatology Forum and accepted by the Union of European Medical Specialists, defended the classification scheme on the basis of the histopathologic changes and genetic mutations shared by actinic keratoses (AKs) and squamous cell carcinomas (SCCs).

"Actinic keratosis is an early stage of cancer. It is not a precursor lesion," declared Dr. Stockfleth, director of the skin cancer clinic at Charité University Hospital, Berlin.

With the incidence of nonmelanoma skin cancer climbing worldwide by 7%–10% per year, the guidelines committee felt that routine treatment of AKs is warranted to combat the problem, he said.

Dr. Irene Leigh, however, argued that categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. The chance that any individual AK will transform into invasive SCC is extremely low, so it is better to view AKs as markers of increased risk of SCC. These AKs arise and often regress in a field of sun-damaged, dysplastic skin that is undergoing a process called field cancerization or simply field change, out of which most SCCs arise, she said.

"I don't call these lesions carcinoma in situ. I call them AKs. I don't think every AK is going to progress to squamous cell carcinoma. There's evidence for regression of AKs, and there's not much evidence for anything else," said Dr. Leigh of the University of Dundee (Scotland).

Dr. Hywel Williams expanded on this theme. "We are dealing with a field change. Surely what we see physically is like mushrooms in a mycelium of squamous metaplasia. The mushrooms pop up and others go down. To me, the idea that by freezing or otherwise treating a single lesion of AK we're dealing with the problem seems delusional," said Dr. Williams, professor of dermatology at the University of Nottingham (England).

"We are still in 2007 deluding ourselves about the value of destructive therapies for visible lesions and playing into the agenda of an enormous industry with vested interest in maintaining this ritual that we have," he added at the congress cosponsored by the Skin Cancer Foundation and Erasmus University, Rotterdam, the Netherlands.

Dr. Jean-Jacques Grob agreed that the case for routinely treating AKs to prevent SCC is weak in immunocompetent patients. Nor is there any persuasive evidence as yet that invasive SCCs can be prevented by treating the field cancerization process itself, although clinical trials involving imiquimod, photodynamic therapy, and other treatments are ongoing, noted Dr. Grob, professor of dermatology at the University of Marseille (France).

"Let's face it, aside from a few studies showing regular use of sunscreens prevents AKs, the field is a mess," Dr. Williams agreed. "There's a shocking lack of good-quality evidence to inform the debate. That's especially painful to see in a condition as common as this."

Categorizing AKs as carcinoma in situ implies an inevitability of progression that bears no relation to reality. DR. LEIGH

LOS ANGELES — The proportion of skin excisions for malignant lesions relative to benign lesions increased between 1993 and 2002, Dr. Marta J. Van Beek said at the annual meeting of the Society for Investigational Dermatology.

That finding "is something that we weren't really expecting to see," said Dr. Van Beek of the University of Iowa, Iowa City.

She and her associates studied CPT data between 1993 and 2002 from a random sample of 5% of Medicare recipients living in nine regions covered by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database.

They weren't surprised to find increasing numbers over time for skin biopsies, shave removals, excisions, and other dermatologic procedures, given the rising incidence of skin cancer. In clinical practice, however, a certain number of benign lesions are biopsied over time to ensure complete ascertainment of malignancies. If clinical thresholds for a skin biopsy remain constant, it would be reasonable to expect a constant ratio of benign to malignant episodes of care over time, even in the setting of an increasing incidence of skin cancer, she explained.

Instead, the rate of benign excisions decreased from 45 per 1,000 Medicare beneficiaries in 1993 to 30/1,000 in 2002, Dr. Van Beek said. Malignant excisions increased from 25/1,000 to 27/1,000 in that period.

Skin biopsies increased from 55/1,000 to 90/1,000 beneficiaries, shave removals increased from 22/1,000 to 38/1,000, and Mohs procedures jumped from 5/1,000 to 11/1,000 beneficiaries.

Since some biopsies or lesion removals are performed not because of suspected cancer but for diagnosis of inflammatory eruptions, or because patients find lesions irritating or unsightly, Dr. Van Beek and her associates created categories that they called malignant, benign, or unknown "episodes of care." The ratio of malignant to benign episodes of care increased from 1.4 in 1993 to 2.2 in 2002, indicating a surge in malignant episodes of care.

Besides the rising incidence of cancer, factors that may have influenced these trends in health care utilization include access to specialist care and changes in coding and billing practices.

LOS ANGELES — The proportion of skin excisions for malignant lesions relative to benign lesions increased between 1993 and 2002, Dr. Marta J. Van Beek said at the annual meeting of the Society for Investigational Dermatology.

That finding "is something that we weren't really expecting to see," said Dr. Van Beek of the University of Iowa, Iowa City.

She and her associates studied CPT data between 1993 and 2002 from a random sample of 5% of Medicare recipients living in nine regions covered by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database.

They weren't surprised to find increasing numbers over time for skin biopsies, shave removals, excisions, and other dermatologic procedures, given the rising incidence of skin cancer. In clinical practice, however, a certain number of benign lesions are biopsied over time to ensure complete ascertainment of malignancies. If clinical thresholds for a skin biopsy remain constant, it would be reasonable to expect a constant ratio of benign to malignant episodes of care over time, even in the setting of an increasing incidence of skin cancer, she explained.

Instead, the rate of benign excisions decreased from 45 per 1,000 Medicare beneficiaries in 1993 to 30/1,000 in 2002, Dr. Van Beek said. Malignant excisions increased from 25/1,000 to 27/1,000 in that period.

Skin biopsies increased from 55/1,000 to 90/1,000 beneficiaries, shave removals increased from 22/1,000 to 38/1,000, and Mohs procedures jumped from 5/1,000 to 11/1,000 beneficiaries.

Since some biopsies or lesion removals are performed not because of suspected cancer but for diagnosis of inflammatory eruptions, or because patients find lesions irritating or unsightly, Dr. Van Beek and her associates created categories that they called malignant, benign, or unknown "episodes of care." The ratio of malignant to benign episodes of care increased from 1.4 in 1993 to 2.2 in 2002, indicating a surge in malignant episodes of care.

Besides the rising incidence of cancer, factors that may have influenced these trends in health care utilization include access to specialist care and changes in coding and billing practices.

LOS ANGELES — The proportion of skin excisions for malignant lesions relative to benign lesions increased between 1993 and 2002, Dr. Marta J. Van Beek said at the annual meeting of the Society for Investigational Dermatology.

That finding "is something that we weren't really expecting to see," said Dr. Van Beek of the University of Iowa, Iowa City.

She and her associates studied CPT data between 1993 and 2002 from a random sample of 5% of Medicare recipients living in nine regions covered by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database.

They weren't surprised to find increasing numbers over time for skin biopsies, shave removals, excisions, and other dermatologic procedures, given the rising incidence of skin cancer. In clinical practice, however, a certain number of benign lesions are biopsied over time to ensure complete ascertainment of malignancies. If clinical thresholds for a skin biopsy remain constant, it would be reasonable to expect a constant ratio of benign to malignant episodes of care over time, even in the setting of an increasing incidence of skin cancer, she explained.

Instead, the rate of benign excisions decreased from 45 per 1,000 Medicare beneficiaries in 1993 to 30/1,000 in 2002, Dr. Van Beek said. Malignant excisions increased from 25/1,000 to 27/1,000 in that period.

Skin biopsies increased from 55/1,000 to 90/1,000 beneficiaries, shave removals increased from 22/1,000 to 38/1,000, and Mohs procedures jumped from 5/1,000 to 11/1,000 beneficiaries.

Since some biopsies or lesion removals are performed not because of suspected cancer but for diagnosis of inflammatory eruptions, or because patients find lesions irritating or unsightly, Dr. Van Beek and her associates created categories that they called malignant, benign, or unknown "episodes of care." The ratio of malignant to benign episodes of care increased from 1.4 in 1993 to 2.2 in 2002, indicating a surge in malignant episodes of care.

Besides the rising incidence of cancer, factors that may have influenced these trends in health care utilization include access to specialist care and changes in coding and billing practices.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Is Gleevec a reasonable therapeutic choice for melanoma?

The question has gotten a fair bit of research attention over the last few years, and for a few specific types of melanoma the outlook is cautiously optimistic, Dr. Philip LeBoit said at the American Academy of Dermatology's summer academy 2007 conference.

Gleevec (imatinib mesylate) will probably not become a first-line therapy for cutaneous melanoma, but it may work for mucosal melanomas, acral melanomas, and others that share genetic similarities to the sort of gastrointestinal lesions that have been highly responsive to this landmark drug. A number of case reports point in this direction, said Dr. LeBoit of the departments of pathology and dermatology at the University of California, San Francisco.

Gleevec was the breakthrough agent representing a class of drugs that target protein tyrosine kinase (PTK), an enzyme that plays an essential role in the proliferation and migration of many kinds of cancer cells. Gleevec-responsive tumors tend to have specific genetic profiles, showing mutations of the c-kit and abl genes, among others.

The drug has been particularly effective against GI stromal tumors, which have distinct c-kit mutations. The good news is that as dermatopathologists and molecular biologists explore genetic profiles of various kinds of skin cancers, they are finding that some melanoma types, especially mucosal melanomas, share these c-kit mutations, said Dr. LeBoit, who has no financial relationship with Novartis, the manufacturer of Gleevec.

"Mucosal melanomas have a lot of c-kit mutations. These tumors are almost impossible to resect. They may be candidates for Gleevec or second-generation drugs of that class," he said. Most mucosal melanomas are positive for c-kit mutations, as are roughly one-third of all cutaneous melanomas.

Dermatopathologists at the M.D. Anderson Cancer Center, Houston, studied before- and after-treatment biopsy specimens from 13 patients with malignant melanoma who were given Gleevec at a dose of 400 mg twice daily for 2 weeks. The drug produced a significant decrease in PTK expression in the tumor tissue, as well as a reduction in the number of malignant melanocytes and the intensity of their proliferation (J. Cutan. Pathol. 2006;33:280–5). The investigators noted that one of the 13 patients showed a "durable clinical response."

Brazilian researchers looked at the impact of Gleevec in tissue samples from uveal melanomas, the most common intraocular form of melanoma. Nearly 80% of the 55 tumors examined were positive for c-kit mutations. Gleevec reduced proliferation of the tumor cells in culture (J. Carcinog. 2005;4:19).

A recent phase II trial, however, showed little clinical impact from Gleevec therapy for cutaneous melanomas (Cancer 2006;106:2005–11).

Dr. Lynn Schuchter of the University of Pennsylvania, Philadelphia, is currently studying Gleevec in combination with temozolomide in 63 patients with advanced melanoma, Dr. LeBoit said. So far, the toxicity profile suggests that the PTK inhibitor is a viable adjunct with no significant added side-effect burden. Clinical outcomes data are not yet available.

It may be that Gleevec only works in tumors with very specific genetic profiles, and the key is to identify tumor susceptibility before treatment, in a way analogous to antibiotic susceptibility testing for microbial pathogens. This, said Dr. LeBoit, is the general trend in cancer therapy: the application of tools like immunohistochemistry and comparative genomic hybridization to subclassify tumors based on their genetic features.

"Cancer is fundamentally a disease of the genome. Something has to be wrong with the cells' DNA. Most cancer cells have gains or losses of whole chromosomes or major parts of chromosomes," he noted.

A few years ago, dermatopathologists were dependent almost exclusively on microscopy because there simply were no practical molecular diagnostic tools, but that scenario is changing fast. Diagnosis of skin cancers like melanoma "is not a simple positive-or-negative, yes-or-no process. We really need to get into the nuclei of cells to see what is going on," Dr. LeBoit said.

NEW YORK — Is Gleevec a reasonable therapeutic choice for melanoma?

The question has gotten a fair bit of research attention over the last few years, and for a few specific types of melanoma the outlook is cautiously optimistic, Dr. Philip LeBoit said at the American Academy of Dermatology's summer academy 2007 conference.

Gleevec (imatinib mesylate) will probably not become a first-line therapy for cutaneous melanoma, but it may work for mucosal melanomas, acral melanomas, and others that share genetic similarities to the sort of gastrointestinal lesions that have been highly responsive to this landmark drug. A number of case reports point in this direction, said Dr. LeBoit of the departments of pathology and dermatology at the University of California, San Francisco.

Gleevec was the breakthrough agent representing a class of drugs that target protein tyrosine kinase (PTK), an enzyme that plays an essential role in the proliferation and migration of many kinds of cancer cells. Gleevec-responsive tumors tend to have specific genetic profiles, showing mutations of the c-kit and abl genes, among others.

The drug has been particularly effective against GI stromal tumors, which have distinct c-kit mutations. The good news is that as dermatopathologists and molecular biologists explore genetic profiles of various kinds of skin cancers, they are finding that some melanoma types, especially mucosal melanomas, share these c-kit mutations, said Dr. LeBoit, who has no financial relationship with Novartis, the manufacturer of Gleevec.

"Mucosal melanomas have a lot of c-kit mutations. These tumors are almost impossible to resect. They may be candidates for Gleevec or second-generation drugs of that class," he said. Most mucosal melanomas are positive for c-kit mutations, as are roughly one-third of all cutaneous melanomas.

Dermatopathologists at the M.D. Anderson Cancer Center, Houston, studied before- and after-treatment biopsy specimens from 13 patients with malignant melanoma who were given Gleevec at a dose of 400 mg twice daily for 2 weeks. The drug produced a significant decrease in PTK expression in the tumor tissue, as well as a reduction in the number of malignant melanocytes and the intensity of their proliferation (J. Cutan. Pathol. 2006;33:280–5). The investigators noted that one of the 13 patients showed a "durable clinical response."

Brazilian researchers looked at the impact of Gleevec in tissue samples from uveal melanomas, the most common intraocular form of melanoma. Nearly 80% of the 55 tumors examined were positive for c-kit mutations. Gleevec reduced proliferation of the tumor cells in culture (J. Carcinog. 2005;4:19).

A recent phase II trial, however, showed little clinical impact from Gleevec therapy for cutaneous melanomas (Cancer 2006;106:2005–11).

Dr. Lynn Schuchter of the University of Pennsylvania, Philadelphia, is currently studying Gleevec in combination with temozolomide in 63 patients with advanced melanoma, Dr. LeBoit said. So far, the toxicity profile suggests that the PTK inhibitor is a viable adjunct with no significant added side-effect burden. Clinical outcomes data are not yet available.

It may be that Gleevec only works in tumors with very specific genetic profiles, and the key is to identify tumor susceptibility before treatment, in a way analogous to antibiotic susceptibility testing for microbial pathogens. This, said Dr. LeBoit, is the general trend in cancer therapy: the application of tools like immunohistochemistry and comparative genomic hybridization to subclassify tumors based on their genetic features.

"Cancer is fundamentally a disease of the genome. Something has to be wrong with the cells' DNA. Most cancer cells have gains or losses of whole chromosomes or major parts of chromosomes," he noted.

A few years ago, dermatopathologists were dependent almost exclusively on microscopy because there simply were no practical molecular diagnostic tools, but that scenario is changing fast. Diagnosis of skin cancers like melanoma "is not a simple positive-or-negative, yes-or-no process. We really need to get into the nuclei of cells to see what is going on," Dr. LeBoit said.

NEW YORK — Is Gleevec a reasonable therapeutic choice for melanoma?

The question has gotten a fair bit of research attention over the last few years, and for a few specific types of melanoma the outlook is cautiously optimistic, Dr. Philip LeBoit said at the American Academy of Dermatology's summer academy 2007 conference.

Gleevec (imatinib mesylate) will probably not become a first-line therapy for cutaneous melanoma, but it may work for mucosal melanomas, acral melanomas, and others that share genetic similarities to the sort of gastrointestinal lesions that have been highly responsive to this landmark drug. A number of case reports point in this direction, said Dr. LeBoit of the departments of pathology and dermatology at the University of California, San Francisco.

Gleevec was the breakthrough agent representing a class of drugs that target protein tyrosine kinase (PTK), an enzyme that plays an essential role in the proliferation and migration of many kinds of cancer cells. Gleevec-responsive tumors tend to have specific genetic profiles, showing mutations of the c-kit and abl genes, among others.

The drug has been particularly effective against GI stromal tumors, which have distinct c-kit mutations. The good news is that as dermatopathologists and molecular biologists explore genetic profiles of various kinds of skin cancers, they are finding that some melanoma types, especially mucosal melanomas, share these c-kit mutations, said Dr. LeBoit, who has no financial relationship with Novartis, the manufacturer of Gleevec.

"Mucosal melanomas have a lot of c-kit mutations. These tumors are almost impossible to resect. They may be candidates for Gleevec or second-generation drugs of that class," he said. Most mucosal melanomas are positive for c-kit mutations, as are roughly one-third of all cutaneous melanomas.

Dermatopathologists at the M.D. Anderson Cancer Center, Houston, studied before- and after-treatment biopsy specimens from 13 patients with malignant melanoma who were given Gleevec at a dose of 400 mg twice daily for 2 weeks. The drug produced a significant decrease in PTK expression in the tumor tissue, as well as a reduction in the number of malignant melanocytes and the intensity of their proliferation (J. Cutan. Pathol. 2006;33:280–5). The investigators noted that one of the 13 patients showed a "durable clinical response."

Brazilian researchers looked at the impact of Gleevec in tissue samples from uveal melanomas, the most common intraocular form of melanoma. Nearly 80% of the 55 tumors examined were positive for c-kit mutations. Gleevec reduced proliferation of the tumor cells in culture (J. Carcinog. 2005;4:19).

A recent phase II trial, however, showed little clinical impact from Gleevec therapy for cutaneous melanomas (Cancer 2006;106:2005–11).

Dr. Lynn Schuchter of the University of Pennsylvania, Philadelphia, is currently studying Gleevec in combination with temozolomide in 63 patients with advanced melanoma, Dr. LeBoit said. So far, the toxicity profile suggests that the PTK inhibitor is a viable adjunct with no significant added side-effect burden. Clinical outcomes data are not yet available.

It may be that Gleevec only works in tumors with very specific genetic profiles, and the key is to identify tumor susceptibility before treatment, in a way analogous to antibiotic susceptibility testing for microbial pathogens. This, said Dr. LeBoit, is the general trend in cancer therapy: the application of tools like immunohistochemistry and comparative genomic hybridization to subclassify tumors based on their genetic features.

"Cancer is fundamentally a disease of the genome. Something has to be wrong with the cells' DNA. Most cancer cells have gains or losses of whole chromosomes or major parts of chromosomes," he noted.

A few years ago, dermatopathologists were dependent almost exclusively on microscopy because there simply were no practical molecular diagnostic tools, but that scenario is changing fast. Diagnosis of skin cancers like melanoma "is not a simple positive-or-negative, yes-or-no process. We really need to get into the nuclei of cells to see what is going on," Dr. LeBoit said.

TORONTO — "Survival of the fittest" might be the best way to explain the genetic and molecular machinery behind cancer metastasis.

Researchers believe that overexpression of some genes in melanoma and other cancers allows some cells to survive the very harsh conditions that occur as they leave a primary tumor, travel to a distant site, and establish a new location for malignancy. "It is a similar theme to Darwin with natural selection, although it works out in a microenvironment," Dr. Youwen Zhou said.

"Why do I think this is a big deal? We still do not have a cure for metastatic melanoma, and next year another 900 or so patients [in Canada] will die from melanoma," Dr. Zhou said.

Melanoma was the sixth most common solid cancer for men in Canada in 2005 and 2006. There were 3,900 new cases last year. Of 840 deaths in 2006 from melanoma, 90% involved metastatic disease, said Dr. Zhou, who is on the faculty in the department of dermatology and skin science at the University of British Columbia, Vancouver.

There are some reasons for optimism, however. Understanding the molecular machinery might permit earlier intervention through better diagnostic or prognostic tools, Dr. Zhou said at the annual conference of the Canadian Dermatology Association.

Serum protein testing, for example, might lead to more accurate estimates of prognosis. The melanoma-inhibiting activity (MIA) protein is detected in high amounts in 100% of patients with metastatic melanoma so far. "About 20% of patients with primary melanoma will have signs of this protein in their serum. If they are negative for MIA protein, not one of them developed metastasis over time," he said.

Genetic insights also may lead to new therapeutic targets. "Selective gene silencing may work to cause metastatic cells to die," Dr. Zhou said.

So how do invasive tumors develop? Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment distant from the primary tumor (Cell 2006;127:679–95).

Other investigators have identified individual genes that are amplified in metastatic melanoma (Cell 2006;125:1269–81).

A high degree of heterogeneity in melanoma tumor cells may in part explain why aggressive gene clones arise.

"If you look at a melanoma clinically, it has signs of molecular and cellular heterogeneity, for example, irregular borders. On a cellular level, pathologists use variation in cell size as a diagnostic factor," he said.

Dominant genetic clones can cause a higher resistance to apoptosis, greater tolerance to hypoxia and nutrient deprivation, altered cell adherence, and increased genomic instability.

The vast majority of the most aberrantly upregulated genes work in concert to modify the microenvironment to their advantage.

Before these breakaway cells become "little tumor thrombi," they must break through local physical barriers, he explained. They do this in part by degrading the collagen matrix. Then they have to overcome the vascular wall and survive the harsh sheering and other forces of the vasculature.

Some will survive intravasation with the right molecular defense mechanisms. Extravasation occurs when they arrive at a destination, change adhesion properties, and again pass through the vascular wall. Finally, the cells must continue to defend themselves against host defenses for distant colonization to be successful, Dr. Zhou said.

Development of novel targeting strategies against this genetic and molecular machinery is needed, he said. Once those strategies are identified, the next step would be large scale trials to assess these therapeutic targets.

TORONTO — "Survival of the fittest" might be the best way to explain the genetic and molecular machinery behind cancer metastasis.

Researchers believe that overexpression of some genes in melanoma and other cancers allows some cells to survive the very harsh conditions that occur as they leave a primary tumor, travel to a distant site, and establish a new location for malignancy. "It is a similar theme to Darwin with natural selection, although it works out in a microenvironment," Dr. Youwen Zhou said.

"Why do I think this is a big deal? We still do not have a cure for metastatic melanoma, and next year another 900 or so patients [in Canada] will die from melanoma," Dr. Zhou said.

Melanoma was the sixth most common solid cancer for men in Canada in 2005 and 2006. There were 3,900 new cases last year. Of 840 deaths in 2006 from melanoma, 90% involved metastatic disease, said Dr. Zhou, who is on the faculty in the department of dermatology and skin science at the University of British Columbia, Vancouver.

There are some reasons for optimism, however. Understanding the molecular machinery might permit earlier intervention through better diagnostic or prognostic tools, Dr. Zhou said at the annual conference of the Canadian Dermatology Association.

Serum protein testing, for example, might lead to more accurate estimates of prognosis. The melanoma-inhibiting activity (MIA) protein is detected in high amounts in 100% of patients with metastatic melanoma so far. "About 20% of patients with primary melanoma will have signs of this protein in their serum. If they are negative for MIA protein, not one of them developed metastasis over time," he said.

Genetic insights also may lead to new therapeutic targets. "Selective gene silencing may work to cause metastatic cells to die," Dr. Zhou said.

So how do invasive tumors develop? Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment distant from the primary tumor (Cell 2006;127:679–95).

Other investigators have identified individual genes that are amplified in metastatic melanoma (Cell 2006;125:1269–81).

A high degree of heterogeneity in melanoma tumor cells may in part explain why aggressive gene clones arise.

"If you look at a melanoma clinically, it has signs of molecular and cellular heterogeneity, for example, irregular borders. On a cellular level, pathologists use variation in cell size as a diagnostic factor," he said.

Dominant genetic clones can cause a higher resistance to apoptosis, greater tolerance to hypoxia and nutrient deprivation, altered cell adherence, and increased genomic instability.

The vast majority of the most aberrantly upregulated genes work in concert to modify the microenvironment to their advantage.

Before these breakaway cells become "little tumor thrombi," they must break through local physical barriers, he explained. They do this in part by degrading the collagen matrix. Then they have to overcome the vascular wall and survive the harsh sheering and other forces of the vasculature.

Some will survive intravasation with the right molecular defense mechanisms. Extravasation occurs when they arrive at a destination, change adhesion properties, and again pass through the vascular wall. Finally, the cells must continue to defend themselves against host defenses for distant colonization to be successful, Dr. Zhou said.

Development of novel targeting strategies against this genetic and molecular machinery is needed, he said. Once those strategies are identified, the next step would be large scale trials to assess these therapeutic targets.

TORONTO — "Survival of the fittest" might be the best way to explain the genetic and molecular machinery behind cancer metastasis.

Researchers believe that overexpression of some genes in melanoma and other cancers allows some cells to survive the very harsh conditions that occur as they leave a primary tumor, travel to a distant site, and establish a new location for malignancy. "It is a similar theme to Darwin with natural selection, although it works out in a microenvironment," Dr. Youwen Zhou said.

"Why do I think this is a big deal? We still do not have a cure for metastatic melanoma, and next year another 900 or so patients [in Canada] will die from melanoma," Dr. Zhou said.

Melanoma was the sixth most common solid cancer for men in Canada in 2005 and 2006. There were 3,900 new cases last year. Of 840 deaths in 2006 from melanoma, 90% involved metastatic disease, said Dr. Zhou, who is on the faculty in the department of dermatology and skin science at the University of British Columbia, Vancouver.

There are some reasons for optimism, however. Understanding the molecular machinery might permit earlier intervention through better diagnostic or prognostic tools, Dr. Zhou said at the annual conference of the Canadian Dermatology Association.

Serum protein testing, for example, might lead to more accurate estimates of prognosis. The melanoma-inhibiting activity (MIA) protein is detected in high amounts in 100% of patients with metastatic melanoma so far. "About 20% of patients with primary melanoma will have signs of this protein in their serum. If they are negative for MIA protein, not one of them developed metastasis over time," he said.

Genetic insights also may lead to new therapeutic targets. "Selective gene silencing may work to cause metastatic cells to die," Dr. Zhou said.

So how do invasive tumors develop? Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenvironment distant from the primary tumor (Cell 2006;127:679–95).

Other investigators have identified individual genes that are amplified in metastatic melanoma (Cell 2006;125:1269–81).

A high degree of heterogeneity in melanoma tumor cells may in part explain why aggressive gene clones arise.

"If you look at a melanoma clinically, it has signs of molecular and cellular heterogeneity, for example, irregular borders. On a cellular level, pathologists use variation in cell size as a diagnostic factor," he said.

Dominant genetic clones can cause a higher resistance to apoptosis, greater tolerance to hypoxia and nutrient deprivation, altered cell adherence, and increased genomic instability.

The vast majority of the most aberrantly upregulated genes work in concert to modify the microenvironment to their advantage.

Before these breakaway cells become "little tumor thrombi," they must break through local physical barriers, he explained. They do this in part by degrading the collagen matrix. Then they have to overcome the vascular wall and survive the harsh sheering and other forces of the vasculature.

Some will survive intravasation with the right molecular defense mechanisms. Extravasation occurs when they arrive at a destination, change adhesion properties, and again pass through the vascular wall. Finally, the cells must continue to defend themselves against host defenses for distant colonization to be successful, Dr. Zhou said.

Development of novel targeting strategies against this genetic and molecular machinery is needed, he said. Once those strategies are identified, the next step would be large scale trials to assess these therapeutic targets.

AMSTERDAM — The appearance of a first squamous cell carcinoma in an organ transplant recipient is an appropriate time to discuss revising the immunosuppressive regimen to prevent subsequent skin cancers, Dr. Sylvie Euvrard said at the 11th World Congress on Cancers of the Skin.

"We think it is crucial. There is no test to assess the right level of immunosuppression. We think in many cases skin cancer means over-immunosuppression," said Dr. Euvrard, a transplant dermatologist at Edouard Herriot Hospital in Lyon, France.

The risk of squamous cell carcinoma (SCC) in organ transplant recipients is up to 250 times greater than in the general population. Roughly 80% of organ transplant recipients (OTRs) who develop an invasive SCC will develop one or more new ones within the next 3 years.

The risk of SCCs in OTRs is of secondary concern to many transplant physicians. Their main focus is on preventing graft rejection, so they are reluctant to fiddle with the immunosuppressive regimen, but they are often persuaded to do so by the argument that SCC in transplant recipients is associated with an increased rate of primary internal malignancies suggesting over-immunosuppression, Dr. Euvrard said.

Both the how and when of modifying immunosuppression to prevent skin cancer in OTRs remain controversial issues that are being addressed by ongoing randomized trials. A case for revising immunosuppression can be made in patients with multiple keratotic skin lesions based upon a recent study in which Dr. Euvrard was a coinvestigator. The study showed that OTRs with 50 or more such lesions had a 12.1-fold increased risk of SCC, compared with those who had none.

There are two general approaches to modification of immunosuppression. One is to reduce the dosing of cyclosporine and/or tacrolimus. The other approach is to substitute an mTOR (mammalian target of rapamycin) inhibitor such as sirolimus or everolimus for the calcineurin inhibitor. The latter approach is particularly attractive in light of evidence from both in vitro and mouse studies that the calcineurin inhibitors have oncogenic effects independent of their immunosuppressive activity, while the mTOR inhibitors have distinct anticancer effects, she said at the congress cosponsored by the Skin Cancer Foundation and the department of dermatology at Erasmus University, Rotterdam.

A recent international study by the Rapamune Maintenance Regimen Study Group bolsters the case for substitution with sirolimus. Three months following renal transplantation, 430 OTRs were randomized to remain on their immediate posttransplant regimen of cyclosporine, sirolimus, and corticosteroids or to withdrawal of cyclosporine and an increase in sirolimus such that trough levels doubled.

At 5 years' follow-up, the median time to a first skin carcinoma was 1,126 days in the cyclosporine withdrawal group, compared with 491 days in controls. There was a reduction in the total number of skin cancers in the cyclosporine withdrawal group as well. Moreover, the incidence of nonskin cancers was 4.0% in the cyclosporine withdrawal group, compared with 9.6% in those who remained on the calcineurin inhibitor (J. Am. Soc. Nephrol. 2006;17:581–9).

Also intriguing was an analysis of the United Network for Organ Sharing's kidney transplant registry, Dr. Euvrard continued. This observational study showed that after 963 days of immunosuppression the incidence of any new malignancy was 0.6% in patients on an mTOR inhibitor without a calcineurin inhibitor, an identical 0.6% in those on drugs from both classes, and 1.8% in patients on cyclosporine/tacrolimus without an mTOR inhibitor (Transplantation 2005;80:883–9).

Dr. Charlotte M. Proby said that at Barts and The London, Queen Mary's School of Medicine and Dentistry, where she practices dermatology, minimizing immunosuppression is the first-line measure when a patient develops skin cancer, even before prescribing acitretin for chemoprevention.

Median time to a skin cancer was 1,126 days in the withdrawal group and 491 days for controls. DR. EUVRARD

AMSTERDAM — The appearance of a first squamous cell carcinoma in an organ transplant recipient is an appropriate time to discuss revising the immunosuppressive regimen to prevent subsequent skin cancers, Dr. Sylvie Euvrard said at the 11th World Congress on Cancers of the Skin.

"We think it is crucial. There is no test to assess the right level of immunosuppression. We think in many cases skin cancer means over-immunosuppression," said Dr. Euvrard, a transplant dermatologist at Edouard Herriot Hospital in Lyon, France.

The risk of squamous cell carcinoma (SCC) in organ transplant recipients is up to 250 times greater than in the general population. Roughly 80% of organ transplant recipients (OTRs) who develop an invasive SCC will develop one or more new ones within the next 3 years.

The risk of SCCs in OTRs is of secondary concern to many transplant physicians. Their main focus is on preventing graft rejection, so they are reluctant to fiddle with the immunosuppressive regimen, but they are often persuaded to do so by the argument that SCC in transplant recipients is associated with an increased rate of primary internal malignancies suggesting over-immunosuppression, Dr. Euvrard said.

Both the how and when of modifying immunosuppression to prevent skin cancer in OTRs remain controversial issues that are being addressed by ongoing randomized trials. A case for revising immunosuppression can be made in patients with multiple keratotic skin lesions based upon a recent study in which Dr. Euvrard was a coinvestigator. The study showed that OTRs with 50 or more such lesions had a 12.1-fold increased risk of SCC, compared with those who had none.

There are two general approaches to modification of immunosuppression. One is to reduce the dosing of cyclosporine and/or tacrolimus. The other approach is to substitute an mTOR (mammalian target of rapamycin) inhibitor such as sirolimus or everolimus for the calcineurin inhibitor. The latter approach is particularly attractive in light of evidence from both in vitro and mouse studies that the calcineurin inhibitors have oncogenic effects independent of their immunosuppressive activity, while the mTOR inhibitors have distinct anticancer effects, she said at the congress cosponsored by the Skin Cancer Foundation and the department of dermatology at Erasmus University, Rotterdam.

A recent international study by the Rapamune Maintenance Regimen Study Group bolsters the case for substitution with sirolimus. Three months following renal transplantation, 430 OTRs were randomized to remain on their immediate posttransplant regimen of cyclosporine, sirolimus, and corticosteroids or to withdrawal of cyclosporine and an increase in sirolimus such that trough levels doubled.

At 5 years' follow-up, the median time to a first skin carcinoma was 1,126 days in the cyclosporine withdrawal group, compared with 491 days in controls. There was a reduction in the total number of skin cancers in the cyclosporine withdrawal group as well. Moreover, the incidence of nonskin cancers was 4.0% in the cyclosporine withdrawal group, compared with 9.6% in those who remained on the calcineurin inhibitor (J. Am. Soc. Nephrol. 2006;17:581–9).

Also intriguing was an analysis of the United Network for Organ Sharing's kidney transplant registry, Dr. Euvrard continued. This observational study showed that after 963 days of immunosuppression the incidence of any new malignancy was 0.6% in patients on an mTOR inhibitor without a calcineurin inhibitor, an identical 0.6% in those on drugs from both classes, and 1.8% in patients on cyclosporine/tacrolimus without an mTOR inhibitor (Transplantation 2005;80:883–9).

Dr. Charlotte M. Proby said that at Barts and The London, Queen Mary's School of Medicine and Dentistry, where she practices dermatology, minimizing immunosuppression is the first-line measure when a patient develops skin cancer, even before prescribing acitretin for chemoprevention.

Median time to a skin cancer was 1,126 days in the withdrawal group and 491 days for controls. DR. EUVRARD

AMSTERDAM — The appearance of a first squamous cell carcinoma in an organ transplant recipient is an appropriate time to discuss revising the immunosuppressive regimen to prevent subsequent skin cancers, Dr. Sylvie Euvrard said at the 11th World Congress on Cancers of the Skin.

"We think it is crucial. There is no test to assess the right level of immunosuppression. We think in many cases skin cancer means over-immunosuppression," said Dr. Euvrard, a transplant dermatologist at Edouard Herriot Hospital in Lyon, France.

The risk of squamous cell carcinoma (SCC) in organ transplant recipients is up to 250 times greater than in the general population. Roughly 80% of organ transplant recipients (OTRs) who develop an invasive SCC will develop one or more new ones within the next 3 years.

The risk of SCCs in OTRs is of secondary concern to many transplant physicians. Their main focus is on preventing graft rejection, so they are reluctant to fiddle with the immunosuppressive regimen, but they are often persuaded to do so by the argument that SCC in transplant recipients is associated with an increased rate of primary internal malignancies suggesting over-immunosuppression, Dr. Euvrard said.

Both the how and when of modifying immunosuppression to prevent skin cancer in OTRs remain controversial issues that are being addressed by ongoing randomized trials. A case for revising immunosuppression can be made in patients with multiple keratotic skin lesions based upon a recent study in which Dr. Euvrard was a coinvestigator. The study showed that OTRs with 50 or more such lesions had a 12.1-fold increased risk of SCC, compared with those who had none.

There are two general approaches to modification of immunosuppression. One is to reduce the dosing of cyclosporine and/or tacrolimus. The other approach is to substitute an mTOR (mammalian target of rapamycin) inhibitor such as sirolimus or everolimus for the calcineurin inhibitor. The latter approach is particularly attractive in light of evidence from both in vitro and mouse studies that the calcineurin inhibitors have oncogenic effects independent of their immunosuppressive activity, while the mTOR inhibitors have distinct anticancer effects, she said at the congress cosponsored by the Skin Cancer Foundation and the department of dermatology at Erasmus University, Rotterdam.

A recent international study by the Rapamune Maintenance Regimen Study Group bolsters the case for substitution with sirolimus. Three months following renal transplantation, 430 OTRs were randomized to remain on their immediate posttransplant regimen of cyclosporine, sirolimus, and corticosteroids or to withdrawal of cyclosporine and an increase in sirolimus such that trough levels doubled.

At 5 years' follow-up, the median time to a first skin carcinoma was 1,126 days in the cyclosporine withdrawal group, compared with 491 days in controls. There was a reduction in the total number of skin cancers in the cyclosporine withdrawal group as well. Moreover, the incidence of nonskin cancers was 4.0% in the cyclosporine withdrawal group, compared with 9.6% in those who remained on the calcineurin inhibitor (J. Am. Soc. Nephrol. 2006;17:581–9).

Also intriguing was an analysis of the United Network for Organ Sharing's kidney transplant registry, Dr. Euvrard continued. This observational study showed that after 963 days of immunosuppression the incidence of any new malignancy was 0.6% in patients on an mTOR inhibitor without a calcineurin inhibitor, an identical 0.6% in those on drugs from both classes, and 1.8% in patients on cyclosporine/tacrolimus without an mTOR inhibitor (Transplantation 2005;80:883–9).

Dr. Charlotte M. Proby said that at Barts and The London, Queen Mary's School of Medicine and Dentistry, where she practices dermatology, minimizing immunosuppression is the first-line measure when a patient develops skin cancer, even before prescribing acitretin for chemoprevention.

Median time to a skin cancer was 1,126 days in the withdrawal group and 491 days for controls. DR. EUVRARD

NEW YORK — A recently discovered chemical in the sap of a weed common to North America and much of the world appeared safe and effective in treating patients with superficial and nodular basal cell carcinoma, according to results presented as a poster at the American Academy of Dermatology's Academy 2007 meeting.

Using the PEP-005 extract of the petty spurge plant (Euphorbia peplus), Dr. Robert H. Rosen, a dermatologist in private practice in Sydney, Australia, and his colleagues, with sponsorship from Peplin Ltd., the manufacturer of the extract, conducted two separate multicenter, randomized, controlled, double-blinded, parallel phase-IIa trials for treatment of superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC).

They recruited 58 patients with nBCC and 60 with sBCC. All participants were white adult women with one basal cell carcinoma on the arm, shoulder, chest, face, neck, abdomen, back, leg, or scalp.

Patients were given a gel vehicle containing one of three concentrations of the drug: 0.0025%, 0.01%, and 0.05%. Each patient received two doses, either on 2 consecutive days or with the second dose 1 week after the first.

Application of the 0.05% concentration PEP005 topical gel overall showed the greatest efficacy in both types of BCC after 85 days, regardless of dosing schedule, Dr. Rosen and colleagues reported.

In the nBCC group, the two dosing schedules combined achieved complete histologic clearance of 25% of lesions (in 4 of 16 patients) and complete or marked clinical clearance (defined as 50%-90% improvement) in 38% of lesions (6 of 16 patients). For sBCC, the two regimens of 0.05% PEP005 achieved complete histologic clearance in 50% (8 of 16 patients) and complete or marked clinical clearance in 69% (11 of 16 patients).

There were no significant differences in safety between the dosing schedules. Among patients with nBCC, the most common local skin response was erythema, with 50% of the 0.05%-strength patients reporting moderate levels and 19% reporting severe erythema. Other responses reported for the 0.05% concentration were itch (moderate in 31% and severe in 0%), edema (31% moderate and 0% severe), scabbing/crusting (31% and 0%), and flaking/scaling/dryness (38% and 6%).

In the patients with sBCC, local skin reactions for the 0.05% PEP005 gel were itch (19% moderate and 0% severe), erythema (63% and 0%), edema (13% and 0%), scabbing/crusting (50% and 6%), flaking/scaling/dryness (25% and 13%), and moderate hypopigmentation (an adverse effect not reported in the nBCC group) in 13%.

The sap of petty spurge (Euphorbia peplus) has been used in traditional medicine as a cure for warts. ©

NEW YORK — A recently discovered chemical in the sap of a weed common to North America and much of the world appeared safe and effective in treating patients with superficial and nodular basal cell carcinoma, according to results presented as a poster at the American Academy of Dermatology's Academy 2007 meeting.

Using the PEP-005 extract of the petty spurge plant (Euphorbia peplus), Dr. Robert H. Rosen, a dermatologist in private practice in Sydney, Australia, and his colleagues, with sponsorship from Peplin Ltd., the manufacturer of the extract, conducted two separate multicenter, randomized, controlled, double-blinded, parallel phase-IIa trials for treatment of superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC).

They recruited 58 patients with nBCC and 60 with sBCC. All participants were white adult women with one basal cell carcinoma on the arm, shoulder, chest, face, neck, abdomen, back, leg, or scalp.

Patients were given a gel vehicle containing one of three concentrations of the drug: 0.0025%, 0.01%, and 0.05%. Each patient received two doses, either on 2 consecutive days or with the second dose 1 week after the first.

Application of the 0.05% concentration PEP005 topical gel overall showed the greatest efficacy in both types of BCC after 85 days, regardless of dosing schedule, Dr. Rosen and colleagues reported.

In the nBCC group, the two dosing schedules combined achieved complete histologic clearance of 25% of lesions (in 4 of 16 patients) and complete or marked clinical clearance (defined as 50%-90% improvement) in 38% of lesions (6 of 16 patients). For sBCC, the two regimens of 0.05% PEP005 achieved complete histologic clearance in 50% (8 of 16 patients) and complete or marked clinical clearance in 69% (11 of 16 patients).

There were no significant differences in safety between the dosing schedules. Among patients with nBCC, the most common local skin response was erythema, with 50% of the 0.05%-strength patients reporting moderate levels and 19% reporting severe erythema. Other responses reported for the 0.05% concentration were itch (moderate in 31% and severe in 0%), edema (31% moderate and 0% severe), scabbing/crusting (31% and 0%), and flaking/scaling/dryness (38% and 6%).

In the patients with sBCC, local skin reactions for the 0.05% PEP005 gel were itch (19% moderate and 0% severe), erythema (63% and 0%), edema (13% and 0%), scabbing/crusting (50% and 6%), flaking/scaling/dryness (25% and 13%), and moderate hypopigmentation (an adverse effect not reported in the nBCC group) in 13%.

The sap of petty spurge (Euphorbia peplus) has been used in traditional medicine as a cure for warts. ©

NEW YORK — A recently discovered chemical in the sap of a weed common to North America and much of the world appeared safe and effective in treating patients with superficial and nodular basal cell carcinoma, according to results presented as a poster at the American Academy of Dermatology's Academy 2007 meeting.

Using the PEP-005 extract of the petty spurge plant (Euphorbia peplus), Dr. Robert H. Rosen, a dermatologist in private practice in Sydney, Australia, and his colleagues, with sponsorship from Peplin Ltd., the manufacturer of the extract, conducted two separate multicenter, randomized, controlled, double-blinded, parallel phase-IIa trials for treatment of superficial basal cell carcinoma (sBCC) and nodular basal cell carcinoma (nBCC).

They recruited 58 patients with nBCC and 60 with sBCC. All participants were white adult women with one basal cell carcinoma on the arm, shoulder, chest, face, neck, abdomen, back, leg, or scalp.

Patients were given a gel vehicle containing one of three concentrations of the drug: 0.0025%, 0.01%, and 0.05%. Each patient received two doses, either on 2 consecutive days or with the second dose 1 week after the first.

Application of the 0.05% concentration PEP005 topical gel overall showed the greatest efficacy in both types of BCC after 85 days, regardless of dosing schedule, Dr. Rosen and colleagues reported.

In the nBCC group, the two dosing schedules combined achieved complete histologic clearance of 25% of lesions (in 4 of 16 patients) and complete or marked clinical clearance (defined as 50%-90% improvement) in 38% of lesions (6 of 16 patients). For sBCC, the two regimens of 0.05% PEP005 achieved complete histologic clearance in 50% (8 of 16 patients) and complete or marked clinical clearance in 69% (11 of 16 patients).

There were no significant differences in safety between the dosing schedules. Among patients with nBCC, the most common local skin response was erythema, with 50% of the 0.05%-strength patients reporting moderate levels and 19% reporting severe erythema. Other responses reported for the 0.05% concentration were itch (moderate in 31% and severe in 0%), edema (31% moderate and 0% severe), scabbing/crusting (31% and 0%), and flaking/scaling/dryness (38% and 6%).

In the patients with sBCC, local skin reactions for the 0.05% PEP005 gel were itch (19% moderate and 0% severe), erythema (63% and 0%), edema (13% and 0%), scabbing/crusting (50% and 6%), flaking/scaling/dryness (25% and 13%), and moderate hypopigmentation (an adverse effect not reported in the nBCC group) in 13%.

The sap of petty spurge (Euphorbia peplus) has been used in traditional medicine as a cure for warts. ©