Melanoma

WAIKOLOA, HAWAII — The incidence of cutaneous T-cell lymphoma has risen dramatically since the early 1970s for reasons that are not known, Dr. Joan Guitart said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Moreover, the best available numbers probably underestimate the true incidence because of reporting delay. Diagnosis of early mycosis fungoides, which is the most common type of cutaneous T-cell lymphoma (CTCL), can be quite difficult as the disease often mimics psoriasis, eczema, and other benign dermatoses, he said.

"Clearly, in the future we will be seeing a lot more CTCL," predicted Dr. Guitart, professor of dermatology at Northwestern University, Chicago.

He cited a population-based study that was conducted by dermatoepidemiologists at Brown University, Providence, R.I. Utilizing registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program, the investigators showed that the annual incidence of CTCL in the United States increased more than threefold from 1973 to 2002.

The researchers found marked racial differences in CTCL.

The annual incidence in blacks was 9.0 cases per 1 million, compared with 6.1 per million in whites. The disease was also substantially more common in men, with an annual incidence of 8.7 per million, compared with 4.6 per million in women.

The racial disparity diminished with age. In contrast, the difference between genders became more pronounced with advancing age but decreased over the course of the study period (Arch. Dermatol. 2007;143:854–9).

The investigators identified substantial geographic differences in CTCL incidence that were consistent with theories holding that environmental or viral exposures may play an etiologic role in the disease.

They also found that higher CTCL rates were associated with indicators of greater socioeconomic status, including median family income, median home value, and percentage of the population with a bachelor's degree or higher, Dr. Guitart noted.

There was no association between the incidence of CTCL and population density, but rates were strongly correlated with physician density, said Dr. Guitart.

The researchers concluded that improved diagnostic tools for CTCL and changes in International Classification of Diseases for Oncology schemes over the years may have contributed to the rising patient numbers but are not sufficient to account for the bulk of the marked increase.

Skin Disease Education Foundation and SKIN &ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

The annual incidence of CTCLin the U.S. increased more than threefold from 1973 to 2002. DR. GUITART

WAIKOLOA, HAWAII — The incidence of cutaneous T-cell lymphoma has risen dramatically since the early 1970s for reasons that are not known, Dr. Joan Guitart said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Moreover, the best available numbers probably underestimate the true incidence because of reporting delay. Diagnosis of early mycosis fungoides, which is the most common type of cutaneous T-cell lymphoma (CTCL), can be quite difficult as the disease often mimics psoriasis, eczema, and other benign dermatoses, he said.

"Clearly, in the future we will be seeing a lot more CTCL," predicted Dr. Guitart, professor of dermatology at Northwestern University, Chicago.

He cited a population-based study that was conducted by dermatoepidemiologists at Brown University, Providence, R.I. Utilizing registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program, the investigators showed that the annual incidence of CTCL in the United States increased more than threefold from 1973 to 2002.

The researchers found marked racial differences in CTCL.

The annual incidence in blacks was 9.0 cases per 1 million, compared with 6.1 per million in whites. The disease was also substantially more common in men, with an annual incidence of 8.7 per million, compared with 4.6 per million in women.

The racial disparity diminished with age. In contrast, the difference between genders became more pronounced with advancing age but decreased over the course of the study period (Arch. Dermatol. 2007;143:854–9).

The investigators identified substantial geographic differences in CTCL incidence that were consistent with theories holding that environmental or viral exposures may play an etiologic role in the disease.

They also found that higher CTCL rates were associated with indicators of greater socioeconomic status, including median family income, median home value, and percentage of the population with a bachelor's degree or higher, Dr. Guitart noted.

There was no association between the incidence of CTCL and population density, but rates were strongly correlated with physician density, said Dr. Guitart.

The researchers concluded that improved diagnostic tools for CTCL and changes in International Classification of Diseases for Oncology schemes over the years may have contributed to the rising patient numbers but are not sufficient to account for the bulk of the marked increase.

Skin Disease Education Foundation and SKIN &ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

The annual incidence of CTCLin the U.S. increased more than threefold from 1973 to 2002. DR. GUITART

WAIKOLOA, HAWAII — The incidence of cutaneous T-cell lymphoma has risen dramatically since the early 1970s for reasons that are not known, Dr. Joan Guitart said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Moreover, the best available numbers probably underestimate the true incidence because of reporting delay. Diagnosis of early mycosis fungoides, which is the most common type of cutaneous T-cell lymphoma (CTCL), can be quite difficult as the disease often mimics psoriasis, eczema, and other benign dermatoses, he said.

"Clearly, in the future we will be seeing a lot more CTCL," predicted Dr. Guitart, professor of dermatology at Northwestern University, Chicago.

He cited a population-based study that was conducted by dermatoepidemiologists at Brown University, Providence, R.I. Utilizing registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program, the investigators showed that the annual incidence of CTCL in the United States increased more than threefold from 1973 to 2002.

The researchers found marked racial differences in CTCL.

The annual incidence in blacks was 9.0 cases per 1 million, compared with 6.1 per million in whites. The disease was also substantially more common in men, with an annual incidence of 8.7 per million, compared with 4.6 per million in women.

The racial disparity diminished with age. In contrast, the difference between genders became more pronounced with advancing age but decreased over the course of the study period (Arch. Dermatol. 2007;143:854–9).

The investigators identified substantial geographic differences in CTCL incidence that were consistent with theories holding that environmental or viral exposures may play an etiologic role in the disease.

They also found that higher CTCL rates were associated with indicators of greater socioeconomic status, including median family income, median home value, and percentage of the population with a bachelor's degree or higher, Dr. Guitart noted.

There was no association between the incidence of CTCL and population density, but rates were strongly correlated with physician density, said Dr. Guitart.

The researchers concluded that improved diagnostic tools for CTCL and changes in International Classification of Diseases for Oncology schemes over the years may have contributed to the rising patient numbers but are not sufficient to account for the bulk of the marked increase.

Skin Disease Education Foundation and SKIN &ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

The annual incidence of CTCLin the U.S. increased more than threefold from 1973 to 2002. DR. GUITART

WAIKOLOA, HAWAII — The phrase "cutaneous T-cell lymphoid dyscrasia" could serve as a novel unifying term for a variety of chronic skin conditions characterized by persistent T-cell clonality without meeting the histologic or clinical criteria for mycosis fungoides, Dr. Joan Guitart proposed at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Cutaneous T-cell lymphoid dyscrasias encompass eight distinct clinicopathologic precancerous entities, and is a better term than "precutaneous T-cell lymphoma" or "premycotic" because most affected patients will in fact have an innocuous, indolent clinical course without ever progressing to overt cutaneous T-cell lymphoma (Arch. Dermatol. 2007;143:921–32).

For example, long-term studies demonstrate that only 10%–15% of patients with parapsoriasis—one form of cutaneous T-cell lymphoid dyscrasia—evolve into mycosis fungoides, explained Dr. Guitart, professor of dermatology at Northwestern University, Chicago. He proposed the following criteria as requisite for cutaneous T-cell lymphoid dyscrasia:

▸ The condition is chronic with a tendency to relapse following topical therapy.

▸ There is no known triggering event, such as the occurrence of T-cell clones in conjunction with rheumatoid arthritis, lupus erythematosus, organ transplants, or other states of long-term immunostimulation. There also is no evidence of allergic reaction, hypersensitivity, or connective-tissue disorder.

▸ There is the presence of one or a few T-cell clones defined by reduced CD7 and CD62L expression in skin specimens.

▸ There is a lack of morphologic evidence for T-cell lymphoma. The dominant lymphocyte is small or intermediate in size.

Other skin disorders fitting the definition include pityriasis lichenoides chronica, idiopathic follicular mucinosis, atypical lymphocytic lobular panniculitis, clonal erythroderma, pigmented purpuric variant, syringolymphoid hyperplasia with alopecia, and hypopigmented interface variant.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

WAIKOLOA, HAWAII — The phrase "cutaneous T-cell lymphoid dyscrasia" could serve as a novel unifying term for a variety of chronic skin conditions characterized by persistent T-cell clonality without meeting the histologic or clinical criteria for mycosis fungoides, Dr. Joan Guitart proposed at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Cutaneous T-cell lymphoid dyscrasias encompass eight distinct clinicopathologic precancerous entities, and is a better term than "precutaneous T-cell lymphoma" or "premycotic" because most affected patients will in fact have an innocuous, indolent clinical course without ever progressing to overt cutaneous T-cell lymphoma (Arch. Dermatol. 2007;143:921–32).

For example, long-term studies demonstrate that only 10%–15% of patients with parapsoriasis—one form of cutaneous T-cell lymphoid dyscrasia—evolve into mycosis fungoides, explained Dr. Guitart, professor of dermatology at Northwestern University, Chicago. He proposed the following criteria as requisite for cutaneous T-cell lymphoid dyscrasia:

▸ The condition is chronic with a tendency to relapse following topical therapy.

▸ There is no known triggering event, such as the occurrence of T-cell clones in conjunction with rheumatoid arthritis, lupus erythematosus, organ transplants, or other states of long-term immunostimulation. There also is no evidence of allergic reaction, hypersensitivity, or connective-tissue disorder.

▸ There is the presence of one or a few T-cell clones defined by reduced CD7 and CD62L expression in skin specimens.

▸ There is a lack of morphologic evidence for T-cell lymphoma. The dominant lymphocyte is small or intermediate in size.

Other skin disorders fitting the definition include pityriasis lichenoides chronica, idiopathic follicular mucinosis, atypical lymphocytic lobular panniculitis, clonal erythroderma, pigmented purpuric variant, syringolymphoid hyperplasia with alopecia, and hypopigmented interface variant.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

WAIKOLOA, HAWAII — The phrase "cutaneous T-cell lymphoid dyscrasia" could serve as a novel unifying term for a variety of chronic skin conditions characterized by persistent T-cell clonality without meeting the histologic or clinical criteria for mycosis fungoides, Dr. Joan Guitart proposed at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Cutaneous T-cell lymphoid dyscrasias encompass eight distinct clinicopathologic precancerous entities, and is a better term than "precutaneous T-cell lymphoma" or "premycotic" because most affected patients will in fact have an innocuous, indolent clinical course without ever progressing to overt cutaneous T-cell lymphoma (Arch. Dermatol. 2007;143:921–32).

For example, long-term studies demonstrate that only 10%–15% of patients with parapsoriasis—one form of cutaneous T-cell lymphoid dyscrasia—evolve into mycosis fungoides, explained Dr. Guitart, professor of dermatology at Northwestern University, Chicago. He proposed the following criteria as requisite for cutaneous T-cell lymphoid dyscrasia:

▸ The condition is chronic with a tendency to relapse following topical therapy.

▸ There is no known triggering event, such as the occurrence of T-cell clones in conjunction with rheumatoid arthritis, lupus erythematosus, organ transplants, or other states of long-term immunostimulation. There also is no evidence of allergic reaction, hypersensitivity, or connective-tissue disorder.

▸ There is the presence of one or a few T-cell clones defined by reduced CD7 and CD62L expression in skin specimens.

▸ There is a lack of morphologic evidence for T-cell lymphoma. The dominant lymphocyte is small or intermediate in size.

Other skin disorders fitting the definition include pityriasis lichenoides chronica, idiopathic follicular mucinosis, atypical lymphocytic lobular panniculitis, clonal erythroderma, pigmented purpuric variant, syringolymphoid hyperplasia with alopecia, and hypopigmented interface variant.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

WAIKOLOA, HAWAII — The standardized, points-based diagnostic algorithm for early mycosis fungoides developed by the International Society for Cutaneous Lymphoma can be helpful in approaching the ambiguous patient with a patchy, thin-plaque rash and some atypia in the biopsy, Dr. Kimberly Bohjanen said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

In the past, such a patient might visit four different physicians and variously receive a diagnosis of parapsoriasis, atopic dermatitis, contact dermatitis, or early classic cutaneous T-cell lymphoma (CTCL), noted Dr. Bohjanen of the University of Minnesota, Minneapolis.

Although the algorithm—codeveloped by the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer—might seem confusing at first, it really is not. In fact, it's akin to the scoring system rheumatologists developed to define systemic lupus, she said.

Four points are required to diagnose early mycosis fungoides. Up to two can come from the clinical exam. The basic clinical criterion is the presence of persistent and/or progressive patches and thin plaques. The additional clinical criteria are a non-sun-exposed "bathing suit"-type lesion distribution, poikiloderma, and variation in lesion size and shape. A patient gets one point for presenting with the basic clinical criterion plus one of the additional criteria, or two points for presenting with the basic criterion plus any two additional clinical criteria.

Up to two points can be awarded based on the histopathologic findings on biopsy.

The basic histopathologic criterion is the presence of a superficial lymphoid infiltrate. If this, plus either of the two additional criteria—epidermotropism without spongiosis, and lymphoid atypia as defined by enlarged, irregular, hyperchromatic nuclei—are met, that's worth one point. If the basic and both additional criteria are present, that's worth two points.

"So basically if you have someone with a classic presentation of CTCL that meets the criteria on clinical exam and then you have a biopsy with all of these features, you've made the diagnosis of CTCL without even going on to immunotyping or T-cell gene rearrangement," she said.

All of this presupposes that the possibility of drug eruption has been ruled out from the outset.

A subsequent biopsy is used to gather material for T-cell gene rearrangement and immunopathologic studies. These studies need to be done routinely because of their value in staging, even in patients who already have four points.

One additional point is awarded for evidence of clonality on T-cell gene rearrangement. The algorithm gives another point if at least one of the following three immunopathologic markers of CTCL is present on the cell surface: less than 50% CD2-positive, CD3-positive, or CD5-positive T cells; less than 10% CD7-positive T cells; and discordance between the epidermal and dermal population of CD2, CD3, CD5, or CD7 T cells, with the antigen deficiency being confined to the epidermis (J. Am. Acad. Dermatol. 2005;53:1053–63).

The new system follows the T (tumor), N (lymph nodes), M (visceral metastases), and B (blood—with or without circulating Sézary cells) format (Blood 2007;110:1713–22). The biggest change was in lymph node staging, which now incorporates clonality, she said.

Dr. Bohjanen disclosed being on the speakers bureau for Abbott Laboratories.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

WAIKOLOA, HAWAII — The standardized, points-based diagnostic algorithm for early mycosis fungoides developed by the International Society for Cutaneous Lymphoma can be helpful in approaching the ambiguous patient with a patchy, thin-plaque rash and some atypia in the biopsy, Dr. Kimberly Bohjanen said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

In the past, such a patient might visit four different physicians and variously receive a diagnosis of parapsoriasis, atopic dermatitis, contact dermatitis, or early classic cutaneous T-cell lymphoma (CTCL), noted Dr. Bohjanen of the University of Minnesota, Minneapolis.

Although the algorithm—codeveloped by the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer—might seem confusing at first, it really is not. In fact, it's akin to the scoring system rheumatologists developed to define systemic lupus, she said.

Four points are required to diagnose early mycosis fungoides. Up to two can come from the clinical exam. The basic clinical criterion is the presence of persistent and/or progressive patches and thin plaques. The additional clinical criteria are a non-sun-exposed "bathing suit"-type lesion distribution, poikiloderma, and variation in lesion size and shape. A patient gets one point for presenting with the basic clinical criterion plus one of the additional criteria, or two points for presenting with the basic criterion plus any two additional clinical criteria.

Up to two points can be awarded based on the histopathologic findings on biopsy.

The basic histopathologic criterion is the presence of a superficial lymphoid infiltrate. If this, plus either of the two additional criteria—epidermotropism without spongiosis, and lymphoid atypia as defined by enlarged, irregular, hyperchromatic nuclei—are met, that's worth one point. If the basic and both additional criteria are present, that's worth two points.

"So basically if you have someone with a classic presentation of CTCL that meets the criteria on clinical exam and then you have a biopsy with all of these features, you've made the diagnosis of CTCL without even going on to immunotyping or T-cell gene rearrangement," she said.

All of this presupposes that the possibility of drug eruption has been ruled out from the outset.

A subsequent biopsy is used to gather material for T-cell gene rearrangement and immunopathologic studies. These studies need to be done routinely because of their value in staging, even in patients who already have four points.

One additional point is awarded for evidence of clonality on T-cell gene rearrangement. The algorithm gives another point if at least one of the following three immunopathologic markers of CTCL is present on the cell surface: less than 50% CD2-positive, CD3-positive, or CD5-positive T cells; less than 10% CD7-positive T cells; and discordance between the epidermal and dermal population of CD2, CD3, CD5, or CD7 T cells, with the antigen deficiency being confined to the epidermis (J. Am. Acad. Dermatol. 2005;53:1053–63).

The new system follows the T (tumor), N (lymph nodes), M (visceral metastases), and B (blood—with or without circulating Sézary cells) format (Blood 2007;110:1713–22). The biggest change was in lymph node staging, which now incorporates clonality, she said.

Dr. Bohjanen disclosed being on the speakers bureau for Abbott Laboratories.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

WAIKOLOA, HAWAII — The standardized, points-based diagnostic algorithm for early mycosis fungoides developed by the International Society for Cutaneous Lymphoma can be helpful in approaching the ambiguous patient with a patchy, thin-plaque rash and some atypia in the biopsy, Dr. Kimberly Bohjanen said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

In the past, such a patient might visit four different physicians and variously receive a diagnosis of parapsoriasis, atopic dermatitis, contact dermatitis, or early classic cutaneous T-cell lymphoma (CTCL), noted Dr. Bohjanen of the University of Minnesota, Minneapolis.

Although the algorithm—codeveloped by the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer—might seem confusing at first, it really is not. In fact, it's akin to the scoring system rheumatologists developed to define systemic lupus, she said.

Four points are required to diagnose early mycosis fungoides. Up to two can come from the clinical exam. The basic clinical criterion is the presence of persistent and/or progressive patches and thin plaques. The additional clinical criteria are a non-sun-exposed "bathing suit"-type lesion distribution, poikiloderma, and variation in lesion size and shape. A patient gets one point for presenting with the basic clinical criterion plus one of the additional criteria, or two points for presenting with the basic criterion plus any two additional clinical criteria.

Up to two points can be awarded based on the histopathologic findings on biopsy.

The basic histopathologic criterion is the presence of a superficial lymphoid infiltrate. If this, plus either of the two additional criteria—epidermotropism without spongiosis, and lymphoid atypia as defined by enlarged, irregular, hyperchromatic nuclei—are met, that's worth one point. If the basic and both additional criteria are present, that's worth two points.

"So basically if you have someone with a classic presentation of CTCL that meets the criteria on clinical exam and then you have a biopsy with all of these features, you've made the diagnosis of CTCL without even going on to immunotyping or T-cell gene rearrangement," she said.

All of this presupposes that the possibility of drug eruption has been ruled out from the outset.

A subsequent biopsy is used to gather material for T-cell gene rearrangement and immunopathologic studies. These studies need to be done routinely because of their value in staging, even in patients who already have four points.

One additional point is awarded for evidence of clonality on T-cell gene rearrangement. The algorithm gives another point if at least one of the following three immunopathologic markers of CTCL is present on the cell surface: less than 50% CD2-positive, CD3-positive, or CD5-positive T cells; less than 10% CD7-positive T cells; and discordance between the epidermal and dermal population of CD2, CD3, CD5, or CD7 T cells, with the antigen deficiency being confined to the epidermis (J. Am. Acad. Dermatol. 2005;53:1053–63).

The new system follows the T (tumor), N (lymph nodes), M (visceral metastases), and B (blood—with or without circulating Sézary cells) format (Blood 2007;110:1713–22). The biggest change was in lymph node staging, which now incorporates clonality, she said.

Dr. Bohjanen disclosed being on the speakers bureau for Abbott Laboratories.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

Early stages of mycosis fungoides should be managed by dermatologists, not ceded to oncologists, as often happens. I would hate to see our great specialty demoted to the treatment of acne warts and cosmetic conditions. Let's not give away this disease, too. It belongs to us.

Especially early on, there's a very important role for skin-directed therapy—and we dermatologists are the experts, not the oncologists.

Abundant evidence shows that pathogenetic events leading to tumor progression in myosis fungoides (MF) occur in the skin, and that skin-directed therapy can induce prolonged remissions.

That's a point particularly worth emphasizing in light of the European Organisation for Research and Treatment of Cancer's current recommendation that "expectant management" is a legitimate option in patients with stage IA disease because they have a normal life expectancy. This recommendation is based on a misinterpretation of the data. What the guideline writers failed to realize is that these stage IA MF patients in the major reported series who are doing so well are actually receiving skin-directed treatment. We really don't have good data on the natural history of mycosis fungoides without treatment, so their conclusions are based on faulty information.

Patients with cutaneous T-cell lymphoma (CTCL) face numerous problems in which dermatologists have special expertise: severe pruritus, xerosis, cosmetic issues, an increase in skin cancers, and numerous cutaneous infectious complications.

In one study of 356 patients with MF or Sézary syndrome, the incidence of cutaneous bacterial infection was 17% per year (JAMA 1992;267:1354–8). The combined annual rate of cutaneous herpes simplex and herpes zoster infections was 3.8%. Extracutaneous CTCL involvement independently predicted a 12-fold increased risk of recurrent bacterial skin infection, a 28-fold increase in disseminated herpesvirus infection, and a rather remarkable 15-fold increase in death from infection.

We, as dermatologists, are very well qualified to manage these infections.

A study recently completed at Northwestern University in Chicago showed roughly a 40% Staphylococcus aureus colonization rate in CTCL patients. Worsening of the skin lesions or a new flare of erythroderma in CTCL patients may be related to a cutaneous infection rather than tumor progression.

At Northwestern, we recommend culturing patients often and utilizing frequent dilute bleach baths to help control S. aureus colonization levels. That's important because S. aureus superantigen has been shown to stimulate tumor-infiltrating lymphocytes, thus encouraging growth of malignant T cells. Treating a concurrent S. aureus skin infection may be sufficient to curtain a Sézary syndrome crisis, for example.

The quality of life issues raised by CTCL are often striking and here again dermatologists can be uniquely helpful. A survey of the Mycosis Fungoides Foundation membership found that 62% of respondents indicated their disease made them feel unattractive. A profound distress over health concerns was nearly universal (Cancer 2006;107:2504–11).

With skin-directed therapies, it is important to apply agents such as topical steroids, nitrogen mustard, and retinoids not only to the actual lesions but for a few centimeters beyond the actual clinical borders. Oncologists generally handle systemic therapies for CTCL, but there has been considerable interest among dermatologists in vorinostat (Zolinza), an oral inhibitor of histone deacetylase (HDAC) approved by the Food and Drug Administration in 2006 for the treatment of CTCL.

I have been less than favorably impressed by the low response rates—24% and 30% in two published trials—as well as the short duration of response and extensive side effects. In general, I think dermatologists feel comfortable prescribing oral treatment, but I would recommend caution on its use. The risk-benefit ratio is not that great, and in any case new HDACs with perhaps a better safety profile and efficacy are in the pipeline.

Dermatology has lost control of too many important diseases like sexually transmitted diseases, connective vascular conditions, and other allergy/immunology conditions. We should not lose track of mycosis fungoides, too.

Early stages of mycosis fungoides should be managed by dermatologists, not ceded to oncologists, as often happens. I would hate to see our great specialty demoted to the treatment of acne warts and cosmetic conditions. Let's not give away this disease, too. It belongs to us.

Especially early on, there's a very important role for skin-directed therapy—and we dermatologists are the experts, not the oncologists.

Abundant evidence shows that pathogenetic events leading to tumor progression in myosis fungoides (MF) occur in the skin, and that skin-directed therapy can induce prolonged remissions.

That's a point particularly worth emphasizing in light of the European Organisation for Research and Treatment of Cancer's current recommendation that "expectant management" is a legitimate option in patients with stage IA disease because they have a normal life expectancy. This recommendation is based on a misinterpretation of the data. What the guideline writers failed to realize is that these stage IA MF patients in the major reported series who are doing so well are actually receiving skin-directed treatment. We really don't have good data on the natural history of mycosis fungoides without treatment, so their conclusions are based on faulty information.

Patients with cutaneous T-cell lymphoma (CTCL) face numerous problems in which dermatologists have special expertise: severe pruritus, xerosis, cosmetic issues, an increase in skin cancers, and numerous cutaneous infectious complications.

In one study of 356 patients with MF or Sézary syndrome, the incidence of cutaneous bacterial infection was 17% per year (JAMA 1992;267:1354–8). The combined annual rate of cutaneous herpes simplex and herpes zoster infections was 3.8%. Extracutaneous CTCL involvement independently predicted a 12-fold increased risk of recurrent bacterial skin infection, a 28-fold increase in disseminated herpesvirus infection, and a rather remarkable 15-fold increase in death from infection.

We, as dermatologists, are very well qualified to manage these infections.

A study recently completed at Northwestern University in Chicago showed roughly a 40% Staphylococcus aureus colonization rate in CTCL patients. Worsening of the skin lesions or a new flare of erythroderma in CTCL patients may be related to a cutaneous infection rather than tumor progression.

At Northwestern, we recommend culturing patients often and utilizing frequent dilute bleach baths to help control S. aureus colonization levels. That's important because S. aureus superantigen has been shown to stimulate tumor-infiltrating lymphocytes, thus encouraging growth of malignant T cells. Treating a concurrent S. aureus skin infection may be sufficient to curtain a Sézary syndrome crisis, for example.

The quality of life issues raised by CTCL are often striking and here again dermatologists can be uniquely helpful. A survey of the Mycosis Fungoides Foundation membership found that 62% of respondents indicated their disease made them feel unattractive. A profound distress over health concerns was nearly universal (Cancer 2006;107:2504–11).

With skin-directed therapies, it is important to apply agents such as topical steroids, nitrogen mustard, and retinoids not only to the actual lesions but for a few centimeters beyond the actual clinical borders. Oncologists generally handle systemic therapies for CTCL, but there has been considerable interest among dermatologists in vorinostat (Zolinza), an oral inhibitor of histone deacetylase (HDAC) approved by the Food and Drug Administration in 2006 for the treatment of CTCL.

I have been less than favorably impressed by the low response rates—24% and 30% in two published trials—as well as the short duration of response and extensive side effects. In general, I think dermatologists feel comfortable prescribing oral treatment, but I would recommend caution on its use. The risk-benefit ratio is not that great, and in any case new HDACs with perhaps a better safety profile and efficacy are in the pipeline.

Dermatology has lost control of too many important diseases like sexually transmitted diseases, connective vascular conditions, and other allergy/immunology conditions. We should not lose track of mycosis fungoides, too.

Early stages of mycosis fungoides should be managed by dermatologists, not ceded to oncologists, as often happens. I would hate to see our great specialty demoted to the treatment of acne warts and cosmetic conditions. Let's not give away this disease, too. It belongs to us.

Especially early on, there's a very important role for skin-directed therapy—and we dermatologists are the experts, not the oncologists.

Abundant evidence shows that pathogenetic events leading to tumor progression in myosis fungoides (MF) occur in the skin, and that skin-directed therapy can induce prolonged remissions.

That's a point particularly worth emphasizing in light of the European Organisation for Research and Treatment of Cancer's current recommendation that "expectant management" is a legitimate option in patients with stage IA disease because they have a normal life expectancy. This recommendation is based on a misinterpretation of the data. What the guideline writers failed to realize is that these stage IA MF patients in the major reported series who are doing so well are actually receiving skin-directed treatment. We really don't have good data on the natural history of mycosis fungoides without treatment, so their conclusions are based on faulty information.

Patients with cutaneous T-cell lymphoma (CTCL) face numerous problems in which dermatologists have special expertise: severe pruritus, xerosis, cosmetic issues, an increase in skin cancers, and numerous cutaneous infectious complications.

In one study of 356 patients with MF or Sézary syndrome, the incidence of cutaneous bacterial infection was 17% per year (JAMA 1992;267:1354–8). The combined annual rate of cutaneous herpes simplex and herpes zoster infections was 3.8%. Extracutaneous CTCL involvement independently predicted a 12-fold increased risk of recurrent bacterial skin infection, a 28-fold increase in disseminated herpesvirus infection, and a rather remarkable 15-fold increase in death from infection.

We, as dermatologists, are very well qualified to manage these infections.

A study recently completed at Northwestern University in Chicago showed roughly a 40% Staphylococcus aureus colonization rate in CTCL patients. Worsening of the skin lesions or a new flare of erythroderma in CTCL patients may be related to a cutaneous infection rather than tumor progression.

At Northwestern, we recommend culturing patients often and utilizing frequent dilute bleach baths to help control S. aureus colonization levels. That's important because S. aureus superantigen has been shown to stimulate tumor-infiltrating lymphocytes, thus encouraging growth of malignant T cells. Treating a concurrent S. aureus skin infection may be sufficient to curtain a Sézary syndrome crisis, for example.

The quality of life issues raised by CTCL are often striking and here again dermatologists can be uniquely helpful. A survey of the Mycosis Fungoides Foundation membership found that 62% of respondents indicated their disease made them feel unattractive. A profound distress over health concerns was nearly universal (Cancer 2006;107:2504–11).

With skin-directed therapies, it is important to apply agents such as topical steroids, nitrogen mustard, and retinoids not only to the actual lesions but for a few centimeters beyond the actual clinical borders. Oncologists generally handle systemic therapies for CTCL, but there has been considerable interest among dermatologists in vorinostat (Zolinza), an oral inhibitor of histone deacetylase (HDAC) approved by the Food and Drug Administration in 2006 for the treatment of CTCL.

I have been less than favorably impressed by the low response rates—24% and 30% in two published trials—as well as the short duration of response and extensive side effects. In general, I think dermatologists feel comfortable prescribing oral treatment, but I would recommend caution on its use. The risk-benefit ratio is not that great, and in any case new HDACs with perhaps a better safety profile and efficacy are in the pipeline.

Dermatology has lost control of too many important diseases like sexually transmitted diseases, connective vascular conditions, and other allergy/immunology conditions. We should not lose track of mycosis fungoides, too.

CHICAGO — Adherence to national cancer treatment guidelines was associated with decreased local and regional recurrence, improved disease-free and overall survival, and decreased treatment-associated morbidity in a study of 327 consecutive clinically node-negative melanoma patients.

A review of cancer registry data at Rush North Shore Medical Center in Skokie, Ill., revealed that 72% of patients were treated in compliance with National Comprehensive Cancer Network (NCCN) recommendations for margins of excision, Dr. Jennifer Erickson Foster and colleagues reported at a symposium sponsored by the Society of Surgical Oncology.

Appropriate lymph node staging and treatment was received by 271 patients or 83%. Interestingly, when treatment was performed by a surgical oncologist, margin compliance was 95% and lymph node compliance 92%, said Dr. Foster, the lead investigator. A recommended completion lymph node dissection was performed for a positive sentinel lymph node in 78% of patients.

Patients treated in a noncompliant fashion with regard to margins had a threefold increase in postoperative complications in comparison with those treated in a compliant fashion. Similarly, patients treated in a lymph node-noncompliant fashion were 2.4 times more likely to have a postoperative complication. Both findings were statistically significant, said Dr. Erickson Foster, who reported no conflicts of interest for the investigators.

Noncompliance with NCCN guidelines for margins of excision was associated with increased locoregional (26% vs. 6%) and distant recurrence (8% vs. 6%), as compared with compliant cases. Locoregional disease alone as the first site of relapse was seen in 33% of lymph node-noncompliant cases vs. 6% of lymph node-compliant cases.

Five-year disease-free survival was higher among margin-compliant cases, compared with margin-noncompliant cases (86% vs. 68%), as was 5-year overall survival (93% vs. 83%). Similar increases in disease-free (85% vs. 54%) and overall (95% vs. 66%) survival were observed with compliance to lymph node staging and treatment recommendations.

The mean follow-up was 51 months (minimum 18 months) and mean age 66 years; 53% of the patients were women, and 32% of melanomas were located on the trunk, a finding consistent with cutaneous melanoma. Postoperative complications were reported in 55 patients (17%), with major complications in 4%, including one myocardial infarction, one pneumothorax, two cases of lymphedema, and two cases of facial nerve injury.

"These findings are provocative and suggest that compliance with NCCN guidelines improves outcomes in clinically node-negative melanoma patients," senior author Dr. Tina J. Hieken, of Rush Medical College, in Chicago, said in an interview. "We recommend that clinicians treating melanoma patients become familiar with these guidelines and utilize them to assist clinical decision making."

During the question-and-answer session, Dr. Foster noted that 20 different physicians representing nine specialties performed melanoma treatment in the study. Compliance did improve among specialties as time went on, but only surgical oncologists had greater than 90% compliance for margins of excision and lymph node staging and treatment.

Audience member Dr. Daniel G. Coit, who cochaired the NCCN guideline committee for melanoma, stressed that noncompliance with recommendations should not be equated with poor medical care. "Guidelines don't define best medical care; the doctors and patients define best medical care," he said.

Both Dr. Foster and Dr. Hieken agreed that physicians regularly depart from guidelines for a variety of reasons, such as aesthetic considerations, patient preferences, patient comorbidities, and tumor features.

"Guidelines are a point of departure," said Dr. Coit of Memorial Sloan-Kettering Cancer Center in New York. "They are not how we must do it, and we need to be very careful about how we define that, because there are other people who don't know that and will be looking at these kinds of presentations very carefully, and they're going to come to the wrong conclusion."

CHICAGO — Adherence to national cancer treatment guidelines was associated with decreased local and regional recurrence, improved disease-free and overall survival, and decreased treatment-associated morbidity in a study of 327 consecutive clinically node-negative melanoma patients.

A review of cancer registry data at Rush North Shore Medical Center in Skokie, Ill., revealed that 72% of patients were treated in compliance with National Comprehensive Cancer Network (NCCN) recommendations for margins of excision, Dr. Jennifer Erickson Foster and colleagues reported at a symposium sponsored by the Society of Surgical Oncology.

Appropriate lymph node staging and treatment was received by 271 patients or 83%. Interestingly, when treatment was performed by a surgical oncologist, margin compliance was 95% and lymph node compliance 92%, said Dr. Foster, the lead investigator. A recommended completion lymph node dissection was performed for a positive sentinel lymph node in 78% of patients.

Patients treated in a noncompliant fashion with regard to margins had a threefold increase in postoperative complications in comparison with those treated in a compliant fashion. Similarly, patients treated in a lymph node-noncompliant fashion were 2.4 times more likely to have a postoperative complication. Both findings were statistically significant, said Dr. Erickson Foster, who reported no conflicts of interest for the investigators.

Noncompliance with NCCN guidelines for margins of excision was associated with increased locoregional (26% vs. 6%) and distant recurrence (8% vs. 6%), as compared with compliant cases. Locoregional disease alone as the first site of relapse was seen in 33% of lymph node-noncompliant cases vs. 6% of lymph node-compliant cases.

Five-year disease-free survival was higher among margin-compliant cases, compared with margin-noncompliant cases (86% vs. 68%), as was 5-year overall survival (93% vs. 83%). Similar increases in disease-free (85% vs. 54%) and overall (95% vs. 66%) survival were observed with compliance to lymph node staging and treatment recommendations.

The mean follow-up was 51 months (minimum 18 months) and mean age 66 years; 53% of the patients were women, and 32% of melanomas were located on the trunk, a finding consistent with cutaneous melanoma. Postoperative complications were reported in 55 patients (17%), with major complications in 4%, including one myocardial infarction, one pneumothorax, two cases of lymphedema, and two cases of facial nerve injury.

"These findings are provocative and suggest that compliance with NCCN guidelines improves outcomes in clinically node-negative melanoma patients," senior author Dr. Tina J. Hieken, of Rush Medical College, in Chicago, said in an interview. "We recommend that clinicians treating melanoma patients become familiar with these guidelines and utilize them to assist clinical decision making."

During the question-and-answer session, Dr. Foster noted that 20 different physicians representing nine specialties performed melanoma treatment in the study. Compliance did improve among specialties as time went on, but only surgical oncologists had greater than 90% compliance for margins of excision and lymph node staging and treatment.

Audience member Dr. Daniel G. Coit, who cochaired the NCCN guideline committee for melanoma, stressed that noncompliance with recommendations should not be equated with poor medical care. "Guidelines don't define best medical care; the doctors and patients define best medical care," he said.

Both Dr. Foster and Dr. Hieken agreed that physicians regularly depart from guidelines for a variety of reasons, such as aesthetic considerations, patient preferences, patient comorbidities, and tumor features.

"Guidelines are a point of departure," said Dr. Coit of Memorial Sloan-Kettering Cancer Center in New York. "They are not how we must do it, and we need to be very careful about how we define that, because there are other people who don't know that and will be looking at these kinds of presentations very carefully, and they're going to come to the wrong conclusion."

CHICAGO — Adherence to national cancer treatment guidelines was associated with decreased local and regional recurrence, improved disease-free and overall survival, and decreased treatment-associated morbidity in a study of 327 consecutive clinically node-negative melanoma patients.

A review of cancer registry data at Rush North Shore Medical Center in Skokie, Ill., revealed that 72% of patients were treated in compliance with National Comprehensive Cancer Network (NCCN) recommendations for margins of excision, Dr. Jennifer Erickson Foster and colleagues reported at a symposium sponsored by the Society of Surgical Oncology.

Appropriate lymph node staging and treatment was received by 271 patients or 83%. Interestingly, when treatment was performed by a surgical oncologist, margin compliance was 95% and lymph node compliance 92%, said Dr. Foster, the lead investigator. A recommended completion lymph node dissection was performed for a positive sentinel lymph node in 78% of patients.

Patients treated in a noncompliant fashion with regard to margins had a threefold increase in postoperative complications in comparison with those treated in a compliant fashion. Similarly, patients treated in a lymph node-noncompliant fashion were 2.4 times more likely to have a postoperative complication. Both findings were statistically significant, said Dr. Erickson Foster, who reported no conflicts of interest for the investigators.

Noncompliance with NCCN guidelines for margins of excision was associated with increased locoregional (26% vs. 6%) and distant recurrence (8% vs. 6%), as compared with compliant cases. Locoregional disease alone as the first site of relapse was seen in 33% of lymph node-noncompliant cases vs. 6% of lymph node-compliant cases.

Five-year disease-free survival was higher among margin-compliant cases, compared with margin-noncompliant cases (86% vs. 68%), as was 5-year overall survival (93% vs. 83%). Similar increases in disease-free (85% vs. 54%) and overall (95% vs. 66%) survival were observed with compliance to lymph node staging and treatment recommendations.

The mean follow-up was 51 months (minimum 18 months) and mean age 66 years; 53% of the patients were women, and 32% of melanomas were located on the trunk, a finding consistent with cutaneous melanoma. Postoperative complications were reported in 55 patients (17%), with major complications in 4%, including one myocardial infarction, one pneumothorax, two cases of lymphedema, and two cases of facial nerve injury.

"These findings are provocative and suggest that compliance with NCCN guidelines improves outcomes in clinically node-negative melanoma patients," senior author Dr. Tina J. Hieken, of Rush Medical College, in Chicago, said in an interview. "We recommend that clinicians treating melanoma patients become familiar with these guidelines and utilize them to assist clinical decision making."

During the question-and-answer session, Dr. Foster noted that 20 different physicians representing nine specialties performed melanoma treatment in the study. Compliance did improve among specialties as time went on, but only surgical oncologists had greater than 90% compliance for margins of excision and lymph node staging and treatment.

Audience member Dr. Daniel G. Coit, who cochaired the NCCN guideline committee for melanoma, stressed that noncompliance with recommendations should not be equated with poor medical care. "Guidelines don't define best medical care; the doctors and patients define best medical care," he said.

Both Dr. Foster and Dr. Hieken agreed that physicians regularly depart from guidelines for a variety of reasons, such as aesthetic considerations, patient preferences, patient comorbidities, and tumor features.

"Guidelines are a point of departure," said Dr. Coit of Memorial Sloan-Kettering Cancer Center in New York. "They are not how we must do it, and we need to be very careful about how we define that, because there are other people who don't know that and will be looking at these kinds of presentations very carefully, and they're going to come to the wrong conclusion."

WAIKOLOA, HAWAII — The "ugly duckling" sign showed impressive sensitivity for melanoma when applied by physicians as well as nonmedically trained individuals for rating melanocytic lesions, according to Dr. Ashfaq A. Marghoob.

The results of this study suggest the ugly duckling sign may be a valuable melanoma screening tool readily teachable to primary care physicians, nurse practitioners, and patients performing periodic skin self-examination, Dr. Marghoob reported at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

"Could this be a new public health message?" he asked. "For the last 20 or 30 years we've been talking about the ABCD features, but maybe we could add something along the lines of, 'Look for the ABCD features, but if you see a lesion on your skin that looks different than the surrounding lesions on your skin—even if it doesn't have the ABCDs—see a dermatologist.'"

The ugly duckling sign was first described in 1998 by Dr. Jean-Jacques Grob of the University of Marseille in Provence, France. It holds that nevi on a given individual tend to resemble each other: "Moles breed true," said Dr. Marghoob, a dermatologist at Memorial Sloan-Kettering Cancer Center, New York.

The ugly duckling—the outlier, the exceptional nevus, the one that looks different from the others—is more likely to be a melanoma, even if it does not exhibit the classic features ascribed to melanoma in the ABCD rule.

The ABCD acronym "has served us well" in the early recognition of melanoma, said Dr. Marghoob, but it has shortcomings: There is morphologic overlap with dysplastic nevi, resulting in many unnecessary excisions. Also, the ABCD criterion does not fit for many thin melanomas.

To test the utility of the ugly duckling sign when applied by a diverse group of people, Dr. Marghoob and coinvestigators assembled a portfolio of digital photographs of the backs of 12 patients at high risk for melanoma. Each of the patients had at least eight dysplastic nevi on their back.

In five patients, one of the skin lesions was a melanoma which was removed and histologically confirmed after the pictures were taken. The photo spread included whole-back overview images as well as clinical closeups of a total of 145 lesions.

The lesion raters consisted of 13 general dermatologists, 8 dermatologists with special expertise in pigmented lesions, 5 nurses, and 8 secretaries and other nonclinical hospital staff. They were asked if any of the 145 nevi differed from the others on the patients' backs.

There was excellent agreement on the ugly duckling sign among observers. All five melanomas but only 3 of 140 benign nevi were identified as ugly duckling lesions by at least two-thirds of the raters. The sensitivity of the ugly duckling sign—that is, the percentage of melanomas identified as "different"—was 100% for the experts, 89% for the general dermatologists, 88% for the nurses, and 85% for the nonclinicians. For the overall group, the sensitivity of the ugly duckling sign was 90% (Arch. Dermatol. 2008;144:58–64).

That 85% sensitivity when the ugly duckling sign was applied by nonclinicians is much higher than the percentage seen in studies of the ABCD method, Dr. Marghoob observed.

He noted that the overall melanoma survival rate in the United States has soared from less than 60% in 1970 to greater than 90% in 2008. This extremely impressive gain is mainly a result of improved detection of early disease, since there are still no effective systemic therapies for advanced melanoma.

Widespread adoption of the ugly duckling sign could be a further step forward in early diagnosis of melanoma. Total body photography, dermoscopy, and confocal microscopy are additional tools likely to lead to further improvements, he said.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

The ABCD acronym 'has served us well' in the early recognition of melanoma, but it has shortcomings. DR. MARGHOOB

WAIKOLOA, HAWAII — The "ugly duckling" sign showed impressive sensitivity for melanoma when applied by physicians as well as nonmedically trained individuals for rating melanocytic lesions, according to Dr. Ashfaq A. Marghoob.

The results of this study suggest the ugly duckling sign may be a valuable melanoma screening tool readily teachable to primary care physicians, nurse practitioners, and patients performing periodic skin self-examination, Dr. Marghoob reported at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

"Could this be a new public health message?" he asked. "For the last 20 or 30 years we've been talking about the ABCD features, but maybe we could add something along the lines of, 'Look for the ABCD features, but if you see a lesion on your skin that looks different than the surrounding lesions on your skin—even if it doesn't have the ABCDs—see a dermatologist.'"

The ugly duckling sign was first described in 1998 by Dr. Jean-Jacques Grob of the University of Marseille in Provence, France. It holds that nevi on a given individual tend to resemble each other: "Moles breed true," said Dr. Marghoob, a dermatologist at Memorial Sloan-Kettering Cancer Center, New York.

The ugly duckling—the outlier, the exceptional nevus, the one that looks different from the others—is more likely to be a melanoma, even if it does not exhibit the classic features ascribed to melanoma in the ABCD rule.

The ABCD acronym "has served us well" in the early recognition of melanoma, said Dr. Marghoob, but it has shortcomings: There is morphologic overlap with dysplastic nevi, resulting in many unnecessary excisions. Also, the ABCD criterion does not fit for many thin melanomas.

To test the utility of the ugly duckling sign when applied by a diverse group of people, Dr. Marghoob and coinvestigators assembled a portfolio of digital photographs of the backs of 12 patients at high risk for melanoma. Each of the patients had at least eight dysplastic nevi on their back.

In five patients, one of the skin lesions was a melanoma which was removed and histologically confirmed after the pictures were taken. The photo spread included whole-back overview images as well as clinical closeups of a total of 145 lesions.

The lesion raters consisted of 13 general dermatologists, 8 dermatologists with special expertise in pigmented lesions, 5 nurses, and 8 secretaries and other nonclinical hospital staff. They were asked if any of the 145 nevi differed from the others on the patients' backs.

There was excellent agreement on the ugly duckling sign among observers. All five melanomas but only 3 of 140 benign nevi were identified as ugly duckling lesions by at least two-thirds of the raters. The sensitivity of the ugly duckling sign—that is, the percentage of melanomas identified as "different"—was 100% for the experts, 89% for the general dermatologists, 88% for the nurses, and 85% for the nonclinicians. For the overall group, the sensitivity of the ugly duckling sign was 90% (Arch. Dermatol. 2008;144:58–64).

That 85% sensitivity when the ugly duckling sign was applied by nonclinicians is much higher than the percentage seen in studies of the ABCD method, Dr. Marghoob observed.

He noted that the overall melanoma survival rate in the United States has soared from less than 60% in 1970 to greater than 90% in 2008. This extremely impressive gain is mainly a result of improved detection of early disease, since there are still no effective systemic therapies for advanced melanoma.

Widespread adoption of the ugly duckling sign could be a further step forward in early diagnosis of melanoma. Total body photography, dermoscopy, and confocal microscopy are additional tools likely to lead to further improvements, he said.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

The ABCD acronym 'has served us well' in the early recognition of melanoma, but it has shortcomings. DR. MARGHOOB

WAIKOLOA, HAWAII — The "ugly duckling" sign showed impressive sensitivity for melanoma when applied by physicians as well as nonmedically trained individuals for rating melanocytic lesions, according to Dr. Ashfaq A. Marghoob.

The results of this study suggest the ugly duckling sign may be a valuable melanoma screening tool readily teachable to primary care physicians, nurse practitioners, and patients performing periodic skin self-examination, Dr. Marghoob reported at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

"Could this be a new public health message?" he asked. "For the last 20 or 30 years we've been talking about the ABCD features, but maybe we could add something along the lines of, 'Look for the ABCD features, but if you see a lesion on your skin that looks different than the surrounding lesions on your skin—even if it doesn't have the ABCDs—see a dermatologist.'"

The ugly duckling sign was first described in 1998 by Dr. Jean-Jacques Grob of the University of Marseille in Provence, France. It holds that nevi on a given individual tend to resemble each other: "Moles breed true," said Dr. Marghoob, a dermatologist at Memorial Sloan-Kettering Cancer Center, New York.

The ugly duckling—the outlier, the exceptional nevus, the one that looks different from the others—is more likely to be a melanoma, even if it does not exhibit the classic features ascribed to melanoma in the ABCD rule.

The ABCD acronym "has served us well" in the early recognition of melanoma, said Dr. Marghoob, but it has shortcomings: There is morphologic overlap with dysplastic nevi, resulting in many unnecessary excisions. Also, the ABCD criterion does not fit for many thin melanomas.

To test the utility of the ugly duckling sign when applied by a diverse group of people, Dr. Marghoob and coinvestigators assembled a portfolio of digital photographs of the backs of 12 patients at high risk for melanoma. Each of the patients had at least eight dysplastic nevi on their back.

In five patients, one of the skin lesions was a melanoma which was removed and histologically confirmed after the pictures were taken. The photo spread included whole-back overview images as well as clinical closeups of a total of 145 lesions.

The lesion raters consisted of 13 general dermatologists, 8 dermatologists with special expertise in pigmented lesions, 5 nurses, and 8 secretaries and other nonclinical hospital staff. They were asked if any of the 145 nevi differed from the others on the patients' backs.

There was excellent agreement on the ugly duckling sign among observers. All five melanomas but only 3 of 140 benign nevi were identified as ugly duckling lesions by at least two-thirds of the raters. The sensitivity of the ugly duckling sign—that is, the percentage of melanomas identified as "different"—was 100% for the experts, 89% for the general dermatologists, 88% for the nurses, and 85% for the nonclinicians. For the overall group, the sensitivity of the ugly duckling sign was 90% (Arch. Dermatol. 2008;144:58–64).

That 85% sensitivity when the ugly duckling sign was applied by nonclinicians is much higher than the percentage seen in studies of the ABCD method, Dr. Marghoob observed.

He noted that the overall melanoma survival rate in the United States has soared from less than 60% in 1970 to greater than 90% in 2008. This extremely impressive gain is mainly a result of improved detection of early disease, since there are still no effective systemic therapies for advanced melanoma.

Widespread adoption of the ugly duckling sign could be a further step forward in early diagnosis of melanoma. Total body photography, dermoscopy, and confocal microscopy are additional tools likely to lead to further improvements, he said.

SDEF and SKIN & ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

The ABCD acronym 'has served us well' in the early recognition of melanoma, but it has shortcomings. DR. MARGHOOB

SAN DIEGO — A custom-designed inhibitor of a mutation in the Hedgehog signaling pathway stimulated antitumor activity in eight of nine patients with locally advanced, multifocal, or metastatic basal cell carcinoma in phase I interim trial results presented at the annual meeting of the American Association for Cancer Research.

Patients in the small, ongoing trial experienced healing of their lesions, diminishment of pain and fatigue, and improvement in dyspnea while taking the study drug GDC-0449 for periods ranging from 120 to 438 days.

"These responses were pretty dramatic, [beginning] within 2–3 weeks of starting the drug," said Dr. Daniel D. Von Hoff, senior investigator and director of translational research for the Translational Genomics Research Institute in Scottsdale, Ariz.

Basal cell carcinoma is the most common malignancy in humans, diagnosed in approximately 1 million U.S. patients per year. While it typically grows slowly and can be managed by local excision or ionizing radiation, it may infiltrate surrounding tissue. In rare cases (less than 0.1%), it becomes metastatic, most commonly to the lung, liver, and/or bone.

The first three patients enrolled in the study received daily doses of 150 mg, 270 mg, and 540 mg, respectively, of GDC-0449, a synthetic, revved-up version of the naturally occurring Hedgehog pathway antagonist cyclopamine. When antitumor activity was confirmed, six more patients were enrolled, all receiving the 150-mg/day dose.

The average patient was aged 61 years (range 42–85 years). Eight were men.

All had undergone surgery (some as many as 20 operations) for their basal cell carcinoma. Four had received radiation, and three were given chemotherapy. Five patients had metastatic disease, two had locally advanced disease of the ear, and two had multifocal disease.

Among four of the patients with metastatic disease, two had a confirmed partial response, one had stable disease, and one progressed while on the study drug and died of his disease. It is too early to assess the response of one recently enrolled patient with metastatic disease, according to Dr. Von Hoff.

In four patients with clinically evaluable locally advanced or multifocal disease, two had a complete response and two had stable disease, meaning that their skin lesions were not advancing.

Metabolic responses to chemotherapy were demonstrated in all five patients who had undergone positron emission tomography evaluations at the time of the presentation, Dr. Van Hoff reported during a late-breaking session.

"Toxicities were relatively mild," he said; they included dysgeusia, an alteration in taste sensations; mild alopecia; mild weight loss; and hyponatremia.

The drug's development represented what Dr. Von Hoff called, "the essence of translational medicine." Molecular biologists first discovered that aberrance in the Hedgehog signaling pathway triggered when patched (PTCH) or smoothened (SMO) gene mutations caused an acceleration of cell growth that proved instrumental in the development of either sporadic or hereditary basal cell carcinoma.

Nature then played a role, he noted.

Serendipitously, it was discovered that cyclopamine, a naturally occurring inhibitor of the SMO mutation, could be found in pregnant ewes that ate corn lilies in the western United States and subsequently gave birth to cyclopslike lambs with oversize heads and a single, central eye.

Genentech Inc., in conjunction with the Curis Inc., developed a synthetic version of cyclopamine 100 times more potent than the version found in corn lilies, naming the agent GDC-0449.

Patients, including Subject #1 in the phase I study, "knew the drug was coming and hung on." Although metastatic basal cell carcinoma is very rare, its prognosis is poor, with a mean survival of approximately 5 months, said Dr. Von Hoff.

Formal discussant Dr. Ervin Epstein of the Children's Hospital Oakland (Calif.) Research Institute noted that many unanswered questions remain about GDC-0449, but he said that, as a "card-carrying dermatologist," he is "full of optimism … that help is on the way."

Dr. Von Hoff receives research grant support from Genentech, developer of GDC-0449. Dr. Epstein is a consultant for Genentech and owns stock in Curis.

SAN DIEGO — A custom-designed inhibitor of a mutation in the Hedgehog signaling pathway stimulated antitumor activity in eight of nine patients with locally advanced, multifocal, or metastatic basal cell carcinoma in phase I interim trial results presented at the annual meeting of the American Association for Cancer Research.

Patients in the small, ongoing trial experienced healing of their lesions, diminishment of pain and fatigue, and improvement in dyspnea while taking the study drug GDC-0449 for periods ranging from 120 to 438 days.

"These responses were pretty dramatic, [beginning] within 2–3 weeks of starting the drug," said Dr. Daniel D. Von Hoff, senior investigator and director of translational research for the Translational Genomics Research Institute in Scottsdale, Ariz.

Basal cell carcinoma is the most common malignancy in humans, diagnosed in approximately 1 million U.S. patients per year. While it typically grows slowly and can be managed by local excision or ionizing radiation, it may infiltrate surrounding tissue. In rare cases (less than 0.1%), it becomes metastatic, most commonly to the lung, liver, and/or bone.

The first three patients enrolled in the study received daily doses of 150 mg, 270 mg, and 540 mg, respectively, of GDC-0449, a synthetic, revved-up version of the naturally occurring Hedgehog pathway antagonist cyclopamine. When antitumor activity was confirmed, six more patients were enrolled, all receiving the 150-mg/day dose.

The average patient was aged 61 years (range 42–85 years). Eight were men.

All had undergone surgery (some as many as 20 operations) for their basal cell carcinoma. Four had received radiation, and three were given chemotherapy. Five patients had metastatic disease, two had locally advanced disease of the ear, and two had multifocal disease.

Among four of the patients with metastatic disease, two had a confirmed partial response, one had stable disease, and one progressed while on the study drug and died of his disease. It is too early to assess the response of one recently enrolled patient with metastatic disease, according to Dr. Von Hoff.

In four patients with clinically evaluable locally advanced or multifocal disease, two had a complete response and two had stable disease, meaning that their skin lesions were not advancing.

Metabolic responses to chemotherapy were demonstrated in all five patients who had undergone positron emission tomography evaluations at the time of the presentation, Dr. Van Hoff reported during a late-breaking session.

"Toxicities were relatively mild," he said; they included dysgeusia, an alteration in taste sensations; mild alopecia; mild weight loss; and hyponatremia.

The drug's development represented what Dr. Von Hoff called, "the essence of translational medicine." Molecular biologists first discovered that aberrance in the Hedgehog signaling pathway triggered when patched (PTCH) or smoothened (SMO) gene mutations caused an acceleration of cell growth that proved instrumental in the development of either sporadic or hereditary basal cell carcinoma.

Nature then played a role, he noted.

Serendipitously, it was discovered that cyclopamine, a naturally occurring inhibitor of the SMO mutation, could be found in pregnant ewes that ate corn lilies in the western United States and subsequently gave birth to cyclopslike lambs with oversize heads and a single, central eye.

Genentech Inc., in conjunction with the Curis Inc., developed a synthetic version of cyclopamine 100 times more potent than the version found in corn lilies, naming the agent GDC-0449.

Patients, including Subject #1 in the phase I study, "knew the drug was coming and hung on." Although metastatic basal cell carcinoma is very rare, its prognosis is poor, with a mean survival of approximately 5 months, said Dr. Von Hoff.

Formal discussant Dr. Ervin Epstein of the Children's Hospital Oakland (Calif.) Research Institute noted that many unanswered questions remain about GDC-0449, but he said that, as a "card-carrying dermatologist," he is "full of optimism … that help is on the way."

Dr. Von Hoff receives research grant support from Genentech, developer of GDC-0449. Dr. Epstein is a consultant for Genentech and owns stock in Curis.

SAN DIEGO — A custom-designed inhibitor of a mutation in the Hedgehog signaling pathway stimulated antitumor activity in eight of nine patients with locally advanced, multifocal, or metastatic basal cell carcinoma in phase I interim trial results presented at the annual meeting of the American Association for Cancer Research.

Patients in the small, ongoing trial experienced healing of their lesions, diminishment of pain and fatigue, and improvement in dyspnea while taking the study drug GDC-0449 for periods ranging from 120 to 438 days.

"These responses were pretty dramatic, [beginning] within 2–3 weeks of starting the drug," said Dr. Daniel D. Von Hoff, senior investigator and director of translational research for the Translational Genomics Research Institute in Scottsdale, Ariz.

Basal cell carcinoma is the most common malignancy in humans, diagnosed in approximately 1 million U.S. patients per year. While it typically grows slowly and can be managed by local excision or ionizing radiation, it may infiltrate surrounding tissue. In rare cases (less than 0.1%), it becomes metastatic, most commonly to the lung, liver, and/or bone.

The first three patients enrolled in the study received daily doses of 150 mg, 270 mg, and 540 mg, respectively, of GDC-0449, a synthetic, revved-up version of the naturally occurring Hedgehog pathway antagonist cyclopamine. When antitumor activity was confirmed, six more patients were enrolled, all receiving the 150-mg/day dose.

The average patient was aged 61 years (range 42–85 years). Eight were men.

All had undergone surgery (some as many as 20 operations) for their basal cell carcinoma. Four had received radiation, and three were given chemotherapy. Five patients had metastatic disease, two had locally advanced disease of the ear, and two had multifocal disease.

Among four of the patients with metastatic disease, two had a confirmed partial response, one had stable disease, and one progressed while on the study drug and died of his disease. It is too early to assess the response of one recently enrolled patient with metastatic disease, according to Dr. Von Hoff.

In four patients with clinically evaluable locally advanced or multifocal disease, two had a complete response and two had stable disease, meaning that their skin lesions were not advancing.

Metabolic responses to chemotherapy were demonstrated in all five patients who had undergone positron emission tomography evaluations at the time of the presentation, Dr. Van Hoff reported during a late-breaking session.

"Toxicities were relatively mild," he said; they included dysgeusia, an alteration in taste sensations; mild alopecia; mild weight loss; and hyponatremia.

The drug's development represented what Dr. Von Hoff called, "the essence of translational medicine." Molecular biologists first discovered that aberrance in the Hedgehog signaling pathway triggered when patched (PTCH) or smoothened (SMO) gene mutations caused an acceleration of cell growth that proved instrumental in the development of either sporadic or hereditary basal cell carcinoma.

Nature then played a role, he noted.

Serendipitously, it was discovered that cyclopamine, a naturally occurring inhibitor of the SMO mutation, could be found in pregnant ewes that ate corn lilies in the western United States and subsequently gave birth to cyclopslike lambs with oversize heads and a single, central eye.

Genentech Inc., in conjunction with the Curis Inc., developed a synthetic version of cyclopamine 100 times more potent than the version found in corn lilies, naming the agent GDC-0449.

Patients, including Subject #1 in the phase I study, "knew the drug was coming and hung on." Although metastatic basal cell carcinoma is very rare, its prognosis is poor, with a mean survival of approximately 5 months, said Dr. Von Hoff.

Formal discussant Dr. Ervin Epstein of the Children's Hospital Oakland (Calif.) Research Institute noted that many unanswered questions remain about GDC-0449, but he said that, as a "card-carrying dermatologist," he is "full of optimism … that help is on the way."

Dr. Von Hoff receives research grant support from Genentech, developer of GDC-0449. Dr. Epstein is a consultant for Genentech and owns stock in Curis.

WAIKOLOA, HAWAII — Researchers, frustrated by more than 3 decades of entirely negative clinical trials that were aimed at establishing new treatments for metastatic melanoma, have pinned their hopes on targeted mitogen-activated protein kinase inhibitors.

"In metastatic melanoma, we have no defensible treatment standard. There are a few treatments that are offered to patients with the possibility of some palliative benefit, but little to no possibility of curative benefit," Dr. Keith T. Flaherty said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

This dismal current state accounts for the hopeful buzz surrounding the investigational targeted mitogen-activated protein (MAP) kinase inhibitors, said Dr. Flaherty, who is on the advisory boards of AstraZeneca Pharmaceuticals LP and Schering-Plough Corp., which are actively pursuing development of targeted inhibitors.

It is unlikely, though, that any of these agents will be effective as single-agent therapy. Multiple concomitant mutations in different signal transduction pathways are a hallmark of metastatic melanoma, so when one pathway is blocked, another is likely to increase compensatory signalling.

"Ultimately, combination targeted therapy is the direction we're going. We think that's what one is going to need to counter the various signal transduction pathways which are simultaneously activated in this disease. It's not a single pathway that drives this disease, and we need to take that complexity into account," said Dr. Flaherty, a medical oncologist who is clinical investigations program leader at the University of Pennsylvania, Philadelphia.

That being said, the field hasn't advanced to the point where definitive clinical trials of combinations of targeted therapies can be done. There simply aren't enough signal transduction inhibitors available.

In the interim, investigators are exploring the therapeutic potential of single-agent MAP kinase pathway inhibitor therapy in combination with conventional chemotherapy. Encouraging preclinical studies suggest that there is a synergistic apoptotic effect, and a few small clinical trials have shown a modest benefit, Dr. Flaherty said.

For example, when sorafenib (Nexavar), the first BRAF inhibitor, was combined with dacarbazine in a phase II randomized trial involving 101 chemotherapy-naive patients, the objective response rate doubled, compared with the 12% figure for dacarbazine alone. Progression-free survival improved from 2.7 months with chemotherapy alone to 4.9 months with combination therapy.

In another randomized phase-II study, however—this one in chemotherapy-refractory patients—the addition of sorafenib brought no benefit over chemotherapy alone. So if sorafenib does enhance the effects of chemotherapy, it's a benefit that seems to be restricted to chemotherapy-naive patients.

The definitive phase III study of this approach is underway: Accrual is nearly complete in a study randomizing 800 metastatic melanoma patients with no prior chemotherapy to carboplatin/paclitaxel alone or combined with sorafenib. The primary end point is overall survival.

Sorafenib has proved to be unimpressive as single-agent therapy in metastatic melanoma. It is an unselective agent that hits numerous other targets in addition to BRAF, and the impedance of these collateral targets may cause toxicity without contributing to efficacy, thereby limiting the ability to deliver enough of the oral drug to inhibit BRAF, Dr. Flaherty explained.

Newer, more potent, and selective orally administered MAP kinase pathway inhibitors are now entering early dose-finding, proof-of-concept clinical trials. These promising agents include RAF265 and PLX4032, by far the most selective of them all, and animal studies suggest that they will be more efficacious than sorafenib.

SDEF and SKIN &ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

'It's not a single pathway that drives this disease, and we need to take that complexity into account.' DR. FLAHERTY

WAIKOLOA, HAWAII — Researchers, frustrated by more than 3 decades of entirely negative clinical trials that were aimed at establishing new treatments for metastatic melanoma, have pinned their hopes on targeted mitogen-activated protein kinase inhibitors.

"In metastatic melanoma, we have no defensible treatment standard. There are a few treatments that are offered to patients with the possibility of some palliative benefit, but little to no possibility of curative benefit," Dr. Keith T. Flaherty said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

This dismal current state accounts for the hopeful buzz surrounding the investigational targeted mitogen-activated protein (MAP) kinase inhibitors, said Dr. Flaherty, who is on the advisory boards of AstraZeneca Pharmaceuticals LP and Schering-Plough Corp., which are actively pursuing development of targeted inhibitors.

It is unlikely, though, that any of these agents will be effective as single-agent therapy. Multiple concomitant mutations in different signal transduction pathways are a hallmark of metastatic melanoma, so when one pathway is blocked, another is likely to increase compensatory signalling.

"Ultimately, combination targeted therapy is the direction we're going. We think that's what one is going to need to counter the various signal transduction pathways which are simultaneously activated in this disease. It's not a single pathway that drives this disease, and we need to take that complexity into account," said Dr. Flaherty, a medical oncologist who is clinical investigations program leader at the University of Pennsylvania, Philadelphia.

That being said, the field hasn't advanced to the point where definitive clinical trials of combinations of targeted therapies can be done. There simply aren't enough signal transduction inhibitors available.

In the interim, investigators are exploring the therapeutic potential of single-agent MAP kinase pathway inhibitor therapy in combination with conventional chemotherapy. Encouraging preclinical studies suggest that there is a synergistic apoptotic effect, and a few small clinical trials have shown a modest benefit, Dr. Flaherty said.

For example, when sorafenib (Nexavar), the first BRAF inhibitor, was combined with dacarbazine in a phase II randomized trial involving 101 chemotherapy-naive patients, the objective response rate doubled, compared with the 12% figure for dacarbazine alone. Progression-free survival improved from 2.7 months with chemotherapy alone to 4.9 months with combination therapy.

In another randomized phase-II study, however—this one in chemotherapy-refractory patients—the addition of sorafenib brought no benefit over chemotherapy alone. So if sorafenib does enhance the effects of chemotherapy, it's a benefit that seems to be restricted to chemotherapy-naive patients.

The definitive phase III study of this approach is underway: Accrual is nearly complete in a study randomizing 800 metastatic melanoma patients with no prior chemotherapy to carboplatin/paclitaxel alone or combined with sorafenib. The primary end point is overall survival.

Sorafenib has proved to be unimpressive as single-agent therapy in metastatic melanoma. It is an unselective agent that hits numerous other targets in addition to BRAF, and the impedance of these collateral targets may cause toxicity without contributing to efficacy, thereby limiting the ability to deliver enough of the oral drug to inhibit BRAF, Dr. Flaherty explained.

Newer, more potent, and selective orally administered MAP kinase pathway inhibitors are now entering early dose-finding, proof-of-concept clinical trials. These promising agents include RAF265 and PLX4032, by far the most selective of them all, and animal studies suggest that they will be more efficacious than sorafenib.

SDEF and SKIN &ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

'It's not a single pathway that drives this disease, and we need to take that complexity into account.' DR. FLAHERTY

WAIKOLOA, HAWAII — Researchers, frustrated by more than 3 decades of entirely negative clinical trials that were aimed at establishing new treatments for metastatic melanoma, have pinned their hopes on targeted mitogen-activated protein kinase inhibitors.

"In metastatic melanoma, we have no defensible treatment standard. There are a few treatments that are offered to patients with the possibility of some palliative benefit, but little to no possibility of curative benefit," Dr. Keith T. Flaherty said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

This dismal current state accounts for the hopeful buzz surrounding the investigational targeted mitogen-activated protein (MAP) kinase inhibitors, said Dr. Flaherty, who is on the advisory boards of AstraZeneca Pharmaceuticals LP and Schering-Plough Corp., which are actively pursuing development of targeted inhibitors.

It is unlikely, though, that any of these agents will be effective as single-agent therapy. Multiple concomitant mutations in different signal transduction pathways are a hallmark of metastatic melanoma, so when one pathway is blocked, another is likely to increase compensatory signalling.

"Ultimately, combination targeted therapy is the direction we're going. We think that's what one is going to need to counter the various signal transduction pathways which are simultaneously activated in this disease. It's not a single pathway that drives this disease, and we need to take that complexity into account," said Dr. Flaherty, a medical oncologist who is clinical investigations program leader at the University of Pennsylvania, Philadelphia.

That being said, the field hasn't advanced to the point where definitive clinical trials of combinations of targeted therapies can be done. There simply aren't enough signal transduction inhibitors available.

In the interim, investigators are exploring the therapeutic potential of single-agent MAP kinase pathway inhibitor therapy in combination with conventional chemotherapy. Encouraging preclinical studies suggest that there is a synergistic apoptotic effect, and a few small clinical trials have shown a modest benefit, Dr. Flaherty said.

For example, when sorafenib (Nexavar), the first BRAF inhibitor, was combined with dacarbazine in a phase II randomized trial involving 101 chemotherapy-naive patients, the objective response rate doubled, compared with the 12% figure for dacarbazine alone. Progression-free survival improved from 2.7 months with chemotherapy alone to 4.9 months with combination therapy.

In another randomized phase-II study, however—this one in chemotherapy-refractory patients—the addition of sorafenib brought no benefit over chemotherapy alone. So if sorafenib does enhance the effects of chemotherapy, it's a benefit that seems to be restricted to chemotherapy-naive patients.

The definitive phase III study of this approach is underway: Accrual is nearly complete in a study randomizing 800 metastatic melanoma patients with no prior chemotherapy to carboplatin/paclitaxel alone or combined with sorafenib. The primary end point is overall survival.

Sorafenib has proved to be unimpressive as single-agent therapy in metastatic melanoma. It is an unselective agent that hits numerous other targets in addition to BRAF, and the impedance of these collateral targets may cause toxicity without contributing to efficacy, thereby limiting the ability to deliver enough of the oral drug to inhibit BRAF, Dr. Flaherty explained.

Newer, more potent, and selective orally administered MAP kinase pathway inhibitors are now entering early dose-finding, proof-of-concept clinical trials. These promising agents include RAF265 and PLX4032, by far the most selective of them all, and animal studies suggest that they will be more efficacious than sorafenib.

SDEF and SKIN &ALLERGY NEWS are wholly owned subsidiaries of Elsevier.

'It's not a single pathway that drives this disease, and we need to take that complexity into account.' DR. FLAHERTY

CHICAGO — Isolated limb infusion, a minimally invasive technique to deliver regional chemotherapy, was useful but not optimal in two melanoma studies presented at a symposium sponsored by the Society of Surgical Oncology.

In the largest isolated limb infusion (ILI) series conducted to date, involving 185 patients with advanced metastatic melanoma confined to the limb, the overall survival rate was 84% at a median follow-up of 20 months, said lead investigator Dr. Hidde Kroon, a fellow at the Sydney Melanoma Unit in Australia, where the study was performed and the technique was developed.

He reported the highest rates to date for complete response (38%) and for partial response (46%) to chemotherapy. Stable disease was seen in 10% of patients and progressive disease in 6%.

In the largest study outside Australia, however, U.S. and Taiwanese investigators concluded that isolated limb infusion was an effective way to regionally administer the cytotoxic agent melphalan, but that its efficacy fell short of isolated limb perfusion (ILP).

Sydney Melanoma Unit Experience

Dr. Kroon said that the duration of response was significantly longer in patients achieving a complete response (median 22 months) than was observed overall (median 13 months) in the Australian study.

"Response rates and duration of response after isolated limb infusion are at the lower end of those reported after conventional isolated limb perfusion," Dr. Kroon acknowledged.

"However, ILI was performed in patients with [higher stages] of disease and more comorbidities, which might explain the lower response rates, since stage of disease is a significant risk factor for responses," he said.

Most patients in the study (134, or 72%) had M.D. Anderson stage IIIA or IIIAB disease, with 3% having stage I, 8% stage II, and 16% stage IV disease.

Isolated limb infusion is essentially a low-flow ILP performed without oxygenation via percutaneous catheters. It is a minimally invasive alternative to the more labor-intensive ILP, requires no routine blood transfusion, and can be easily repeated if necessary, Dr. Kroon explained. Results have been promising, but it has not been established whether it is equally effective as isolated limb perfusion.

Patients in the Australian series were treated from 1992 to 2006 with a single isolated limb infusion of melphalan and actinomycin D for 20–30 minutes under mild hyperthermic conditions. Their mean age was 74 years (range, 29–93 years), and the majority (62%) were female. Disease was present in the lower limb in 172 patients, and in the upper limb in 13.

The response rate significantly decreased with increasing stage of disease, Dr. Kroon said.

Response rates were 83% in stage I patients, 53% in stage II, 43% in stage IIIA, 33% in stage IIIAB, and 23% in stage IV.

Median overall survival was 38 months, but increased significantly to 53 months in patients achieving a complete response, he reported.

In a multivariate analysis, independent prognostic factors for complete response were lower disease stage (hazard ratio, 1.69) and greater increase in CO₂ level during the procedure (HR, 1.65).

The procedure was well tolerated, with only five patients developing grade 4 toxicity, and there were no amputations, said Dr. Kroon, who reported no conflicts of interest.

"We conclude that isolated limb infusion is a safe and effective alternative to conventional isolated limb perfusion to treat advanced metastatic melanoma in a limb," he said.

U.S./Taiwanese Experience

Lead investigator Dr. Georgia Beasley of the Duke University Medical Center in Durham, N.C., and associates compared outcomes after 59 ILP treatments in 54 patients against outcomes after 61 ILI treatments in 58 patients, all with in-transit malignant melanoma of the extremity.

Among 50 evaluable ILI patients, complete response was reported in 15 (30%), partial response in 7 (14%), stable disease in 5 (10%), and progressive disease in 23 (46%). The median duration of complete response was 12 months.

Isolated limb perfusion was associated with significantly better response at 3 months (complete response, 57%; partial response, 31%; and no response, 12%); however, significantly more ILP patients had grade 3 or greater toxicity, Dr. Beasley said.

There were nine compartment syndromes and two amputations among ILP patients, versus four compartment syndromes and no amputations among ILI patients.

"In our experience, limb infusion using melphalan did not appear to be as effective as limb perfusion, although the toxicity appears less," Dr. Beasley said.

The investigators noted that correcting the melphalan dose for ideal body weight appeared to minimize toxicity without altering response rates; 66% of ILI patients had their dose corrected, versus only 22% of ILP patients.

CHICAGO — Isolated limb infusion, a minimally invasive technique to deliver regional chemotherapy, was useful but not optimal in two melanoma studies presented at a symposium sponsored by the Society of Surgical Oncology.

In the largest isolated limb infusion (ILI) series conducted to date, involving 185 patients with advanced metastatic melanoma confined to the limb, the overall survival rate was 84% at a median follow-up of 20 months, said lead investigator Dr. Hidde Kroon, a fellow at the Sydney Melanoma Unit in Australia, where the study was performed and the technique was developed.

He reported the highest rates to date for complete response (38%) and for partial response (46%) to chemotherapy. Stable disease was seen in 10% of patients and progressive disease in 6%.

In the largest study outside Australia, however, U.S. and Taiwanese investigators concluded that isolated limb infusion was an effective way to regionally administer the cytotoxic agent melphalan, but that its efficacy fell short of isolated limb perfusion (ILP).

Sydney Melanoma Unit Experience

Dr. Kroon said that the duration of response was significantly longer in patients achieving a complete response (median 22 months) than was observed overall (median 13 months) in the Australian study.

"Response rates and duration of response after isolated limb infusion are at the lower end of those reported after conventional isolated limb perfusion," Dr. Kroon acknowledged.

"However, ILI was performed in patients with [higher stages] of disease and more comorbidities, which might explain the lower response rates, since stage of disease is a significant risk factor for responses," he said.

Most patients in the study (134, or 72%) had M.D. Anderson stage IIIA or IIIAB disease, with 3% having stage I, 8% stage II, and 16% stage IV disease.

Isolated limb infusion is essentially a low-flow ILP performed without oxygenation via percutaneous catheters. It is a minimally invasive alternative to the more labor-intensive ILP, requires no routine blood transfusion, and can be easily repeated if necessary, Dr. Kroon explained. Results have been promising, but it has not been established whether it is equally effective as isolated limb perfusion.

Patients in the Australian series were treated from 1992 to 2006 with a single isolated limb infusion of melphalan and actinomycin D for 20–30 minutes under mild hyperthermic conditions. Their mean age was 74 years (range, 29–93 years), and the majority (62%) were female. Disease was present in the lower limb in 172 patients, and in the upper limb in 13.

The response rate significantly decreased with increasing stage of disease, Dr. Kroon said.

Response rates were 83% in stage I patients, 53% in stage II, 43% in stage IIIA, 33% in stage IIIAB, and 23% in stage IV.

Median overall survival was 38 months, but increased significantly to 53 months in patients achieving a complete response, he reported.

In a multivariate analysis, independent prognostic factors for complete response were lower disease stage (hazard ratio, 1.69) and greater increase in CO₂ level during the procedure (HR, 1.65).

The procedure was well tolerated, with only five patients developing grade 4 toxicity, and there were no amputations, said Dr. Kroon, who reported no conflicts of interest.

"We conclude that isolated limb infusion is a safe and effective alternative to conventional isolated limb perfusion to treat advanced metastatic melanoma in a limb," he said.

U.S./Taiwanese Experience

Lead investigator Dr. Georgia Beasley of the Duke University Medical Center in Durham, N.C., and associates compared outcomes after 59 ILP treatments in 54 patients against outcomes after 61 ILI treatments in 58 patients, all with in-transit malignant melanoma of the extremity.

Among 50 evaluable ILI patients, complete response was reported in 15 (30%), partial response in 7 (14%), stable disease in 5 (10%), and progressive disease in 23 (46%). The median duration of complete response was 12 months.

Isolated limb perfusion was associated with significantly better response at 3 months (complete response, 57%; partial response, 31%; and no response, 12%); however, significantly more ILP patients had grade 3 or greater toxicity, Dr. Beasley said.

There were nine compartment syndromes and two amputations among ILP patients, versus four compartment syndromes and no amputations among ILI patients.

"In our experience, limb infusion using melphalan did not appear to be as effective as limb perfusion, although the toxicity appears less," Dr. Beasley said.

The investigators noted that correcting the melphalan dose for ideal body weight appeared to minimize toxicity without altering response rates; 66% of ILI patients had their dose corrected, versus only 22% of ILP patients.

CHICAGO — Isolated limb infusion, a minimally invasive technique to deliver regional chemotherapy, was useful but not optimal in two melanoma studies presented at a symposium sponsored by the Society of Surgical Oncology.

In the largest isolated limb infusion (ILI) series conducted to date, involving 185 patients with advanced metastatic melanoma confined to the limb, the overall survival rate was 84% at a median follow-up of 20 months, said lead investigator Dr. Hidde Kroon, a fellow at the Sydney Melanoma Unit in Australia, where the study was performed and the technique was developed.

He reported the highest rates to date for complete response (38%) and for partial response (46%) to chemotherapy. Stable disease was seen in 10% of patients and progressive disease in 6%.

In the largest study outside Australia, however, U.S. and Taiwanese investigators concluded that isolated limb infusion was an effective way to regionally administer the cytotoxic agent melphalan, but that its efficacy fell short of isolated limb perfusion (ILP).

Sydney Melanoma Unit Experience

Dr. Kroon said that the duration of response was significantly longer in patients achieving a complete response (median 22 months) than was observed overall (median 13 months) in the Australian study.

"Response rates and duration of response after isolated limb infusion are at the lower end of those reported after conventional isolated limb perfusion," Dr. Kroon acknowledged.

"However, ILI was performed in patients with [higher stages] of disease and more comorbidities, which might explain the lower response rates, since stage of disease is a significant risk factor for responses," he said.

Most patients in the study (134, or 72%) had M.D. Anderson stage IIIA or IIIAB disease, with 3% having stage I, 8% stage II, and 16% stage IV disease.

Isolated limb infusion is essentially a low-flow ILP performed without oxygenation via percutaneous catheters. It is a minimally invasive alternative to the more labor-intensive ILP, requires no routine blood transfusion, and can be easily repeated if necessary, Dr. Kroon explained. Results have been promising, but it has not been established whether it is equally effective as isolated limb perfusion.

Patients in the Australian series were treated from 1992 to 2006 with a single isolated limb infusion of melphalan and actinomycin D for 20–30 minutes under mild hyperthermic conditions. Their mean age was 74 years (range, 29–93 years), and the majority (62%) were female. Disease was present in the lower limb in 172 patients, and in the upper limb in 13.

The response rate significantly decreased with increasing stage of disease, Dr. Kroon said.

Response rates were 83% in stage I patients, 53% in stage II, 43% in stage IIIA, 33% in stage IIIAB, and 23% in stage IV.

Median overall survival was 38 months, but increased significantly to 53 months in patients achieving a complete response, he reported.

In a multivariate analysis, independent prognostic factors for complete response were lower disease stage (hazard ratio, 1.69) and greater increase in CO₂ level during the procedure (HR, 1.65).

The procedure was well tolerated, with only five patients developing grade 4 toxicity, and there were no amputations, said Dr. Kroon, who reported no conflicts of interest.

"We conclude that isolated limb infusion is a safe and effective alternative to conventional isolated limb perfusion to treat advanced metastatic melanoma in a limb," he said.

U.S./Taiwanese Experience

Lead investigator Dr. Georgia Beasley of the Duke University Medical Center in Durham, N.C., and associates compared outcomes after 59 ILP treatments in 54 patients against outcomes after 61 ILI treatments in 58 patients, all with in-transit malignant melanoma of the extremity.

Among 50 evaluable ILI patients, complete response was reported in 15 (30%), partial response in 7 (14%), stable disease in 5 (10%), and progressive disease in 23 (46%). The median duration of complete response was 12 months.

Isolated limb perfusion was associated with significantly better response at 3 months (complete response, 57%; partial response, 31%; and no response, 12%); however, significantly more ILP patients had grade 3 or greater toxicity, Dr. Beasley said.

There were nine compartment syndromes and two amputations among ILP patients, versus four compartment syndromes and no amputations among ILI patients.

"In our experience, limb infusion using melphalan did not appear to be as effective as limb perfusion, although the toxicity appears less," Dr. Beasley said.

The investigators noted that correcting the melphalan dose for ideal body weight appeared to minimize toxicity without altering response rates; 66% of ILI patients had their dose corrected, versus only 22% of ILP patients.

SAN ANTONIO — The treatment of most patients who have mycosis fungoides is well within the purview of dermatologists.

"It's very rewarding caring for these patients, because they respond to so many different therapies," Dr. L. Frank Glass said at the annual meeting of the American Academy of Dermatology.

In fact, most patients do very well and don't die from this disease, which is the most common of the cutaneous T-cell lymphomas. Its treatment resembles that of a chronic disease, such as psoriasis, more than that of a terminal illness, said Dr. Glass of the University of South Florida, Tampa.

From topical steroids and retinoids to alkylating agents and phototherapy, the range of treatments for cutaneous T-cell lymphomas is expansive and provides options for successfully treating the many variants of the disease. Furthermore, these are treatments with which dermatologists, compared with other specialists, have the most extensive experience.

"We're used to using retinoids orally," he said, noting that even imiquimod—another drug with which dermatologists have extensive experience—is considered an off-label option for the treatment of mycosis fungoides.

Dermatologists will mainly see patients with disease up to the limited patch-plaque stage. Disease progression in these patients tends to be limited, and some patients with very early-stage disease have been shown to have the same survival as the general population.

At least one study has shown that those patients who receive conservative sequential therapy do as well as those patients who receive aggressive chemotherapy and radiation treatment, Dr. Glass explained.

Even with patients who have more advanced tumor-stage disease that requires multispecialty care, dermatologists can continue to play a role in treatment, thanks to the following modalities now available:

▸ Topical corticosteroids. Class I corticosteroids tend to work best for mycosis fungoides patients, but should be avoided in those with atrophic disease variants. When they are appropriate, corticosteroids tend to work well for itching and redness. Corticosteroids are particularly useful as adjuvants with other therapies.

▸ Phototherapy. PUVA is best, but narrow-band phototherapy offers more convenience and also has good results. The choice depends on the stage and type of lesion, as well as patient risk factors, Dr. Glass said.

Although response rates are similar with PUVA and narrow-band light, there are some questions about the durability of response with narrow-band light and whether thicker lesions respond as well to this form of phototherapy. In those with higher melanoma risk, however, narrow-band light may be safer.

Phototherapy is great as a maintenance therapy, but in those with progressive disease, relapse rates increase and combination therapy with a systemic agent may be necessary.

▸ Extracorporeal photophoresis. This treatment is quite effective, particularly in patients with erythrodermic mycosis fungoides and Sézary syndrome. It is the treatment of choice for the former, and is "the beginning of treatment" for the latter, he said.

▸ Bexarotene. Topical bexarotene is promising, with a similar mechanism of action to other retinoids, but at nearly $2,000 per tube it is too expensive to be considered a viable option at this time, Dr. Glass noted.

Oral bexarotene is more accessible and works well in combination with other therapies, such as PUVA.

Using oral bexarotene in a combination allows the dosage of both agents to be reduced, thus maintaining good response but reducing the risk of adverse effects, such as hypertriglyceridemia and hypothyroidism.

However, Dr. Glass noted that when he uses bexarotene in combination with another treatment for sustained therapy, he brings in an internist to ensure that the patient doesn't have an increased cardiac risk or a metabolic problem "down the road."

Nonetheless, combination therapy is "pretty effective and can certainly be initiated" by dermatologists with fewer side effects, he said.

SAN ANTONIO — The treatment of most patients who have mycosis fungoides is well within the purview of dermatologists.

"It's very rewarding caring for these patients, because they respond to so many different therapies," Dr. L. Frank Glass said at the annual meeting of the American Academy of Dermatology.

In fact, most patients do very well and don't die from this disease, which is the most common of the cutaneous T-cell lymphomas. Its treatment resembles that of a chronic disease, such as psoriasis, more than that of a terminal illness, said Dr. Glass of the University of South Florida, Tampa.

From topical steroids and retinoids to alkylating agents and phototherapy, the range of treatments for cutaneous T-cell lymphomas is expansive and provides options for successfully treating the many variants of the disease. Furthermore, these are treatments with which dermatologists, compared with other specialists, have the most extensive experience.

"We're used to using retinoids orally," he said, noting that even imiquimod—another drug with which dermatologists have extensive experience—is considered an off-label option for the treatment of mycosis fungoides.

Dermatologists will mainly see patients with disease up to the limited patch-plaque stage. Disease progression in these patients tends to be limited, and some patients with very early-stage disease have been shown to have the same survival as the general population.

At least one study has shown that those patients who receive conservative sequential therapy do as well as those patients who receive aggressive chemotherapy and radiation treatment, Dr. Glass explained.

Even with patients who have more advanced tumor-stage disease that requires multispecialty care, dermatologists can continue to play a role in treatment, thanks to the following modalities now available:

▸ Topical corticosteroids. Class I corticosteroids tend to work best for mycosis fungoides patients, but should be avoided in those with atrophic disease variants. When they are appropriate, corticosteroids tend to work well for itching and redness. Corticosteroids are particularly useful as adjuvants with other therapies.

▸ Phototherapy. PUVA is best, but narrow-band phototherapy offers more convenience and also has good results. The choice depends on the stage and type of lesion, as well as patient risk factors, Dr. Glass said.

Although response rates are similar with PUVA and narrow-band light, there are some questions about the durability of response with narrow-band light and whether thicker lesions respond as well to this form of phototherapy. In those with higher melanoma risk, however, narrow-band light may be safer.

Phototherapy is great as a maintenance therapy, but in those with progressive disease, relapse rates increase and combination therapy with a systemic agent may be necessary.

▸ Extracorporeal photophoresis. This treatment is quite effective, particularly in patients with erythrodermic mycosis fungoides and Sézary syndrome. It is the treatment of choice for the former, and is "the beginning of treatment" for the latter, he said.

▸ Bexarotene. Topical bexarotene is promising, with a similar mechanism of action to other retinoids, but at nearly $2,000 per tube it is too expensive to be considered a viable option at this time, Dr. Glass noted.

Oral bexarotene is more accessible and works well in combination with other therapies, such as PUVA.

Using oral bexarotene in a combination allows the dosage of both agents to be reduced, thus maintaining good response but reducing the risk of adverse effects, such as hypertriglyceridemia and hypothyroidism.

However, Dr. Glass noted that when he uses bexarotene in combination with another treatment for sustained therapy, he brings in an internist to ensure that the patient doesn't have an increased cardiac risk or a metabolic problem "down the road."

Nonetheless, combination therapy is "pretty effective and can certainly be initiated" by dermatologists with fewer side effects, he said.

SAN ANTONIO — The treatment of most patients who have mycosis fungoides is well within the purview of dermatologists.

"It's very rewarding caring for these patients, because they respond to so many different therapies," Dr. L. Frank Glass said at the annual meeting of the American Academy of Dermatology.

In fact, most patients do very well and don't die from this disease, which is the most common of the cutaneous T-cell lymphomas. Its treatment resembles that of a chronic disease, such as psoriasis, more than that of a terminal illness, said Dr. Glass of the University of South Florida, Tampa.

From topical steroids and retinoids to alkylating agents and phototherapy, the range of treatments for cutaneous T-cell lymphomas is expansive and provides options for successfully treating the many variants of the disease. Furthermore, these are treatments with which dermatologists, compared with other specialists, have the most extensive experience.

"We're used to using retinoids orally," he said, noting that even imiquimod—another drug with which dermatologists have extensive experience—is considered an off-label option for the treatment of mycosis fungoides.

Dermatologists will mainly see patients with disease up to the limited patch-plaque stage. Disease progression in these patients tends to be limited, and some patients with very early-stage disease have been shown to have the same survival as the general population.

At least one study has shown that those patients who receive conservative sequential therapy do as well as those patients who receive aggressive chemotherapy and radiation treatment, Dr. Glass explained.

Even with patients who have more advanced tumor-stage disease that requires multispecialty care, dermatologists can continue to play a role in treatment, thanks to the following modalities now available:

▸ Topical corticosteroids. Class I corticosteroids tend to work best for mycosis fungoides patients, but should be avoided in those with atrophic disease variants. When they are appropriate, corticosteroids tend to work well for itching and redness. Corticosteroids are particularly useful as adjuvants with other therapies.

▸ Phototherapy. PUVA is best, but narrow-band phototherapy offers more convenience and also has good results. The choice depends on the stage and type of lesion, as well as patient risk factors, Dr. Glass said.

Although response rates are similar with PUVA and narrow-band light, there are some questions about the durability of response with narrow-band light and whether thicker lesions respond as well to this form of phototherapy. In those with higher melanoma risk, however, narrow-band light may be safer.

Phototherapy is great as a maintenance therapy, but in those with progressive disease, relapse rates increase and combination therapy with a systemic agent may be necessary.

▸ Extracorporeal photophoresis. This treatment is quite effective, particularly in patients with erythrodermic mycosis fungoides and Sézary syndrome. It is the treatment of choice for the former, and is "the beginning of treatment" for the latter, he said.

▸ Bexarotene. Topical bexarotene is promising, with a similar mechanism of action to other retinoids, but at nearly $2,000 per tube it is too expensive to be considered a viable option at this time, Dr. Glass noted.

Oral bexarotene is more accessible and works well in combination with other therapies, such as PUVA.

Using oral bexarotene in a combination allows the dosage of both agents to be reduced, thus maintaining good response but reducing the risk of adverse effects, such as hypertriglyceridemia and hypothyroidism.

However, Dr. Glass noted that when he uses bexarotene in combination with another treatment for sustained therapy, he brings in an internist to ensure that the patient doesn't have an increased cardiac risk or a metabolic problem "down the road."

Nonetheless, combination therapy is "pretty effective and can certainly be initiated" by dermatologists with fewer side effects, he said.