- Email: [email protected]
C034 Sunlight and skin cancer
Courses
- European
Photodermatology
Group:
Photobiology
system by inhibiting the activity of antigen presenting cells and by inducing the release of immuno-suppressive cytokines like interleukin 10. Since particular immunosuppressive effects can be reversed by inducing DNA repair, DNA damage appears to be a critical event during UV-induced immunosuppression. Moreover, UV light induces melanin synthesis in melanocytes. Recently, it was recognized that free pyrimidine dimers which emerge as a consequence of DNA repair are ultimately responsible for induction of pigmentation. Moreover, free pyrimidine dimers enhance DNA repair, thereby acting in an autocrine like manner. I CO31 The molecular bases of tanning J.-P. Ortonne. U385 INSERM, Fact& de Medecine, Dermatologie,
H6pital
de I’Archet,
Nice,
Service
de
France
Ultraviolet radiation is the main physiological stimulus for human skin pigmentation. However, the molecular mechanisms inderlying this process are still not fully understood. The tanning response has two distinct phases: the first, immediate pigment darkening is caused by UV-induced chemical modifications of preexisting melanins in the epidermis and involves no new pigment synthesis. The second, termed delayed tanning is the result of new synthesis and redistribution of melanins in epidermal cells. Delayed tanning is manifested histologically by increases in melanocyte number and degree of melanization and extent of melanosome transfer to keratinocytes. The molecular mechanisms by which the UV-induced signal is transduced to melanocytes is not understood. UV-photons interact with numerous molecules within cells, but available data support a role for photochemical reactions involving membrane lipids and DNA, more specifically DNA photoproducts in the induction of melanogenesis. Although the UV-induced signal transduction in melanocytes is not yet characterized, it is likely that UV-photons are absorbed by several target molecules relevant for cellular signalling and it appears that numerous signal transduction pathways are stimulated. The mechanisms by which the tyrosinase and tyrosinase-related genes are activated by UV also remains to be elucidated. Ultraviolet irradiation directly affect melanocytes as demonstrated by the increased melanogenesis induced by UV in pure culture of pigment cells. However, ultraviolet-induced melanogenesis involves other cell types such as fibroblasts and keratinocytes that produce a number of growth factors, cytokines and inflammatory mediators that affect melanocyte proliferation, dendricity and melanin synthesis such as Endothelin-1, proopiomelanocortin and its derived peptides, neurotrophins, bFGF, PGEZ, Nitric oxide . Tanning has been suggested to be one part of a eukaryotic SOS response to damage ultraviolet irradiation that has evolved over time to provide a protective tan in skin (BA Gil&rest et al, Photobiol. 1996; 63: l-10). For a long time, it is known that the different melanins have not the same photoprotective potential. The recent identification of the genes controlling the switch between eu. and pheomelanogenesis and the association of variants of one of these genes with the phototype characterized by fair skin and red hair demonstrates that a molecular classification of human phototypes will be established in the near future.
-Normal
CO32 El
Effects
of UV Radiation
on the Skin
S65
Photoageing and chronic effects
M. Garmyn. UZ Leuven,
Leuven,
Belgium
Photoageing represents a superimposition of chronic cumulative photodamage on the process of intrinsic aging. The clinical picture of photoageing includes coarseness, wrinkling, laxity, irregular pigmentation, atrophy, and a variety of benign, premalignant and malignant neoplasms. Dermal elastosis, deposition of amorphous elastin fibers in the papillary dermis below an apparently spared grenz zone, is the histological hallmark of photoageing. The dermis also displays degradation of collagen fibers and an increase in proteo- and glycosaminoglycans. Photoaged epidermis is histologically characterized by alternating area’s of severe atrophy and hyperplasia, some degree of nuclear atypia in both keratinocytes and melanocytes and a reduced number of Langerhans cells. Photoageing also occurs at the level of individual skin cells, reflected in a decrease in culture lifespan and decreased or paradoxical response to growth factors. At the molecular level, photoageing affects basal and UV induced expression of specific genes involved in epidermal growth and differentiation. In the dermis solar elastosis is associated with an increased abundance of elastin and fibrillin mRNA’s and changes in immunostaining for the proteoglycans decorin and versican are accompanied by similar alterations in mRNA expression. Very modest UV exposures of intact skin have been shown to induce transcription factors AP- 1 and NF-kB, which then upregulate the activity of matrix degrading metalloproteinases, suggesting a mechanism for solar elastosis. Reactive oxygen species, generated by UV, have been implicated in the upregulation of these enzymes. I CO33 Mechanisms of UV carcinogenesis F.R. de Gruijl’, R.J.W. Berg’, H. van Steeg’, H.J. van Kranen’. ’ Utrecht Univ., Utrecht; 2Natl. Inst. Health & Environment/RIVM,
Bilthoven,
The Netherlands
Defective DNA repair, as in Xeroderma pigmentosum, results in dramatic increases in skin cancer risk, both in humans and in UV-irradiated XPA knock out mice. Apparently, this repair is crucial for our survival in an environment where solar UV radiation is such a prominent ubiquitous carcinogenic factor. Mutations found in the ~53 tumor suppressor gene from human skin carcinomas (also from XP patients) clearly point at UVB radiation as the culprit: nearly all occur at dipyrimidine sites, preferential target sites of UVB. Such mutations are also found in experimentally W-induced murine carcinomas, and we found that microscopic foci of cells with mutant ~53 could be detected long before tumors appeared. InXPA k.o. mice these foci occur at a dramatically increased rate, but the ultimate tumors show a surprisingly low percentage with ~53 mutations (cc10%). Clearly other genes besides p53 play an important role.
CO34 Sunlight and skin cancer Robin Marks. University Dermatology, Australia
St Vincent’s
of Melbourne, Department of Hospital Melbourne, Fitzroy 3065,
Most people these days agree that sunlight plays a role in the development of skin cancer. Epidemiological studies initially
S66
Courses
-
Contact
Dermatitis:
suggested fairly simplistic mechanisms of sunlight in inducing these tumours. They included the suggestions that non melanoma skin cancer was due predominantly to cumulative exposure over the years and melanoma was induced by episodic high-dose exposure to sunlight, particularly in childhood. Recent epidemiological studies have suggested that the nature of sunlight exposure required to induce the common sun-related skin cancers including melanoma, basal cell carcinoma and squamous cell carcinoma may not be as clear-cut as previously considered. There are some data that suggest that cumulative exposure is important in melanoma, just as there are data to suggest that episodic high-dose exposure in childhood is important for basal cell carcinoma particularly, but probably also for squamous cell carcinoma. There seems little doubt that heavy exposure to sunlight in childhood predisposes to skin cancers of all types. This is probably in both an initiating and promoting capacity. It seems also that sunlight exposure in adulthood is important in promotion of all the tumours related to sunlight that have been initiated in childhood. The lack of clarity obtained from epidemiological studies on the nature of sunlight exposure and induction of skin cancer is probably a reflection of both the complexity of carcinogenesis, and also the limitations of epidemiological techniques in determining exactly what were the past sunlight exposures that individuals have experienced.
Useful
Patch Test Batteries
cons: - Batteries are always limited and incomplete and often not sufficiently up to date; - Often contain “infrequent” allergens; - Take up much space on the patient’s back, with the risk that some patches will fall off, - Have set concentrations and vehicles and so ignore individual sensitivity thresholds; - Risk producing mutiple positive tests for chemically relates substances, such as acrylates; - Give a false sense of security. ElCO37 Series for shoes and clothing dermatitis P. Podmore. Altnagelvin Area Hospital, Londonderry, Northern Ireland
Shoe allergic contact dermatitis is surprisingly rare but when it occurs it is seriously incapacitating as avoidance is difficult. In this talk I plan to discuss the diagnosis of Shoe and Clothing Dermatitis, identify the common culprit allergens and thus delineate a series which should provide a good diagnostic yield. I would also propose to discuss the advice we can give our patients and consider the longterm prognosis of their problem. I CO38 Patch test battery for plastics L. Kanerva, R. Jolanki, T. Estlander. Section of Dermatology,
Contact Dermatitis: Useful Patch Test Batteries
Univ.
Hosp.,
ElCO36 The use of patch-test batteries: Pros and
cons
Hospital,
of Occupational
Denmark
The diagnosis of allergic contact dermatitis requires selection of the appropriate chemicals or compounds for patch testing depending on the clinical pattern of dermatitis and exposure history. The standard series detects about 6040% of contact allergies. Supplementary allergens are necessary for detecting the remaining allergies. These extra allergens may be chosen one by one based on exposure history or selected as a test series containing the most frequent allergens in certain products or in certain occupations. What are the advantages and limitations of patch test batteries? How to make the best use of patch test batteries? Selected batteries will be reviewed.
A. Goossens. University
Institute
Table Compound
ElCO35 Useful patch test batteries K.E. Andersen. Odense
Finnish
Leuven,
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Belgium
Pros: - Promotes “standardised” testing; - Covers “important allergens” in each domain; - May shorten the time needed to determine the risk factors; - Initially requires less knowledge of materials and expertise in each specific domain on the part of the examiner; - Are useful when the composition of the products with which the patient has come in contact is not known.
Health,
Helsinki,
Finland
We patch test with an extensive series of plastic chemicals. The table shows statistics from 3 years.
18 19 20 21 22 23 24 25
Hydroquinon Dibutyl phthalate Phenyl salicylate Dioctyl phthalate 2.6-Di-terr-burl-4-cresol (BHT) ’ 2(2-Hydroxy-5-methylphenyl)benzotriazol Benzoylperoxide 1,4-Butanediol dimethacrylate Azodiisobutyrodinitrile Bisphenol A Tricresyl phosphate Phenol formaldehyde resin Triphenyl phosphate Toluenesulfonamide formaldehyde resin Resorcinol monobenzoate Z-Phenylindole 2-terr-Butvl-Lmetboxypienol (BHA) Triethylenetetramine (TETA) Dietylenebiamine (DETA) Diaminodiphenylmetane (MDA) Abitol Hexamethylenetetramine 4-tert-Butylphenol Tolunenediisocvanate (TDI) Dipheoylmetba&4,4&o’ cyanate (MDI)
% we 1.0 5.0 1.0 2.0 2.0
From c cc c c
No. of Irritant patients reactions 11 173 2 173 173 173 173
1.0
c
173
1.0 2.0
c c
173 171
1.0 1.0 5.0 5.0; 1.0 5.0 10.0
c c c c c c
173 174 173 173 174 174
1.0 2.0 2.0
c c c
173 172 173
1 1
0.5 aq/pet
C
18/156
2/l
1.0 0.5
c c
174 174
1
174 174 174 181156 181156
6
10.0 c 2.0 c 1.0 c 0.1: 1.5 C. 0 0.1; 1.5 C, 0
12
: o/3 O/l
Allergic reactions
- European
Photodermatology
Group:
Photobiology
system by inhibiting the activity of antigen presenting cells and by inducing the release of immuno-suppressive cytokines like interleukin 10. Since particular immunosuppressive effects can be reversed by inducing DNA repair, DNA damage appears to be a critical event during UV-induced immunosuppression. Moreover, UV light induces melanin synthesis in melanocytes. Recently, it was recognized that free pyrimidine dimers which emerge as a consequence of DNA repair are ultimately responsible for induction of pigmentation. Moreover, free pyrimidine dimers enhance DNA repair, thereby acting in an autocrine like manner. I CO31 The molecular bases of tanning J.-P. Ortonne. U385 INSERM, Fact& de Medecine, Dermatologie,
H6pital
de I’Archet,
Nice,
Service
de
France
Ultraviolet radiation is the main physiological stimulus for human skin pigmentation. However, the molecular mechanisms inderlying this process are still not fully understood. The tanning response has two distinct phases: the first, immediate pigment darkening is caused by UV-induced chemical modifications of preexisting melanins in the epidermis and involves no new pigment synthesis. The second, termed delayed tanning is the result of new synthesis and redistribution of melanins in epidermal cells. Delayed tanning is manifested histologically by increases in melanocyte number and degree of melanization and extent of melanosome transfer to keratinocytes. The molecular mechanisms by which the UV-induced signal is transduced to melanocytes is not understood. UV-photons interact with numerous molecules within cells, but available data support a role for photochemical reactions involving membrane lipids and DNA, more specifically DNA photoproducts in the induction of melanogenesis. Although the UV-induced signal transduction in melanocytes is not yet characterized, it is likely that UV-photons are absorbed by several target molecules relevant for cellular signalling and it appears that numerous signal transduction pathways are stimulated. The mechanisms by which the tyrosinase and tyrosinase-related genes are activated by UV also remains to be elucidated. Ultraviolet irradiation directly affect melanocytes as demonstrated by the increased melanogenesis induced by UV in pure culture of pigment cells. However, ultraviolet-induced melanogenesis involves other cell types such as fibroblasts and keratinocytes that produce a number of growth factors, cytokines and inflammatory mediators that affect melanocyte proliferation, dendricity and melanin synthesis such as Endothelin-1, proopiomelanocortin and its derived peptides, neurotrophins, bFGF, PGEZ, Nitric oxide . Tanning has been suggested to be one part of a eukaryotic SOS response to damage ultraviolet irradiation that has evolved over time to provide a protective tan in skin (BA Gil&rest et al, Photobiol. 1996; 63: l-10). For a long time, it is known that the different melanins have not the same photoprotective potential. The recent identification of the genes controlling the switch between eu. and pheomelanogenesis and the association of variants of one of these genes with the phototype characterized by fair skin and red hair demonstrates that a molecular classification of human phototypes will be established in the near future.
-Normal
CO32 El
Effects
of UV Radiation
on the Skin
S65
Photoageing and chronic effects
M. Garmyn. UZ Leuven,
Leuven,
Belgium
Photoageing represents a superimposition of chronic cumulative photodamage on the process of intrinsic aging. The clinical picture of photoageing includes coarseness, wrinkling, laxity, irregular pigmentation, atrophy, and a variety of benign, premalignant and malignant neoplasms. Dermal elastosis, deposition of amorphous elastin fibers in the papillary dermis below an apparently spared grenz zone, is the histological hallmark of photoageing. The dermis also displays degradation of collagen fibers and an increase in proteo- and glycosaminoglycans. Photoaged epidermis is histologically characterized by alternating area’s of severe atrophy and hyperplasia, some degree of nuclear atypia in both keratinocytes and melanocytes and a reduced number of Langerhans cells. Photoageing also occurs at the level of individual skin cells, reflected in a decrease in culture lifespan and decreased or paradoxical response to growth factors. At the molecular level, photoageing affects basal and UV induced expression of specific genes involved in epidermal growth and differentiation. In the dermis solar elastosis is associated with an increased abundance of elastin and fibrillin mRNA’s and changes in immunostaining for the proteoglycans decorin and versican are accompanied by similar alterations in mRNA expression. Very modest UV exposures of intact skin have been shown to induce transcription factors AP- 1 and NF-kB, which then upregulate the activity of matrix degrading metalloproteinases, suggesting a mechanism for solar elastosis. Reactive oxygen species, generated by UV, have been implicated in the upregulation of these enzymes. I CO33 Mechanisms of UV carcinogenesis F.R. de Gruijl’, R.J.W. Berg’, H. van Steeg’, H.J. van Kranen’. ’ Utrecht Univ., Utrecht; 2Natl. Inst. Health & Environment/RIVM,
Bilthoven,
The Netherlands
Defective DNA repair, as in Xeroderma pigmentosum, results in dramatic increases in skin cancer risk, both in humans and in UV-irradiated XPA knock out mice. Apparently, this repair is crucial for our survival in an environment where solar UV radiation is such a prominent ubiquitous carcinogenic factor. Mutations found in the ~53 tumor suppressor gene from human skin carcinomas (also from XP patients) clearly point at UVB radiation as the culprit: nearly all occur at dipyrimidine sites, preferential target sites of UVB. Such mutations are also found in experimentally W-induced murine carcinomas, and we found that microscopic foci of cells with mutant ~53 could be detected long before tumors appeared. InXPA k.o. mice these foci occur at a dramatically increased rate, but the ultimate tumors show a surprisingly low percentage with ~53 mutations (cc10%). Clearly other genes besides p53 play an important role.
CO34 Sunlight and skin cancer Robin Marks. University Dermatology, Australia
St Vincent’s
of Melbourne, Department of Hospital Melbourne, Fitzroy 3065,
Most people these days agree that sunlight plays a role in the development of skin cancer. Epidemiological studies initially
S66
Courses
-
Contact
Dermatitis:
suggested fairly simplistic mechanisms of sunlight in inducing these tumours. They included the suggestions that non melanoma skin cancer was due predominantly to cumulative exposure over the years and melanoma was induced by episodic high-dose exposure to sunlight, particularly in childhood. Recent epidemiological studies have suggested that the nature of sunlight exposure required to induce the common sun-related skin cancers including melanoma, basal cell carcinoma and squamous cell carcinoma may not be as clear-cut as previously considered. There are some data that suggest that cumulative exposure is important in melanoma, just as there are data to suggest that episodic high-dose exposure in childhood is important for basal cell carcinoma particularly, but probably also for squamous cell carcinoma. There seems little doubt that heavy exposure to sunlight in childhood predisposes to skin cancers of all types. This is probably in both an initiating and promoting capacity. It seems also that sunlight exposure in adulthood is important in promotion of all the tumours related to sunlight that have been initiated in childhood. The lack of clarity obtained from epidemiological studies on the nature of sunlight exposure and induction of skin cancer is probably a reflection of both the complexity of carcinogenesis, and also the limitations of epidemiological techniques in determining exactly what were the past sunlight exposures that individuals have experienced.
Useful
Patch Test Batteries
cons: - Batteries are always limited and incomplete and often not sufficiently up to date; - Often contain “infrequent” allergens; - Take up much space on the patient’s back, with the risk that some patches will fall off, - Have set concentrations and vehicles and so ignore individual sensitivity thresholds; - Risk producing mutiple positive tests for chemically relates substances, such as acrylates; - Give a false sense of security. ElCO37 Series for shoes and clothing dermatitis P. Podmore. Altnagelvin Area Hospital, Londonderry, Northern Ireland
Shoe allergic contact dermatitis is surprisingly rare but when it occurs it is seriously incapacitating as avoidance is difficult. In this talk I plan to discuss the diagnosis of Shoe and Clothing Dermatitis, identify the common culprit allergens and thus delineate a series which should provide a good diagnostic yield. I would also propose to discuss the advice we can give our patients and consider the longterm prognosis of their problem. I CO38 Patch test battery for plastics L. Kanerva, R. Jolanki, T. Estlander. Section of Dermatology,
Contact Dermatitis: Useful Patch Test Batteries
Univ.
Hosp.,
ElCO36 The use of patch-test batteries: Pros and
cons
Hospital,
of Occupational
Denmark
The diagnosis of allergic contact dermatitis requires selection of the appropriate chemicals or compounds for patch testing depending on the clinical pattern of dermatitis and exposure history. The standard series detects about 6040% of contact allergies. Supplementary allergens are necessary for detecting the remaining allergies. These extra allergens may be chosen one by one based on exposure history or selected as a test series containing the most frequent allergens in certain products or in certain occupations. What are the advantages and limitations of patch test batteries? How to make the best use of patch test batteries? Selected batteries will be reviewed.
A. Goossens. University
Institute
Table Compound
ElCO35 Useful patch test batteries K.E. Andersen. Odense
Finnish
Leuven,
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Belgium
Pros: - Promotes “standardised” testing; - Covers “important allergens” in each domain; - May shorten the time needed to determine the risk factors; - Initially requires less knowledge of materials and expertise in each specific domain on the part of the examiner; - Are useful when the composition of the products with which the patient has come in contact is not known.
Health,
Helsinki,
Finland
We patch test with an extensive series of plastic chemicals. The table shows statistics from 3 years.
18 19 20 21 22 23 24 25
Hydroquinon Dibutyl phthalate Phenyl salicylate Dioctyl phthalate 2.6-Di-terr-burl-4-cresol (BHT) ’ 2(2-Hydroxy-5-methylphenyl)benzotriazol Benzoylperoxide 1,4-Butanediol dimethacrylate Azodiisobutyrodinitrile Bisphenol A Tricresyl phosphate Phenol formaldehyde resin Triphenyl phosphate Toluenesulfonamide formaldehyde resin Resorcinol monobenzoate Z-Phenylindole 2-terr-Butvl-Lmetboxypienol (BHA) Triethylenetetramine (TETA) Dietylenebiamine (DETA) Diaminodiphenylmetane (MDA) Abitol Hexamethylenetetramine 4-tert-Butylphenol Tolunenediisocvanate (TDI) Dipheoylmetba&4,4&o’ cyanate (MDI)
% we 1.0 5.0 1.0 2.0 2.0
From c cc c c
No. of Irritant patients reactions 11 173 2 173 173 173 173
1.0
c
173
1.0 2.0
c c
173 171
1.0 1.0 5.0 5.0; 1.0 5.0 10.0
c c c c c c
173 174 173 173 174 174
1.0 2.0 2.0
c c c
173 172 173
1 1
0.5 aq/pet
C
18/156
2/l
1.0 0.5
c c
174 174
1
174 174 174 181156 181156
6
10.0 c 2.0 c 1.0 c 0.1: 1.5 C. 0 0.1; 1.5 C, 0
12
: o/3 O/l
Allergic reactions