Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study.

BACKGROUND: Photodynamic therapy (PDT) is an attractive therapy for nonmelanoma skin cancers and actinic keratoses (AKs). Daylight-mediated PDT is a simple and tolerable treatment procedure for PDT. Methyl aminolaevulinate (MAL)-PDT is approved for the treatment of thin or nonhyperkeratotic AKs on the face and scalp. However, thick AK lesions are often treated as well when present in the field-cancerized treatment area. OBJECTIVES: In a randomized multicentre study to evaluate efficacy of daylight-mediated PDT for different severity grades of AKs. METHODS: One hundred and forty-five patients with a total of 2768 AKs (severity grades I-III) of the face and scalp were randomized to either 1½ or 2½ h exposure groups. After application of a sunscreen (sun protection factor 20) and gentle lesion preparation, MAL was applied to the entire treatment area. Patients left the clinic immediately after application and exposed themselves to daylight according to randomization. Daylight exposure was monitored with a wrist-borne dosimeter. RESULTS: No difference in lesion response was found between the 1½ and 2½ h exposure group. The mean lesion response rate was significantly higher in grade I lesions (75·9%) than in grade II (61·2%) and grade III (49·1%) lesions (P < 0·0001). Most grade II (86%) and III AKs (94%) were in complete response or reduced to a lower lesion grade at follow-up. Large variations in response rate of grade II and III AKs were found between centres. No association was found between response rate and light dose in patients who received an effective light dose of > 3·5 J cm(-2). CONCLUSIONS: Daylight-mediated PDT of moderate to thick AKs was less effective than daylight-mediated PDT of thin AKs especially in some centres. However, nearly all thicker lesions (grades II and III) were reduced to a lower lesion grade at 3 months after a single treatment of daylight-mediated PDT.

A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp.

BACKGROUND: Actinic keratoses (AKs) are common dysplastic skin lesions that may differentiate into invasive squamous cell carcinomas. Although a superior cosmetic outcome of photodynamic therapy (PDT) is advantageous compared with equally effective treatments such as cryotherapy and curettage, the inconvenience of clinic attendance and discomfort during therapy are significant drawbacks. Daylight-mediated PDT could potentially reduce these and may serve as an alternative to conventional PDT. OBJECTIVES: To compare the efficacy of methyl aminolaevulinate (MAL)-PDT with 1½ vs. 2½ h of daylight exposure in a randomized multicentre study. METHODS: One hundred and twenty patients with a total of 1572 thin AKs of the face and scalp were randomized to either 1½- or 2½-h exposure groups. After gentle lesion preparation and application of a sunscreen of sun protection factor 20, MAL was applied to the entire treatment area. Immediately after, patients left the clinic and exposed themselves to daylight according to the randomization. Daylight exposure was monitored with a wristwatch dosimeter and patients scored their pain sensation during treatment. RESULTS: The mean lesion response rate at 3 months was 77% in the 1½-h group and 75% in the 2½-h group (P = 0·57). The mean duration of daylight exposure was 131 and 187 min in the two groups. The mean overall effective light dose was 9·4 J cm(-2) (range 0·2-28·3). Response rate was not associated with effective daylight dose, exposure duration, treatment centre, time of day or time of year during which the treatment was performed. Treatment was well tolerated, with a mean ± SD maximal pain score of 1·3 ± 1·5. CONCLUSIONS: Daylight-mediated MAL-PDT is an effective, convenient and nearly pain-free treatment for patients with multiple thin AKs. Daylight-mediated PDT procedures were easily performed and 2 h of daylight exposure resulted in uniformly high response rates when conducted in the period from June to October in Nordic countries.

Pain induced by photodynamic therapy of warts.

BACKGROUND: Photodynamic therapy with topical 5-aminolevulinic acid (ALA), followed by irradiation with red light (ALA-PDT), is used for non-melanoma skin cancer and other dermatological diseases. Pain during and after light exposure is a well-known adverse advent that may be a limiting factor for treatment, particularly, in viral warts. METHODS: To assess the pain induced by ALA-PDT, we asked 45 patients enrolled in a randomized, placebo-controlled trial with six consecutive ALA- and placebo-PDT treatments for recalcitrant foot and hand warts to fill in questionnaires about pain immediately and 24 h after each treatment. RESULTS: Immediately and 24 h after each of the six treatments, pain intensity was significantly higher in warts treated with ALA-PDT than in warts treated with placebo-PDT (P<0.028). Severe or unbearable pain was reported from a median of 17% (6-31%) of the ALA -treated warts and from a median of 2% (0-15%) from the placebo-treated warts immediately after the treatments. With increasing treatments, no significant change in pain intensity was observed and no significant relation was found between the pain intensity and the relative change in wart area. The pain was primarily characterized as burning and shooting. The pain lasted about 30 h (range: 1-96 h). CONCLUSION: We conclude that pain induced by ALA-PDT is of such intensity in about one-fifth of the warts that pain relief is indicated.

Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment.

BACKGROUND: Conventional treatment of basal cell carcinoma (BCC) causes morbidity and/or disfigurement in some patients because of the location (e.g. mid-face) and size of the lesion. OBJECTIVES: Following reports that such difficult-to-treat BCC lesions have been treated successfully with topical methyl aminolaevulinate (MAL) photodynamic therapy (PDT), a multicentre study was performed to determine the response of such BCC to MAL-PDT. METHODS: An open, uncontrolled, prospective, multicentre study was conducted comprising patients with superficial and/or nodular BCC who were at risk of complications, poor cosmetic outcome, disfigurement and/or recurrence using conventional therapy. Patients were given one or two cycles within 3 months of topical MAL-PDT, each consisting of two treatments 1 week apart. Tumour response was assessed clinically at 3 months after the last PDT, with histological confirmation of all lesions in clinical remission. The cosmetic outcome was rated. Patients with a BCC in remission will be followed up for 5 years for recurrence, of which the 24-month follow-up is reported here. Ninety-four patients with 123 lesions were enrolled and treated with MAL-PDT at nine European primary care and referral university hospitals. An independent blinded study review board (SRB) retrospectively excluded nine patients and a total of 15 lesions from the efficacy analysis, for not having a difficult-to-treat BCC according to the protocol. RESULTS: The lesion remission rate at 3 months was 92% (45 of 49) for superficial BCC, 87% (45 of 52) for nodular BCC, and 57% (four of seven) for mixed BCC, as assessed by clinical examination, and 85% (40 of 47), 75% (38 of 51), and 43% (three of seven), respectively, as assessed by histological examination and verified by the SRB. At 24 months after treatment, the overall lesion recurrence rate was 18% (12 of 66). The cosmetic outcome was graded as excellent or good by the investigators in 76% of the cases after 3 months follow-up, rising to 85% at 12 months follow-up, and 94% at 24 months follow-up. CONCLUSIONS: Topical MAL-PDT is effective in treating BCC at risk of complications and poor cosmetic outcome using conventional therapy. MAL-PDT preserves the skin and shows favourable cosmetic results.

Can autofluorescence demarcate basal cell carcinoma from normal skin? A comparison with protoporphyrin IX fluorescence.

Fluorescence detection may help to demarcate skin cancer from normal skin, thus to reduce the potential of incomplete treatment resulting from unawareness of tumour extension in surrounding skin. In this study we evaluated the difference between autofluorescence of basal cell carcinomas (n = 21) and the normal-appearing skin surrounding them. Referring to the difference found, a point-by-point measurement was taken from the tumour lesions outwards to the surrounding skin to locate the differentiation point of autofluorescence on the skin. Protoporphyrin IX fluorescence was measured from the same spots using the same procedure, after the tumours and the surrounding skin had been treated with topical 5-aminolevulinic acid methyl ester cream. The point-by-point measurement enabled us to locate the vanishing point of the protoporphyrin IX peak, which was compared with the differentiation point of autofluorescence to assess the utility of autofluorescence in tumour demarcation. Illuminated by 370 nm light, both the tumour and surrounding skin emitted a fluorescence with peak intensity at 455+/-3 nm. The peak intensity was 53% (18-84%) (median, range) lower in the tumours than in normal skin (p<0.001). In 78% of the measurements, the differentiation point of the autofluorescence was within 3mm of the vanishing point of the protoporphyrin IX peak. Autofluorescence may be used in BCC demarcation.

Autofluorescence of human skin is age-related after correction for skin pigmentation and redness.

When measuring the skin fluorescence in vivo, the absorption of chromophores such as melanin and hemoglobin often contribute predominantly to the changes in fluorescence and obscure the information from the fluorophores. We measured in vivo the collagen-linked 375 nm fluorescence (excitation: 330 nm) and 455 nm fluorescence (excitation: 370 nm) from nonexposed buttock skin of healthy volunteers. Skin pigmentation and redness of the same sites were quantified by reflectance of the skin at 555 nm and 660 nm. Multiple regression analysis was used to find the correlation between the fluorescence and skin pigmentation and redness. The fluorescence was corrected for the impact of pigmentation and redness according to the equation found in the regression analyses. The age-related trend of the fluorescence was evaluated. The 375 nm fluorescence showed positive relation to age, whereas the 455 nm fluorescence showed no significant relation to age. The increasing rate of the 375 nm fluorescence (logarithm transformed) was 2% per year, which is comparable with previously published data. The results suggest that the correction of the autofluorescence intensity for skin pigmentation and redness is valid, and the 375 nm skin autofluorescence may be used as a biologic marker of skin aging in vivo.

Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: randomised double-blind trial.

BACKGROUND: Photodynamic therapy (PDT) with topical 5-aminolaevulinic acid (ALA) followed by irradiation with incoherent light (ALA-PDT) for recalcitrant warts have had beneficial results. Therefore, we undertook a randomised, parallel, double-blind clinical trial of ALA-PDT versus placeboPDT for recalcitrant foot and hand warts. METHODS: Recalcitrant foot and hand warts were randomly assigned to six repetitive ALA-PDT or placebo-PDT interventions combined with standard treatment encompassing paring followed by a keratolytic (Verucid). Standardised photographs of each wart were taken before, during (week 7) and after treatment (weeks 14 and 18). The area of each wart compared with entry area was the primary outcome variable, measured from photographs by an evaluator unaware of treatment allocation for intervention. Pain intensity immediately and 24 h after each intervention was assessed by a five-point scale. FINDINGS: A total of 232 foot and hand warts in 45 patients were entered into the trial: 117 warts were allocated to ALA-PDT and 115 warts to placebo-PDT. In week 14, the median relative reduction in wart area was 98% in the ALA-PDT group (interquartile range 100%, 55%) versus 52% (100%, 0) in the placebo group (p=0.0006). In week 18, the median relative reduction in wart area was 100% in the ALA-PDT group (100%, 57%) versus 71% (100%, 0) in the placebo-PDT arm (p=0.008). Both the number of vanishing warts and the difference in relative wart area of persisting warts at week 14 and 18 were significant (p<0.05) in favour of ALA-PDT. Significantly more ALA-PDT warts were graded at a higher pain intensity after treatment than placebo-PDT warts. INTERPRETATION: ALA-PDT is superior to placebo-PDT when both wart area and number of vanishing warts are considered.

Recalcitrant hand and foot warts successfully treated with photodynamic therapy with topical 5-aminolaevulinic acid: a pilot study.

The purpose of this pilot study was to determine if photodynamic therapy with topical application of 5-aminolaevulinic acid followed by irradiation with incoherent filtered and unfiltered light (ALA-PDT) is an effective therapy for recalcitrant hand and foot warts. In 30 patients with recalcitrant warts, 49 regions with a total of 250 warts were randomized to one of the following five treatments: (i) ALA-PDT with white light applied three times within 10 days (W3); (ii) ALA-PDT with white light applied once (W1); (iii) ALA-PDT with red light applied three times within 10 days (R3); (iv) ALA-PDT with blue light applied three times within 10 days (B3), and (v) cryotherapy applied up to four times within 2 months (CRYO). The ALA-PDT treatment modality was repeated in case of partially responding warts. Significantly more warts were completely healed after W3 and W1 than after R3, B3 and CRYO (P < 0.01): 73% of the warts treated with W3 were completely healed, 71% after W1, 42% after R3, 23% after B3 and 20% after CRYO. No scars were observed in the ALA-PDT treated areas and patients treated for foot warts were all able to walk after the treatment. No recurrences in completely responding ALA-PDT treated warts were observed after 12 months of follow-up. In conclusion, photodynamic therapy with topical 5-aminolaevulinic acid followed by irradiation with white light is a promising treatment for recalcitrant hand and foot warts.

Photodynamic therapy with topical delta-aminolevulinic acid delays UV photocarcinogenesis in hairless mice.

Photodynamic therapy (PDT) with topical application of delta-aminolevulinic acid (ALA) followed by irradiation with visible light (ALA-PDT) is a relatively new and promising experimental treatment of superficial premalignant and malignant skin neoplasms. The purpose of this study was to determine whether ALA-PDT can prevent photocarcinogenesis in hairless mice exposed to solar UV. A total of 140 mice was divided into seven groups of 20 mice each. Group 1: solar-UV exposure. Group 2: solar UV and a cream base+visible light once a week. Group 3: solar UV and ALA-PDT once a week. Group 4: solar UV and ALA-PDT once every second week. Group 5: solar UV and ALA-PDT every fourth week. Group 6: ALA-PDT once a week. Group 7: no treatment. The time to first and to second tumor > or = 1 mm was registered. Predefined endpoints, such as one tumor > or = 4 mm or an area of small confluent tumors on the back of the mice were criteria for withdrawal from the experiment. The time to first and to second tumor was significantly longer in the ALA-PDT-treated mice than in mice only exposed to solar UV and solar-UV/cream base-visible light (P < 0.005). However, we observed an increased death and accident rate in the ALA-PDT-treated groups compared to the groups not treated with ALA-PDT (chi-square test, P = 0.0250). Significantly more ALA-PDT-treated mice were withdrawn because of a tumor > or = 4 mm (P = 0.0005). The UV unexposed mice developed no tumors. Repetitive treatments with ALA-PDT delay photoinduced carcinogenesis in mice.

Sunscreens used at the beach do not protect against erythema: a new definition of SPF is proposed.

Since sunscreens are recommended by doctors and used all over the world to protect against sun induced erythema, it is important to evaluate if sunscreens are used as recommended and if the intended effect is achieved. We refer to the findings of several studies performed on people at risk of sun-burning at beaches in the vicinity of Copenhagen, Denmark. On a sunny day at the beach 65% of the sunbathers used one or more sunscreens. Of these, 46% used the sunscreen all over the body and a median sun protection factor (SPF) of 5-6 was used. The sunbathers used 0.5 mg/cm2 of sunscreen independent of skin type. Of the sunscreen users, 43% applied the sunscreen after arriving at the beach and 43% reapplied the sunscreen after swimming. The sun exposure time and the sun exposure dose were almost identical among sunscreen users and non-users. Self-assessed redness of the skin demonstrated that more sunscreen users than non-users reported to be red the day after sun exposure, 42 and 34%, respectively. Theoretical calculations support this findings and show a drastic reduction in the achieved photoprotection if a thinner layer than in the test situation is used. Sunscreens do not protect against erythema if not used as intended. Instead of changing people's habits, we suggest modifying the test method by adjusting the amount of sunscreen to that used in real life situations, 0.5 mg/cm2.

What do Danes know about naevi, skin cancer and melanoma? Experience from a dermatological out-patient clinic.

A survey of public knowledge about naevi, melanoma/ skin cancer and sunscreens was undertaken in Denmark at a time when no public awareness campaign had taken place. A total of 339 study subjects, aged 18-79 years, was recruited at our dermatology outpatient clinic, and data were collected by a self-administered questionnaire. The study group differed from the population in that females and the younger age groups were over-represented. A knowledge score was calculated. Males, the oldest age group and those with shortest school education were less knowledgeable. The study revealed several points of public uncertainty and ignorance with regard to early signs of melanoma and risk factors, which need to be emphasized in future public education.

Photodynamic therapy with 5-aminolevulinic acid in the treatment of actinic cheilitis.

Three patients with cheilitis were successfully treated by photodynamic therapy using the topical application of 5-aminolevulinic acid (ALA), followed by irradiation with incoherent visible light. The three patients had had, for several years, disabling lesions on the lower lip, and histopathological examination showed dysplastic lesions without signs of carcinoma. Conventional treatments were ineffective. During photodynamic therapy, all patients reported a burning sensation when irradiated at the ALA treated area, diminishing immediately after removal of the light source, and vanishing within 4 days after treatment. Superficial peeling began 4 days after treatment, and lasted some months. Follow-up, after 6 and 12 months, did not reveal any sign of recurrence.

Købner reaction induced by photodynamic therapy using delta-aminolevulinic acid. A case report.

We report a case of psoriasis reactivation following photodynamic therapy with delta-aminolevulinic acid. An 84-year-old women received several UVB treatment sessions because of severe psoriasis at her crura in the period from 1960 to 1990. Since then her psoriasis had been inactive. In 1994 she was admitted to our out-patient clinic because of multiple dysplastic lesions as well as multiple carcinomas at her crura. Surgical intervention was impossible and retinoids were not tolerated. She was treated with photodynamic therapy, which provoked a Købner reaction followed by a severe reactivation of the otherwise inactive psoriasis. Whether photodynamic therapy is used for the treatment of multiple dysplastic lesions in a psoriasis patient or for the treatment of psoriasis it seems important to be aware of this adverse effect. This is the first report of Købner reaction following photodynamic therapy.

Sun-protection behaviour and self-assessed burning tendency among sunbathers.

A total of 805 sunbathing Caucasians were interviewed about sunprotection behaviour and self-assessed burning tendency. Sixty-seven percent of the interviewed sunbathers used one or more sunscreen factors. Sunscreen-users and nonusers were exposed to the sun 206 min and 197 min (P = 0.186), respectively. The sunscreen users were exposed to a marginally higher UV dose than non-sunscreen users, 4.8 SED versus 4.5 SED (P = 0.0348). The rate of sunscreen users was significantly higher among subjects who stated that they always were sunburnt in the spring when not using a sunscreen than subjects who stated that they never were sunburnt in the spring when not using a sunscreen (P = 0.0001). However, when comparing subjects that always burn in the spring and subjects that never burn in the spring, we found no significant difference between level of the sun-protection factor (P = 0.11) nor the duration of sun exposure (P = 0.967), nor to which UV doses the subjects were exposed (P = 0,562). Furthermore we found that the interviewed sunbathers interpreted to "be sunburnt" as more severe than "to turn red". Public campaigns recommend the use of sun protection cream when sunbathing without using other sun protective strategies; however, the use of sun protection cream is inadequate among sunbathers. More education is required to persuade those with more sun-sensitive skin to use a higher protection-factor, to reduce sun exposure at times when UV radiation is most intense, and to reduce the duration of exposure.

Sun exposure and sunscreen use among sunbathers in Denmark.

Eight hundred and eight sunbathing Danes were interviewed in order to register the duration of sun exposure and sunscreen use. The mean sun exposure time, 203 min, was found to be independent of sex, age and use of sunscreen. Overall, sunscreens were used by 65%, 73% of the females and 52% of the males. The median sun protection factor used by subjects older than 10 years was 5; in the case of children 10 years or younger, it was 12. Eight per cent of the interviewed subjects used more than one factor. Fifty-seven per cent of the sunscreen users applied the sunscreen prior to arriving at the beach. The sun exposure time was not significantly different in the group of subjects using sunscreens, compared to the group of subjects not using sunscreens. This study indicates that sunscreen users may not increase their exposure to the sun.

Differentiation of inflicted dermal burns by high-frequency ultrasound scanning: An animal experiment.

BACKGROUND/AIMS: The depth of experimentally inflicted superficial/partial dermal burns and deep dermal burns were non-invasively evaluated using a 30 MHz B-mode high-frequency ultrasound scanner. MATERIAL/METHODS: Superficial and deep burns were produced in 10 Harley female albino guinea pigs. Ultrasound scanning was performed immediately after, and 24, 48, 72 and 96 postbum. Specimens for histology were obtained after 72 h. RESULTS: The echo reflection at the dermis-subcutaneous interface was easily defined 2 days after burn infliction in all superficial/partial dermal burns, whereas it was disturbed and not detected in any deep dermal burn. CONCLUSIONS: It is concluded from our study that the ultrasonography of the deep dermis, especially the dermis-subcutaneous interface, is of major importance in the diagnostic and prognostic evaluations of burns.

Metastatic behavior and tumorigenicity of a human melanoma cell line (MM-RU) after injection into nude mice.

The ability of the human amelanotic melanoma cell line MM-RU to produce experimental metastases and to grow tumors at subcutaneous inoculation sites in 4-week-old nude mice was examined. After i.v. inoculation of 10(6) cells, all injected mice (n = 21) developed consistent numbers of metastatic pulmonary colonies within 32 days. The coefficients of variation for the number of colonies were between 17%-23% in three independent experiments. Survival time after i.v. inoculation was 63 +/- 7 days (mean +/- SD) (n = 20). Within 20 days, subcutaneous inoculation of 5 x 10(6) cells resulted in tumor growths of 13 +/- 3 mm (mean +/- SD) at the inoculation sites in all nude mice (n = 12). The MM-RU cell line seems to be a simple, fast vehicle for testing the effect of melanoma growth modulators on experimental pulmonary metastases as well as on subcutaneously growing melanoma.