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[Modern treatment modalities in actinic keratoses of the skin].

It has been estimated that approximately 4 million Germans are suffering from actinic keratoses, which are considered as a carcinoma in situ today. Typically, actinic keratoses appear in sun-exposed skin areas, conventionally they have been treated by curettage and cryotherapy. In the last years, new therapeutic modalities with a high efficacy and patient contentment are available. Among these, the photodynamic therapy (PDT), the anti-tumor treatment with 3 % Diclofenac in 2.5 % hyaluronic acid as well as the introduction of Imiquimod as an immune response modifier are the most important. The rate of complete clearance from actinic keratoses varies between 50 and 90 % in clinical trials. In contrast to the conventional treatment modalities, these new options promise advantages in the treatment of field and offer excellent cosmetic outcomes, too. This overview will report on the actual treatment opportunities and a careful consideration in the year 2006.

Cryosurgery↗

Induction of oxidative cell damage by photo-treatment with zinc meta N-methylpyridylporphyrin.

We have previously reported that isomeric Zn(II) N-methylpyridylporphyrins (ZnTM-2(3,4)-PyP4 + ) can act as photosensitizers with efficacy comparable to that of hematoporphyrin derivative (HpD) in preventing cell proliferation and causing cell death in vitro. To better understand the biochemical basis of this activity, the effects of photo-activated ZnTM-3-PyP4 + on GSH/GSSG ratio, lipid peroxidation, membrane permeability, oxidative DNA damage, and the activities of SOD, catalase, glutathione reductase, and glutathione peroxidase were evaluated. Light exposure of ZnTM-3-PyP4 + -treated colon adenocarcinoma cells caused a wide spectrum of oxidative damage including depletion of GSH, inactivation of glutathione reductase and glutathione peroxidase, oxidative DNA damage and peroxidation of membrane lipids. Cell staining with Hoechst-33342 showed morphological changes consistent with both necrotic and apoptotic death sequences, depending upon the presence of oxygen.

Catalase↗

ALA/PDT in the treatment of actinic keratosis: spot versus confluent therapy.

BACKGROUND: Actinic keratosis (AK) represents commonly occurring, atypical keratinocytic proliferations confined to the epidermis. While it is the standard of care to destroy AK, few advances have been made to the traditional approaches of physical ablation (e.g. cryosurgery, curettage) and chemotherapeutics (e.g. topical 5-fluorouracil). The recent advances in photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA) offer a novel, safe, and effective approach to AK therapy. OBJECTIVE: To evaluate the safety and efficacy of 20% ALA solution and blue light for the treatment of multiple facial AK. PATIENTS/METHODS: A total of 32 patients were offered either partial treatment (i.e. individual target lesions treated) or confluent treatment (i.e. entire region treated). At 15-20 hours after ALA solution application, treated areas were exposed to visible blue light for 16 minutes and 40 seconds. RESULTS: ALA/PDT treatment resulted in a rapid resolution of multiple AK lesions with a limited period of associated photosensitivity. Side effects experienced by individual patients were found to be influenced by a number of factors: use of analgesic and topical anesthetic agents, body region treated, partial versus confluent treatment, and light exposure time. CONCLUSION: Twenty per cent ALA/PDT offers a safe, effective, and cost-efficient means of managing multiple AK lesions per treatment session with a low recurrence rate. In addition to a favorable tolerability profile, most patients also achieved an improvement in skin texture.

Adult↗

Remember to consider dermatophyte infection when dealing with recalcitrant dermatoses.

BACKGROUND: Superficial fungal infections of the skin are among the most common infections encountered in medicine. The diagnosis is easily confirmed with simple office-based procedures. In certain clinical situations, the diagnosis can be elusive. METHODS: We analyzed clinical data on five patients who came in referral for treatment of a recalcitrant dermatosis. RESULTS: All patients had their diagnosis confirmed by a positive potassium hydroxide preparation from skin scrapings or by a skin biopsy positive for fungal elements. All showed clinical improvement and ultimate resolution of their skin lesions with topical and/or systemic antifungal therapy. CONCLUSIONS: Diagnosis can be complicated by previous use of corticosteroid-containing topical and/or systemic agents, a clinical history closely resembling that of a photosensitive disorder, and a lack of clinical-histopathologic correlation. Laboratory procedures and skin biopsy of an ambiguous appearing lesion can be diagnostic, but an accurate diagnosis is dependent on communication between the clinician and the pathologist. We recommend that office-based procedures be done early in treatment so that subsequent efforts can be directed toward providing appropriate therapies.

Adolescent↗

Topical photodynamic therapy in the treatment of actinic keratoses and Bowen's disease in transplant recipients.

BACKGROUND: Transplant recipients (TR) have a dramatically increased risk for widespread epithelial neoplasms of the skin. Thus, there is a need to treat initial stages of these neoplasms such as actinic keratoses (AK) and Bowen's disease (BD) to prevent progression to invasive and potentially fatal squamous cell carcinoma. Topical photodynamic therapy (PDT) has been proven to be an effective treatment for AK and BD in immunocompetent patients, but no prospective trials in immunocompromised TR have been performed so far. METHODS: Twenty TR and 20 controls with histologically confirmed AK or BD underwent either a single or two consecutive treatments of topical PDT in an open trial. The application of 20% 5-aminolevulinic acid (ALA) for 5 hours was followed by illumination with 75 J/cm2 of visible light delivered at 80 mW/cm2 by an incoherent light source. RESULTS: The overall complete response rates in TR at 4, 12, and 48 weeks were 0.86, 0.68, and 0.48, respectively. The cure rates in both patient groups were comparable at 4 weeks but were significantly lower in TR than in controls at 12 and 48 weeks (P<0.05). Side effects included erythema, edema, and crust formation after illumination. Cosmetic results were excellent without scar formation or alterations in pigmentation. CONCLUSIONS: Topical PDT with 20% 5-ALA is an effective and safe treatment for AK and BD in immunosuppressed TR, with initial response rates comparable with those in immunocompetent patients. It is particularly useful in TR because of the possibility for repeated treatment of large lesional areas.

Administration, Topical↗

Microscopic photosensitization: a new tool to investigate the role of mitochondria in cell death.

Active involvement of mitochondria in cell death has been well-documented, but local apoptotic signaling between subsets of mitochondria has been poorly explored to date. Using mitochondrially localized CMXRos as a photosensitizer coupled to laser irradiation by confocal laser scanning microscopy, we demonstrate that partial irradiation of about half the mitochondria in human 143B TK- cells induces rapid loss of mitochondrial membrane potential (DeltaPsi(m)) in nonirradiated mitochondria. Cells so partially irradiated show apoptotic indications, including mobilization of cytochrome c and binding of annexin V within 2 h following irradiation. The loss of DeltaPsi(m) in nonirradiated mitochondria did not occur in cells photoirradiated in the absence of CMXRos. Increasing the proportion of irradiated mitochondria in each cell (up to about 50%) generated a correspondingly greater percentage of cells in which nonirradiated mitochondria lost DeltaPsi(m) and which also showed apoptotic indications. Only at the highest level of irradiation (global for all mitochondria in one cell) were signs of necrosis evident (judged by uptake of propidium iodide). Because laser irradiation is specific to the subpopulation of mitochondria targeted, the data imply that a signal emanating from irradiated mitochondria is processed by their nonirradiated counterparts. We conclude that intermitochondrial signaling occurs in the subcellular response to induction of apoptosis.

Annexin A5↗

A simple method for diagnosing xeroderma pigmentosum variant.

Patients with xeroderma pigmentosum variant have been diagnosed based on a post-replication repair assay using their cells together with their clinical manifestations. We present here an alternative simple method for the diagnosis of xeroderma pigmentosum variant that measures three cellular markers for DNA repair by autoradiography, unscheduled DNA synthesis, recovery of RNA synthesis, and recovery of replicative DNA synthesis after ultraviolet irradiation. Fibroblasts from a patient are plated on three coverslips parallel with normal cells (control). Unscheduled DNA synthesis, recovery of RNA synthesis, and recovery of replicative DNA synthesis after ultraviolet irradiation in the patient's cells are compared with those of adjacent normal cells by counting numbers of grains on nuclei for each coverslip. Of the hereditary photosensitive disorders including xeroderma pigmentosum, Cockayne syndrome, and newly established ultraviolet-sensitive syndrome, only xeroderma pigmentosum variant cells exhibit normal unscheduled DNA synthesis, normal recovery of RNA synthesis, but reduced recovery of replicative DNA synthesis (approximately 50% of that of control cells). This reduction of DNA synthesis is enhanced in the presence of caffeine. Because each disorder yields a different combination of these three markers, this method also provides a systematic basis for the diagnosis of these diseases.

Autoradiography↗

Phototoxicity of lumidoxycycline.

Doxycycline (DOTC) is a photosensitizing drug whose mechanism of phototoxicity is complicated by the large variety of stable photoproducts formed. To assess the role of a DOTC photoproduct, lumidoxycycline (LuDOTC), in the photosensitization mechanism of DOTC, MGH-U1 human bladder carcinoma cells were treated in vitro with either DOTC or LuDOTC, and irradiated with the 351-nm emission of an argon-ion laser. Both DOTC and LuDOTC were phototoxic and caused radiant-exposure-dependent inhibition of cellular incorporation of tritiated thymidine. On an absorbed-photon basis, DOTC was about five times as phototoxic as LuDOTC. Cellular uptake of DOTC was about five times as great as that of LuDOTC. Epifluorescence microscopy showed localization of LuDOTC predominantly within cellular membranes, particularly of mitochondria, as well as a low level of LuDOTC fluorescence diffusely within the cytoplasm. Epifluorescence microscopy of cells labeled with the mitochondrial probe, rhodamine 123, showed mitochondrial fragmentation and altered mitochondrial membrane integrity after LuDOTC photosensitization; these effects depended on radiant exposure and were partially reversible by 24 h after irradiation. For both DOTC and LuDOTC, phototoxicity was increased by irradiation in the presence of deuterium oxide and decreased in the presence of sodium azide, effects consistent with an important mechanistic role for singlet oxygen, O2(1 delta g), in the injury. In solution, LuDOTC and DOTC had similar quantum yields for generation of O2(1 delta g) as measured by time-resolved spectroscopy and by O2(1 delta g) trapping. LuDOTC was photostable in solution, but DOTC underwent significant photodegradation. These data demonstrate that DOTC photo-products such as LuDOTC have significant photobiologic activity and may play an important role in the phototoxicity mechanism of DOTC.

Doxycycline↗

A case of photocontact urticaria induced by photodynamic therapy with topical 5-aminolaevulinic acid.

Photodynamic therapy (PDT) with topical application of 5-aminolaevulinic acid (ALA) is a promising new treatment option for the management of various cutaneous malignancies. Generally, topical ALA-based PDT has relatively insignificant adverse effects of transient character; these include itching, stinging or burning pain and slight to moderate erythema. We describe the first case of photocontact urticaria induced by topical ALA-based PDT for the treatment of unilesional mycosis fungoides. Although the first treatment session resulted merely in mild erythema, the second PDT caused marked urticaria corresponding to the PDT-applied area with an intolerable stinging sensation. A photopatch test demonstrated that black light and visible light irradiation after topical ALA provoked an urticarial reaction in the patient's uninvolved skin. These observations suggested an allergic pathogenesis for the wheal formation induced by PDT with topical ALA in this case. Photocontact urticaria should be considered as a possible adverse effect in ALA-based PDT.

Administration, Topical↗

A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients.

BACKGROUND: Transplant recipients have an increased propensity to develop multiple actinic keratoses, which demonstrate an increased transformation rate into invasive squamous cell carcinoma. OBJECTIVE: To evaluate the efficacy and tolerability of topical photodynamic therapy with the new highly tumour-selective photosensitizer methyl aminolaevulinate vs. placebo in the treatment of actinic keratoses in transplant recipients. METHODS: Seventeen transplant recipients with a total number of 129 mild to moderate actinic keratoses were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Two lesional areas within a patient were randomized for two consecutive treatments of topical photodynamic therapy 1 week apart using either methyl aminolaevulinate or placebo cream. Sites were illuminated with 75 J cm(-2) of visible light delivered at 80 mW cm(-2) by a noncoherent light source. Complete resolution and reduction in the number or size of actinic keratoses within the lesional area relative to the initial findings were evaluated at weeks 4, 8 and 16 after treatment. RESULTS: The lesional areas treated with methyl aminolaevulinate were clinically cleared in 13 of 17 patients at 16 weeks. A partial response was recorded in a further three. No reduction in the size or number of actinic keratoses was observed in one area treated with methyl aminolaevulinate and in all placebo-treated areas. Adverse events, such as erythema, oedema and crust formation, were mild to moderate, and treatment was well tolerated by all patients. CONCLUSION: Photodynamic therapy using methyl aminolaevulinate is a safe and effective treatment for actinic keratoses in transplant recipients. It may also reduce the risk of transformation of actinic keratoses to invasive, potentially fatal, squamous cell carcinoma.

Adult↗

Photodynamic therapy of actinic keratosis at varying fluence rates: assessment of photobleaching, pain and primary clinical outcome.

BACKGROUND: Although photodynamic therapy (PDT) is becoming an important treatment method for skin lesions such as actinic keratosis (AK) and superficial basal cell carcinoma, there are still discussions about which fluence rate and light dose are preferable. Recent studies in rodents have shown that a low fluence rate is preferable due to depletion of oxygen at high fluence rates. However, these results have not yet been verified in humans. OBJECTIVES: The objective was to investigate the impact of fluence rate and spectral range on primary treatment outcome and bleaching rate in AK using aminolaevulinic acid PDT. In addition, the pain experienced by the patients has been monitored during treatment. PATIENTS/METHODS: Thirty-seven patients (mean age 71 years) with AK located on the head, neck and upper chest were treated with PDT, randomly allocated to four groups: two groups with narrow filter (580-650 nm) and fluence rates of 30 or 45 mW cm(-2), and two groups with broad filter (580-690 nm) and fluence rates of 50 or 75 mW cm(-2). The total cumulative light dose was 100 J cm(-2) in all treatments. Photobleaching was monitored by fluorescence imaging, and pain experienced by the patients was registered by using a visual analogue scale graded from 0 (no pain) to 10 (unbearable pain). The primary treatment outcome was evaluated at a follow-up visit after 7 weeks. RESULTS: Our data showed a significant correlation between fluence rate and initial treatment outcome, where lower fluence rate resulted in favourable treatment response. Moreover, the photobleaching dose (1/e) was found to be related to fluence rate, ranging from 4.5 +/- 1.0 J cm(-2) at 30 mW cm(-2), to 7.3 +/- 0.7 J cm(-2) at 75 mW cm(-2), indicating higher oxygen levels in tissue at lower fluence rates. After a cumulative light dose of 40 J cm(-2) no further photobleaching took place, implying that higher doses are excessive. No significant difference in pain experienced by the patients during PDT was observed in varying the fluence rate from 30 to 75 mW cm(-2). However, the pain was found to be most intense up to a cumulative light dose of 20 J cm(-2). CONCLUSIONS: Our results imply that the photobleaching rate and primary treatment outcome are dependent on fluence rate, and that a low fluence rate (30 mW cm(-2)) seems preferable when performing PDT of AK using noncoherent light sources.

Aged↗

Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study.

BACKGROUND: Actinic keratosis (AK), the most common premalignant skin condition, can represent a management challenge. Treatment should not only be effective, but also well tolerated and allow for good cosmesis on typical sun-exposed highly visible body sites. OBJECTIVES: The primary objective was to compare the lesion response and subject preference for topical methyl aminolaevulinate (MAL)-photodynamic therapy (PDT) vs. cryotherapy for the treatment of AK. METHODS: In this 24-week, multicentre, randomized, intraindividual (right-left) study, subjects received both one treatment session of MAL-PDT and a double freeze-thaw cryotherapy; the treatments were randomly allocated to either side of the face/scalp. Lesions with a noncomplete response were retreated after 12 weeks. The primary assessments were the subject's overall preference and lesion response at week 24. Secondary assessments included lesion response at week 12, cosmetic outcome, subject and investigator cosmetic outcome preference at week 24, and investigator overall preference at week 24. Skin discomfort and adverse events were also evaluated. RESULTS: In total, 119 subjects with 1,501 lesions were included in the study. At week 12, treatment with MAL-PDT resulted in a significantly larger rate of cured lesions relative to cryotherapy (percentage lesion reduction from baseline: 86.9% vs. 76.2%; P < 0.001). At week 24, both treatment groups showed a high rate of cured lesions (89.1% for MAL-PDT vs. 86.1% for cryotherapy; P = 0.20; 95% confidence interval: -1.62 to 7.67). Results for subject and investigator preferences as well as cosmetic outcome favoured MAL-PDT. Both treatment regimens were safe and well tolerated. CONCLUSIONS: The present study shows that, when treated with both MAL-PDT and cryotherapy, subjects significantly prefer MAL-PDT treatment for AK. MAL-PDT is an attractive treatment option for AK, with comparable efficacy and superior cosmetic outcomes compared with double freeze-thaw cryotherapy.

Aged↗