European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 2: emerging indications - field cancerization, photorejuvenation and inflammatory/infective dermatoses.

In addition to approved indications in non-melanoma skin cancer in immunocompetent patients, topical photodynamic therapy (PDT) has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immune-competent individuals. PDT using a nanoemulsion of ALA in a daylight or conventional PDT protocol has been approved for use in field cancerization, although evidence of the potential of the treatment to prevent new SCC remained limited. High-quality evidence supports a strong recommendation for the use of topical PDT in photorejuvenation as well as for acne, refractory warts, cutaneous leishmaniasis and in onychomycosis, although these indications currently lack approvals for use and protocols remain to be optimized, with more comparative evidence with established therapies required to establish its place in practice. Adverse events across all indications for PDT can be minimized through the use of modified and low-irradiance regimens, with a low risk of contact allergy to photosensitizer prodrugs, and no other significant documented longer-term risks with no current evidence of cumulative toxicity or photocarcinogenic risk. The literature on the pharmacoeconomics for using PDT is also reviewed, although accurate comparisons are difficult to establish in different healthcare settings, comparing hospital/office-based therapies of PDT and surgery with topical ointments, requiring inclusion of number of visits, real-world efficacy as well as considering the value to be placed on cosmetic outcome and patient preference. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical photodynamic therapy in Dermatology prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1: treatment delivery and established indications - actinic keratoses, Bowen's disease and basal cell carcinomas.

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas. Recurrence rates when standard treatment protocols are used are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as lesional and field therapies and has the potential to delay/reduce the development of new lesions. A protocol using daylight to treat actinic keratoses is widely practised, with conventional PDT using a red light after typically a 3-h period of occlusion employed for other superficial skin cancer indications as well as for actinic keratoses when daylight therapy is not feasible. PDT is a well-tolerated therapy although discomfort associated with conventional protocol may require pain-reduction measures. PDT using daylight is associated with no or minimal pain and preferred by patient. There is an emerging literature on enhancing conventional PDT protocols or combined PDT with another treatment to increase response rates. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical PDT in dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.

Topical resiquimod dosing regimens in patients with multiple actinic keratoses: a multicentre, partly placebo-controlled, double-blind clinical trial.

BACKGROUND: Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. OBJECTIVES: To investigate the optimal dosing regimens of the Toll-like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. METHODS: In a multicentre, partly placebo-controlled, double-blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once-daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment-free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. RESULTS: Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment-related adverse reactions. CONCLUSIONS: Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.

The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients.

The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro- and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta-genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co-factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post-transplant keratinocyte cancers.

Impact of UVA on pruritus during UVA/B phototherapy of inflammatory skin diseases: a randomized double-blind study.

BACKGROUND: Narrowband (TL-01) UVB phototherapy (UVB nb) is effective in treating inflammatory skin disease. The addition of UVA is traditionally advocated to reduce pruritus, but lacks evidence for this recommendation. OBJECTIVES: The aim of this study was to assess the effect of UVB nb and UVA phototherapy in combination compared against UVB nb monotherapy on pruritus, disease activity and quality of life. METHODS: In this double-blind randomized clinical trial, 53 patients suffering from inflammatory skin diseases with pronounced itching (Visual Analogue Scale (VAS) for pruritus ≥5) were randomized into two treatment groups. One group received UVB nb (311 nm) phototherapy alone and another group received a combination of UVB nb and UVA (320-400 nm) phototherapy. UV therapy was performed three times per week over 16 weeks. Pruritus (VAS and 5-D itch score), disease activity and quality of life (Dermatology Life Quality Index, DLQI) were assessed at baseline and weeks 4, 8, 12 and 16. RESULTS: In both treatment groups, there was a reduction in pruritus scores, disease activity and DLQI. No difference in pruritus score, disease activity and quality of life could be detected between the group receiving UVB nb alone and those receiving UVB nb combined with UVA. CONCLUSIONS: Phototherapy with UVB nb alone, and UVB nb combined with UVA are equally effective in treating inflammatory skin disease and indifferent in reducing disease-associated pruritus. Given this non-inferiority for UVB nb monotherapy, the recommendation of adding UVA to UVB nb phototherapy for pruritic inflammatory skin disease should be abandoned.

Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: a cohort study.

BACKGROUND: Organ transplant recipients (OTRs) have a highly increased risk of cutaneous squamous cell carcinomas (SCCs). Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive SCCs in OTRs. OBJECTIVES: To investigate the impact of painful vs. painless skin lesions and SCC vs. other skin lesions on the overall mortality risk in OTRs. METHODS: We followed 410 OTRs from 10 different centres across Europe and North America between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC, and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis, and risk factors were analysed with Cox proportional hazard analysis. RESULTS: There was an increased overall mortality risk in OTRs who reported painful vs. painless skin lesions, with a hazard ratio (HR) of 1·6 [95% confidence interval (CI) 0·97-2·7], adjusted for age, sex and other relevant factors. There was also an increased overall mortality risk in OTRs diagnosed with SCC compared with other skin lesions, with an adjusted HR of 1·7 (95% CI 1·0-2·8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTRs with SCC. CONCLUSIONS: We suggest that OTRs have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC.

Exposure to moxifloxacin and cytomegalovirus replication is associated with skin squamous cell carcinoma development in lung transplant recipients.

BACKGROUND: Lung transplant recipients (LTR) are at increased risk for squamous cell carcinoma of the skin (SCC), but risk factors (RF) are incompletely understood. OBJECTIVE: To assess associations between exposure to certain medications and viral infections, and subsequent SCC development. METHODS: Retrospective study examining incidence and potential RF for SCC in LTR transplanted from 1992 to 2010 followed up at one centre. Cumulative incidence and Cox proportional hazards regression models were used to evaluate RF in the first year post-transplant for SCC formation during the follow-up. RESULTS: In 205 analysed LTR, 46 patients were diagnosed with SCC during a median follow-up of 4.9 years. The cumulative incidences of first SCC were 16.7% and 34.1%, for 5 and 10 years post-transplantation respectively. Multivariable analysis identified CMV replication (HR 7.69, 95% CI 2.93-20.2, P < 0.001) and moxifloxacin exposure (HR 2.35, 95% CI 1.15-4.81, P = 0.020) during the first year post-transplantation as independent RF for SCC development during follow-up. CONCLUSION: In our cohort, moxifloxacin use and CMV replication during the first year post-transplantation were associated with increased risk for SCC. These two factors could be indicators of over-immunosuppression. Their role in SCC development requires investigations in larger cohorts and prospective studies.

Spectophotometric intracutaneous analysis: an investigation on photodamaged skin of immunocompromised patients.

BACKGROUND: SIAscopy (Spectrophotometric Intracutaneous Analysis) enables non-invasive analysis of the skin. OBJECTIVE: We wanted to determine whether SIAscopy is able to detect and differentiate the skin chromophores melanin, collagen and haemoglobin and the influence of immunosuppressive drugs and other known risk factors for non-melanoma skin cancer (NMSC). METHODS: Volunteers and patients were measured by SIAscopy at six spots on sun-exposed and two spots on sun-protected skin. Measurements were transformed by SIAmetrics into arbitrary units and statistically analysed. RESULTS: Melanin was shown to be higher with age (+1.73759 a.u.; P < 0.0001), sun exposure (+47.03998 a.u.; P < 0.0001), immunosuppression (+10.48526 a.u.; P < 0.0001) and lower in males (-26.50952 a.u.; P < 0.0001). Collagen was lower with increasing age (-0.29162 a.u.; P < 0.0001) and sun exposure (-6.85586 a.u.; P < 0.0001) but higher with male sex (+8.34251 a.u.; P < 0.0001) and immunosuppression (+5.79171 a.u.; P = 0.0001). Haemoglobin was lower with increasing age (-0.23833 a.u.; P = 0.0005), but higher with male sex (+18.51976 a.u.; P < 0.0001) and sun exposure (+13.74523 a.u.; P < 0.0001). Haemoglobin content was not associated to immunosuppression. CONCLUSION: Our results encourage the use of SIAscopy as a tool to better gauge an individual patient's NMSC risk factors. Further studies should help to better delineate SIAscopy as a prognostic tool.

A multifaceted intervention: no increase in general practitioners' competence to diagnose skin cancer (minSKIN) - randomized controlled trial.

BACKGROUND: General practitioners (GPs) play crucial roles in early detection of skin cancer. A pilot-study found a positive short-term effect of a 1-day dermatologic education programme on GPs' diagnostic competence. OBJECTIVE: To determine effects of a multifaceted intervention, including technical equipment and continuing feedback by a dermatologist, on GPs' diagnostic skills regarding skin cancer. METHODS: Randomized controlled trial with 78 GPs of the Canton of Zurich, Switzerland. INTERVENTION: GPs in intervention group received a 1-day training, a Lumio (magnifying glass with polarized light, 3Gen), a Nikon digital camera and - during 1 year - feedback on skin lesion pictures sent to the dermatologist. GPs in control group only received the 1-day training. PRIMARY OUTCOME: structured assessment of GP's diagnostic skills in correctly diagnosing images of skin lesions regarding skin cancer. At baseline prior to intervention (T0), after the full-day training course in both groups (T1), and after 1 year of continuing feedback (T2) to the intervention group. MEASURES: Non-parametric unpaired (Wilcoxon-Mann-Whitney) tests were used to compare numbers of correctly classified skin lesions between both groups at T2 and for the change between T1 and T2. RESULTS: At T0, both groups classified a median of 23 skin lesions of the 36 images correctly. This value rose to 28 for both groups at T1 and fell to 24 for both groups at T2. No difference between control and intervention group at T2. Furthermore, we compared differences in the sum scores per GP between T1 and T2 for each group. Also in this comparison, no difference between control and intervention group was found. CONCLUSION AND RELEVANCE: No long-term effect of the multifaceted intervention was found on the competence to diagnose skin cancer by GPs. The positive short-term effect of the 1-day dermatologic education programme did not persist over 12 months.

Pain identifies squamous cell carcinoma in organ transplant recipients: the SCOPE-ITSCC PAIN study.

Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient-reported warning signals predicting the presence of invasive SCC.Patient-reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy-proven diagnoses. Receiver-operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient-reported warning signals and the occurrence of SCC. Pain was an independent predictive patient-reported warning signal for a biopsy-proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4(95% confidence interval: 2.4­8.2). Higher scores on the visual analog scale (VAS) for pain were associated witha greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1to 3, 4 to 6 and 7 to 10 were 4.9 (2.2­10.5), 2.3 (0.96­5.5)and 16.5 (3.6­75.8), respectively. Pain is the most powerful patient-reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.

Subacute cutaneous lupus erythematosus triggered by radiotherapy.

BACKGROUND: The origin of collagen autoimmune diseases is not fully understood. Some studies postulate a mechanism of molecular mimicry or heterologous immunity following viral infections triggering autoimmunity. Apart from infections, other exogenous factors such as visible light or X-rays have been reported to incite autoimmunity. CASE REPORT: We report a case of histologically and serologically confirmed subacute lupus erythematosus (SCLE) following radiotherapy for breast cancer. DISCUSSION: The close temporal and spatial correlation between radiotherapy and onset of SCLE in this patient suggests that an autoimmune reaction may have been triggered locally by functionally altering the immune system and breaking self-tolerance.

Lichenoid Drug Eruption following Intravenous Application of Orally Formulated Diamorphine, a Semisynthetic Heroin.

BACKGROUND: Lichen planus is a common skin disorder of unknown etiology. Most cases are idiopathic, but substances such as gold, antimalarials, penicillamine, thiazide diuretics, ß-blockers, arsenic and nonsteroidal anti-inflammatory drugs have been implicated as trigger factors. CASE PRESENTATION: We report the case of a lichenoid eruption in a male drug addict who administered oral heroin (diamorphine) intravenously. Diamorphine was stopped immediately. Following topical steroids, phototherapy and oral acitretin, the lesions gradually disappeared. A lymphocyte transformation test was negative for pure morphine and codeine. DISCUSSION: A coincidental association between the intravenous application of orally formulated semisynthetic heroin and the lichenoid eruption cannot be completely ruled out. However, the diagnosis of a lichenoid drug eruption is favoured over idiopathic lichen planus because of the clear chronological correlation between drug use and appearance as well as drug withdrawal and disappearance of the skin lesions, and because of a flare-up following repeated intravenous application of diamorphine.

Primary cutaneous posttransplant lymphoproliferative disorders in solid organ transplant recipients: a multicenter European case series.

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.

[Phototherapy and carcinogenesis]. / Phototherapie und karzinogenese.

Phototherapy successfully uses the short-term effects of ultraviolet light against inflammation and proliferation. For its long-term effects, however, ultraviolet light was recently classified as a carcinogen. The wave spectrum employed in phototherapy has various carcinogenic effects in experimental systems, most notably DNA mutations in keratinocytes. Clinically, PUVA increases the risk for squamous cell carcinoma of the skin, especially after following 350 or more phototherapy sessions over a lifetime. Melanoma and genital skin cancer are not increased by PUVA alone. Previous UV damage, immunosuppression and other systemic treatments increase cutaneous carcinogenesis through PUVA. In contrast, broad-band UVB, narrow-band UVB and UVA1 have not yet been linked to cutaneous carcinogenesis, but will need careful follow-up in larger studies. Phototherapy remains a safe treatment modality, provided that the indication is well-founded, previous exposure and co-carcinogens are considered, and short and dose-intensive treatment protocols are favored, PUVA is chosen as second-line treatment that should not be used for more than a lifetime total of 250-300 phototherapy sessions.

Photodynamic therapy for actinic keratosis in organ transplant patients.

BACKGROUND: The incidence of actinic keratoses (AK) and non-melanoma skin cancer (NMSC) in organ transplant recipients (OTRs) is significantly higher than in immunocompetent patients. Rates of progression and recurrence following treatment are higher too, in part due to the effects of the immunosuppressant drugs. Conventional therapies for AK, using curettage, cryotherapy, surgical excision, topical therapies and photodynamic therapy (PDT), are often less effective, and may be inappropriate, for treating the greater numbers and extent of lesions in OTRs. Moreover, there are no specific protocols for treating this patient population that take into account the need for more frequent treatment and the increased pain associated with treating larger areas. OBJECTIVES: Recently, a pan-European group of dermatologists with expertise in this area met to share current best practice in PDT for the treatment of AK in OTRs. METHODS: The group identified areas where PDT currently is not meeting the needs of these patients and discussed how these gaps might be addressed. RESULTS/CONCLUSIONS: This position article summarizes those discussions and makes recommendations concerning a standardized protocol for treating OTRs, for a large randomized controlled trial to provide robust data on safety, efficacy and optimal pain control, and to provide pharmaco-economics data that can be used to support extended reimbursement in this patient group. The authors also recommend a second clinical trial to further investigate induced immunosuppression with PDT in healthy volunteers.

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

BACKGROUND: Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. OBJECTIVES: To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. METHODS: The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. RESULTS: Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. CONCLUSIONS: The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.