Expert Recommendations on Facilitating Personalized Approaches to Long-term Management of Actinic Keratosis: The Personalizing Actinic Keratosis Treatment (PAKT) Project.

Actinic keratoses are pre-malignant skin lesions that require personalized care, a lack of which may result in poor treatment adherence and suboptimal outcomes. Current guidance on personalizing care is limited, notably in terms of tailoring treatment to individual patient priorities and goals and supporting shared decision-making between healthcare professionals and patients. The aim of the Personalizing Actinic Keratosis Treatment panel, comprised of 12 dermatologists, was to identify current unmet needs in care and, using a modified Delphi approach, develop recommendations to support personalized, long-term management of actinic keratoses lesions. Panellists generated recommendations by voting on consensus statements. Voting was blinded and consensus was defined as ≥ 75% voting 'agree' or 'strongly agree'. Statements that reached consensus were used to develop a clinical tool, of which, the goal was to improve understanding of disease chronicity, and the need for long-term, repeated treatment cycles. The tool highlights key decision stages across the patient journey and captures the panellist's ratings of treatment options for attributes prioritized by patients. The expert recommendations and the clinical tool can be used to facilitate patient-centric management of actinic keratoses in daily practice, encompassing patient priorities and goals to set realistic treatment expectations and improve care outcomes.

Classifying Real-world Macroscopic Images in the Primary-Secondary Care Interface using Transfer Learning: Implications for Development of Artificial Intelligence Solutions using Non- dermoscopic Images.

BACKGROUND: Application of deep learning to diagnostic dermatology has been the subject of numerous studies, with some reporting skin lesion classification performance on curated datasets comparable to that of experienced dermatologists. Most skin disease images encountered in clinical settings are macroscopic, without dermoscopic information, and exhibit considerable variability. Further research is necessary to determine the generalisability of deep learning algorithms across populations and acquisition settings. OBJECTIVES: We assessed the extent to which deep learning can generalise to non-dermoscopic datasets acquired at the primary-secondary care interface in the National Health Service (NHS). We explored how to obtain clinically satisfactory performance on non-standardised, real-world local data without availability of large diagnostically labelled local datasets. We measured the impact of pre-training deep learning algorithms on external, public-domain datasets. METHODS: Diagnostic macroscopic image datasets were created from previous referrals from primary to secondary care. These included 2213 images referred from primary care practitioners in NHS Tayside and 1510 images from NHS Forth Valley acquired by medical photographers. Two further datasets with identical diagnostic labels were obtained from public domain sources, namely the International Skin Imaging Collaboration (ISIC) dermoscopic dataset and the SD-260 non-dermoscopic dataset. Deep learning algorithms, specifically SWIN transformers and an EfficientNets, were trained using data from each of these datasets. Algorithms were also fine-tuned on images from the NHS datasets after pre-training on different data combinations, including the larger public domain datasets. ROC curves and area under such curves (AUC) were used to assess performance. RESULTS: SWIN transformers tested on Forth Valley data had AUCs of 0.85 and 0.89 when trained on SD-260 and Forth Valley data, respectively. Training on SD-260 followed by fine-tuning of Forth Valley data gave an AUC of 0.91. Similar effects of pre-training and tuning on local data were observed using Tayside data, and EfficientNets. Pre-training on the larger dermoscopic image dataset (ISIC-2019) provided no additional benefit. CONCLUSIONS: Pre-training on public macroscopic images, followed by tuning to local data, gave promising results. Further improvements are needed to afford deployment in real clinical pathways. Larger datasets local to the target domain might be expected to yield further improved performance.

Polyolefin-Polar Block Copolymers from Versatile New Macromonomers.

A new metallocene-based polymerization mechanism is elucidated in which a zirconium hydride center inserts α-methylstyrene at the start of a polymer chain. The hydride is then regenerated by hydrogenation to release a polyolefin containing a single terminal α-methylstyrenyl group. Through the use of the difunctional monomer 1,3-diisopropenylbenzene, this catalytic hydride insertion polymerization is applied to the production of linear polyethylene and ethylene-hexene copolymers containing an isopropenylbenzene end group. Conducting simple radical polymerizations in the presence of this new type of macromonomer leads to diblock copolymers containing a polyolefin attached to an acrylate, methacrylate, vinyl ester, or styrenic segments. The new materials are readily available and exhibit interfacial phenomena, including the mediation of the mixing of immiscible polymer blends.

Low-Dose 0.5% 5-Fluorouracil/10% Salicylic Acid Topical Solution in the Treatment of Actinic Keratoses.

BACKGROUND: Actinic keratosis (AK) lesions have the potential to develop into invasive squamous cell carcinomas (SCCs), and approaches to treatment are evolving to try to reduce the burden of SCC. OBJECTIVE: To present the published clinical research surrounding the use of 0.5% 5-fluorouracil with 10% salicylic acid (low-dose 5-FU/SA) for the treatment of hyperkeratotic AKs. METHOD: A review of published clinical evidence for low-dose 5-FU/SA for the treatment of AKs. The articles were selected following a MEDLINE database search of the combined terms fluorouracil, salicylic acid and actinic keratosis which represent the peer review publications of clinical studies that primarily investigate the use of Actikerall in AK. RESULTS: Combining low-dose 5-FU with keratolytic SA is associated with high rates of histologic clearance, reduction in lesion number/area, and sustained clinical response in clinical study and the clinical practice setting. Low-dose 5-FU/SA has also been evaluated using imaging to detect the progression of subclinical AK lesions through a course of the field-directed treatment. CONCLUSION: Low-dose 5-FU/SA is an effective and well-tolerated treatment option licensed for the lesion-directed treatment of mild-to-moderate hyperkeratotic AK lesions.

Review of the European Society for Photodynamic Therapy (Euro-PDT) Annual Congress 2022.

This article reviews the 2022 European Society for Photodynamic Therapy (Euro-PDT) Annual Congress. PDT has been investigated for the treatment of a broad number of oncologic, infectious and inflammatory indications. New studies confirm the potential for wider use of topical PDT for acne and photoaging, as well as several uncommon conditions including tinea capitis, Mycobacterium marinum, cutaneous alternariosis, resistant acral warts, eyelid Bowen's disease, mycosis fungoides, pseudolymphoma, and graft-versus-host disease. Hidradenitis suppurativa patients may also benefit from intra-lesional PDT. Several methods of delivering PDT have been validated, including conventional, daylight and artificial daylight PDT. Light-emitting fabrics have emerged as an innovative solution to the delivery of uniform light over the scalp as well as anatomically-challenging sites, with opportunities now to control and monitor these devices via mobile phone applications. Pre-treatment of patients with thicker, more difficult-to-treat actinic keratoses (AK) with calcitriol appears to be a practical approach to increasing efficacy, although this is associated with increased local skin reactions. Sequential treatment of AK and photoaging with daylight-PDT and injectable NASHA gel indicates that these two therapeutic approaches offer complementary effects. Potential biomarkers may help predict responsiveness of patients with field cancerization and AK receiving daylight PDT. Over-expression of the proto-oncogene, Myc, has been observed in poor responders, whilst the tumour suppressor gene, PTEN, showed under-expression. The potential for use and methods of delivery of topical PDT for dermatological indications continue to expand the enhanced choice of treatment offered to patients.

Rapid Expansion of a Teledermatology Web Application for Digital Dermatology Assessment Necessitated by the COVID-19 Pandemic: Retrospective Evaluation.

BACKGROUND: The COVID-19 pandemic necessitated a change in the provision of outpatient care in dermatology. OBJECTIVE: A novel, asynchronous, digital consultation platform was codeveloped with 2 National Health Service dermatology teams to improve access and enhance choice in outpatient care. METHODS: The rollout of the platform was accelerated during the initial COVID-19 lockdown, and its wider use across 2 Scottish health boards was retrospectively evaluated. Integrated with the hospital booking system and electronic patient record, the platform provides an alternative to face-to-face consultations, using information and images submitted by the patients. RESULTS: In total, 297 new patient consultations and 108 return patient consultations were assessed, and 80% (324/405) of the images submitted were of satisfactory quality. The consultations were, on average, 3 minutes shorter than equivalent face-to-face interactions, and a total of 5758 km of patient travel was avoided. Outcomes included web-based reviews (66/405, 16.3%), face-to-face reviews (190/405, 46.9%), biopsies (46/405, 11.4%), discharge (89/405, 22%), and other treatments or investigations (14/405, 3.5%). High levels of patient satisfaction (92/112, 82.1%) were reported. CONCLUSIONS: Digital dermatology assessments are now included in the choices for consultation types that are available to patients, helping to augment service capacity during pandemic recovery.

Review of the European Society for Photodynamic Therapy (Euro-PDT) Annual Congress 2020.

This article reviews the 2020 European Society for Photodynamic Therapy (Euro-PDT) Annual Congress. Cutting edge studies included assessment of immunohistochemical variables influencing response of basal cell carcinomas and Bowen's disease to PDT with p53, the only biomarker associated with good response in both conditions. A further study indicated that analysis of molecular markers, such as PIK3R1, could help select patients with actinic keratoses who demonstrate the best response to daylight PDT. Novel delivery protocols include artificial daylight, and laser-assisted and textile PDT. The meeting learnt of novel indications including antimicrobial PDT, as well as methods to optimise daylight PDT, including combination therapy for actinic keratoses. Adverse events were reviewed and options for painless and efficient PDT assessed, including the effect of reduced drug-light interval. A smartphone application was also evaluated which may be used to assist clinicians and patients in effective dosing and timing of daylight PDT via computational algorithms using data from earth observation satellites, to send light and ultraviolet dose information directly to patients' smart phones.

End-functional polyolefins for block copolymer synthesis.

Polyolefins that contain polar functionalities are highly desired because they could extend the range of applications of these low production cost materials by modifying surface and other interfacial properties. Block copolymers containing polyolefin and polar segments are among the most sought-after architectures because of their ability to span the phase boundaries. This review focusses on the end-functionalisation of polyolefins by catalytic olefin polymerisation processes, almost invariably by metal-catalysed routes, followed by the growth polar blocks by various polymerisation techniques.

Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer collaborated to develop recommendations on diagnosis and treatment of BCC. A new classification into 'easy-to-treat (common) BCC and 'difficult-to-treat' BCC is proposed. Diagnosis is based on clinicodermatoscopic features for 'easy-to-treat' BCCs. Histopathological confirmation is mandatory in ambiguous lesions and in BCCs located in high-risk areas. The first-line treatment of 'easy-to-treat' BCC is complete surgery. Microscopically controlled surgery shall be offered for high-risk BCC, recurrent BCC and BCC in critical anatomical sites. Topical therapies (5% imiquimod, 5% fluorouracil) and destructive approaches (curettage, electrocautery, cryotherapy, laser ablation) should be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial BCC and thin nodular BCC. The therapy for a 'difficult-to-treat' BCC should preferentially be discussed by a multidisciplinary tumour board. Hedgehog inhibitors, vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCCs. Immunotherapy with anti-programmed cell death 1 (PD-1) antibodies is a promising therapeutic option, currently being investigated in clinical trials. Radiotherapy represents a valid alternative to surgery for BCC on the face, especially in elderly patients. In patients with naevoid basal cell carcinoma syndrome (NBCCS), close surveillance and regular skin examinations are required to diagnose and treat BCCs at early stage. Long-term follow-up is recommended in patients with high-risk BCC subtypes, high-risk sites, multiple BCCs and NBCCS.

Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial.

This multicentre, randomized study compared photodynamic therapy using topical methyl aminolaevulinate (MAL PDT), a non-invasive modality, with cryotherapy for treatment of superficial basal cell carcinoma. Sixty patients with 114 lesions were treated with MAL cream (160 mg/g) applied for 3 hours before illumination (570-670 nm, light dose 75 J/cm) (1 session), and 58 with 105 lesions received cryotherapy (2 freeze-thaw cycles). Patients with an incomplete response at 3 months received 2 further MAL PDT sessions (n = 20) or repeat cryotherapy (n = 16). 100 lesions treated with MAL PDT and 93 lesions treated with cryotherapy were in complete response at 3 months after the last treatment and evaluable for recurrence over 5 years. There was no difference in 5-year recurrence rates with either treatment (20% with cryotherapy vs. 22% with MAL PDT, p = 0.86). However, more patients had an excellent cosmetic outcome with MAL PDT (60% vs. 16% with cryotherapy, p = 0.00078). These results provide support for the use of MAL PDT as a non-invasive, selective treatment alternative for primary superficial basal cell carcinoma.

A synthesis of the world's guidelines on photodynamic therapy for non-melanoma skin cancer.

Photodynamic therapy (PDT), using topically administered photosensitizing agents, is widely approved as a treatment for certain nonmelanoma skin cancers. As a tissue-sparing non-surgical modality, there is great potential for PDT to enhance the choice of therapies available to treat, and potentially prevent, skin cancer. Treatment-specific guidelines have assessed the evidence for various photosensitizing agents and light sources, dosimetry, and evaluate reported adverse effects. Discomfort is frequently experienced during treatment but no analgesia was required in most pivotal lesion-directed studies. Durability of response has been assessed with studies of PDT for basal cell carcinomas (BCC) extending to 5 years and beyond, 2 years for Bowen's disease and up to 1 year for actinic keratoses (AK). Disease-specific guidelines consider the place for topical PDT in routine clinical practice recognizing that PDT is typically office/clinic-based and usually initiated by specialists. Where updated guidelines are awaited, national and international consensus publications offer recommendations, including on the use of daylight to activate the photosensitizer for treating AK. Reviewed studies indicate equivalent efficacy of daylight PDT, but greatly reduced pain compared with conventional PDT. Guidelines and consensus publications also consider the place of PDT in treating skin lesions arising in organ transplant recipients and in the potential for PDT to delay/prevent the development of nonmelanoma skin cancers. There is now a substantial evidence-base to support the use of topical PDT in routine clinical practice with daylight PDT indicated for AK, providing suitable outside climate, whilst conventional PDT remains suitable for AK, Bowen's Disease, superficial and certain thin nodular BCC.

Daylight Photodynamic Therapy for Actinic Keratoses.

Topical photodynamic therapy (PDT) using daylight is effective in the treatment of actinic keratoses (AKs), offering the potential for treatment of large fields such as full face and balding scalp, but with minimal therapy-associated pain. Comparison with conventional PDT indicates similar efficacy for thin and moderate-thickness AKs, but with significantly less discomfort/pain, driving a patient preference for daylight-mediated PDT (DL-PDT) compared with conventional PDT using high-intensity office/hospital-based light sources. Treatment protocol involves the application of a photosensitizing agent without occlusion and subsequent exposure to ambient daylight within 30 min, with patients exposed to daylight for 1.5-2.0 h. Pivotal randomized controlled trials in Europe and Australia have confirmed the efficacy of methyl aminolevulinic acid (MAL) DL-PDT in comparison with conventional MAL-PDT for mild and moderate-thickness lesions on the face and scalp. Initial clearance rates of 70-89% are reported. DL-PDT using a nanoemulsion aminolevulinic acid (ALA) has recently been shown to be at least as effective as MAL DL-PDT in treating mild and moderate-thickness AKs. DL-PDT may offer a better-tolerated method for treating patients with extensive AK disease. There is emerging literature on the potential for field PDT to reduce the number of new AKs developing, potentially preventing/slowing skin cancer development. Conventional PDT remains established as a therapy for Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas (BCCs), and AKs. The evidence for the use of DL-PDT beyond AK is limited, although has been reported in actinic cheilitis, superficial BCC, and acne and cutaneous leishmaniasis. There is emerging interest in combination therapy for AK, using one or more field therapies such as DL-PDT as an option to complement with localized treatment for residual lesions. We review current recommendations and consider the appropriate place for DL-PDT in our treatment armamentarium.

Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005.

Topical photodynamic therapy (PDT) is used to treat nonmelanoma skin cancers, such as actinic keratoses, Bowen's disease, and basal cell carcinoma (superficial and nodular). This article presents up-to-date, practical, evidence-based recommendations on the use of topical PDT using 5-aminolevulinic acid or methyl aminolevulinate for the treatment (and prevention) of nonmelanoma skin cancers. A systematic literature review was conducted (using MEDLINE), and recommendations were made on the basis of the quality of evidence for efficacy, safety/tolerability, cosmetic outcome, and patient satisfaction/preference. Topical PDT is highly effective in the treatment of actinic keratoses, Bowen's disease, superficial and thin nodular basal cell carcinomas, with cosmesis typically superior to that achieved with existing standard therapies. PDT may also be a means of preventing certain nonmelanoma skin cancers in immunosuppressed patients.

Methyl aminolevulinate: actinic keratoses and Bowen's disease.

Topical photodynamic therapy (PDT) using the methyl ester of 5-aminolaevulinic acid (MAL) is an effective therapy for actinic keratoses and Bowen's disease. Thin and moderate thickness facial actinic keratoses respond best, with clearance rates equivalent or superior (depending on protocol) to current therapy, and with notably superior cosmetic outcome. Patients with areas of field cancerization and organ transplant recipients may particularly benefit from topical MA-PDT. The response rate of Bowen's disease to MAL-PDT is also at least equivalent to cryotherapy and 5-fluorouracil, again with superior cosmesis. Patients with large or multiple lesions of Bowen's disease or those in whom standard therapy, including surgery, is relatively contraindicated may particularly benefit from PDT.

Cyclooxygenase in Cancer Prevention and Treatments for Actinic Keratosis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a chemically diverse class of drugs that target the cyclooxygenase (COX) pathway and have anti-inflammatory, analgesic, and antipyretic properties. Elevated expression of COX-2 has been associated with tumor progression in skin cancer through multiple mechanisms. We present evidence for a chemoprotective effect of NSAIDs and discuss potential mechanisms of action of COX-2 in cancer. We also discuss the challenges associated with the treatment of actinic keratosis and the factors that should be taken into consideration when selecting a treatment regimen. A range of treatments are reviewed, with an emphasis on combination therapies.

The cost-effectiveness of 5-FU-SA in the treatment of actinic keratoses of the face and scalp in the UK secondary care setting.

OBJECTIVE: The objective of this analysis was to estimate the relative cost-effectiveness of Actikerall 1 (5-FU-SA) vs cryotherapy in a secondary care setting in the UK, for lesion-directed treatment in patients with actinic keratoses (AK) of the face and scalp. METHODS: The model was a simple decision tree, with a 6-month time horizon. The perspective was that of the UK National Health Service (NHS). Modeled treatment effects included reported per-patient histological clearance and recurrence rates. Cost inputs comprised professional consultation time and cost of medication. Health-related utility estimation followed previously published methodology. Adverse events were not modeled. The key data and model structural assumptions followed expected UK practice. One-way and probabilistic sensitivity analyses were conducted to assess structural and parameter uncertainty. RESULTS: 5-FU-SA was found to be less costly (-£204) and more effective (+0.001 QALY) in base case and sensitivity analyses. In the probabilistic analysis there was 100% probability of being cost-effective over cryotherapy at £20,000 willingness to pay. Cost of professional time was a key driver of the model outcome. 5-FU-SA remained dominant across a range of scenario analyses, including exploration of assumptions around setting of care. LIMITATIONS: The time horizon of the analysis was short and data were not extrapolated beyond the duration of the clinical trial; however, this approach is consistent with likely follow-up of an AK patient. The clinical outcomes observed in the trial were based on a large proportion of cryotherapy patients undergoing an additional cycle of treatment; this may not occur or be required in an experienced secondary care setting. CONCLUSION: 5-FU-SA could be considered as a cost-effective choice for treatment of AK lesions of the face and scalp in secondary and mixed care settings in the UK. Use of 5-FU-SA in patients who would otherwise be managed with cryotherapy has the potential to result in cost savings.

A consensus on the use of daylight photodynamic therapy in the UK.

BACKGROUND: Actinic keratoses (AKs) are a consequence of chronic exposure to ultraviolet radiation. Treatment of chronically photo-damaged skin and AKs is driven by risk of progression to squamous cell carcinoma, as well as for symptomatic relief. Conventional photodynamic therapy (c-PDT) is indicated when AKs are multiple or confluent and if patients respond poorly or are unable to tolerate other therapies. c-PDT is limited by the field size that can be treated in single sessions and can cause significant discomfort. OBJECTIVE: Recent studies investigated daylight illumination to activate protoporphyrin IX and daylight-PDT (d-PDT) is now licensed in the UK for face and scalp AKs. A group of experts met to discuss application of d-PDT with methyl aminolevulinate (MAL) and develop a UK consensus statement, specific to UK weather conditions. METHODS: The UK consensus recommendations were reached among eight experts, who reviewed recent studies on d-PDT, assessed UK meteorological data and discussed personal experiences of d-PDT for AKs. RESULTS: Recommendations from these discussions provide guidance on d-PDT use, specifically regarding patient selection, therapeutic indications, when to treat, skin preparation, MAL application and daylight exposure for patients with AKs. CONCLUSIONS: This UK expert consensus provides practical guidance for UK application of d-PDT.

Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial.

OBJECTIVE: To compare the efficacy, tolerability, and cosmetic outcome of photodynamic therapy (PDT) using topical methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ. DESIGN: Randomized, placebo-controlled study, with follow-up at 3 and 12 months after last treatment. SETTING: Forty outpatient dermatology centers in 11 European countries. PATIENTS: Random sample of 225 patients with histologically confirmed squamous cell carcinoma in situ (lesion size, 6-40 mm) and no evidence of progression. INTERVENTIONS: Treatment with PDT with methyl aminolevulinate (160 mg/g; n = 96) or matching placebo cream (n = 17), cryotherapy (n = 82), or topical fluorouracil (5% cream; n = 30). Methyl aminolevulinate or placebo cream was applied for 3 hours before illumination with broadband red light (75 J/cm2, 570-670 nm). Treatment was repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 weeks. Lesions with a partial response at 3 months were re-treated. MAIN OUTCOME MEASURES: Clinically verified complete response of lesions; blinded and on-site assessment of cosmetic outcome (4-point rating scale). RESULTS: At 12 months, the estimated sustained lesion complete response rate with methyl aminolevulinate PDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT vs 66% with cryotherapy and 76% with fluorouracil, and was maintained at 12 months. CONCLUSION: Methyl aminolevulinate PDT is an effective treatment option for squamous cell carcinoma in situ, with excellent cosmesis.

15th Annual Congress of the European Society for Photodynamic Therapy in Barcelona, Spain, February 12-13th 2016.

UNLABELLED: We provide a summary of the presentations made at the recent Euro-PDT annual Congress. Presentations covered developments in topical photodynamic therapy (PDT) pertaining to dermatological applications. Recognizing the high prevalence and chronicity of actinic keratosis, one of the approved indications for PDT, there were recommendations to pursue field therapy to treat clinical and preclinical lesions. A separate section was reserved to review the strong evidence for the use of daylight PDT for actinic keratosis and experience of use of this well tolerated form of PDT was reported from several countries. Several presentations covered the remaining approved uses of topical PDT, Bowen's disease and basal cell carcinomas, as well as considering its role in so far unapproved indications including photorejuvenation. FUNDING: Galderma.