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Actinic keratoses: immuno-histochemical response to MAL-PDT (methyl-aminolevulinate photodynamic therapy). Baseline vitamin D receptor (VDR) expression (A) did not significantly change after treatment (B). Baseline P53 (C) and Ki67 (E) expression significantly decreased (D and F, respectively) after PDT.
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In mouse models of squamous cell carcinoma, pre-treatment with calcitriol prior to photodynamic therapy with aminolevulinic acid (ALA) enhances tumor cell death. We have evaluated the association between vitamin D status and the response of actinic keratoses to photodynamic therapy with methylaminolevulinate. Twenty-five patients with actinic kerat...
Citations
... The other available lesion-directed or field-directed therapies for AK, including cryosurgery, laser treatment, and topical drugs, vary widely in factors such as duration, efficacy, cosmetic outcomes, and cost, and direct comparison of the different modalities is restricted due to few ''head-to-head'' studies [1,3,10]. One study has suggested that the patient's blood serum profile may affect treatment efficacy; Moreno et al. reported that a poorer response of AK to MAL-PDT may occur with a deficient vitamin D status [14]. Thus, the choice of treatment is guided by patient-, lesion-/field-, and treatment-specific factors prioritizing personalized AK care [1,3]. ...
Methyl aminolevulinate (MAL) is a topical compound approved for use with photodynamic therapy (PDT) for the treatment of actinic keratosis (AK) and field cancerization in certain countries. There exists a high burden of disease for patients with AK: repeated treatments are required, there is a known risk of progression to keratinocyte carcinoma, and cosmetic appearance is affected. Delivery of PDT using MAL is a flexible treatment strategy available in many forms; red light, daylight, or artificial daylight can be used for illumination, all of which result in high AK clearance rates and low recurrence. MAL-PDT protocols continue to evolve to further improve adherence and treatment outcomes. Here, we used PubMed to search MEDLINE to identify guidelines, consensus recommendations, and studies describing the use of MAL for the treatment of AK. The aim of this targeted review is to consider various MAL-PDT treatment strategies on the basis of published literature, with a focus on personalizing treatment for the heterogeneous AK population.
... Theoretically, vitamin D metabolites may protect the skin from damaging oxidative stress, photoaging, premalignant skin lesions, and carcinogenesis induced by UV radiation, in addition to the modulation of the cutaneous immune system [29,30], although clinical studies on human subjects dealing with the role of vitamin D in these carcinogenetic events are sparse. However, there are recent reports showing that serum 25(OH)-D3 level or vitamin D supplementation is positively associated with a better outcome of head actinic keratosis treatment with photodynamic therapy [31,32]. In this present cross-sectional study, the purpose was to investigate whether an oral vitamin D supplementation can have associations with cutaneous photoaging level, actinic keratoses, pigment cell nevi, and skin cancers. ...
... Possibly this picture can be turned to be clear by increasing the number of study subjects. Nevertheless, prospective follow-up studies and intervention trials with oral or topical vitamin D supplements are needed to demonstrate a possible causal connection of vitamin D to photoaging, actinic keratoses, and SCC, like the studies published recently on the positive effect of vitamin D in the photodynamic therapy of actinic keratoses [31,32], or the study suggesting a reduced risk of SCC by the combination of calcium and vitamin D [28]. ...
There are conflicting results on the role of vitamin D system in cutaneous carcinogenesis. Therefore, it was investigated whether the use of oral vitamin D supplements associates with photoaging, actinic keratoses, pigment cell nevi, and skin cancers. In this cross-sectional study, 498 adults (aged 21-79 years, 253 males, 245 females, 96 with immunosuppression) subjects at risk of any type of skin cancer were examined, and possible confounding factors were evaluated. The subjects were divided into three groups based on their self-reported use of oral vitamin D supplements: non-use, occasional use, or regular use. The serum level of 25-hydroxyvitamin-D3 was analyzed in 260 subjects. In 402 immunocompetent subjects, vitamin D use did not associate with photoaging, actinic keratoses, nevi, basal, and squamous cell carcinoma. In contrast, there were lower percentages of subjects with a history of past or present melanoma (32/177, 18.1% versus 32/99, 32.3%, P = 0.021) or any type of skin cancer (110/177, 62.1% versus 74/99, 74.7%, P = 0.027) among regular users compared to non-users. In the logistic regression analysis, the odds ratio for melanoma was 0.447 (P = 0.016, 95% confidence interval, 0.231-0.862) among regular users. Furthermore, the investigator-estimated risk class of skin cancers was significantly lower among regular users. Serum 25-hydroxyvitamin-D3 did not show marked associations with skin-related parameters. The results on 96 immunosuppressed subjects were somewhat similar, although the number of subjects was low. In conclusion, regular use of vitamin D associates with fewer melanoma cases, when compared to non-use, but the causality between them is obscure.
... and induces uncontrolled proliferation, which is an early event in the progression of AK to SCC. 10 PDT. 19 The mechanisms through which VD may influence the response of AK to IM are unknown; however, VD has proved antiproliferative and differentiation-promoting effects on keratinocytes through up-regulation of p53 20 or through the intervention of the immune system. 21 We suggest 25(OH)D serum level be considered a biochemical biomarker of response of AK to IM that should be checked before treating to enhance this response. ...
... VDR recently gained attention regarding its role in epidermal carcinogenesis. 22 In line with this study, our research group verified that MAL-PDT might be able to increase keratinocytic VDR expression in AK. 19 In consequence, either IM or PDT may improve dysplastic keratinocyte sensitivity to serum VD, thus supplying other way through which PDT and IM interact with VD triggering its antioncogenic effects on keratinocytic neoplasms such as AK. ...
Vitamin D serum levels, and keratinocytic basal expression of VDR before treatment of actinic keratoses have been previously reported as possible biomarkers of the response of AK to treatments. We intended to evaluate the association between these and other serum and immunohistochemical parameters with the response of AK to treatment with topical ingenol mebutate. Twenty‐five patients with actinic keratoses on the head were treated with topical ingenol mebutate 0.015% gel once daily for three days. Biopsies were taken at baseline and six weeks after treatment. Immuno‐histochemical staining was performed for VDR, P53, Ki67, Aurora B, Survivin and β‐catenin. Basal serum 25(OH)D levels were determined. IM was more effective for KIN I and II AKs than in KIN III, and histological responders showed significantly higher serum VD levels (30.278 (SD 8.839) ng/ml) than non‐responders (21.14 (SD 7.079) ng/ml, p= 0.023). In addition, mean basal expression of VDR (45.63 (SD 16,105) %) increased significantly (57.92 (SD 14.738) %, p=0.003) after treatment with IM. A significant decrease after treatment in the expression of several markers of aggressiveness and progression to SCC, namely P53, Ki‐67, aurora B kinase and survivin, was also observed. Our results support a relationship between vitamin D status and the response of actinic keratoses to treatment with topical ingenol mebutate, suggesting that its previous correction to proper serum levels in VD‐deficient patients could improve the response of AK to the treatment.
... It is now known that calcitriol promotes the repair of UVinduced mutations in keratinocytes by increasing functional P53 and has several antitumor effects on epidermal tumors through the immune system. The transcriptional profile of calcitriol-treated healthy keratinocytes was examined, showing upregulation of approximately 82 genes and downregulation of 16 other genes [38]. One example of the analysis of the effect of calcitriol on the patient's body is the study conducted by Anand et al. ...
Photodynamic therapy is an unconventional yet increasingly common method of treating dermatological diseases and cancer that is implemented more often in adults than in children. Current clinical uses include treatment of actinic keratosis, superficial basal cell carcinomas, and acne. Despite its high efficiency, photodynamic therapy support supplements have recently been reported in the literature, including calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, and vitamin D3 cholecalciferol. In clinical trials, photodynamic therapy enhanced with vitamin D or D3 supplementation has been reported for treatment of squamous cell skin cancers, actinic keratosis, and psoriasis. Experimental research on the effect of photodynamic therapy with vitamin D or D3 has also been carried out in breast cancer cell lines and in animal models. The aim of this review is to evaluate the usefulness and effectiveness of vitamin D and D3 as supports for photodynamic therapy. For this purpose, the Pubmed and Scopus literature databases were searched. The search keyword was: “vitamin D in photodynamic therapy”. In the analyzed articles (1979–2022), the authors found experimental evidence of a positive effect of vitamin D and D3 when used in conjunction with photodynamic therapy. An average of 6–30% (in one case, up to 10 times) increased response to photodynamic therapy was reported in combination with vitamin D and D3 as compared to photodynamic therapy alone. Implementing vitamin D and D3 as a supplement to photodynamic therapy is promising and may lead to further clinical trials and new clinical methodologies.
... Systemic delivery of calcitriol is easily performed in mice and increases the tumoral accumulation of PpIX up to 10-fold, while in humans, high calcitriol levels are associated with the risk of developing hypercalcemia. Interestingly, the deficiency of serum vitamin D is associated with poorer responses of AKs to MAL-PDT [46] and, thus, further studies are needed to investigate its role in the treatment of AKs. ...
Photodynamic therapy (PDT) is a highly effective and widely adopted treatment strategy for many skin diseases, particularly for multiple actinic keratoses (AKs). However, PDT is ineffective in some cases, especially if AKs occur in the acral part of the body. Several methods to improve the efficacy of PDT without significantly increasing the risks of side effects have been proposed. In this study, we reviewed the combination-based PDT treatments described in the literature for treating AKs; both post-treatment and pretreatment were considered including topical (i.e., diclofenac, imiquimod, adapalene, 5-fluorouracil, and calcitriol), systemic (i.e., acitretin, methotrexate, and polypodium leucotomos), and mechanical–physical (i.e., radiofrequency, thermomechanical fractional injury, microneedling, microdermabrasion, and laser) treatment strategies. Topical pretreatments with imiquimod, adapalene, 5-fluorouracil, and calcipotriol were more successful than PDT alone in treating AKs, while the effect of diclofenac gel was less clear. Both mechanical laser treatment with CO2 and Er:YAG (Erbium:Yttrium–Aluminum–Garnet) as well as systemic treatment with Polypodium leucotomos were also effective. Different approaches were relatively more effective in particular situations such as in immunosuppressed patients, AKs in the extremities, or thicker AKs. Conclusions: Several studies showed that a combination-based approach enhanced the effectiveness of PDT. However, more studies are needed to further understand the effectiveness of combination therapy in clinical practice and to investigate the role of acitretin, methotrexate, vitamin D, thermomechanical fractional injury, and microdermabrasion in humans.
... Vitamin D (VD) is a prohormone involved in a broad range of functions in the organism that has been shown to exert protective effects against several types of cancer [1] and skin aging [2] , among others. In the human epidermis, exposure to sunlight -ultraviolet B radiation (UVB, 280-315 nm) -promotes the transformation of 7-dehydrocholesterol to previtamin D 3 , which undergoes thermal isomerization into cholecalciferol, also known as vitamin D 3 [ Figure 1]. ...
Photoaging and carcinogenesis are facilitated by oxidative stress, inflammation, angiogenesis, and extracellular matrix (ECM) remodeling. Oxidative effects include DNA damage, membrane oxidation, lipid peroxidation, and alterations in the expression of p53 and antioxidant enzymes. The inflammatory and angiogenesis mediators include interleukin-1, tumor necrosis factor-α, interleukin-8, transforming growth factor-β, and vascular endothelial growth factor. ECM remodeling includes alterations in the expression and organization of collagen, elastin, matrix metalloproteinases, and elastase. 1α, 25-dihydroxy-vitamin D3 has antioxidant, anti-inflammatory, and ECM regulatory properties, and can counteract the processes that facilitate photoaging and carcinogenesis. This review provides an overview of the beneficial effects of vitamin D supplementation at a molecular level, followed by a brief discussion regarding its use as a supplement.
Zusammenfassung
Aktinische Keratosen (AK) sind frühe kutane Plattenepithelkarzinome (PEK) in situ. Chronische UV‐Exposition der Haut und weitere individuelle Faktoren wie anhaltende Immunsuppression sind Risikofaktoren für ihre Entwicklung und maligne Transformation. Weniger das klinische Erscheinungsbild (Olsen I–III) der AK als vielmehr histologische Kriterien wie basale Zellatypien (AK I) und basale Keratinozytenproliferation (PRO‐Score) scheinen das Risiko einer malignen Transformation zu bestimmen. Allerdings werden auf Grund der Invasivität der Probebiopsie diese histologischen Kriterien nicht regelhaft bestimmt. Nichtinvasive bildgebende Verfahren, wie die optische Kohärenztomographie (OCT) und die konfokale Lasermikroskopie (KLM), können bei der klinischen Differenzierung zwischen AK, Morbus Bowen und PEK helfen. Die konfokale Line‐Field‐OCT (LC‐OCT) ermöglicht darüber hinaus bei zellulärer Auflösung die nichtinvasive Bestimmung des PRO‐Score. Zur Therapie der AK sind sowohl läsions‐ als auch feldgerichtete Verfahren zugelassen. Sie müssen unter Berücksichtigung individueller Risikofaktoren und Präferenzen des Patienten ausgewählt werden. Allerdings treten in bis zu 85% der Fälle behandelter AK innerhalb eines Jahres Rezidive auf. Inwieweit diese bildgebenden Technologien geeignet sind, die nichtinvasive Nachsorge von AK zu ermöglichen und Rezidive beziehungsweise invasiven Progress frühzeitig zu erkennen, muss in weiteren klinischen Studien evaluiert werden.
Actinic keratosis (AK) is considered a chronic and recurring in situ skin neoplasia, with a possible transformation into invasive squamous cell carcinoma (SCC). Among others, predominant risk factors for development of AK are UV‐light exposure and immunosuppression. Basal epidermal keratinocyte atypia (AK I) and proliferation (PRO score) seem to drive malignant transformation, rather than clinical appearance of AK (Olsen I–III). Due to the invasiveness of punch biopsy, those histological criteria are not regularly assessed. Non‐invasive imaging techniques, such as optical coherence tomography (OCT), reflectance confocal microscopy (RCM) and line‐field confocal OCT (LC‐OCT) are helpful to distinguish complex cases of AK, Bowen's disease, and SCC. Moreover, LC‐OCT can visualize the epidermis and the papillary dermis at cellular resolution, allowing real‐time PRO score assessment. The decision‐making for implementation of therapy is still based on clinical risk factors, ranging from lesion‐ to field‐targeted and ablative to non‐ablative regimens, but in approximately 85% of the cases a recurrence of AK can be observed after a 1‐year follow‐up. The possible beneficial use of imaging techniques for a non‐invasive follow‐up of AK to detect recurrence or invasive progression early on should be subject to critical evaluation in further studies.
D Vitamini Kimyasal Yapısı ve Metabolizması Hülya Cenk D Vitamini Ve Genetik Aydın Rüstemoğlu D Vitamininin Normal Serum Düzeyleri, D Vitamin Düzeylerini Etkileyen Faktörler Ve D Vitamini Yetmezliği Sabiye Akbulut Serum D Vitamininin Ölçümü Andaç Uzdoğan, Çiğdem Yücel D Vitamini Biyoyararlanımı ve Doğal Beslenme Kaynakları Atilla Çifci, Halil İbrahim Yakut Sistemik D Vitamini Tedavi Ajanları, Biyoyararlanımı ve Tedavi Yönetimi Işıl Deniz Oğuz Topikal D Vitamini Tedavisi, Tedavi Yönetimi ve Kullanıldığı Hastalıklar Dursun Türkmen Deride D Vitamini Sentezi Mekanizmaları Abdullah Demirbaş, Ömer Faruk Elmas Güneşten Koruyucu Kullanımı ve D Vitamini Nursel Dilek, Yunus Saral D Vitamininin Deri Yapısı ve Fizyolojisine Etkisi Pelin Hızlı Deri Yaşlanması ve D Vitamini Ülker Gül Psoriasis ve D Vitamini Ülker Gül Psöriatik Artrit ve D Vitamini Mehmet Uçar Atopik Dermatit ve D Vitamini Ayşegül Ertuğrul, İlknur Bostancı Mast Hücresi ve Kutanöz Mastositozda D Vitamini Selçuk Doğan, Tülin Çataklı, İlknur Bostancı Ürtiker ve D Vitamini Kemal Özyurt Kaşıntı ve D Vitamini Kübra Yüce Atamulu Likenoid Dermatozlar ve D Vitamini Nihal Altunışık Vitiligo ve D Vitamini Ayşe Akbaş Melasma ve D Vitamini İbrahim Etem Arıca Rozase ve D Vitamini Nalan Saraç Akne ve D Vitamini Selma Korkmaz Hidradenitis Süpürativa ve D Vitamini Yılmaz Ulaş Seboreik Dermatit ve D Vitamini Dilek Başaran Otoimmün Büllöz Hastalıklar ve D Vitamini Sezgi Sarıkaya Solak Bağ Doku Hastalıkları ve D Vitamini Kevser Gök Behçet Hastalığı ve D Vitamini Şule Ketenci Ertaş, Ragıp Ertaş İdiyopatik Fotodermatozlar ve D Vitamini Bülent Nuri Kalaycı İktiyozis ve D Vitamini Tubanur Çetinarslan Epidermolizis Bülloza ve Vitamin D Eda Haşal Kseroderma Pigmentozum, Epidermodisplasia Verrusiformis ve D Vitamini Derya Yayla Nevüsler ve D Vitamini Serpil Şener, Suat Sezer Aktinik Keratoz ve Seboreik Keratozda D Vitamini Mahmut Sami Metin Deri Maliniteleri ve D Vitamini Sevda Önder Vaskülitler ve Vitamin D Havva Hilal Ayvaz Venöz Trombozis ve D Vitamini Cahit Yavuz Yara İyileşmesi ve D Vitamini Bülent Nuri Kalaycı Diyabetik Ayak Ülseri ve D Vitamini Gözde Ulutaş Demirbaş, Abdullah Demirbaş Granülomatöz Hastalıklar ve D Vitamini Selma Bakar Dertlioğlu Deri Enfeksiyonları ve Vitamin D Atıl Avcı Oral Mukoza Hastalıkları ve D Vitamini Ali İhsan Güleç Tırnak Sağlığı ve Hastalıklarında D Vitamini Hülya Cenk Alopesiler ve D Vitamini Munise Daye Hirsutizm ve D Vitamini Efşan Gürbüz Yontar Sistemik Kortikosteroid Kullanımında D Vitamini Desteği Selma Korkmaz Fototerapi ve D Vitamini Tuğba Özkök Akbulut Covıd-19 Ve Vitamin D Sibel Altunışık Toplu D Vitamini Tedavisinin Yan Etkileri ve D Vitamini Tedavisi Sürecinde Dikkat Edilecek Hususlar Dursun Türkmen, Nihal Altunışık D Vitamini Ve İlaç İlaç Etkileşimleri Şule Gökşin D Vitamini İntoksikasyonu Bedriye Müge SÖNMEZ
Photodynamic therapy (PDT) is a nonscarring cancer treatment in which a pro‐drug (5‐ aminolevulinic acid , ALA) is applied, converted into a photosensitizer (protoporphyrin IX, PpIX) which is then activated by visible light. ALA‐PDT is now popular for treating nonmelanoma skin cancer (NMSC), but can be ineffective for larger skin tumors, mainly due to inadequate production of PpIX. Work over the past two decades has shown that differentiation‐promoting agents, including methotrexate (MTX), 5‐fluorouracil (5FU) and vitamin D (Vit D) can be combined with ALA‐PDT as neoadjuvants to promote tumor‐specific accumulation of PpIX, enhance tumor‐selective cell death, and improve therapeutic outcome. In this review, we provide a historical perspective of how the combinations of differentiation‐promoting agents with PDT (cPDT) evolved, including Initial discoveries, biochemical and molecular mechanisms, and clinical translation for the treatment of NMSCs. For added context, we also compare the differentiation‐promoting neoadjuvants with some other clinical PDT combinations such as surgery, laser ablation, iron‐chelating agents (CP94), and immunomodulators that do not induce differentiation. Although this review focuses mainly on the application of cPDT for NMSCs, the concepts and findings described here may be more broadly applicable towards improving the therapeutic outcomes of PDT treatment for other types of cancers.
