Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10-4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10-2, p = 2.8 × 10-2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10-2, p = 3.2 × 10-2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10-1, p = 3.4 × 10-2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10-2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10-4-3.1 × 10-3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10-3-2.8 × 10-3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10-3), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10-4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.

Treatment Outcomes of Adjunct and Stand-alone Photodynamic Therapy in Patients With Extramammary Paget Disease: A Literature Review.

BACKGROUND: Extramammary Paget disease (EMPD) is a rare malignant neoplasm arising from apocrine gland-bearing skin. The surgical management of EMPD is often coupled with noninvasive techniques including cryotherapy, ablative lasers, topical chemotherapies, and photodynamic therapy (PDT). The specificity and preservation of tissue that PDT with photosensitizers 5-aminolevulinic acid or 5-methyl aminolevulinate allows makes it a potential treatment of EMPD. METHODS: The authors present a review of 13 studies, from 2002 to 2019, examining the reported efficacy of PDT alone and adjunctive PDT in EMPD treatment. RESULTS: In the 52 patients with 56 lesions who received stand-alone PDT, 20 lesions (35.7%, n = 20/56) experienced complete resolution, 31 lesions (55.4%, n = 31/56) experienced partial resolution, 5 lesions (8.9%, n = 5/56) failed to demonstrate response to treatment, and 23 lesions (41.1%, n = 23/56) had recurrence. In the 56 patients with 66 lesions that received adjunctive PDT paired with surgery ( n = 55/66), imiquimod ( n = 4/66), holmium laser and surgery ( n = 1/66), Mohs surgery ( n = 2/66), and combined surgery, imiquimod, and 5-fluorouracil ( n = 1/66), 34 lesions (51.5%) experienced complete resolution, 27 lesions (40.9%) experienced partial resolution, 5 lesions (7.6%) failed to demonstrate any response to treatment, and 16 lesions (24.2%) had EMPD recurrence. CONCLUSION: Further studies with larger sample size are needed to consolidate these findings and inform clinical decisions.