Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia
Dan F. Spandau, … , Robert Hoopes, Jeffrey B. Travers
Dan F. Spandau, … , Robert Hoopes, Jeffrey B. Travers
Published August 24, 2021
Citation Information: J Clin Invest. 2021;131(19):e150972. https://doi.org/10.1172/JCI150972.
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Clinical Research and Public Health Dermatology

Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia

Abstract

BACKGROUND The loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC.METHODS A human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion.RESULTS Xenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs).CONCLUSION The elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATION ClinicalTrials.gov (NCT03906253).FUNDING National Institutes of Health, Veterans Administration.

Authors

Dan F. Spandau, Roy Chen, Jeffrey J. Wargo, Craig A. Rohan, David Southern, Angela Zhang, Mathew Loesch, Jonathan Weyerbacher, Sunil S. Tholpady, Davina A. Lewis, Matthew Kuhar, Kenneth Y. Tsai, Amber J. Castellanos, Michael G. Kemp, Michael Markey, Elizabeth Cates, Amy R. Williams, Christina Knisely, Sabina Bashir, Ryan Gabbard, Robert Hoopes, Jeffrey B. Travers

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Figure 2

Hyperproliferation of human epidermis induced by UVB is exacerbated by inhibiting the IGF-1R.

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Hyperproliferation of human epidermis induced by UVB is exacerbated by i...
Human skin obtained from discarded abdominoplasty surgeries was grafted onto immunodeficient mice and treated as described in Figure 1. These results were obtained from 3 biological replicates, each time containing groups of at least 4 mice per treatment. (A) Representative sections of human skin xenografts were stained with antibodies to the proliferation marker Ki67 (SP6 clone) and nuclei identified by DAPI staining. (B) Sections of skin stained with H&E were digitized and the area of the epidermis and length of the basement membrane were determined using Nikon Elements software. The relative thickness of the epidermis was then determined by dividing the area by the basement membrane length. Average areas indicated by black bars and standard deviation represented by gray boxes (DMSO no UVB, 8 images; DMSO chronic UVB, 12 images; AG538 no UVB, 7 images; AG538 chronic UVB, 16 images). (C) Sections of human skin stained with α-Ki67 as in C were imaged and quantified for Ki67(+) cells using Nikon Elements software. Black bars indicate averages and gray boxes represent the standard deviation of counts from 5 images (no UVB controls), 20 images (DMSO, chronic UVB), or 32 images (AG538, chronic UVB). P values shown derived from 2-tailed Student t test. The absence of P values indicates a lack of statistically significant difference between data shown.