Discrepancies in Non-Mohs Micrographic Surgery for Non-melanoma Skin Cancer Between Lighter-Skinned and Darker-Skinned Patients.

BACKGROUND: Non-melanoma skin cancer (NMSC) is highly prevalent in the United States, with darker-skinned patients (DSP) exhibiting lower incidence but increased morbidity and mortality. The purpose of this study is to elucidate NMSC disparities between DSP (Fitzpatrick skin phototype IV or more) and lighter-skinned patients (LSP, Fitzpatrick skin phototype III or less), focusing on surgical features of non-Mohs micrographic surgery-treated NMSC. METHODS: This retrospective cohort study included LSP and DSP diagnosed with either basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in an academic dermatology setting. Variables collected included age, gender, type of NMSC, location, staging, time-to-diagnosis (TTD), pre-operative lesion size, and post-operative defect size. Categorical variables were reported as counts and percentages, while the association between categorical variables was assessed using a two-tailed Fisher's test. A paired t-test was used to determine the association between continuous variables. P-values <0.05 were considered statistically significant. RESULTS: A total of 27 patients with NMSC were identified, of which 9 (33.3%) were DSP. Patients of darker skin were predominantly female (n=7; 77.8%), while no gender predilection was found in LSP (n=9; 50.0% female; p=0.23). Time-to-diagnosis was significantly longer in DSP than in LSP (61.3 weeks vs 25.1 weeks, respectively; p = 0.02). Despite this, there was no statistical difference in terms of staging, pre-operative lesion size (11.89 mm in DSP vs 10.76 mm in LSP, p=0.75), and post-operative defect size (45.56 ± 29.21 mm in DSP vs 31.22 ± 19.60 mm in LSP; p=0.33). CONCLUSIONS: Darker-skinned patients had a longer TTD without staging differences. Our study confirms the need for reducing TTDs for NMSC in DSP. Action initiatives include continued educational efforts to increase awareness of NMSC risk in DSP and more rigorous routine skin cancer screening.

Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors.

Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory "danger" signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A2A receptor (A2AR) antagonist, was administered 1 h before bilateral IRI in WT, A2AR KO (Adora2a-/- ) or CD73-/- mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a-/- mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73-/- mice, which lack a 5'-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A2AR-and non-A2AR-dependent signaling pathways.

Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment.

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5'-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-ß immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73-/- kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.