Faculty Bibliography

INTRODUCTION/BACKGROUND:The purpose of this study is to systematically review data pertaining to breast cancer and radiation-induced skin reactions in patients with skin of color (SOC), as well as data pertaining to objective measurements of skin pigmentation in the assessment of radiation dermatitis (RD). METHODS AND MATERIALS/METHODS:We conducted a systematic review utilizing MEDLINE electronic databases to identify published studies until August 2022. Key inclusion criteria included studies that described RD in breast cancer with data pertaining to skin of color and/or characterization of pigmentation changes after radiation. RESULTS:We identified 17 prospective cohort studies, 7 cross-sectional studies, 5 retrospective studies and 4 randomized controlled trials. Prospective cohort and retrospective series demonstrate worse RD in African American (AA) patients using subjective physician-graded scales. There is more limited data in patients representing other non-White racial subgroups with SOC. 2 studies utilize patient reported outcomes and 15 studies utilize objective methods to characterize pigmentation change after radiation. There are no prospective and randomized studies that objectively describe pigmentation changes with radiotherapy in SOC. CONCLUSIONS:AA patients appear to have worse RD outcomes, though this is not uniformly observed across all studies. There are no studies that describe objective measures of RD and include baseline skin pigmentation as a variable, limiting the ability to draw uniform conclusions on the rate and impact of RD in SOC. We highlight the importance of objectively characterizing SOC and pigmentation changes before, during and after radiotherapy to understand the incidence and severity of RD in SOC.

Purpose/Objective(s): Radiation dermatitis (RD) is common after RT for breast cancer with data indicating potentially worse RD in African American (AA) patients (pts). Current measures of RD, such as the CTCAE, do not include hyperpigmentation, which may disproportionately affect how RD is classified and treated in pts with skin of color (SOC). We aim to characterize RD in SOC and identify factors, including baseline skin pigmentation (BSP) that predict RD. Materials/Methods: Pts treated with whole breast (WB) or chest wall (CW) with regional nodal RT or high tangents with 50 Gy in 25 fractions from 2015-2018 were identified. Three dermatologists independently classified BSP using photographs from CT simulation based on the Fitzpatrick scale ([FS], range=I-VI; I=light/pale white to VI=black/ very dark brown). SOC was defined as FS IV-VI. Pt characteristics were investigated for association with interventions to treat RD, clinician-graded acute RD, and late skin toxicity (NCI CTCAE scale) with Chi-squared and logistic regression analyses.
Result(s): 325 pts met eligibility criteria (58 African American [AA], 42 Asian, 151 Caucasian, 77 other). 40% (n=129) had SOC, 60% underwent CW RT, 40% WB RT and 82% had systemic therapy. Pts with SOC were more likely to be Hispanic (14% vs 8% p=0.007), AA (43% vs 1%, p<0.001) and have greater mean BMI (28.0 vs 26.5, p=0.02). Acute grade 2/3 RD was lower in SOC (FS I 60%, FS II 63%, FS III 52%, FS IV 64%, FS V 40%, FS VI 41%; p=0.049). Increased BSP (OR 0.83; p=0.01) and AA pts (OR: 0.22; p<0.001) had lower odds of acute grade 2/3 RD, whereas bolus and dosimetric parameters such as increased PTV volume had increased odds. On multivariable analysis (MVA), AA pts and bolus remained significant (OR: 0.14, p=0.01; OR: 6.63 p<0.001, respectively). Topical steroid use to treat RD was less frequent and oral analgesic use was more frequent in SOC (43% vs 63%, p<0.001; 50% vs 38%, p=0.05, respectively). Pts with increased BSP (OR 0.73, p<0.001), AA race (OR 0.19, p<0.001) and greater BMI had lower use of topical interventions whereas any boost phase, bolus, IMN RT and increased PTV volume had greater use. On MVA, AA pts (OR 0.27, p=0.04), boost (OR 2.04, p=0.033), IMN RT (OR 2.73, p=0.003) and PTV V105% (OR=1.002, p=0.03) retained significance. Late grade 2/3 hyperpigmentation was greater in SOC (16% vs 3%, p=0.01). Increased BSP (OR 2.14, p=0.001), AA pts (OR 8.18, p=0.02), bolus and CW boost had greater odds of grade 2/3 hyperpigmentation. On MVA, increased BSP (OR: 3.76, p=0.03) and bolus (OR: 14.1, p=0.01) retained significance.
Conclusion(s): We found less clinician-graded acute RD in SOC and AA pts, less frequent use of topical interventions but more oral analgesic use. We also found higher rates of late pigmentation change with increased BSP independent of race. These findings suggest that RD may be under-diagnosed in SOC. This study confirms the necessity for objective measures of RD that account for variability in BSP to accurately classify the severity of radiation skin toxicity in SOC and treat accordingly.
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The development of immunotherapy has led to a paradigm shift in the treatment of both solid and hematologic malignancies. As immunomodulatory therapies are employed with increasing frequency, a greater number of immune-related adverse reactions are being reported, and the majority of these involve the skin. As a result, dermatologists are increasingly becoming involved in the management of these cutaneous adverse reactions-often providing critical recommendations regarding ongoing cancer treatment. Cutaneous immune-related adverse reactions can vary significantly from patient to patient, making early recognition and timely intervention imperative to mitigate associated morbidity and potential treatment interruption. Although there is considerable overlap in the cutaneous adverse events caused by these immune checkpoint inhibitors, specific eruptions are characteristically associated with particular checkpoint inhibitors. In addition, a patient's comorbidities or immune status can play a significant role in the presentation and management of such adverse reactions. This review characterizes and provides management guidelines for the various cutaneous toxicities associated with checkpoint inhibitor therapy, including CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. © 2020 Elsevier Inc. All rights reserved.

The advent of immune checkpoint inhibition represents a paradigm shift in the treatment of an increasing number of cancers. However, the incredible therapeutic promise of immunotherapy brings with it the need to understand and manage its diverse array of potential adverse events. The skin is the most common site of immune-related adverse vents (irAEs), which can present with a wide variety of disparate morphologies and severities. These toxicities can endanger patient health and the ability to continue on therapy. This review summarizes our current understanding of the presentation and management of the most common and clinically significant cutaneous irAEs associated with immune checkpoint inhibitor (ICI) therapy. Effective management of these cutaneous irAEs requires an understanding of their morphology, their appropriate clinical characterization, and their potential prognostic significance. Their treatment is additionally complicated by the desire to minimize compromise of the patient's anti-neoplastic regimen and emphasizes the use of non-immunosuppressive interventions whenever possible. However, though cutaneous irAEs represent a challenge to both oncologist and dermatologist alike, they offer a unique glimpse into the mechanisms that underlie not only carcinogenesis, but many primary dermatoses, and may provide clues to the treatment of disease even beyond cancer.

BACKGROUND:There is little evidence to guide surgical management of biopsies yielding the histologic descriptor atypical intraepidermal melanocytic proliferation (AIMP). OBJECTIVE:Determine frequency of and factors associated with melanoma and melanoma in-situ (MIS) diagnoses after excision of AIMP and evaluate margins used to completely excise AIMP. METHODS:Retrospective, cross-sectional study of 1127 biopsies reported as AIMP and subsequently excised within one academic institution. RESULTS:Melanoma (in situ, stage 1A) was diagnosed after excision in 8.2% (92/1127) of AIMP samples. Characteristics associated with melanoma/MIS diagnosis included age 60-79 years (odds ratio [OR] 8.1, 95% confidence interval [CI] 2.5-26.2), age ≥80 years (OR 7.2, 95% CI 1.7-31.5), head/neck location (OR 4.9, 95% CI 3.1-7.7), clinical lesion partially biopsied (OR 11.0, 95% CI 6.7-18.1), and lesion extending to deep biopsy margin (OR 15.1, 95% CI 1.7-136.0). Average ± standard deviation surgical margin used to excise AIMP lesions was 4.5 ± 1.8 mm. LIMITATIONS/CONCLUSIONS:Single-site, retrospective, observational study; interobserver variability across dermatopathologists. CONCLUSION/CONCLUSIONS:Dermatologists and pathologists can endeavor to avoid ambiguous melanocytic designations whenever possible through excisional biopsy technique, interdisciplinary communication, and ancillary studies. In the event of AIMP biopsy, physicians should consider the term a histologic description rather than a diagnosis, and, during surgical planning, use clinicopathologic correlation while bearing in mind factors that might predict true melanoma/MIS.

OBJECTIVE:Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1. APPROACH AND RESULTS:Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1(fl/fl)Abcg1(fl/fl)Ldlr(-/-) mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1(fl/fl)Abcg1(fl/fl) bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC-Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC-Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs. CONCLUSIONS:These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.

Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.