RESUMEN
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: Single-site, retrospective, observational study; interobserver variability across dermatopathologists. CONCLUSION: 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.
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Neoplasias de Cabeza y Cuello/diagnóstico , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Piel/patología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biopsia , Niño , Estudios Transversales , Procedimientos Quirúrgicos Dermatologicos , Diagnóstico Diferencial , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Márgenes de Escisión , Melanoma/patología , Persona de Mediana Edad , Estudios Retrospectivos , Factores Sexuales , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
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.
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Transportador 1 de Casete de Unión a ATP/deficiencia , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/deficiencia , Aorta Torácica/metabolismo , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Colesterol/metabolismo , Células Endoteliales/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Animales , Aorta Torácica/patología , Aorta Torácica/fisiopatología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Trasplante de Médula Ósea , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Endoteliales/patología , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Noqueados , Monocitos/metabolismo , Neovascularización Fisiológica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenotipo , Placa Aterosclerótica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Flujo Sanguíneo Regional , Neovascularización Retiniana/genética , Neovascularización Retiniana/metabolismo , Factores de Tiempo , Técnicas de Cultivo de Tejidos , Irradiación Corporal TotalRESUMEN
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.
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Comunicación Celular , Microambiente Celular , Células Endoteliales de la Vena Umbilical Humana/citología , Macrófagos/citología , Modelos Biológicos , Neovascularización Fisiológica , Pericitos/citología , Receptores Notch/metabolismo , Animales , Línea Celular , Polaridad Celular , Supervivencia Celular , Técnicas de Cocultivo , Técnicas de Silenciamiento del Gen , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Células Mieloides/citología , Células Mieloides/metabolismo , Pericitos/metabolismo , Proteínas Serrate-Jagged/metabolismo , Transducción de SeñalRESUMEN
The Notch signalling pathway is a key regulator of developmental and tumour angiogenesis. Inhibition of Delta-like 4 (Dll4)-mediated Notch signalling results in hyper-sprouting, demonstrating that Notch regulates tip-stalk cell identity in developing tissues and tumours. Paradoxically, Dll4 blockade leads to reduced tumour growth because the newly growing vessels are poorly perfused. To explore the potential for targeting Notch, we developed Notch inhibitors, termed the Notch1 decoys. A Notch1 decoy variant containing all 36 epidermal growth factor (EGF)-like repeats of the extracellular domain of rat Notch1 has been shown to inhibit both Dll and Jagged class Notch ligands. Thus this Notch1 decoy functions differently than Dll4-specific blockade, although it has the potential to inhibit Dll4 activity. Expression of the Notch1 decoy in mice disrupted tumour angiogenesis and inhibited tumour growth. To understand the mechanism by which Notch blockade acts, it is important to note that Notch can function in multiple cell types that make up the vasculature, including endothelial cells and perivascular cells. We investigated Notch function in retinal microglia and determined how myeloid-expressed Notch can influence macrophages and angiogenesis. We found that myeloid-specific loss of Notch1 reduced microglia recruitment and led to improper microglia localization during retinal angiogenesis. Thus either pharmacological inhibition of Notch signalling or genetic deficiencies of Notch function in microglia leads to abnormal angiogenesis.
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Neovascularización Patológica , Receptores Notch/fisiología , Humanos , Neoplasias/irrigación sanguínea , Neoplasias/patología , Receptores Notch/metabolismo , Transducción de SeñalRESUMEN
Notch is a critical regulator of angiogenesis, vascular differentiation, and vascular integrity. We investigated whether Notch signaling affects macrophage function during retinal angiogenesis in mice. Retinal macrophage recruitment and localization in mice with myeloid-specific loss of Notch1 was altered, as these macrophages failed to localize at the leading edge of the vascular plexus and at vascular branchpoints. Furthermore, these retinas were characterized by elongated endothelial cell sprouts that failed to anastomose with neighboring sprouts. Using Notch reporter mice, we demonstrate that retinal macrophages localize between Dll4-positive tip cells and at vascular branchpoints, and that these macrophages had activated Notch signaling. Taken together, these data demonstrate that Notch signaling in macrophages is important for their localization and interaction with endothelial cells during sprouting angiogenesis.
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Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Macrófagos/metabolismo , Neovascularización Fisiológica , Receptor Notch1/metabolismo , Retina/metabolismo , Transducción de Señal , Animales , Movimiento Celular , Células Endoteliales/citología , Endotelio Vascular/citología , Endotelio Vascular/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica , Macrófagos/citología , Ratones , Ratones Noqueados , Receptor Notch1/genética , Retina/anatomía & histología , Retina/crecimiento & desarrollo , Retina/fisiologíaRESUMEN
INTRODUCTION: 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: 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.
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Neoplasias de la Mama , Radiodermatitis , Pared Torácica , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Pigmentación de la Piel , Pared Torácica/efectos de la radiación , Estudios Prospectivos , Estudios Retrospectivos , Estudios Transversales , Radiodermatitis/etiología , Radiodermatitis/epidemiologíaRESUMEN
PURPOSE: Acute radiation dermatitis (ARD) is common after radiation therapy for breast cancer, with data indicating that ARD may disproportionately affect Black or African American (AA) patients. We evaluated the effect of skin of color (SOC) on physician-reported ARD in patients treated with radiation therapy. METHODS AND MATERIALS: We identified patients treated with whole breast or chest wall ± regional nodal irradiation or high tangents using 50 Gy in 25 fractions from 2015 to 2018. Baseline skin pigmentation was assessed using the Fitzpatrick scale (I = light/pale white to VI = black/very dark brown) with SOC defined as Fitzpatrick scale IV to VI. We evaluated associations among SOC, physician-reported ARD, late hyperpigmentation, and use of oral and topical treatments for RD using multivariable models. RESULTS: A total of 325 patients met eligibility, of which 40% had SOC (n = 129). On multivariable analysis, Black/AA race and chest wall irradiation had a lower odds of physician-reported grade 2 or 3 ARD (odds ratio [OR], 0.110; 95% confidence interval [CI], 0.030-0.397; P = .001; OR, 0.377; 95% CI, 0.161-0.883; P = .025), whereas skin bolus (OR, 8.029; 95% CI, 3.655-17.635; P = 0) and planning target volume D0.03cc (OR, 1.001; 95% CI, 1.000-1.001; P = .028) were associated with increased odds. On multivariable analysis, SOC (OR, 3.658; 95% CI, 1.236-10.830; P = .019) and skin bolus (OR, 26.786; 95% CI, 4.235-169.432; P = 0) were associated with increased odds of physician-reported late grade 2 or 3 hyperpigmentation. There was less frequent use of topical steroids to treat ARD and more frequent use of oral analgesics in SOC versus non-SOC patients (43% vs 63%, P < .001; 50% vs 38%, P = .05, respectively). CONCLUSIONS: Black/AA patients exhibited lower odds of physician-reported ARD. However, we found higher odds of late hyperpigmentation in SOC patients, independent of self-reported race. These findings suggest that ARD may be underdiagnosed in SOC when using the physician-rated scale despite this late evidence of radiation-induced skin toxicity.
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Hiperpigmentación , Traumatismos por Radiación , Radiodermatitis , Pared Torácica , Humanos , Pared Torácica/efectos de la radiación , Pigmentación de la Piel , Mama , Radiodermatitis/etiología , Traumatismos por Radiación/complicaciones , Hiperpigmentación/etiologíaRESUMEN
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.
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Erupciones por Medicamentos/etiología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Erupciones Acneiformes , Alopecia , Diagnóstico Diferencial , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/terapia , Femenino , Humanos , Erupciones Liquenoides , Activación de Linfocitos , Masculino , Guías de Práctica Clínica como Asunto , Prurito , Sarcoidosis , Síndrome de Sweet , Linfocitos T/inmunología , Vasculitis , VitíligoAsunto(s)
Veteranos , Humanos , Veteranos/estadística & datos numéricos , Masculino , Estados Unidos , Persona de Mediana Edad , Femenino , Hospitales de Veteranos/estadística & datos numéricos , United States Department of Veterans Affairs/estadística & datos numéricos , United States Department of Veterans Affairs/organización & administración , Examen Físico/métodos , Examen Físico/normas , Examen Físico/estadística & datos numéricos , Cooperación del Paciente/estadística & datos numéricos , Anciano , PielAsunto(s)
Eosinofilia , Foliculitis , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Masculino , Foliculitis/diagnóstico , Foliculitis/patología , Eosinofilia/diagnóstico , Eosinofilia/patología , Persona de Mediana Edad , Enfermedades Cutáneas Vesiculoampollosas/diagnóstico , Enfermedades Cutáneas Vesiculoampollosas/patología , Enfermedades Cutáneas Vesiculoampollosas/etiología , Infecciones por VIH/complicacionesRESUMEN
UNLABELLED: A proangiogenic role for Jagged (JAG)-dependent activation of NOTCH signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of Delta-like ligand (DLL)-class and JAG-class ligand-receptor interactions, and developed NOTCH decoys that function as ligand-specific NOTCH inhibitors. N110-24 decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro, and retinal angiogenesis, demonstrating that JAG-dependent NOTCH signal activation promotes angiogenesis. In tumors, N110-24 decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG-NOTCH signaling uniquely inhibited expression of antiangiogenic soluble (s) VEGFR1/sFLT1. N11-13 decoy interfered with DLL1-DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis, and in tumors. Thus, blockade of JAG- or DLL-mediated NOTCH signaling inhibits angiogenesis by distinct mechanisms. JAG-NOTCH signaling positively regulates angiogenesis by suppressing sVEGFR1-sFLT1 and promoting mural-endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth. SIGNIFICANCE: This is the first report identifying unique regions of the NOTCH1 extracellular domain that interact with JAG-class and DLL-class ligands. Using this knowledge, we developed therapeutic agents that block JAG-dependent NOTCH signaling and demonstrate for the first time that JAG blockade inhibits experimental tumor growth by targeting tumor angiogenesis.
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Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias/irrigación sanguínea , Neoplasias/terapia , Receptor Notch1/administración & dosificación , Receptores Notch/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/administración & dosificación , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/genética , Animales , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/terapia , Unión Proteica , Receptor Notch1/química , Receptor Notch1/genética , Receptores Notch/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Transducción de SeñalRESUMEN
Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.
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Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Células del Estroma/patología , Animales , Anticuerpos Monoclonales/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Técnicas de Silenciamiento del Gen , Proteínas Hedgehog/deficiencia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Inmunoglobulina G/farmacología , Ratones , Ratones Transgénicos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Distribución Aleatoria , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Transducción de Señal , Células del Estroma/metabolismoAsunto(s)
Algoritmos , Anticuerpos Monoclonales/uso terapéutico , Blefaritis/tratamiento farmacológico , Cicatriz/tratamiento farmacológico , Conjuntivitis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Biopsia , Blefaritis/complicaciones , Blefaritis/diagnóstico , Cicatriz/diagnóstico , Cicatriz/etiología , Conjuntiva/patología , Conjuntivitis/complicaciones , Conjuntivitis/diagnóstico , Párpados/patología , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Angiogenesis is the process of developing vascular sprouts from existing blood vessels. Luminal endothelial cells convert into "tip" cells that contribute to the development of a multicellular stalk, which then undergoes lumen formation. In this review, we consider a variety of cellular and molecular pathways that mediate these transitions. We focus first on Notch signaling in cell fate determination as a mechanism to define tip and stalk cells. We next discuss the current models of lumen formation and describe new players in this process, such as chloride intracellular channel proteins. Finally, we consider the possible medical therapeutic benefits of understanding these processes and acknowledge potential obstacles in drug development.