RESUMEN
INTRODUCTION: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma. METHODS: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas. RESULTS: By Kaplan-Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank p values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival (p = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher's exact test, high PARP1 expression correlated with highly mitogenic tumors (p = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors (p = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression (p = 0.0001) and mitotic index (p = 0.0052) were observed. CONCLUSION: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Membrana Mucosa/patología , Poli(ADP-Ribosa) Polimerasa-1/genética , Neoplasias Cutáneas/genética , Regulación hacia Arriba/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Estimación de Kaplan-Meier , Modelos Lineales , Melanoma/patología , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Úlcera/patología , Adulto JovenRESUMEN
The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120â¯h using mass spectrometry techniques, we demonstrated that fractional CO2 laser pretreatment (196â¯microchannels/cm2, 852⯵m ablation depth) leads to rapid drug uptake in 1500⯵m deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5â¯h, Pâ¯=â¯0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5â¯days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatinâ¯+â¯5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Fluorouracilo/administración & dosificación , Rayos Láser , Administración Cutánea , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Cisplatino/farmacocinética , Cisplatino/toxicidad , Quimioterapia Combinada , Femenino , Fluorouracilo/farmacocinética , Fluorouracilo/toxicidad , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Absorción Cutánea , Porcinos , Distribución TisularRESUMEN
The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes, tumoral FoxP3+ with tumoral CD8+ lymphocytes, and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed. By univariate analyses, tumor thickness >4 mm predicted poorer progression-free survival, melanoma-specific survival, and overall survival. PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. By multivariate analyses, high peritumoral FoxP3+ lymphocytes independently predicted better melanoma-specific survival (P = .023), and tumor thickness independently predicted poorer progression-free survival (P = .05) and overall survival (P = .039). In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy.
Asunto(s)
Antígeno B7-H1/biosíntesis , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Linfocitos T Reguladores/inmunología , Neoplasias de la Vulva/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/biosíntesis , Humanos , Estimación de Kaplan-Meier , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Neoplasias de la Vulva/mortalidad , Neoplasias de la Vulva/patología , Adulto JovenRESUMEN
Erythema elevatum diutinum (EED) is a rare, chronic small-vessel vasculitis that presents as firm, red, violaceous, or brown papules and nodules on the extensor surfaces of the limbs. Oral dapsone is considered first-line therapy for EED; in the current case report, a patient presenting with EED began dapsone treatment and symptoms subsided within two weeks. Seven months later, the patient became pregnant and stopped dapsone owing to her concerns with dapsone use during pregnancy, resulting in recurrence of EED symptoms. We present a novel treatment approach with oral sulfasalazine, which was given to the patient in lieu of dapsone and resulted in complete resolution of EED symptoms.