Dynamics of clinical biomarkers as predictors of immunotherapy benefit in metastatic melanoma patients

Purpose Baseline LDH, derived neutrophil–lymphocyte ratio (dNLR) and immune-related adverse events (irAEs) are associated with outcomes of patients with metastatic melanoma (MM). We hypothesized whether dynamic shifts in LDH, dNLR and incidence of irAEs may impact the prognosis of MM patients treated with anti-CTLA4 or anti-PD1 as single agents. Methods Retrospective analysis of medical charts from MM patients with prospective monitoring of dNLR, LDH values and irAE incidence. Primary endpoint was overall survival (OS).Results Patients switching from either high dNLR (≥2.5) to low dNLR (HR: 0.14; 0.03–0.74; p = 0.02) or high LDH (≥1.5 × ULN) to low LDH levels (HR: 0.08; 0.01–0.68; p = 0.02) had significantly better OS than those with high dNLR or LDH scores at the end of cycle 2. Longer OS was also observed in patients developing irAEs ≥ grade 2 as compared to no irAEs (HR: 0.2; 0.05–0.89; p = 0.03).Conclusions We found that major shifts in dNLR and LDH measures from baseline to cycle 2 measures and shifts from baseline to cycle 2 are significantly associated with OS in MM patients receiving single agent anti-PD1 therapy. Laboratory changes and clinical variables may help optimize prognostic estimates. (AU)

Dynamics of clinical biomarkers as predictors of immunotherapy benefit in metastatic melanoma patients.

PURPOSE: Baseline LDH, derived neutrophil-lymphocyte ratio (dNLR) and immune-related adverse events (irAEs) are associated with outcomes of patients with metastatic melanoma (MM). We hypothesized whether dynamic shifts in LDH, dNLR and incidence of irAEs may impact the prognosis of MM patients treated with anti-CTLA4 or anti-PD1 as single agents. METHODS: Retrospective analysis of medical charts from MM patients with prospective monitoring of dNLR, LDH values and irAE incidence. Primary endpoint was overall survival (OS). RESULTS: Patients switching from either high dNLR (≥2.5) to low dNLR (HR: 0.14; 0.03-0.74; p = 0.02) or high LDH (≥1.5 × ULN) to low LDH levels (HR: 0.08; 0.01-0.68; p = 0.02) had significantly better OS than those with high dNLR or LDH scores at the end of cycle 2. Longer OS was also observed in patients developing irAEs ≥ grade 2 as compared to no irAEs (HR: 0.2; 0.05-0.89; p = 0.03). CONCLUSIONS: We found that major shifts in dNLR and LDH measures from baseline to cycle 2 measures and shifts from baseline to cycle 2 are significantly associated with OS in MM patients receiving single agent anti-PD1 therapy. Laboratory changes and clinical variables may help optimize prognostic estimates.

Aspectos médico-legales de la teledermatología / Medicolegal Aspects of Teledermatology

La práctica de la teledermatología (TD) durante la pandemia de COVID-19 ha facilitado la atención dermatológica especializada en una situación de crisis, evitando desplazamientos innecesarios, sin poner en riesgo la seguridad de pacientes y dermatólogos. Sin embargo, también ha puesto en evidencia distintos aspectos éticos y médico-legales que plantea esta práctica médica. La consulta médica no presencial constituye un acto médico, aplicándosele todas las consideraciones y consecuencias éticas y médico-legales de cualquier relación médico-paciente. Debe garantizarse el derecho a la autonomía del paciente, el secreto profesional, la protección de datos, la intimidad y la confidencialidad. El paciente debe aceptar la TD, mediante el consentimiento informado, considerando de interés establecer una cláusula de salvaguarda. Se precisan pautas de actuación bien definidas y una legislación uniforme para preservar una máxima seguridad de los datos transferidos, así como una formación adecuada para prevenir posibles situaciones de lo que podría denominarse «telemalpraxis»

Teledermatology has facilitated specialist care during the crisis caused by the coronavirus disease 2019 pandemic, eliminating unnecessary office visits and the possible exposure of patients or dermatologists. However, teledermatology brings forward certain ethical and medicolegal questions. A medical consultation in which the patient is not physically present is still a medical act, to which all the usual ethical and medicolegal considerations and consequences apply. The patient's right to autonomy and privacy, confidentiality, and data protection must be guaranteed. The patient must agree to remote consultation by giving informed consent, for which a safeguard clause should be included. Well-defined practice guidelines and uniform legislation are required to preserve the highest level of safety for transferred data. Adequate training is also needed to prevent circumstances involving what might be termed «telemalpractice»

Medicolegal Aspects of Teledermatology. / Aspectos médico-legales de la teledermatología.

Teledermatology has facilitated specialist care during the crisis caused by the coronavirus disease 2019 pandemic, eliminating unnecessary office visits and the possible exposure of patients or dermatologists. However, teledermatology brings forward certain ethical and medicolegal questions. A medical consultation in which the patient is not physically present is still a medical act, to which all the usual ethical and medicolegal considerations and consequences apply. The patient's right to autonomy and privacy, confidentiality, and data protection must be guaranteed. The patient must agree to remote consultation by giving informed consent, for which a safeguard clause should be included. Well-defined practice guidelines and uniform legislation are required to preserve the highest level of safety for transferred data. Adequate training is also needed to prevent circumstances involving what might be termed «telemalpractice¼.

Funciones de los tutores de residentes de Dermatología / Functions of Dermatology Residents' Supervisors

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Análisis de la proporción de derivaciones potencialmente evitables desde Atención Primaria a Dermatología por lesiones quísticas o tumorales benignas en España. Datos del estudio DIADERM / Proportion of Potentially Avoidable Referrals From Primary Care to Dermatologists for Cystic Lesions or Benign Neoplasms in Spain: Analysis of Data From the DIADERM Study

Antecedentes y objetivo: Las lesiones cutáneas constituyen un motivo de consulta frecuente en Atención Primaria (AP). Aquellas que no supongan un problema de salud, sino una cuestión estética, no deben ser tratadas en el Sistema Nacional de Salud, según la legislación vigente. El objetivo de este trabajo es estimar qué porcentaje de derivaciones remitidas desde AP a Dermatología por lesiones quísticas o tumores benignos corresponde a lesiones que podríamos considerar potencialmente evitables. Material y método: Utilizamos los diagnósticos principales de los pacientes derivados de AP, recogidos en el estudio representativo nacional DIADERM. Cada uno de los diagnósticos derivados fue clasificado como potencialmente evitable si se correspondía con alguno de los diagnósticos con criterio de alta desde AP, establecidos en el documento de consenso propuesto por la sección territorial andaluza de la Academia Española de Dermatología y Venereología. Resultados: Se recogieron datos de 2.171 motivos principales de consulta derivados de AP como primeras consultas. De estos, 686 (31,6%) son diagnósticos que podrían corresponderse con derivaciones potencialmente evitables por lesiones quísticas o tumorales benignas. Un 22% (478) del total de las consultas fueron dadas de alta en la primera visita. Los diagnósticos más frecuentes entre estos fueron las queratosis seborreicas (9,3%) y los nevus melanocíticos (8,6%). Conclusiones: La proporción de derivaciones potencialmente evitables a Dermatología desde AP por lesiones quísticas y tumorales benignas supone casi un tercio de las consultas. El conocimiento de la realidad asistencial de nuestro entorno puede ser útil para mejorar la planificación, la formación y la gestión sanitaria

Background and objective: Skin lesions are a common reason for consulting a primary care physician. Current legislation in Spain states that purely aesthetic skin problems that do not pose a health problem are not to be treated within the National Health Service. The aim of this study was to estimate the proportion of referrals from primary care physicians to dermatologists that were for cystic lesions or benign tumors and could potentially have been avoided. Material and methods: We consulted cases registered in the DIADERM study dataset, which is representative of dermatology practice in Spain, and collected the main diagnoses given on referring patients from primary care. A referral diagnosis was classified as potentially avoidable if it corresponded to one of the primary care discharge diagnoses listed in a consensus paper of the Andalusian section of the Spanish Academy of Dermatology and Venereology (AEDV). Results: We collected 2171 main reasons for first-visit referrals to dermatologists; 686 of them (31.6%) were for cystic lesions or benign tumors and classified as potentially avoidable. In 478 cases (22%) the patients were discharged on the first visit. The most frequent diagnoses in such cases were seborrheic keratosis (9.3%) and melanocytic nevus (8.6%). Conclusions: Nearly a third of referrals from primary care to a dermatologist were for cystic lesions and benign tumors and could have been avoided. A clearer understanding of our caseload can be useful for improving planning, training, and health care system management

Proportion of Potentially Avoidable Referrals From Primary Care to Dermatologists for Cystic Lesions or Benign Neoplasms in Spain: Analysis of Data From the DIADERM Study. / Análisis de la proporción de derivaciones potencialmente evitables desde Atención Primaria a Dermatología por lesiones quísticas o tumorales benignas en España. Datos del estudio DIADERM.

BACKGROUND AND OBJECTIVE: Skin lesions are a common reason for consulting a primary care physician. Current legislation in Spain states that purely aesthetic skin problems that do not pose a health problem are not to be treated within the National Health Service. The aim of this study was to estimate the proportion of referrals from primary care physicians to dermatologists that were for cystic lesions or benign tumors and could potentially have been avoided. MATERIAL AND METHODS: We consulted cases registered in the DIADERM study dataset, which is representative of dermatology practice in Spain, and collected the main diagnoses given on referring patients from primary care. A referral diagnosis was classified as potentially avoidable if it corresponded to one of the primary care discharge diagnoses listed in a consensus paper of the Andalusian section of the Spanish Academy of Dermatology and Venereology (AEDV). RESULTS: We collected 2171 main reasons for first-visit referrals to dermatologists; 686 of them (31.6%) were for cystic lesions or benign tumors and classified as potentially avoidable. In 478 cases (22%) the patients were discharged on the first visit. The most frequent diagnoses in such cases were seborrheic keratosis (9.3%) and melanocytic nevus (8.6%). CONCLUSIONS: Nearly a third of referrals from primary care to a dermatologist were for cystic lesions and benign tumors and could have been avoided. A clearer understanding of our caseload can be useful for improving planning, training, and health care system management.

Vitamin D deficiency in solid-organ transplant recipients from a Spanish Mediterranean population.

BACKGROUND: Solid-organ transplant recipients (SOTRs) are at risk of developing vitamin D deficiency, mainly caused by reduced sunlight exposure with subsequent low vitamin D synthesis in the skin. AIM: To analyse whether SOTRs from a Spanish Mediterranean region were vitamin D-deficient. METHODS: This was a cross-sectional, descriptive and observational study in a transplantation-specialized Dermatological Unit from a Mediterranean area to determine the calcidiol levels of a cohort of 78 consecutively attending patients not receiving vitamin D supplements. Serum 25(OH)D3 levels were determined and clinical characteristics were collected. Logistic regression analysis was used to analyse variables associated with dichotomized 25(OH)D3 levels (≤ or > 10 ng/mL). RESULTS: The cohort comprised 30 lung, 29 kidney and 19 liver transplant recipients. Mean calcidiol was 18 ± 9 ng/mL. Deficiency of 25(OH)D3 was present in 19% of patients, while 68% had insufficient levels and 13% had sufficient levels. Following multivariate logistic regression analysis, the season of blood sampling remained the only predictor of deficient 25(OH)D3 levels. CONCLUSION: Despite living in a mid-latitude country with sunny weather, our SOTR population was at high risk of developing hypovitaminosis D, especially in autumn/winter. Avoiding sun exposure is important to prevent skin cancer, but careful monitoring of vitamin D status is recommended, with supplementation if hypovitaminosis D is detected.

ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment.

Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.

Contenidos fundamentales de la Dermatología en el grado de medicina en España. Recomendaciones del grupo de profesores de la Academia Española de Dermatología y Venereología / Core Content for Undergraduate Medical Education in Spain: Recommendations of the Instructors’ Group of the Spanish Academy of Dermatology and Venereology (AEDV)

ANTECEDENTES: Los problemas dermatológicos constituyen uno de los motivos de consulta más frecuentes en atención primaria. En los últimos años, como consecuencia de la adaptación al espacio europeo de educación superior, en muchos planes de estudios se ha reducido el tiempo destinado al aprendizaje de la dermatología. MATERIAL Y MÉTODOS: Para consensuar los contenidos básicos del programa de dermatología en el pregrado, se remitió electrónicamente una encuesta a los 57 miembros de grupo de profesores de la Academia Española de Dermatología y Venereología para establecer cuáles deberían ser los objetivos de aprendizaje de la asignatura en España. Se incluyeron 131 objetivos previamente seleccionados, buscándose un consenso mediante el método Delphi sobre los objetivos importantes o muy importantes (puntuación ≥ 4). RESULTADOS: Se obtuvieron 19 respuestas (33%). Tras una segunda ronda de consenso 68 objetivos alcanzaron una puntuación≥4 de promedio en la escala de Likert. Destacan que los graduados conozcan la estructura y las funciones de la piel, las infecciones bacterianas, víricas, micóticas y de transmisión sexual frecuentes, las 4 principales dermatosis inflamatorias, algunos problemas comunes como el prurito y la alopecia en placas, el manejo de dermatosis urgentes, la púrpura y el eritema nudoso como signos de enfermedad interna y reconocer algunos tumores cutáneos benignos y el cáncer de piel, así como la prevención de las enfermedades de transmisión sexual y del cáncer cutáneo. Además, durante las prácticas clínicas, deberían adquirir las habilidades de comunicación necesarias para realizar una entrevista y redactar una historia clínica dermatológica y una hoja de derivación. Conclusiones; Se definen los contenidos considerados fundamentales para impartir en las facultades de medicina y recomendados por el grupo de profesores y docentes de la Academia Española de Dermatología y Venereología

BACKGROUND: Skin problems are among the most frequent reasons for seeking medical attention in primary care. In recent years, as a result of the process of adapting medical curricula to the requirements of the European Higher Education Area, the amount of time students spend learning the concepts of dermatology has been reduced in many universities. MATERIAL AND METHODS: In order to reach a consensus on core content for undergraduate education in dermatology, we sent a survey to the 57 members of the instructors' group of the Spanish Academy of Dermatology and Venereology (AEDV), asking their opinions on what objectives should be set for a dermatology course in Spain. A total of 131 previously selected objectives were listed. We then applied the Delphi method to achieve consensus on which ones the respondents considered important or very important (score ≥ 4 on a Likert scale). RESULTS: Nineteen responses (33%) were received. On the second round of the Delphi process, 68 objectives achieved average scores of at least 4. The respondents emphasized that graduates should understand the structure and functions of the skin and know about bacterial, viral, and fungal skin infections, the most common sexually transmitted diseases (STDs), and the 4 main inflammatory dermatoses. Students should also learn about common complaints, such as itching and bald patches; the management of dermatologic emergencies; purpura and erythema nodosum as signs of internal disease; and the prevention of STDs and skin cancer. During clinical clerkships students should acquire the communication skills they will need to interview patients, write up a patient's medical history, and refer the patient to a specialist. CONCLUSIONS: The AEDV's group of instructors have defined their recommendations on the core content that medical faculties should adopt for the undergraduate subject of dermatology in Spain

Core Content for Undergraduate Medical Education in Spain: Recommendations of the Instructors' Group of the Spanish Academy of Dermatology and Venereology (AEDV).

BACKGROUND: Skin problems are among the most frequent reasons for seeking medical attention in primary care. In recent years, as a result of the process of adapting medical curricula to the requirements of the European Higher Education Area, the amount of time students spend learning the concepts of dermatology has been reduced in many universities. MATERIAL AND METHODS: In order to reach a consensus on core content for undergraduate education in dermatology, we sent a survey to the 57 members of the instructors' group of the Spanish Academy of Dermatology and Venereology (AEDV), asking their opinions on what objectives should be set for a dermatology course in Spain. A total of 131 previously selected objectives were listed. We then applied the Delphi method to achieve consensus on which ones the respondents considered important or very important (score≥4 on a Likert scale). RESULTS: Nineteen responses (33%) were received. On the second round of the Delphi process, 68 objectives achieved average scores of at least 4. The respondents emphasized that graduates should understand the structure and functions of the skin and know about bacterial, viral, and fungal skin infections, the most common sexually transmitted diseases (STDs), and the 4 main inflammatory dermatoses. Students should also learn about common complaints, such as itching and bald patches; the management of dermatologic emergencies; purpura and erythema nodosum as signs of internal disease; and the prevention of STDs and skin cancer. During clinical clerkships students should acquire the communication skills they will need to interview patients, write up a patient's medical history, and refer the patient to a specialist. CONCLUSIONS: The AEDV's group of instructors have defined their recommendations on the core content that medical faculties should adopt for the undergraduate subject of dermatology in Spain.

Use of biological treatments in patients with hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic skin disease which causes a great impact in the quality of life. Multiple therapeutic options have been proposed, and recently the potential use of biological drugs in severe cases has been postulated. MATERIAL AND METHODS: A retrospective study from seven tertiary Spanish centers reviewing the charts of patients with HS treated with biological drugs was performed. Retrieved information included epidemiological data, clinical features, pain intensity, Hurley stage, laboratory data and therapeutic outcomes. RESULTS: Nineteen patients were included in the study; 10 men (52.6%) and 9 women. Eight patients (42%) showed a Hurley severity stage II and 11 a stage III (57.8%). Adalimumab was prescribed as the first biological treatment in nine out of 19 cases (47.3%), whereas infliximab was prescribed in seven cases (36.8%), ustekinumab in two cases (10.5%) and etanercept in one (5.2%). A complete response was observed in three patients (two cases with infliximab and one case with ustekinumab), a partial improvement in 10 patients and in six patients no clinical improvement was noted. One patient referred worsening of the skin symptoms. In 6 cases, a second biological treatment was prescribed. In three of such cases, a partial improvement was noted, whereas in three cases no clinical improvement was observed. In two cases a switch to a third biological drug was indicated, with a partial improvement in one case. DISCUSSION AND CONCLUSIONS: Biological drugs could be a potential and effective therapeutic option for patients with severe HS. Complete and persistent clinical responses are rarely obtained (15%) and partial responses are achieved in approximately 50% of patients. No specific markers for a therapeutic response have been identified. No definitive conclusions regarding the most effective biological drug for HS could be drawn. Higher dosage schedules seem to be associated with higher response rates. The lack of response of one particular drug does not preclude a potential efficacy to another biological treatment.

Fiebre y lesiones cutáneas en un paciente con enfermedad granulomatosa crónica / Fever and skin lesions in a patient with chronic granulomatous disease

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Enfermedad del injerto contra el huésped crónica liquenoide con patrón blaschkoide / Lichenoid Chronic Graft-vs-Host Disease Following Blaschko Lines

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Human beta papillomavirus DNA study in primary cutaneous squamous cell carcinomas and their corresponding metastases.

The association between beta human papillomavirus (HPV) types and cutaneous squamous cell carcinomas (cSCCs) is controversial. Several studies have found such an association, especially at early stages of carcinogenesis, but the presence of beta HPV types in aggressive cSCCs has only been reported in three patients previously. We aimed to search for beta HPV DNA in primary cSCCs and their corresponding lymph node metastases in a series of patients. The presence of DNA from 25 beta HPV types was determined using a multiplex PCR protocol in 35 primary cSCCs from 35 patients and their corresponding lymph node metastases. DNA from beta HPV types was detected in 9 % of primary cSCCs and in 13 % of metastases. No primary cutaneous SCC or lymphatic metastases were found to share the same HPV DNA. These data suggest that beta HPV types do not play an etiopathogenic role in advanced stages of squamous cell carcinogenesis.