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Background: The main purpose of this article is to introduce a universal mathematics-aided vaccine design method against malignant melanoma based on neoantigens. The universal method can be adapted to the mutanome of each patient so that a specific candidate vaccine can be tailored for the corresponding patient. Methods: We extracted the 1134 most frequent mutations in melanoma, and we associated each of them to a vector with 10 components estimated with different bioinformatics tools, for which we found an aggregated value according to a set of weights, and then we ordered them in decreasing order of the scores. Results: We prepared a universal table of the most frequent mutations in melanoma ordered in decreasing order of viability to be used as candidate vaccines, so that the selection of a set of appropriate peptides for each particular patient can be easily and quickly implemented according to their specific mutanome and transcription profile. Conclusions: We have shown that the techniques that are commonly used for the design of personalized anti-tumor vaccines against malignant melanoma can be adapted for the design of universal rankings of neoantigens that originate personalized vaccines when the mutanome and transcription profile of specific patients is considered, with the consequent savings in time and money, shortening the design and production time. This research was funded by Basque Government grant number IT456-22, and by UPV/EHU and BCAM grant number US21/27.

Cutaneous melanoma is the most aggressive of skin tumors. In order to discover new biomarkers that could help us improve prognostic prediction in melanoma patients, we have searched for germline DNA variants associated with melanoma progression. Thus, after exome sequencing of a set of melanoma patients and healthy control individuals, we identified rs1042602, an SNP within TYR, as a good candidate. After genotyping rs1042602 in 1025 patients and 773 healthy donors, we found that the rs1042602-A allele was significantly associated with susceptibility to melanoma (CATT test: p = 0.0035). Interestingly, we also observed significant differences between patients with good and bad prognosis (5 years of follow-up) (n = 664) (CATT test for all samples p = 0.0384 and for men alone p = 0.0054). Disease-free-survival (DFS) analyses also showed that patients with the A allele had shorter DFS periods. In men, the association remained significant even in a multivariate Cox Proportional-hazards model, which was adjusted for age at diagnosis, Breslow thickness, ulceration and melanoma subtype (HR 0.4; 95% confidence interval (CI) 0.20–0.83; p = 0.0139). Based on our results, we propose that rs1042602-A is a risk allele for melanoma, which also seems to be responsible for a poorer prognosis of the disease, particularly in men. This research was funded by grants from the Department of Economic Development, Sustainability and the Environment of the Basque Government (Spain) (KK2017-041 and KK2020-00069 to M.D.B. and S.A.), the Basque Government (Basque Country Research Groups IT1693-22 to S.A. as Co IP), the University of the Basque Country (UPV/EHU) (GIU17/066 to M.D.B.), the Spanish Ministry of Science and Education (MINECO) (PCIN-2015-241 to M.D.B.) and by the ECSEL JU European project ASTONISH (grant number 692470 to M.D.B.).

In the last few years, the importance of neoantigens in the development of personalized antitumor vaccines has increased remarkably. In order to study whether bioinformatic tools are effective in detecting neoantigens that generate an immune response, DNA samples from patients with cutaneous melanoma in different stages were obtained, resulting in a total of 6048 potential neoantigens gathered. Thereafter, the immunological responses generated by some of those neoantigens ex vivo were tested, using a vaccine designed by a new optimization approach and encapsulated in nanoparticles. Our bioinformatic analysis indicated that no differences were found between the number of neoantigens and that of non-mutated sequences detected as potential binders by IEDB tools. However, those tools were able to highlight neoantigens over non-mutated peptides in HLA-II recognition (p-value 0.03). However, neither HLA-I binding affinity (p-value 0.08) nor Class I immunogenicity values (p-value 0.96) indicated significant differences for the latter parameters. Subsequently, the new vaccine, using aggregative functions and combinatorial optimization, was designed. The six best neoantigens were selected and formulated into two nanoparticles, with which the immune response ex vivo was evaluated, demonstrating a specific activation of the immune response. This study reinforces the use of bioinformatic tools in vaccine development, as their usefulness is proven both in silico and ex vivo.

espanolIntroduccion: El carcinoma de celulas de Merkel (CCM) es una neoplasia cutanea infrecuente y de pronostico pobre. No hay consenso para abordar su manejo. Material y metodos: Realiza-mos una busqueda de pacientes con diagnostico histologico de CCM entre 1998 y 2018 (n = 20), en la base de datos de nuestro hospital. Recogimos las siguientes variables: sexo, edad, historia de inmunosupresion y de cancer cutaneo no melanoma y me-lanoma maligno, sospecha diagnostica inicial, tamano tumoral, localizacion, estadificacion, tratamientos recibidos, evolucion y supervivencia. Resultados: La mayoria de las lesiones (40%) se localizaban en la cabeza y cuello, y 50% tenian un tamano de 2 a 5 cm. Ochenta y cinco por ciento de los pacientes recibio tratamiento quirurgico y 75% radioterapia. Cincuenta por ciento de los pacientes presentaron recidivas, todas en los primeros dos anos. Hemos observado que la supervivencia es mayor en los pacientes con lesiones menores de 2 cm, localizadas en extremidades, con positividad para poliomavirus, en los que recibieron radioterapia adyuvante y no presentan margenes quirurgicos afectados. Conclusiones: Hemos identificado cinco factores asociados con una mayor supervivencia que, aunque no son estadisticamente significativos (por el tamano muestral), son clinicamente relevantes y coinciden con los de otras series. EnglishIntroduction: Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with a poor prognosis. There is no consensus to address its management. Material and methods: We performed a search of patients with histological diagnosis of MCC from 1998 to 2018 (n = 20), in the database of our hospital and we collected next data: sex, age, history of immunosuppression, skin cancer no melanoma and malignant melanoma, initial diagnosis suspicion, tumor size, location, staging, treatments received, evolution and survival. Results:The majority of lesions (40%) were located in the face and neck and 50% had 2 to 5 cm. 85% of the patients received surgical treatment, 75% had RT. 50% of patients had recurrence, all before the first 24 months. In our sample, we observed that survival is greater in patients with lesions smaller than 2 cm, located in extremities, positive for polyomavirus, in those who have received adjuvant RT and in those without affected surgical. Conclusions: We have observed five factors associated with grater survival, which, although not statistically significant, are clinically relevant and concur with those of other series

Resumen Antecedentes y objetivo Previamente se habia iniciado el proceso metodologico para la validacion transcultural al idioma espanol de la escala Hair Specific Skindex-29 (HSS-29), que mide el impacto de la alopecia androgenica femenina sobre la calidad de vida relacionada con la salud (CVRS). Para finalizar el proceso, el objetivo del estudio fue completar la validacion a traves de la determinacion de su sensibilidad al cambio y su correlacion con una escala generalista de CVRS (SF-12). Material y metodo Se establecieron dos visitas, una basal y otra tras 6 meses de tratamiento con suplemento alimenticio con actividad inhibidora de la enzima 5-alfa reductasa. En cada visita, investigadores y pacientes valoraron la gravedad de la alopecia mediante la escala Sinclair, el estado de la apariencia del cabello, y se administraron las escalas HSS-29 y SF-12. Resultados Participaron 983 mujeres con alopecia androgenica. La media de puntuacion en la escala HSS-29 cambio de 27,5 ± 18,7 en la visita basal a 19,3 ± 15,7 en la de seguimiento, y sus dimensiones funcional, emocional y sintomatica tambien cambiaron significativamente. Tanto las diferencias entre basal y seguimiento en el indice HSS-29 global como en cada una de sus dimensiones se correlacionaron significativamente con las diferencias encontradas en las dimensiones de SF-12. Los coeficientes de correlacion de Pearson oscilaron entre −0,1 y −0,4, y en todos los casos el grado de significacion fue p Conclusiones La version en espanol de la escala HSS-29 posee sensibilidad, es decir, detecta cambios relacionados con la calidad de vida cuando las condiciones objetivas varian. Igualmente, se observo una correlacion entre las escalas HSS-29 y SF-12.

espanolIntroduccion: La hidradenitis supurativa (HS) es una dermatosis inflamatoria cronica que afecta a la unidad pilosebacea en las grandes areas intertriginosas. La inflamacion cronica de larga evolucion favorece el desarrollo del carcinoma de celulas escamosas (CCE) sobre lesiones de HS. Esta complicacion es mas frecuente en varones y en las regiones glutea o perineal. Caso clinico: Varon de 57 anos con HS grave (Hurley III) con >30 anos de evolucion, de predominio en gluteos y resistente a multiples tratamientos; desarrollo un carcinoma epidermoide infiltrante sobre lesiones de HS. Al momento del diagnostico mostraba adenopatias locorregionales de gran tamano. Se descarto el tratamiento quirurgico o radioterapico y se trato con quimioterapia paliativa. Discusion: La infeccion por el virus del papiloma humano (HPV) y otros cofactores parecen intervenir en la transformacion maligna de las lesiones. El retraso diagnostico y una alta capacidad de proyectar metastasis le confieren al carcinoma epidermoide sobre la HS un mal pronostico y elevada mortalidad. Conclusion: Ante una HS avanzada, de larga evolucion y resistente al tratamiento, sobre todo si asienta en la region glutea, se deben tomar multiples biopsias profundas para detectar de manera temprana el desarrollo de un posible carcinoma epidermoide sobre las lesiones. EnglishIntroduction: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects the folliculosebaceous unit in large intertriginous body areas. Longstanding inflammation might lead to the development of a squamous cell carcinoma arising in HS lesions, which is more likely to occur in males and at the gluteal or perineal sites. Case report: A 57-year-old man with an over 30-year history of severe HS (Hurley III) involving the buttocks and refractory to a wide variety of treatments developed a squamous cell carcinoma over HS lesions. He presented large locoregional lymphadenopathies at diagnosis. Surgery and radiotherapy were dismissed and he was treated with palliative chemotherapy. Discussion: Human papillomavirus (HPV) and other cofactors seem to be involved in the malignant transformation of the lesions. Due to the common delayed diagnosis and its high metastatic ability, prognosis is poor and mortality rates high. Conclusion: Areas of non-healing wounds should be cautiously observed and multiple deep biopsies carried out in patients suffering from longstanding and resistant HS, especially if they involve the buttocks or perineum, in order to detect the development of a squamous cell carcinoma arising in HS lesions at an early stage.

Importance Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

The choice of treatment in cutaneous T-cell lymphomas (CTCLs) depends on the clinical stage of the disease and the patient's general condition. To date, there is no curative treatment for this disease, and the objective is to control the symptoms and prevent the disease from progressing. Bexarotene is an X receptor-specific retinoid with anti-tumor activity. Its use as treatment for CTCLs refractory to at least one prior systemic therapy has been approved by the FDA.We carried out a descriptive study of 9 patients treated with bexarotene in the Lymphoma Unit of our department. We analyzed the clinical characteristics of the patients and the efficacy of the treatment, and we collected data on the side effects that appeared.The overall response to the treatment was 44.4% (4/9). 2 patients had full remission and 2 had partial remission. Tolerance to the treatment was good, and the most frequent side effects were hypertriglyceridemia, hypercholesterolemia and central hypothyroidism.Even though this is a series of only 9 patients, the results that we obtained are similar to ones previously described. Bexarotene is an effective therapeutic option in this heterogeneous group of diseases.