Did COVID-19 lockdown delay actually worsen melanoma prognosis?

Abstract Background: The COVID-19 lockdown possibly meant a delay in the diagnosis and treatment of melanoma and therefore, worsening its prognosis. This unique situation of diagnosis deferral is an exceptional opportunity to investigate melanoma biology. Objectives: To evaluate the immediate and mid-term impact of diagnosis delay on melanoma. Methods: A retrospective observational study of melanoma diagnosed between March 14th 2019 and March 13th 2021. We compared the characteristics of melanomas diagnosed during the first 6-month period after the lockdown instauration and a second period after recovery of normal activity with the same periods of the previous year, respectively. Results: A total of 119 melanomas were diagnosed. There were no differences in age, sex, incidence, location, presence of ulceration or mitoses, and in situ/invasive melanoma rate (p > 0.05). After the recovery of the normal activity, Breslow thickness increased in comparison with the previous year (2.4 vs 1.9 mm, p < 0.05) resulting in a significant upstaging according to the AJCC 8th ed. (p < 0.05). Study limitations: The main limitation is that this is a single-center study. Conclusions: The COVID-19 lockdown implied a diagnosis delay leading to a mid-term increase in Breslow thickness and an upstaging of invasive melanomas. However, the detection deferral did not result in a higher progression of in situ to invasive melanoma, in our sample.

Dabrafenib plus trametinib versus nivolumab for advanced melanoma / Dabrafenib más trametinib versus nivolumab para el tratamiento del melanoma avanzado

Introduction The incidence of cutaneous melanoma has increased worldwide over the years, and an incidence of 3 cases per 100,000 men and women is estimated in Chile. Though most of the patients are diagnosed at an early stage of the disease and have a good prognosis, advanced melanoma has poor survival results. For the treatment of melanoma, the combination of dabrafenib plus trametinib has been demonstrated to improve the outcome versus dabrafenib alone, but only indirect evidence is available for its efficacy and safety compared with immunotherapy, like nivolumab. The aim of this study is to review the available evidence to report results of efficacy and safety of dabrafenib plus trametinib in comparison with nivolumab in metastatic melanoma. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews selected, reanalyzed data of primary studies, and generated a summary of the findings table using the GRADE approach. Results and conclusions We identified five systematic reviews, including seven studies overall that included one intervention of our interest, of which all were randomized trials. We only found indirect evidence comparing dabrafenib plus trametinib versus nivolumab that came from Network Meta-Analyses. We concluded that it is not possible to decide if dabrafenib plus trametinib is a better strategy for advanced melanoma treatment than nivolumab because the certainty of the evidence is very low for efficacy and safety outcomes.

Introducción La incidencia de melanoma cutáneo ha aumentado a nivel mundial con el paso de los años, estimándose en Chile una incidencia de 3 casos por 100.000 hombres y mujeres. Aunque la mayoría de los pacientes son diagnosticados en etapas tempranas de la enfermedad y tienen un buen pronóstico, el melanoma avanzado tiene malos resultados de sobrevida. Para el tratamiento del melanoma, se ha demostrado que la combinación de dabrafenib más trametinib mejora el resultado frente a dabrafenib solo, pero sólo se dispone de evidencia indirecta sobre su eficacia y seguridad en comparación con la inmunoterapia, como nivolumab. Métodos Se realizaron búsquedas en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, que se mantiene mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Se extrajeron los datos de las revisiones sistemáticas seleccionadas, se reanalizaron los datos de los estudios primarios y se generó una tabla de resumen de los hallazgos utilizando el enfoque GRADE. Resultados y conclusiones Se identificaron cinco revisiones sistemáticas, incluyendo siete estudios en total que incluían una intervención de nuestro interés, de los cuales todos eran ensayos aleatorizados. Se concluyó que no es posible decidir si dabrafenib más trametinib es una mejor estrategia para el tratamiento del melanoma avanzado que nivolumab porque la certeza de las pruebas es muy baja para los resultados de eficacia y seguridad.

Melanoma primario maligno variedad rabdoide. A Propósitode un caso / Malignant primary melanoma rhabdoid variety. about a case

Resumen El melanoma primariovariedad rabdoide es unapresentación pocofrecuente.Reconocido como un subtipo histopatológico distinto de melanoma maligno generalmente observado en tumores metastásicos o recurrentes.El diagnóstico definitivo requiere el estudio de inmunomarcación y la identificación de células neoplásicas con marcadores melanocíticos. Clínicamente se han reportado mayormente de tipo nodular y amelanótico.

Summary Rhabdoid melanoma has been recognized as a histopathological subtype of malignant melanoma. It generally presents as a recurrent tumor, so its presentation as a primary lesion is infrecuent.Definitive diagnosis requires the study of immunostaining and the identification of neoplastic cells with melanocytic markers. Clinically, mostly nodular and amelanotic types have been reported.

Serratus plane block with sedation for patients submitted to axillary dissection: a prospective case series / Bloqueio do plano do músculo serrátil guiado por ultrassonografia associado à sedação venosa como técnica anestésica em cirurgia de linfadenectomia axilar: uma série de casos prospectiva

ABSTRACT Axillary dissection is a standard surgical procedure for stage III skin and soft tissue tumors and is usually performed under general anesthesia. This study aimed to investigate the feasibility of performing axillary dissection with Serratus muscle plane block plus intravenous sedation. Fifteen patients undergoing axillary dissection were prospectively recruited. The patients were evaluated during their pre-operative anesthetic appointment, during their procedure, and at post-operative days 1 and 30. The blockade was performed superficial to the Serratus muscle at the level of fourth rib. Sedation was performed using propofol, fentanyl, dexmedetomidine, and S-ketamine. None of the patients required conversion to general anesthesia. Surgeons showed a highly positive response when asked about the anesthetic technique, and most of them found the technique "indistinguishable" from general anesthesia. The median (interquartile range) pain scores at rest over all time frames was 0 (0-0). Furthermore, no patients developed nausea, hemodynamic instability, or any complications associated with the technique. The Serratus plane block associated with intravenous sedation proved feasible for axillary lymphadenectomy, however, further clinical trials should evaluate potential advantages compared to other techniques.

RESUMO A linfadenectomia axilar é um procedimento cirúrgico padrão para tratamento de tumores de pele e partes moles no estádio III e usualmente é realizada sob anestesia geral. A presente serie de casos prospectiva tem por objetivo investigar a viabilidade da realização da linfadenectomia axilar com o uso do bloqueio do plano do músculo serrátil anterior associado a sedação endovenosa. Foram incluídos 15 pacientes no estudo. Os participantes foram recrutados e avaliados durante consulta pré-anestésica ambulatorial, acompanhados durante o dia da cirurgia, no primeiro e no trigésimo dias de pós-operatório. O bloqueio foi realizado anterior ao músculo serrátil anterior ao nível da quarta costela na linha axilar média. A sedação foi realizada com o uso de propofol, fentanil, dexmedetomidina e dextrocetamina. Não houve necessidade de conversão para anestesia geral em nenhum paciente. Os cirurgiões apresentaram resposta altamente positiva quando questionados sobre a técnica anestésica, considerando na maior parte dos casos "indistinguível" da anestesia geral. A mediana (intervalo interquartil) da dor em repouso em todos os momentos avaliados foi 0 (0-0). Além disso, nenhum paciente desenvolveu náuseas, vômitos, instabilidade hemodinâmica ou qualquer complicação relacionada à técnica empregada. O bloqueio do plano do músculo Serrátil anterior associado a sedação venosa se mostrou viável para execução de linfadenectomia axilar, entretanto ensaios clínicos adicionais são necessários para avaliar potenciais vantagens em comparação com outras técnicas.

Lesiones metastásicas a glándula tiroides. Una serie de casos / Metastatic lesions to the thyroid gland. Case series

Las lesiones metastásicas representan hasta un 3 % de los tumores malignos de la glándula tiroides. La mayoría de los casos se originan de tumores de células renales y de pulmón. El abordaje diagnóstico implica una alta sospecha clínica en pacientes con primarios conocidos, sin embargo, puede ser la manifestación inicial de una enfermedad maligna extensa no diagnosticada hasta en un 20 % a 40 % de los pacientes. La biopsia por aguja fina ha demostrado buen rendimiento para el diagnóstico de los nódulos metastásicos. El pronóstico y la opción del tratamiento quirúrgico dependen del control local del primario y del estado de la enfermedad sistémica asociada, por lo tanto, debe ser individualizado. Por lo general, hasta un 80 % de los pacientes con compromiso de la tiroides tienen enfermedad metastásica multiorgánica, y la intención del tratamiento quirúrgico es con fines paliativos para prevenir las complicaciones derivadas de la extensión local de la enfermedad a las estructuras del tracto aerodigestivo superior en el cuello. Se presenta a continuación, una serie de seis casos de pacientes con lesiones metastásicas a glándula tiroides con primarios en riñón, mama y de melanomas

Metastatic lesions represent up to 3% of malignant tumors of the thyroid gland. Most cases originate from lung and renal cell tumors. The diagnostic approach implies a high clinical suspicion in patients with known primaries, however, it can be the initial manifestation of an extensive undiagnosed malignant disease in up to 20% to 40% of patients. Fine-needle biopsy has shown good performance for the diagnosis of metastatic nodules. The prognosis and the option of surgical treatment depend on the local control of the primary condition and the state of the associated systemic disease, therefore it must be individualized. In general, up to 80% of patients with thyroid involvement have multi-organ metastatic disease and surgical treatment is intended to be palliative to prevent complications resulting from local extension of the disease to structures of the upper aerodigestive tract in the neck. A case series of six patients with metastatic lesions to the thyroid gland with primaries in the kidney, breast and melanomas is presented below

Photosensitive rash induced by nivolumab

Abstract The therapeutic approach to metastatic melanoma has revolutionized the clinical course of this disease. Since 2011, different immunotherapeutic drugs have been approved. Nivolumab is a humanized immunoglobulin IgG4 monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with his ligand PD-L1. The authors present a new case of photosensitivity induced by nivolumab. The photo exposed distribution of the eruption, the sun exposure prior to the beginning of the eruption, and the chronological relationship with the beginning of the treatment are data that have allowed us to confirm the suspected clinical diagnosis.

Predictive factors of melanoma thickness

Abstract Background: Melanoma thickness is a relevant prognostic marker that is crucial for staging and its calculation relies on the histopathological examination. There is a risk of thickness underestimation with an incisional biopsy if the latter is not performed on a tumor area where the thickness is maximal. This occurrence may have an impact on a therapeutic decision, particularly regarding the excision margins and the need for sentinel lymph node biopsy. Objective: To assess the association between melanoma thickness and dermoscopic, demographic, epidemiological and clinical variables, aiming to identify predictive factors of thickness >1 mm. Methods: This was an observational and cross-sectional study, carried out on patients diagnosed with melanoma, from a single center over a time span of four years. Anatomopathological (thickness), dermoscopic, demographic, epidemiological, and clinical variables were collected. The associations between the variables with melanoma thickness were assessed. Results: A total of 119 patients were included. The presence of atypical vessels on the dermoscopic examination was an independent predictive factor of thickness >1 mm. Conversely, an atypical reticular pattern predicted melanoma thickness <1 mm. The presence of ephelides and a previous history of sunburn were also associated with melanomas thinner than 1 mm in the univariate analysis. Study limitations: The lack of data related to some variables and the absence of an optimal correlation between the dermoscopic and the anatomopathological examination constituted study limitations. Conclusion: An atypical vascular pattern on dermoscopy is associated with thickness >1 mm, helping with the choice of the optimal site to perform an incisional biopsy when an excisional biopsy is not feasible.

Cutaneous melanoma diagnosis delay: socioeconomic and demographic factors influence

SUMMARY OBJECTIVE: Malignant cutaneous melanoma is the most aggressive type of skin cancer, and its early detection and prompt initiation of treatment play an important role in reducing disease-associated morbidity and mortality. Many factors influence the diagnosis of melanoma, and its recognition is essential for the development of strategies for its early detection. This study was carried out to Identify the main variables related to the delay in diagnosis of Malignant Cutaneous Melanoma and correlate them with the time interval for making the definitive diagnosis. METHODS: Retrospective analysis of 103 patient records from January 2015 to December 2020 correlating social, economic, demographic, and cultural factors with the time elapsed between the onset of symptoms and the diagnosis of malignant cutaneous melanoma. RESULTS: The average time to seek medical services from the onset of symptoms was 29.54 months. The mean time for a referral from the primary to the referral service was 1.35 months, and the factors that contributed to a faster diagnosis were lesion Breslow (>1 mm), lesion growth, income range (≤1.5 minimum wages), lower phototypes (I and II), not having gone to the Basic Healthcare Units, profession (household), smoking, and type of housing. CONCLUSIONS: Our findings demonstrate that there is still a great delay in the recognition of signs and symptoms related to the diagnosis of malignant cutaneous melanoma in our country, influenced by several socioeconomic and demographic factors.

Ganglio centinela positivo en melanoma: factores predictivos y resultados del vaciamiento ganglionar / Positive sentinel lymph node in melanoma: predictive factors and results of completion lymph node dissection

RESUMEN Antecedentes: la biopsia del ganglio centinela (GC) es la técnica aceptada para determinar el pronóstico en estadios iniciales de melanoma cutáneo. La ventaja del vaciamiento ganglionar (VG) cuando el GC resulta positivo ha sido recientemente cuestionada. Objetivo: describir los porcentajes y factores asociados a metástasis en el GC, y en los ganglios no centinela (GnC) en los VG de pacientes con GC positivo. Material y métodos: se llevó a cabo un estudio retrospectivo de los registros clínicos y patológicos de 139 pacientes operados por melanoma cutáneo entre enero de 2012 y diciembre de 2019. Resultados: a 96 (69%) pacientes se les realizó biopsia de GC. El promedio de edad fue 61,7 años ± 17,5 (19-93); 53 (55,2%) fueron hombres. La lesión primaria estuvo ubicada en: extremidades 47 (49%), tronco 39 (40,6%), cabeza y cuello 10 (10,4%). El promedio de espesor de Breslow fue 5,01 mm (1,05- 50 mm) y se encontró ulceración en 35 casos (36,4%). El GC fue identificado en todas las oportunidades y en 39 (40,6%) fue positivo. Hubo asociación con el espesor ≥ 3 mm (p = 0,000017) y con la ulceración (p = 0,0011). A los pacientes con GC positivo se les efectuó el VG del territorio afectado: 23 axilar, 10 inguinal y 6 cervical. Veintitrés (59%) presentaron metástasis en GnC. Se asoció con el espesor (p = 0,022) y la ulceración (p = 0,019). Conclusión: existió un alto porcentaje de GnC positivos en la población estudiada, vinculado al espesor y la ulceración. Estas características, así como la dificultad de un estricto seguimiento, inducen a no abandonar el VG en pacientes con GC positivo.

ABSTRACT Background: Sentinel lymph node (SLN) biopsy is the technique accepted to determine the prognosis of early cutaneous melanomas. The advantage of lymph node dissection (LND) when SLN biopsy is positive has recently been questioned. Objective: The aim of this study is to describe the percentages and factors associated with SLN and non-sentinel node (NSN) metastases in LNDs of SLN-positive patients. Material and methods: The clinical records and pathology reports of 139 patients undergoing surgery for cutaneous melanoma between January 2012 and December 2019 were retrospectively reviewed. Results: Ninety-six (69%) patients underwent SLN biopsy. Mean age was 61.7 ± 17.5 years (19-93) and 53 (55.2%) were men. The primary lesion was located in the extremities in 47 (49%) cases, in the trunk in 39 (40.6%), and in the head and neck in 10 (10.4%). Mean Breslow thickness was 5.01 mm (1.05-50 mm) and ulceration was found in 35 cases (36.4%). The SLN was identified in all the cases and was positive in 39 (40.6%). There was an association with thickness ≥ 3 mm (p = 0.000017) and ulceration (p = 0.0011). Those patients with positive SLN biopsy underwent LND of the territory involved: axillary in 23, inguinal in 10 and cervical in 6. Twenty-three (59%) presented NSLN metastases and were associated with thickness (p = 0.022) and ulceration (p = 0.019). Conclusion: There was a high percentage of positive NSLN in the population studied which was associated with thickness and ulceration. These characteristics and the difficulty to achieve strict follow-up are the reasons for completion LND in SLN-positive patients.

Sinonasal Mucosal Melanoma: A Population-based Comparison of the EUROCARE and SEER Registries

Abstract Introduction Sinonasal melanomas are rare tumors with no comparative survival studies between Europe and the US. Objective To provide a population-based survival analysis between the two continents. Methods The European Cancer Registry (EUROCARE) and the United States Surveillance, Epidemiology, and End Results (SEER) databases were queried to identify patients diagnosed with sinonasal melanoma between 2000 and 2007. Relative survival (RS) data were grouped by age, gender, geographic region, extent of disease, and treatment modality. Results A total of 1,294 cases were identified between 2000 and 2007 (935 from EUROCARE-5 and 359 from SEER). Females were most commonly identified in Europe (56.4%) and in the US (54.9%). Patients over the age of 65 years comprised the greatest proportion of patients in Europe (70%) and in the US (71%). By region, Southern Europe had the highest 5-year RS (31.6%, 95% confidence interval [CI] = [21.3-42.5%]), and Eastern Europe the lowest (16.5%, [7.5-28.5%]). The aggregate European 5-year RS was 25.4% [21.8-29.1%] and the U.S. was (29.7%, [23.6-36%]). Conclusions Althoughincreasinginincidence, sinonasal melanomas remain rare. Women were more commonly affected. The most common age group was those older than 65 years, although age did not confer a prognostic value. The most common subsite was the nasalcavity followedbythe maxillarysinus.Five-yearRSwas similar betweencontinents withaninverse relationship between extentofdiseaseand survival. The treatment of choice throughout Europe and the US remains primarily surgical.

Melanoma nodular amelanótico: a propósito de un caso / Amelanotic nodular melanoma: a case report

RESUMEN Introducción: El melanoma es un tumor maligno de estirpe melanocítica que constituye el sexto cáncer más frecuente en la población general y tiene una alta capacidad para producir metástasis. Aproximadamente el 95% de los melanomas primarios pertenecen a cuatro tipos clínico-patológicos: extensivo superficial, nodular, lentigo maligno y lentiginoso acral. El 5% restante corresponde a variantes menos frecuentes entre las que se encuentra el melanoma amelanótico, que representa entre el 0.4-27.5% de los casos de este subgrupo. Objetivo: Presentar un caso de un melanoma amelanótico, como una variante que puede acompañar a cualquier otro tipo clínico de melanoma, en este caso a uno de tipo nodular,lesión que, debido a su disminución o ausencia de pigmento, puede conducir a errores diagnósticos que inciden en la demora en el tratamiento y reducen la sobrevida de los pacientes que lo padecen. Caso Clínico: Se presenta el caso de un paciente de sexo masculino de 75 años que acude por presentar una lesión tumoral exofítica en la frente, de aproximadamente un año de evolución. Al examen físico se observa la lesión tumoral cupuliforme, eritematosa y brillante, que bajo dermatoscopio de luz polarizada muestra un patrón vascular polimorfo a predominio de vasos lineales gruesos. Se plantean varios diagnósticos diferenciales entre los que se destacan: carcinoma basocelular, granuloma piógeno, linfoma y metástasis cutáneas; se realiza una toma de muestra para biopsia y técnicas de tinción con inmunohistoquímica, que confirman el diagnóstico de melanoma, se decide exéresis de la tumoración con márgenes y seguimiento multidisciplinario del caso. Conclusiones: Las variantes hipo/amelanóticas del melanoma son poco frecuentes y su diagnóstico presenta dificultades que suelen generar demoras que influyen en el tratamiento y pronóstico de la enfermedad. La dermatoscopía se presenta como una herramienta sumamente útil que puede aumentar la sospecha diagnóstica de estos tumores, aunque el estudio histopatológico continúa siendo el patrón de referencia para el diagnóstico, así como para el abordaje terapéutico y seguimiento ulteriores.

ABSTRACT Introduction: Melanoma is a malignant melanocytic tumor that constitutes the sixth most frequent cancer in the general population and has a high capacity to produce metastasis. Approximately 95% of primary melanomas belong to four clinicopathological types: extensive superficial, nodular, lentigo maligna, and acral lentiginous. The remaining 5% correspond to less frequent variants, among which is amelanotic melanoma, that represents between 0.4-27.5% of the cases in this subgroup. Objective: To present a case of an amelanotic melanoma, as a variant that can accompany any other clinical type of melanoma, in this case a nodular type, a lesion that, due to its decrease or absence of pigment, can lead to diagnostic errors that affect the delay in treatment and reduce the survival of patients who suffer from it. Clinical Case: The case of a 75-year-old male patient who presents with an exophytic tumor lesion on the forehead of approximately one year of evolution. Physical examination reveals a bright, erythematous, dome-shaped tumor which shows a polymorphous vascular pattern with a predominance of thick linear vessels under a polarized light dermatoscope. Several differential diagnoses are proposed, among which the following stand out: basal cell carcinoma, pyogenic granuloma, lymphoma, and skin metastases; a sample is taken for biopsy and staining techniques with immunohistochemistry, which confirm the diagnosis of melanoma, it is decided to excise the tumor with margins and multidisciplinary follow-up of the case. Conclusions: The hypo / amelanotic variants of melanoma are rare and their diagnosis presents difficulties that usually generate delays that influence the treatment and prognosis of the disease. Dermoscopy is presented as an extremely useful tool that can increase the diagnostic suspicion of these tumors, although the histopathological study continues being the gold standard for diagnosis, as well as for the therapeutic approach and subsequent follow-up.

Oral Mucosal Melanoma: A Case Report and Literature Review

ABSTRACT: Oral mucosal melanoma is an unusual and aggressive malignant tumor that mainly affects the palate of men aged between 50 and 60 years. We present a literature review focusing on the etiopathogenesis and the clinicopathologic features of this entity. In addition, we reported a rare case of an oral mucosal melanoma arising in the left cheek of a 60-yea r- old man. Computed tomography scan revealed infiltration of the tumor to other anatomic structures including the maxillary sinus, the zygomatic bone and the pterygoid processes. Based on its extension, the lesion was considered inoperable and treatment with three-dimensional conformal radiation therapy was proposed but the patient only attended to the first session and died from cancer progression 6 months after the diagnosis. This paper reinforces the importance of inclusion of this malignant tumor in the differential diagnosis of pigmented lesions of the oral mucosa.

RESUMEN: El melanoma de la mucosa oral es un tumor maligno inusual y agresivo que afecta principalmente al paladar de hombres de entre 50 y 60 años. Presentamos una revisión bibliográfica centrada en la etiopatogenia y las características clínico-patológicas de esta entidad. Además, reportamos un caso raro de melanoma de la mucosa oral que surgió en la mejilla izquierda de un hombre de 60 años. La tomografía computarizada reveló la infiltración del tumor a otras estructuras anatómicas, incluido el seno maxilar, el hueso cigomático y los procesos pterigoideos. En base a su extensión, la lesión se consideró inoperable y se propuso tratamiento con radioterapia conformada tridimensional pero el paciente solo asistió a la primera sesión y falleció por progresión del cáncer 6 meses después del diagnóstico. Este trabajo refuerza la importancia de la inclusión de este tumor maligno en el diagnóstico diferencial de las lesiones pigmentadas de la mucosa oral.

Bullous Melanoma: should the thickness of the bullous lesion be included in Breslow depth measurement?

Abstract Bullous melanoma represents a rare variant of melanoma, especially in patients without underlying bullous cutaneous disease. Few cases have been described in the literature, including cases of melanoma in patients with bullous epidermolysis or Hailey-Hailey disease. The histopathological diagnosis of bullous melanoma does not show any difficulties, except for the measurement of the Breslow index. The rarity of this case, the dilemma of how to measure the Breslow index and the importance of an early diagnosis motivated this report.

Melanoma del cuerpo ciliar en un adulto joven: reporte de caso / Ciliary body melanoma in a young adult: a case report

Resumen Reporte de un caso: Femenino de 29 años de edad sin comorbilidades, con baja visual progresiva en ojo derecho de 1 mes de evolución. A la exploración oftalmológica agudeza visual de ese ojo en 20/80, conjuntiva bulbar superior con vaso centinela, masa retroiridiana color naranja vascularizada que subluxa el cristalino hacia inferior. Por ultrabiomicroscopía se evidencia una masa en domo dependiente del cuerpo ciliar de 4.87x5.74mm con reflectividad interna media y regular. Se realiza primeramente BAAF reportando melanoma, después se hace enucleación con resultado histopatológico de melanoma amelanótico. Posterior, se realiza implante de prótesis cosmética y se encuentra en seguimiento por oncología sin presentar datos de actividad tumoral después de 4 años. Discusión: Los melanomas uveales son la causa más común de tumores malignos intraoculares primarios en adultos, localizados principalmente en coroides (90%), siendo extremadamente rara su aparición en el cuerpo ciliar (6%) e iris (4%). El abordaje de un tumor del cuerpo ciliar debe incluir una anamnesis y exploración física completa con estudios paraclínicos adecuados para poder discernir entre los diagnósticos diferenciales. El ultrasonido ocular es el estudio auxiliar más importante ya que brinda características típicas propias del tumor. El tratamiento continúa basado en el COMS con un pronóstico sombrío. Los factores de mal pronóstico son presencia de metástasis, tamaño del tumor, extensión extraocular y estirpe epitelioide. Limitaciones: No se contaban con todas las alternativas de tratamiento. Originalidad: Caso inusual en pacientes jóvenes y por su sitio.

Abstract: Case report: 29-year-old female with no comorbidities, with progressive vision loss in the right eye of 1 month's evolution. On ophthalmological examination, visual acuity was 20/80, superior bulbar conjunctiva with sentinel vessel, vascularised orange retroiridian mass generating a lens subluxation inferiorly. Ultrabiomicroscopy revealed a dome-shaped mass dependent on the ciliary body measuring 4.87x5.74mm with medium and regular internal reflectivity. A FNA was done and melanoma was reported, then enucleation was performed with histopathological findings of amelanotic melanoma. Subsequently, a cosmetic prosthesis was implanted and the patient has been followed up by oncology with no evidence of tumour activity after 4 years. Discussion: Uveal melanomas are the most common cause of primary intraocular malignant tumours in adults, mainly located in the choroid (90%), being extremely rare in the ciliary body (6%) and iris (4%). The approach to a ciliary body tumour should include a complete anamnesis and physical examination with appropriate paraclinical studies to be able to discern between differential diagnoses. Ocular ultrasound is the most important ancillary study as it provides typical features of the tumour. Treatment is still based on COMS and the prognosis remains poor. Poor prognostic factors are the presence of metastases, tumour size, extraocular extension and epithelioid lineage. Limitations: Not all treatment alternatives were available. Originality: Unusual case in young patients and because of its site.

Panoftalmitis: presentación atípica de un melanoma coroideo

RESUMEN La panoftalmitis es una forma rara y grave ocular de presentación del melanoma coroideo, por lo que, ante la presencia de una masa intraocular e inflamación de todas las estructuras intraoculares, con extensión extraescleral y los tejidos vecinos de la órbita, debe considerarse el diagnóstico diferencial de esta neoplasia maligna. Se presenta el caso de un paciente masculino de 83 años de edad, con diagnóstico de panoftalmitis como presentación atípica de un melanoma coroideo. Acudió a consulta de Cuerpo de Guardia de Oftalmología con dolor ocular intenso en ojo derecho, acompañado de náuseas y vómitos. Se constató, al examen, hipertensión ocular, que evolucionó tórpidamente durante su ingreso, con inflamación intraocular con extensión extraescleral. Se le realizaron ultrasonido ocular y tomografía axial computarizada de órbitas y se diagnosticó una panoftalmitis secundaria a un melanoma coroideo. Los hallazgos clínicos de esta forma atípica de presentación se mostraron, cuyo tratamiento definitivo es la enucleación. El diagnóstico histológico de melanoma maligno coroideo necrótico fue confirmado.

ABSTRACT Panophthalmitis is a rare and severe ocular form of presentation of choroid melanoma, therefore, in the presence of intraocular mass and inflammation of all intraocular structures, with extra-scleral extension and to the tissues neighboring the orbit, the differential diagnosis of this malignant neoplasia should be considered. The case presented deals with a male patient, aged 83 years, with diagnosis of panophthalmitis as atypical presentation of choroid melanoma. He assisted to the consultation of Ophthalmology Emergency with intense ocular pain in the right eye, accompanied by nausea and vomits. On examination, ocular hypertension was observed, that torpidly evolved during admission, with intraocular inflammation with extra-scleral extension. He had ocular ultrasound and computed axial tomography of orbits and was diagnosed with panophthalmitis secondary to choroid melanoma. The clinical findings of this atypical presentation form showed, whose definite treatment is enucleation. Histological diagnosis of necrotic choroid malignant melanoma was confirmed.

Diagnostic and prognostic significance of long noncoding RNA LINC00173 in patients with melanoma

SUMMARY OBJECTIVE: A growing volume of literature has suggested long noncoding RNAs (lncRNAs) as important players in tumor progression. In this study, we aimed to investigate the expression and prognostic value of lncRNA LINC00173 (LINC00173) in melanoma. METHODS: LINC00173 expression was measured in 163 paired cancerous and noncancerous specimen samples by real-time polymerase chain reaction. The correlations between LINC00173 expression with clinicopathological characteristics and prognosis were analyzed by chi-square test, log-rank test, and multivariate survival analysis. Receiver-operating characteristic curves were used for the assessment of the diagnostic value of LINC00173 for melanoma patients. RESULTS: The expression level of LINC00173 in melanoma specimens was distinctly higher than that in adjacent non-neoplasm specimens (p<0.01). Besides, LINC00173 was expressed more frequently in patients with advanced melanoma than in patients with early melanoma. Multivariate assays confirmed that LINC00173 expression level was an independent prognostic predictor of melanoma patients (p<0.05). CONCLUSION: Our data indicated that LINC00173 expression could serve as an unfavorable prognostic biomarker for melanoma patients.

Melanoma amelanótico acral / Acral amelanotic melanoma

O melanoma amelanótico acral é raro e pode mimetizar muitas entidades, como poroma écrino, carcinoma de células escamosas, verruga plantar e úlceras crônicas. Devido a esta variedade de possíveis diagnósticos diferenciais, é um diagnóstico difícil e, muitas vezes, tardio. As características da dermatoscopia podem ajudar no diagnóstico precoce. O clínico deve ter esse diagnóstico em mente ao se deparar com uma lesão rosada, de crescimento progressivo e formato irregular, principalmente se localizada nas mãos e nos pés.

Acral amelanotic melanoma is rare and can mimic many entities, such as eccrine poroma, squamous cell carcinoma, plantar wart, and chronic ulcers. Due to the variety of possible differential diagnoses, it is a challenging and frequently late diagnosis. Dermoscopy features can help in early diagnosis. The dermatologist should keep this diagnosis in mind when faced with a pink, progressively growing, irregularly shaped lesion, mainly if located on the hands and feet.

Avaliação de uma intervenção educativa sobre câncer de pele realizada no contexto da pandemia da covid-19 / Evaluation of an educational intervention on skin cancer in the context of the covid-19 pandemic

Introdução: o câncer de pele é uma das neoplasias prevalentes, e o melanoma consiste em sua forma mais agressiva por ser responsável pela maioria das mortes devido ao seu alto potencial metastático. O diagnóstico precoce afeta o prognóstico do paciente e pode ser estimulado educando-se a população quanto à realização do autoexame da pele e ao reconhecimento de características marcantes das lesões. Objetivos: avaliar o impacto de uma intervenção educativa em vídeo sobre câncer de pele com a aplicação de questionário antes e após a intervenção. Métodos: estudo prospectivo quase-experimental que incluiu os pacientes assistidos no Serviço de Dermatologia de um hospital público de Belo Horizonte. Resultados: 196 pacientes foram incluídos. Apesar de a maioria dos participantes reconhecer a importância do acompanhamento com o médico dermatologista (81,1%), a maior parte desconhecia o melanoma (70,9%). Houve significativa mudança no conhecimento sobre neoplasias de pele, principalmente no que diz respeito ao mnemônico do ABCDE (p<0,01). Conclusões: a intervenção educativa contribuiu para aumentar significativamente o conhecimento dos participantes acerca do câncer de pele. Com as restrições de contato impostas pela pandemia da COVID-19, ações que disseminem informações e estimulem o autoexame da pele se tornam ainda mais essenciais visando ao diagnóstico precoce

Introduction: Skin cancer is one of the most prevalent neoplasms, and melanoma is its most aggressive form. It is responsible for most deaths due to its high metastatic potential. The early diagnosis affects the patients' prognosis and can be encouraged by educating the population regarding self-examination of the skin and recognition of salient characteristics of the lesions. Objectives: To evaluate the impact of an educational video intervention on skin cancer with the application of a questionnaire before and after the intervention. Methods: Prospective quasi-experimental study that included patients assisted in the dermatology service of a public hospital in Belo Horizonte. Results: 196 patients were included. Although most participants recognized the importance of monitoring with a dermatologist (81.1%), most were unaware of melanoma (70.9%). There was a significant change in knowledge about skin neoplasms, especially regarding the ABCDE mnemonic (P<0.01). Conclusions: The educational intervention contributed to increasing significantly the participants' knowledge about skin cancer. With the contact restrictions imposed by the COVID-19 pandemic, actions that disseminate information and encourage self-examination of the skin become even more essential for early diagnosis.

Application of CRISPR-Cas9 to interrogate novel gene functions in cutaneous melanoma

Melanoma accounts for 3% of skin neoplasms and is the leading cause of death from skin disorders worldwide. The high mortality rate associated with this disease stems from the high capacity of melanoma patients to develop metastases and treatment relapse with inhibitors of the MAPK signaling pathway (such as BRAF inhibitors), commonly used in melanoma therapy. Thus, the investigation of genes involved in the mechanisms of melanoma development is essential for new and more effective therapeutic strategies. Hence, we describe in this thesis two projects involving the genes SIN3B and IRF4 as possible biomarkers for cutaneous melanoma. Initially, through bioinformatics analyses performed by our group, an upregulation of SIN3B was found in metastatic melanomas. This result together with the understanding of SIN3B role in regulating gene expression and oncogenic transformation, prompted us to describe in this thesis some mechanisms by which SIN3B may influence melanoma development. We then sought to characterize the gene function using SIN3B-deleted cells, generated by the CRISPR-Cas9 methodology. Initially, we observed increased SIN3B expression in BRAF-mutant metastatic melanomas, where we noted that the long splicing variant of the gene (NM_001297595.1) was effectively prevalent in melanomas. Subsequently, we designed gRNAs between the exons 2 and 3 of the human SIN3B gene and engineered three knockout clones and three control clones (containing empty lentiCRISPRv2 plasmid) from different melanoma cell lines (SKMEL28, A2058, and A375). Through functional analyses, it was observed that the absence of the gene did not interfere in the proliferation of tumor cells; however, it led to a decrease in invasive properties. These results were verified by Boyden chamber assays and transcriptome analysis (total RNA sequencing of deleted cells), where a decrease in migration and motility pathways was observed. Additionally, a screening of synthetically lethal genes with SIN3B was performed with a genome wide CRISPR library. These results showed that USP7 and STK11 genes, which belong to the FoxO signaling pathway, were essential in SIN3B-depleted melanoma cells. Finally, through a collaborative project with the Wellcome Trust Sanger Institute, previous large-scale sequencing analyses demonstrated that deletion of the IRF4 gene was lethal for melanoma cells. Accordingly, we performed IRF4 silencing in vitro and noticed that the lack of IRF4 promotes cell death and apoptosis, independently of MYC and MITF, known in the literature to be downstream targets of this gene. Therefore, these data suggest that IRF4 plays a vital role in melanoma cell survival. Taken together, both works herein described in this thesis demonstrate how CRISPR-Cas9 can be applied to study the functions and mechanisms of genes involved in melanoma progression, collectively helping in the development of more effective therapeutic strategies for this tumor

O melanoma representa 3% dos tipos de neoplasias cutâneas e é a maior causa das mortes por distúrbios de pele no mundo. A alta taxa de mortalidade associada à essa doença advém da alta capacidade de pacientes com melanoma desenvolverem metástases, e apresentarem recidiva após tratamento com inibidores da via de sinalização MAPK (como da proteína BRAF), comumente utilizados no tratamento de pacientes metastáticos. Assim, a investigação de genes envolvidos nos mecanismos de desenvolvimento do melanoma é primordial para novas estratégias terapêuticas mais efetivas. Dessa forma, descrevemos no presente trabalho dois projetos envolvendo os genes SIN3B e IRF4 como possíveis biomarcadores para melanoma cutâneo. Em análises prévias de bioinformática realizados pelo nosso grupo, SIN3B foi identificado tendo maior expressão em melanomas metastáticos. Além disso, diversos estudos mostraram que o gene está envolvido na regulação da expressão gênica e transformação oncogênica. Dessa forma, descrevemos nessa tese alguns mecanismos pelos quais SIN3B pode influenciar no desenvolvimento do melanoma, através da caracterização funcional de células SIN3B-deletadas pela metodologia CRISPR-Cas9. Inicialmente, observamos aumento na expressão de SIN3B em melanomas metastáticos BRAF-mutados, onde notamos que a variante de splicing longa do gene (NM_001297595.1), era efetivamente prevalente em melanomas. Assim, desenhamos sequências de RNA guias entre os éxons 2 e 3 do gene SIN3B humano e, obtivemos três clones knockout e outros três clones controle (contendo plasmídeo vazio) em diferentes linhagens de melanoma (SKMEL28, A2058 e A375), para caracterização funcional. Observou-se que a ausência do gene não interferiu na proliferação das células tumorais, contudo, acarretou na diminuição de processos invasivos. Esses resultados foram averiguados através de ensaios em câmara de Boyden e análises de transcriptoma (sequenciamento de RNA total das células deletadas), onde notou-se diminuição das vias de migração e motilidade. Adicionalmente, um rastreamento de genes sinteticamente letais com SIN3B foi realizado com uma biblioteca de CRISPR capaz de silenciar todo o genoma. Esses resultados mostraram que os genes USP7 e STK11, ambos pertencentes à via de sinalização de FoxO, são essenciais nas células SIN3B deletadas. Por fim, através de um projeto colaborativo com o Wellcome Trust Sanger Institute, análises prévias de sequenciamento de larga escala demonstraram que a deleção do gene IRF4 era letal para células de melanoma. Dessa forma, realizamos o silenciamento de IRF4 in vitro e notamos que a ausência do gene promove morte celular e apoptose, independentemente de MYC e MITF, conhecidos na literatura por serem alvos downstream do gene. Portanto, esses dados sugerem que IRF4 tem um papel importante na sobrevivência de células de melanoma. Em conjunto, ambos trabalhos descritos nessa tese, demonstram como a metodologia CRISPR-Cas9 pode auxiliar no entendimento de processos importantes para a malignidade do melanoma e contribuir para estratégias terapêuticas mais efetivas para esse tumor

Estudo do composto STX140, um análogo do estradiol, em linhagens de melanoma humano / STX140 compound study in human melanoma

O câncer de pele pode ser classificado como não melanoma e melanoma. O melanoma apresenta baixa incidência entre os cânceres de pele, porém é a forma mais letal e é considerado um dos tipos mais resistentes ao tratamento. Devido à infiltração de células malignas nos tecidos, vasos linfáticos e vasos sanguíneos, o melanoma invade e se espalha rapidamente. Suas metástases são frequentemente localizadas em linfonodos, cérebro, fígado e outros órgãos. Melanomas metastáticos abrigam múltiplas mutações gênicas e muitos tumores apresentam resistência aos tratamentos, como por exemplo com inibidores BRAF, devido à mutações e ativação de vias paralelas. Ou seja, existe uma necessidade clara da busca de novas opções de tratamento. Em trabalho realizado por nosso grupo, Massaro et al mostraram que o derivado de estradiol 2- Metoxiestradiol induz apoptose em células de melanoma e senescência. Neste sentido, o composto STX140, (um análogo do estradiol com biodisponibilidade superior), que já se mostrou eficaz no combate ao câncer de mama em diversos estudos in vitro e in vivo, será então avaliado para sua ação no melanoma de forma inédita. Este trabalho teve como principal objetivo explorar a ação antitumoral em células de melanoma do composto STX140, especialmente a indução de senescência. Utilizando a cultura de células de melanoma foram realizados os ensaios de: viabilidade celular - IC50, formação de colônias, análise do ciclo celular e caracterização de morte celular por citometria de fluxo, ensaio In vitro scratch, coloração para ß-galactosidase, PCR quantitativo e ELISA. Os resultados mostraram que o composto STX140: diminui a viabilidade celular, inibe a proliferação, formação de colônias e migração em linhagens de melanoma (não resistentes e resistentes ao vemurafenibe, inibidor de BRAF). Além do mais, o composto atuou diminuindo a secreção da interleucina pró-tumoral IL-8 em células resistentes. O STX140 induziu senescência nas células de melanoma que foram positivas para ß-galactosidase, também havendo aumento da expressão de genes chave de vias de senescência (CDKN1A e GADD45A) nas células de melanoma resistentes tratadas com o composto. Em conclusão, o STX140 mostrou ter um potencial antitumoral contra o melanoma, diminuindo sua viabilidade celular, inibindo sua proliferação e migração, induzindo senescência, diminuindo a secreção de interleucina pró- tumoral, com efeito mais acentuado nas linhagens de melanoma resistente

Skin cancer can be classified as non-melanoma and melanoma. Melanoma has a low incidence among skin cancers, but it is the most lethal form and is considered one of the most resistant to treatment. Due to the infiltration of malignant cells into tissues, lymphatic vessels and blood vessels, melanoma invades and spreads rapidly. Its metastases are often located in lymph nodes, brain, liver and other organs. Metastatic melanomas presents multiple gene mutations and many tumors are resistant to treatments, such as with BRAF inhibitors, due to mutations and activation of parallel pathways. In other words, there is a clear need to search for new treatment options. In work carried out by our group, Massaro et al showed that the estradiol derivative 2- Methoxyestradiol induces apoptosis in melanoma cells and senescence. In this sense, the compound STX140, (an estradiol analogue with superior bioavailability), which has already been shown to be effective against breast cancer in vitro and in vivo studies will be then evaluated for its action on melanoma. The main objective of this work is to explore the antitumor action of the compound STX140 in melanoma cells, especially the induction of senescence. Using the melanoma cell culture the following assays were performed: cell viability - IC50, clonogenic, cell cycle analysis and cell death characterization by flow cytometry, wound assay, staining for ß-galactosidase, quantitative PCR and ELISA. Preliminary data from this work showed that the compound STX140: decreases cell viability, inhibits proliferation, colony formation and migration in melanoma cell lines (non-resistant and resistant to vemurafenib, BRAF inhibitor). It also decreased the secretion of pro-tumor interleukin IL-8 in resistant cells. STX140 induced senescence in melanoma cells, that were positive for ß-galactosidase, and there was also increased expression of key genes of senescence pathways (CDKN1A and GADD45A) in resistant melanoma cells treated with the compound. In conclusion, STX140 has been shown to have antitumor potential against melanoma, decreasing its cell viability, inhibiting its proliferation and migration, inducing senescence, decreasing pro-tumor interleukin secretion, with a more pronounced effect on resistant melanoma cell lines