ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation.

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. METHODS: Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. RESULTS: Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. CONCLUSION: We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.

Potential predictive value of cofilin-1 for metastasis occurrence in a small cohort of Argentinian patients with mid-low Breslow thickness melanoma.

Nowadays, histopathological criteria for melanocytic lesions are the mainstay prognostic factors for melanoma. However, there are cases in which these parameters fall short to predict melanoma spread. We recently demonstrated a correlation of cofilin-1 levels, a key protein for tumor invasion, with different histopathological parameters associated with melanoma malignancy as well as a negative correlation with survival. In order to broaden our previous findings, we aim to estimate the probability of a melanoma to metastasize as a function of both a conventional histopathological parameter (Breslow thickness, BT) and cofilin-1's immunohistochemical expression levels, which we propose as a potential marker for metastasis. We used a Bayesian approach to analyze clinical and cofilin-1 datasets formerly obtained from a patients' small cohort diagnosed with malignant melanocytic lesions since 2000 until 2008; classified at different tumor stages with or without detected metastasis and with at least 5 years of clinical follow-up. Low BT values exhibited wide variance to predict metastasis occurrence, while the differential diagnostic value of cofilin-1 confirmed BT diagnosis or resulted more precise to predict outcome. Particularly, the probability of metastasis estimation improved when cofilin-1 was combined with BT for specific cases, where BT displayed large uncertainties. Our analysis and the cofilin-1 determination provided statistically significant prognostic value in mid-low BT melanomas, which could complement further evaluation criteria to assist diagnosis and treatment decision-making. Moreover, the combined use of cofilin-1 with BT, if validated in follow-up studies, would be feasible to help patients' selection for treatment and optimize health resources.

Ganglio centineaa en melanoma de cara: abordaje inicaal / Sentinel ganglion in melanoma of the face: an initial approach

A pesar de las campañas preventivas no se ha logrado disminuir la incidencia de las neoplasias cutáneas, probablemente por las alteraciones de la capa de ozono, con el consecuente aumento de la radiación ultravioleta, por eso en países del trópico se presentan lesiones como el melanoma de piel, que es considerado como una de las lesiones tumorales más agresivas. La cara y el cuello son zonas del cuerpo con una alta exposición solar, reflejándose en un mayor número de casos de este sombrío tumor. El mayor factor pronóstico en contra de los pacientes que padecen esta enfermedad es la presencia de metástasis ganglionares, por eso el grupo tratante debe esclarecer si están presentes, debido a esto hace varias décadas se realizan disecciones de cuello profilácticas, pero en la mayoría de los casos los ganglios extirpados son negativos. Una posible solución para evitar esto, es la extracción del o de los primeros ganglios que drenan el sitio del tumor primario (Ganglio Centinela). En el área de cabeza y cuello usualmente están presentes varios a la vez, lo que dificulta tomar la decisión de cuál extirpar. En nuestro grupo hemos iniciado la estandarización de esta técnica, y como abordaje inicial se realizó el primer caso de una paciente con melanoma de la cara a quien se practicó resección local amplia del tumor y extracción de los centinelas marcados por linfogammagrafía y a la vez disección de los relevos ganglionares positivos para drenaje demostrados por este estudio de medicina nuclear.

In spite of preventative campaigns having been mounted, it still has not been possible to reduce cutaneous neoplasia incidence, probably due to alterations in the ozone layer. This has led to a consequent increase in ultraviolet radiation and thus lesions occurring in tropical countries such as skin cancer (melanoma), considered as being one of the most aggressive tumour lesions. The face and neck are the body areas having the highest exposure to the sun, being reflected in a greater number of such tumour cases. The presence of ganglion metastasis is the greatest negative prognostic factor for patients suffering from this disease; the treating group must thus clarify whether this is present as prophylactic neck dissections were made several decades ago, but the ganglions so removed were negative in most cases. Extracting the first ganglions draining the primary tumour site (sentinel ganglion) represents a possible solution for avoiding this. Several of them are usually present at the same time in the head and neck area, thereby hampering taking a decision as to which should be removed. Our group has begun to standardise such technique; an initial approach has involved the first case of a patient with melanoma of the face who underwent wide local resection of the tumour and extraction of the sentinel ganglions. These were dyed and lymphogammagraphy was used, at the same time as dissection of positive ganglion relief for drainage, as demonstrated by this nuclear medicine study.

Situación del melanoma maligno cutáneo en el Hospital Militar Central Lima, 1985û2007 / Situation of cutaneous malignant melanoma at "Hospital Militar Central-Lima", 1985-2007

El Melanoma Maligno Cutáneo es el más letal de los tumores de la piel. Afecta especialmente a individuos de raza blanca con antecedentes de exposición intensa a la luz solar, mientras que en pieles más oscuras tiene mayor incidencia en áreas poco expuestas. Objetivo: Conocer las características epidemiológicas, clínicas e histopatológicas de la población con Melanoma Maligno Cutáneo y determinar el tiempo de sobrevida posterior al diagnóstico. Material y métodos: Se analizaron retrospectivamente las historias clínicas y láminas histopatológicas de 40 pacientes en el Hospital Militar Central con diagnóstico de Melanoma Maligno Cutáneo durante los años 1985-2007. Para la evaluación de la sobrevida, se ubicó al paciente/familiares. El análisis estadístico se realizó mediante el método de Kaplan-Meier. Resultados: La edad media fue de 60,7 años, siendo el grupo etáreo mayormente afectado el de 70-79 años en ambos sexos. Hombres fueron el 70% y mujeres el 30%. No se identificó Melanoma Maligno Cutáneo familiar. El tiempo de enfermedad promedio previo al diagnóstico fue de 25,1 meses. La localización mayormente afectada fue la extremidad inferior (55%), específicamente el pie (86,4%). El 17,5% fueron de raza blanca. Los tipos clínico-histológicos más frecuentes fueron el acral (52,8%) y el nodular (22,2%). La mayor frecuencia de Melanoma Maligno Cutáneo correspondió al Nivel Clark IV y Breslow mayor que 2mm. La sobrevida acumulada a 1 año fue 81,8%; a 5 años 41,8% y a 10 años 25,9%. Conclusión: El melanoma lentiginoso acral en los pies, es el tipo clínico-histológico más frecuentemente encontrado en el Hospital Militar Central. La sobrevida fue mayor cuando el Índice de Breslow fue 1mm y el Nivel de Clark III.

The cutaneous malignant melanoma is the more letal skin tumor. It specially affects white persons with previous intense exposition to light radiation, in those with more pigmented skin affects less exposed body areas. Objective: To know clinical, epidemiologic and histopathologic features of those with cutaneous malignant melanoma and to determine the period of life after diagnosis. Material and methods: The patient records and histopathology slides of 40 patients with cutaneous malignant melanoma between 1985 and 2007 were retrospectively analyzed. For evaluation of time of life after diagnosis the patient or relatives were interviewed. Statistical analysis was made with Kaplan-Meier method. Results: The median age was 60,7 years and more affected was the age range of 70-79 years in both sexes. Seventy per-cent were men and 30% women. No cases of familial cutaneous malinant melanoma was identified. The average time of illness until diagnosis was 25,1 months. Inferior extremity wasmore affected (55%), specially the foot (86,4%). Only 17,5% were whites. The clinic histology type more frequently found was acral (52,8%) and nodular (22,2%). More frequently the cutaneous malignant melanoma belonged to Clark IV level and Breslow more than 2 mm. At one year 81,8% were alive; at 5 years the 41,8% and at 10 years the 25,9%. Conclusion: Acral lentiginous melanoma of feet was the most common type found. The overlive was high when Breslow Index was equal or less than 1 mm and Clark level was III or less.