Josep M. Casanova

Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines

Background  Cutaneous malignant melanoma is an aggressive type of skin cancer which causes disproportionate mortality in young and middle‐aged adults. Once disseminated, melanoma can be considered an incurable disease, highly resistant to standard antineoplastic treatment, such as chemotherapy or radiation therapy. The proteasome represents a novel target for cancer therapy that can potentially be used in melanoma.

Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway

Despite the use of multiple therapeutic strategies, metastatic melanoma remains a challenge for oncologists. Thus, new approaches using combinational treatment may be used to try to improve the prognosis of this disease. In this report, we have analyzed the expression of receptor tyrosine kinases (RTKs) in melanoma specimens and in four metastatic melanoma cell lines. Both melanoma specimens and cell lines expressed RTKs, suggesting that they may represent eventual targets for multitargeted tyrosine kinase inhibitor, Suntinib. Sunitinib reduced the proliferation of two melanoma cell lines (M16 and M17) and increased apoptosis in one of them (M16). Moreover, the two metastatic melanoma cell lines harbored an activated receptor (PDGFRα and VEGFR, respectively), and Sunitinib suppressed the phosphorylation of the RTKs and their downstream targets Akt and ribosomal protein S6, in these two cell lines. Similar results were obtained when either PDGFRα or VEGFR2 expression was silenced by lentiviral‐mediated short‐hairpin RNA delivery in M16 and M17, respectively. To evaluate the interaction between Sunitinib and Bortezomib, median dose effect analysis using MTT assay was performed, and combination index was calculated. Bortezomib synergistically enhanced the Sunitinib‐induced growth arrest in Sunitinib‐sensitive cells (combination index < 1). Moreover, LY294002, a PI3K inhibitor, sensitized melanoma cells to Bortezomib treatment, suggesting that downregulation of phospho‐Akt by Sunitinib mediates the synergy obtained by Bortezomib + Sunitinib cotreatment. Altogether, our results suggest that melanoma cells harboring an activated RTK may be clinically responsive to pharmacologic RTK inhibition by Sunitinib, and a strategy combining Sunitinib and Bortezomib, may provide therapeutic benefit.

Dermatosis infantiles en la consulta de Dermatología de un hospital general universitario en España

Resumen Introduccion y objetivos La Dermatologia Pediatrica es una subespecialidad relativamente nueva sobre la que existen pocos estudios epidemiologicos. Nos proponemos determinar la carga de trabajo que representa en una consulta de Dermatologia general y cuales son los motivos de consulta mas frecuentes en nuestro centro en este grupo de edad. Metodos Estudio descriptivo del registro del Servicio de Dermatologia sobre las visitas realizadas a pacientes de ≤ 16 anos de edad en el ano 2005 y sus diagnosticos. Resultados La Dermatologia Pediatrica representa el 12,1 % de nuestra carga de trabajo (1.329/10.998 visitas fueron a ≤ 16 anos). Por grupos, los tumores y las infecciones fueron los diagnosticos mas frecuentes, ya que entre ambos representan el 55,4 % del total. A distancia les siguen los eczemas (15,0 %) y las enfermedades anexiales (8,8 %). El diagnostico individual mas frecuente fue nevo melanocitico (19,8 %), seguido de verruga virica (12,1 %), dermatitis atopica (8,9 %), molusco contagioso (8,4 %) y acne (7,0 %). Conclusiones En la mayoria de paises desarrollados la dermatitis atopica es el diagnostico mas frecuente en los ninos. En nuestro estudio los nevos melanociticos ocupan el primer lugar, lo que quiza refleje que existan mas ninos con multiples nevos porque se toma el sol en exceso, o por la melanofobia existente entre la poblacion. Tambien es posible que en nuestra area exista menos dermatitis atopica que en paises mas industrializados del norte de Europa. Se deberian impulsar conductas de fotoevitacion y fotoproteccion durante la epoca infantil. Ello podria contribuir a frenar, en nuestro medio, el incremento del melanoma en el adulto.

Expression of Somatostatin Receptors in Human Melanoma Cell Lines: Effect of Two Different Somatostatin Analogues, Octreotide and SOM230, on Cell Proliferation

Somatostatin analogues (SAs) are potential anticancer agents. This study was designed to investigate the expression of somatostatin receptors (SSTRs) in melanoma cells and the effect of two SAs on cell proliferation and viability. Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and SOM230. Expression of SSTR1, SSTR2, SSTR3 and SSTR5 was assessed by real-time polymerase chain reaction. Proliferation, viability and cell death were assessed using standard assays. Inhibition was modelled by mixed-effect regression. Melanoma cells expressed one or more SSTR. Both SAs inhibited proliferation of most melanoma cell lines, but inhibition was < 50%. Neither SA affected cell viability or induced cell death. The results suggest that melanoma cell lines express SSTRs. The SAs investigated, under the conditions used in this study, did not, however, significantly inhibit melanoma growth or induce cell death. Novel SAs, combination therapy with SAs and their anti-angiogenic properties should be further investigated.

Síndrome de Sweet con lesiones ampollosas

We present a case of Sweets syndrome with atypical lesions, characterized by erythematous plaques, vesicles and bullous lesions. Skin lesions in patients with an underlying malignancy are more frequently atypical and with vesicular, bullous or even ulcerative characteristics, in addition to the typical plaques and nodules. However, the case presented is not associated with malignancy, despite the fact that these processes, particularly hematologic ones, should be suspected.

El portafolio como herramienta de formación y evaluación de los residentes de Dermatología (II)

A portfolio is a collection of material documenting reflection about practice. It contains documents (eg, case histories and questionnaires the resident has used), images, and video recordings that reveal that an individual has acquired the competencies needed for professional practice. This assessment tool simultaneously supports learning and provides evidence for certifying competence. The adoption of portfolio use by a dermatology department requires the support of both the training supervisor and the chief of department. The learning objectives defined by the National Board for Medical-Surgical Dermatology and Venereology must be taken into consideration so that ways to assess each objective can be included; this approach supports holistic ongoing education as well as the certification of competencies the resident finally achieves. Use of portfolios in medical residency training can improve on current assessment methods, which we believe lack precision. We propose that portfolios gradually begin to replace the residents training log. We are currently developing an online software application that will facilitate the use of portfolios.

Childhood Dermatosis in a Dermatology Clinic of a General University Hospital in Spain

BACKGROUND AND OBJECTIVES Pediatric dermatology is a relatively new subspecialty for which few epidemiological studies are available. We aimed to determine the work load associated with this subspecialty and the most common presenting complaints among pediatric patients in the general dermatology clinic of our hospital. METHODS A descriptive study was performed based on hospital records to analyze patients aged 16 years or under seen in our department in 2005 and their diagnoses. RESULTS Pediatric dermatology accounts for 12.1 % of the work load in our department (1,329/10,998 patients were <or= 16 years old). By disease groups, tumors and infections were the most common diagnoses and accounted for 55.4 % of all cases. A long way behind was eczema (15.0 %) and diseases affecting hair follicles, nails, and sweat and sebaceous glands (8.8 %). The most common individual diagnosis was melanocytic nevus (19.8 %), followed by viral warts (12.1 %), atopic dermatitis (8.9 %), molluscum contagiosum (8.4 %), and acne (7.0 %). CONCLUSIONS In most developed countries, atopic dermatitis is the most common dermatologic disease in children. In our study, however, melanocytic nevus was the most common presenting complaint, reflecting perhaps that there are more children in Spain with multiple nevi due to overexposure to sunlight or because of concern about melanoma among the population. Another possibility is that Spain has fewer cases of atopic dermatitis than more industrialized countries in northern Europe. Measures to avoid exposure to sunlight and use of sunscreen should be promoted during infancy. This could help slow the increase of melanoma in the adult population.

Cyclin D1 localizes in the cytoplasm of keratinocytes during skin differentiation and regulates cell-matrix adhesion.

The function of Cyclin D1 (CycD1) has been widely studied in the cell nucleus as a regulatory subunit of the cyclin-dependent kinases Cdk4/6 involved in the control of proliferation and development in mammals. CycD1 has been also localized in the cytoplasm, where its function nevertheless is poorly characterized. In this work we have observed that in normal skin as well as in primary cultures of human keratinocytes, cytoplasmic localization of CycD1 correlated with the degree of differentiation of the keratinocyte. In these conditions, CycD1 co-localized in cytoplasmic foci with exocyst components (Sec6) and regulators (RalA), and with β1 integrin, suggesting a role for CycD1 in the regulation of keratinocyte adhesion during differentiation. Consistent with this hypothesis, CycD1 overexpression increased β1 integrin recycling and drastically reduced the ability of keratinocytes to adhere to the extracellular matrix. We propose that localization of CycD1 in the cytoplasm during skin differentiation could be related to the changes in detachment ability of keratinocytes committed to differentiation.

Grover’s disease in patients with chronic renal failure receiving hemodialysis: Clinicopathologic review of 4 cases

In 4 patients undergoing hemodialysis for chronic renal failure, a transient or persistent, papular and keratotic eruption developed on the trunk and arms. Histologic examination disclosed focal acantholysis with dyskeratosis. The lesions were clinically and histologically indistinguishable from those of Grovers disease. A possible association with Grovers disease and chronic renal failure and/or hemodialysis is postulated. Possible implicated pathogenic mechanisms are discussed. We suggest that Grovers disease should be included in the differential diagnosis of cutaneous eruptions in patients with chronic renal failure.

Squamous Cell Carcinoma Developing in Jadassohn's Sebaceous Nevus: Case Report and Review of the Literature

Nevus sebaceous (or Jadassohn’s sebaceous nevus or organoid nevus) is a well-known congenital skin hamartoma involving ectodermand mesoderm-derived structures that usually appears in the head and face area. During childhood, the lesion remains static but, during puberty, grows and becomes more evident and verrucous. These changes reveal growth of pilosebaceous and apocrine elements, probably because of the influence of androgens.