Ramón Egido

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.

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.

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.

Pleomorphic adenoma with extensive myoepithelial component (myoepithelioma) of the lower eyelid.

A 58-year-old woman presented with a nodular lesion on the medial part of her left lower eyelid. The lesion had been removed 10 years ago, but showed subsequent recurrence with slow growth. The lesion was again partially removed at another institution prior to presentation. Afterward removal, the persistent lesion had rapid growth. On presentation to us, the lesion showed a clinical appearance that was very similar to a nodular basal cell carcinoma. A pentagonal full-thickness resection biopsy was performed. The pathologic study revealed clusters of tumor cells and some ductal proliferations. Immunohistochemistry demonstrated positive staining for p63, S-100, and smooth muscle actin. No atypia was observed. A diagnosis of pleomorphic adenoma with extensive myoepithelial component (myoepithelioma) was made. The authors conclude that myoepithelioma should be considered in the differential diagnosis of nodular recurrent masses in the eyelids of adults. Definitive diagnosis is possible only after surgical biopsy.

Síndrome de Bart asociado a epidermólisis ampollosa hereditaria letal (Herlitz)

We present the case of a newborn with congenital absence of skin in the anterior part of the left leg that shortly after developed bulla and erosions in hands, feet, ears, buttocks and mouth. The cutaneous biopsy and ultrastructural and immunohistochemical studies showed a subepidermal bulla in the lamina lucida, absence of hemidesmosomes and marked decrease of laminin 5, thus establishing the diagnosis of Bart syndrome associated to the Herlitz form of lethal junctional epidermolysis bullosa. Bart syndrome consists of congenital and localized absence of skin, nail abnormalities and mucoc-cutaneous bullae. It is usually associated to dystrophic epidermolysis bullosa. The Herlitz form of junctional epidermolysis bullosa is a rare variant, usually lethal that is produced by mutations in the genes coding for the anchor protein laminin 5. To our knowledge this is the second case that reports an association between Bart syndrome and lethal junctional epidermolysis bullosa and the first in which the results of immunofluorescence mapping are published.

Bowen's Disease Associated with Human Papillomavirus Infection of the Nail Bed

A 54-year-old right-handed woman presented with a few-month history of progressive right thumbnail dystrophy. She had an asymptomatic hyperkeratotic plaque under her nail that had caused onycholysis and had extended to the nail folds. No other digits were involved, and no signs of lymphadenopathy were detected. The lesion had been biopsied twice and diagnosed as a viral wart. There was no previous history of trauma or exposure to arsenic. Past medical history included ischemic heart disease, arterial hypertension, diabetes mellitus, and a hysterectomy 13 years earlier because of a disease whose diagnosis the patient did not remember. A complete excision of the finger lesion was performed. The histopathological analysis showed a papillomatous and highly hyperkeratotic lesion with an epithelial architectural disorder, numerous dyskeratotic keratinocytes, and large atypical cells with large nuclei in the upper layers of the epidermis (Figure 1). No signs of koilocytosis or any other histopathological changes associated with human papilloma virus (HPV) infection were observed. A diagnosis of digital Bowen’s disease was made.

Dermatosis ampollosa crónica benigna infantil (dermatosis IgA lineal de la infancia)

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Nuevas dianas terapéuticas en el melanoma

Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have cargado de http://www.actasdermo.org el 27/03/2016. Copia para uso personal, se prohibe la transmision de este documento por cualquier medio o formato. Molecular targets; BRAF; yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; ity inhibitors in melanomas carrying c-kit mutations; and antic-kit tyrosine kinase activ C-kit; Anti CTLA-4 cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted Con posterioridad a la redaccion de este manuscrito, en julio de 2011, la Agencia Europea del Medicamento (EMA) aprobo Ipilimumab (Yervoy®) para el tratamiento del melanoma avanzado (metastasico o irresecable) resistente a, al menos, un tratamiento previo (ya aprobado por la FDA en marzo del 2011). En agosto del 2011, la FDA aprobo PLX4032 o Vemurafenib (Zelboraf®) como tratamiento de primera linea del melanoma metastasico y/o irresecable quirurgicamente. ∗ Autor para correspondencia. Correo electronico: marti@medicina.udl.cat (R.M. Marti). 0001-7310/