Treatment of advanced, recurrent, resistant to previous treatments basal and squamous cell skin carcinomas with a synergistic formulation of interferons. Open, prospective study

<p>Abstract</p> <p>Background</p> <p>Aggressive non-melanoma skin cancer (deeply infiltrating, recurrent, and morphea form lesions) are therapeutically challenging because they require considerable tissue loss and may demand radical disfiguring surgery. Interferons (IFN) may provide a non-surgical approach to the management of these tumors. The aim of this work was to evaluate the effect of a formulation containing IFNs-α and -γ in synergistic proportions on patients with recurrent, advanced basal cell (BCC) or squamous cell skin carcinomas (SCSC).</p> <p>Methods</p> <p>Patients with extensive, recurrent, resistant to other procedures BCC or SCSC received the IFN formulation peri- and intralesionally, three times per week for 3 weeks. They had been previously treated with surgery and/or radiotherapy or chemotherapy. Thirteen weeks after the end of treatment, the original lesion sites were examined for histological evidence of remaining tumor.</p> <p>Results</p> <p>Sixteen elder (median 70 years-old) patients were included. They beared 12 BCC and 4 SCSC ranging from 1.5 to 12.5 cm in the longest dimension. At the end of treatment 47% CR (complete tumor elimination), 40% PR (>30% tumor reduction), and 13% stable disease were obtained. None of the patients relapsed during the treatment period. The median duration of the response was 38 months. Only one patient with complete response had relapsed until today. Principal adverse reactions were influenza-like symptoms well known to occur with interferon therapy, which were well tolerated.</p> <p>Conclusion</p> <p>The peri- and intralesional combination of IFNs-α and -γ was safe and showed effect for the treatment of advanced, recurrent and resistant to previous treatments of BCC and SCSC in elder patients. This is the first report of such treatment in patients with advance non-melanoma skin cancer. The encouraging result justifies further confirmatory trials.</p> <p>Trial registration</p> <p>Current Controlled Trials RPCEC00000052.</p

Primary cutaneous marginal zone lymphoma in children: a report of 3 cases and review of the literature

Primary cutaneous marginal zone lymphoma (PCMZL) is one of the most common cutaneous B-cell lymphomas. It affects mostly patients in their fourth decade and manifests with multifocal nodules mostly on the arms and upper trunk in more than half of the patients. PCMZL is, however, rare in children and adolescents, with only 20 cases reported in patients aged 20 and younger. The authors present 3 cases of PCMZL in teenagers. The patients were 2 girls aged 18 and 13 and a 17-year-old boy. Two patients presented with multiple lesions involving various anatomic sites, whereas in 1 patient, 2 small closely opposed papules on the abdomen were seen. Histopathologically, the characteristic appearance of PCMZL was found in 3 of 4 specimens, with nodular infiltrates composed of small lymphocytes in the interfollicular compartment, reactive germinal centers, and plasma cells in small clusters mainly at the periphery of the infiltrates, whereas 1 specimen showed a dense lymphocytic infiltrate with small granulomas. Clonality was demonstrated by monotypic immunoglobulin light chain expression and/or monoclonal rearrangement of the immunoglobulin heavy chain genes. No Borrelia burgdorferi was identified on serology or by polymerase chain reaction in any of the cases. Treatment included excision or administration of antibiotics with complete remission in all the 3 patients indicating that PCMZL in children and young adolescents follows the same indolent course with a tendency for recurrences, but excellent prognosis as in adults. The pertinent literature on PCZL in childhood and adolescence is reviewed

Paradoxical effects of T-cadherin on squamous cell carcinoma : up- and down-regulation increase xenograft growth by distinct mechanisms

Mechanisms underlying cutaneous squamous cell carcinoma (SCC) tumour growth and invasion are incompletely understood. Our previous pathological and in vitro studies suggest that cell surface glycoprotein T-cadherin (T-cad) might be a controlling determinant of the behaviour of SCC. Here we used a murine xenograft model to determine whether T-cad modulates SCC tumour progression in vivo. Silencing or up-regulation of T-cad in A431 (shTcad or Tcad(+) , respectively) both resulted in increased tumour expansion in vivo. To explain this unanticipated outcome, we focused on proliferation, apoptosis and angiogenesis/lymphangiogenesis, which are important determinants of the progression of solid tumours in vivo. shTcad exhibited enhanced proliferation potential in vitro and in vivo, and their signalling response to EGF was characterized by a higher Erk1/2:p38MAPK activity ratio, which has been correlated with more aggressive tumour growth. T-cad over-expression did not affect proliferation but staining for cleaved caspase 3 revealed a minimal occurrence of extensive apoptosis in Tcad(+) tumours. Immunofluoresence staining of xenograft sections revealed increased intra-tumoural total microvessel (CD31(+)) and lymphatic vessel (LYVE-1(+)) densities in Tcad(+) tumours. shTcad tumours exhibited decreased microvessel and lymphatic densities. Tcad(+) expressed higher levels of transcripts for VEGF-A, VEGF-C and VEGF-D in vitro and in vivo. Culture supernatants collected from Tcad(+) enhanced sprout outgrowth from spheroids composed of either microvascular or lymphatic endothelial cells, and these in vitro angiogenic and lymphangiogenic responses were abrogated by inclusion of neutralizing VEGF antibodies. We conclude that T-cad can exert pleiotropic effects on SCC progression; up- or down-regulation of T-cad can promote SCC tumour expansion in vivo but through distinct mechanisms, namely enhancement of angio/lymphangiogenic potential or enhancement of proliferation capaci

T-Cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma: impact on cell motility

Genetic and epigenetic studies in different cancers, including cutaneous carcinomas, have implicated T-cadherin (T-cad) as a tumor suppressor. Immunohistochemical and in vitro studies have suggested that T-cad loss promotes incipient invasiveness in cutaneous squamous cell carcinoma (SCC). Molecular mechanisms are unknown. This study found that the main consequence of T-cad silencing in SCC is facilitation of ligand-dependent EGFR activation, whereas T-cad overexpression impedes EGFR activation. Gain- and loss-of-function studies in A431 SCC cells demonstrate T-cad-controlled responsiveness to EGF with respect to pharmacological inhibition of EGFR and to diverse signaling and functional events of the EGFR activation cascade (EGFR phosphorylation, internalization, nuclear translocation, cell retraction/de-adhesion, motility, invasion, integrin β1, and Rho small GTPases such as RhoA, Rac1, and Cdc42 activation). Further, T-cad modulates the EGFR pathway activity by influencing membrane compartmentalization of EGFR; T-cad upregulation promotes retention of EGFR in lipid rafts, whereas T-cad silencing releases EGFR from this compartment, rendering EGFR more accessible to ligand stimulation. This study reveals a mechanism for fine-tuning of EGFR activity in SCC, whereby T-cad represents an auxiliary "negative" regulator of the EGFR pathway, which impacts invasion-associated behavioral responses of SCC to EGF. This action of T-cad in SCC may serve as a paradigm explaining other malignancies displaying concomitant T-cad loss and enhanced EGFR activity