Carcinoma cuniculatum in course of etanercept: blocking autoimmunity but propagation of carcinogenesis?

Carcinoma cuniculatum (CC) or verrucous squamous cell carcinoma is a rare variant of squamous cell carcinoma with low incidence of metastasis. It mainly affects men during the fifth-sixth decade of life, arising mostly on the weight-bearing surface of the foot, but it can also be found in other body areas. The favorable effects on the psoriatic, rheumatoid, juvenile polyarthritis as well as the ankylosing spondylitis after the application of Tumour Necrosis Factor (TNF)-alpha inhibitors, like etanercept, presume the availability of similarity between the etiopathogenetic mechanisms which are responsible for the generation of the inflammatory cascade. According to the latest studies, the sensitivity of the patients to TNF-alpha inhibitors could be genetically determined and may also be due to certain genetic polymorphisms of the NLP3 and CARD8 zones of the inflammasome. The blocking of the inflammatory reaction within the borderlines of the psoriatic arthritis could also be accepted as something of a "double edged sword". There is a growing volume of literary data which informs us of the clinical manifestation, not only of skin, but also of other types of tumors after the application of TNF-alpha inhibitors. This inevitably generates the hypothesis that within a certain group of patients the TNF-alpha inhibitors have some additional, and currently obscure, effects on presumably key regulatory proteins of the so-called extrinsic apoptotic pathway. Other proteins of the human inflammasome could be also implicated in the regulation of the programmed cell death and the carcinogenesis - there are speculations, that the adapter protein, ASC/TMS1, could be one of these. The present study describes the case of a patient who developed a rare form of skin tumor - epithelioma cuniculatum - whilst undergoing etanercept therapy for psoriatic arthritis. Under discussion are the possible critical connections in the complex regulatory "networks" of the inflammatory processes, the programmed cell death (apoptosis) and the carcinogenesis which, in the near or distant future, could become the objects of a targeted therapy

Cephalosporin-induced Hemolytic Anemia in a Sicilian Child.

A 27-month-old child developed acute hemolysis on two occasions after the administration of cephalosporin. On the first occasion, hemolysis was intravascular and was due to the formation of complexes between antibodies and the drug, which bound to red blood cells and caused severe hemolysis. On the second occasion, hemolysis was extravascular and was probably due to antibody-dependent cell mediated cytotoxicity. Marked increases in levels of CD19(+), and CD57(+) CD8(+) cells were detected among the subpopulations of the patient's lymphocytes but only in the level of CD19(+) cells from the patient's father, after incubation of a sample of whole blood with a solution of cephalosporins. These results might explain the differences between the immune response of the patient and those of other members of his family and of an unrelated control

Nectin like -5 overexpression correlates with the malignant phenotype in cutaneous melanoma

NECL-5 is involved in regulating cell--cell junctions, in cooperation with cadherins, integrins and platelet-derived growth factor receptor, that are essential for intercellular communication. Its role in malignant transformation was previously described. It has been reported that transformation of melanocytes is associated with altered expression of adhesion molecules suggesting the potential involment of NECL-5 in melanoma development and prognosis. To shed light on this issue, the expression and the role of NECL-5 in melanoma tissues was investigated by bioinformatic and molecular approaches. NECL-5 was up-regulated both at the mRNA and the protein levels in WM35, M14 and A375 cell lines compared with normal melanocytes. A subsequent analysis in primary and metastatic melanoma specimens confirmed "in vitro" findings. NECL-5 overexpression was observed in 53 of 59 (89.8%) and 12 of 12 (100%), primary melanoma and melanoma metastasis, respectively; while, low expression of NECL-5 was detected in 12 of 20 (60%) benign nevi. A significant correlation of NECL-5 overexpression was observed with most of known negative melanoma prognostic factors, including lymph-node involvement (P = 0.009) and thickness (P = 0.004). Intriguingly, by analyzing the large series of melanoma samples in the Xu dataset, we identified the transcription factor YY1 among genes positively correlated with NECL-5 (r = 0.5). The concordant computational and experimental data of the present study indicate that the extent of NECL-5 expression correlates with melanoma progression

Detection of BRAF gene mutation in primary choroidal melanoma tissue.

Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. In contrast, several studies report lack of BRAF mutations in uveal melanoma including primary and metastatic choroidal and ciliary body melanomas. To our knowledge, for the first time, here we report a case of choroidal melanoma harboring the BRAF mutation (V600E). The activation of RAF/MEK/ERK pathway, although independent of BRAF mutation, was reported in uveal melanoma. The presence of V600E mutation indicates that the RAF/MEK/ERK pathway, in addition to cutaneous melanoma progression, may play a role in the choroidal melanoma development

Increased Levels of NF-kB-Dependent Markers in Cancer-Associated Deep Venous Thrombosis

<div><p>Several studies highlight the role of inflammatory markers in thrombosis as well as in cancer. However, their combined role in cancer-associated deep vein thrombosis (DVT) and the molecular mechanisms, involved in its pathophysiology, needs further investigations. In the present study, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), matrix metalloproteases-9 (MMP-9), vascular endothelial growth factor (VEGF), tissue factor (TF), fibrinogen and soluble P-selectin, were analyzed in plasma and in monocyte samples from 385 cancer patients, of whom 64 were concomitantly affected by DVT (+). All these markers were higher in cancer patients DVT+ than in those DVT-. Accordingly, significantly higher NF-kB activity was observed in cancer patients DVT+ than DVT-. Significant correlation between data obtained in plasma and monocyte samples was observed. NF-kB inhibition was associated with decreased levels of all molecules in both cancer DVT+ and DVT-. To further demonstrate the involvement of NF-kB activation by the above mentioned molecules, we treated monocyte derived from healthy donors with a pool of sera from cancer patients with and without DVT. These set of experiments further suggest the significant role played by some molecules, regulated by NF-kB, and detected in cancer patients with DVT. Our data support the notion that NF-kB may be considered as a therapeutic target for cancer patients, especially those complicated by DVT. Treatment with NF-kB inhibitors may represent a possible strategy to prevent or reduce the risk of DVT in cancer patients.</p></div

Cytokines secretion in monocytes from cancer patients with and without DVT.

<p>Levels of IL-6, TNF-α, IL-1β, and VEGF were measured in supernatants of purified monocytes from cancer patients with and without DVT by a sensitive enzyme-linked immunosorbent assay (ELISA). The results are shown as the means ± SD.</p

Spearman correlation coefficients between <i>in vivo</i> and <i>in vitro</i> marker concentrations.

<p>DVT, deep vein thrombosis. A positive strong correlation between the plasma cytokines, angiogenic and coagulation markers and the secretion <i>in vitro</i> of the same markers in two groups of cancer patients with and without DVT.</p

Plasma levels of inflammation, angiogenic and coagulation markers from controls and cancer with and without deep vein thrombosis.

<p>Abbreviations: DVT, deep vein thrombosis; IL-6, interleukin-6; TNF- α, tumor necrosis factor-α; IL-1β, interleukin-1β; CRP, C-reactive protein; MMP-9, matrix metalloproteinase-9; VEGF, vascular endothelial growth factor; TF, tissue factor; soluble P-selectin (sP-selectin). Significant differences among inflammatory, angiogenic and coagulation markers were evident in cancer patients with and without DVT compared to controls with further increments in DVT cancer patients. P value are given using analysis of variance (ANOVA test, in the case of three groups) or t-test (two groups).</p

Cytokines secretion in monocytes from cancer patients with and without DVT.

<p>Levels of IL-6, TNF-α, IL-1β, and VEGF were measured in supernatants of purified monocytes from cancer patients with and without DVT by a sensitive enzyme-linked immunosorbent assay (ELISA). The results are shown as the means ± SD.</p

Serum-dependent activation of nuclear factor (NF)–NF-kB p65 subunit in healthy monocytes.

<p>Monocytes from 25 healthy controls were evaluated for NF-kB activation after they were cultured for 20 hours in medium supplemented with either 40% serum from three groups. Monocytes (5x10⁵) from 25 healthy donors were cultured for 20 hours in medium (RPMI 1640) supplemented with either 40% serum derived from 64 cancer patients DVT+ and 257 DVT- with the highest cytokines plasma levels (> 75th percentile) or 40% serum derived from 100 healthy donors with the lowest cytokines values (< 25th percentile). The incubation of healthy monocytes with pooled sera derived from cancer patients DVT+ (sCADVT+) or DVT- (sCADVT-) induced a significant increase of NF-kB activity compared with that derived from healthy controls (HM) after treatment with sera from healthy controls (SH) (P<0.0001). An higher NF-kB p65 subunit activation was observed in monocytes stimulated by sera from cancer patients DVT+ compared to that stimulated by sera derived from DVT- (P<0.001) (t-test). No NF-kB p65 subunit activation was observed in monocytes stimulated with sera derived from healthy controls.</p