<i>TP53</i> Gene Status Affects Survival in Advanced Mycosis Fungoides

TP53 is frequently mutated in different types of neoplasms including leukemia and lymphomas. Mutations of TP53 have also been reported in mycosis fungoides (MF), the most common type of cutaneous lymphoma. However, little is known about the frequency, spectrum of mutations and their prognostic significance in MF. In this study we have optimized the protocol for Sanger sequencing of TP53 using DNA extracted from archival paraffin-embedded biopsies. Of 19 samples from patients with stage IIB MF or higher, 31% harboured mutations in TP53. Overall survival of the patients with mutated TP53 was significantly shorter than median survival in the age- and stage-matched patients treated in our Institution. Distribution of mutations was heterogenous in TP53 exons, however C>T transitions were common suggesting the causal role of ultraviolet radiation. We propose that TP53 mutation status would be useful for risk stratification of patients with advanced MF

The principles of the therapy of primary cutaneous lymphomas

Chłoniaki skóry wywodzą sie z komórek T (> 70%) lub rzadziej komórek B i definiuje się je jako pierwotnie skórne, jeżeli przy rozpoznaniu nie stwierdzono zmian w węzłach chłonnych, szpiku czy narządach wewnętrznych. Leczenie pierwotnych chłoniaków skóry jest zagadnieniem interdyscyplinarnym, na pograniczu dermatologii, hematologii i onkologii. W obecnej klasyfikacji EORTC-WHO wyróżnia się 19 jednostek chorobowych, z których najczęstsza, ziarniniak grzybiasty (mycosis fungoides), ma przebieg powolny i stosunkowo łagodny. W leczeniu wczesnych stadiów ziarniniaka grzybiastego nie zaleca się ogólnej chemioterapii, a leczenie prowadzi się głównie przy użyciu terapii lokalnej (fototerapia, radioterapia) ewentualnie w połączeniu z interferonem i beksarotenem. W stadiach bardziej zaawansowanych chemioterapię stosuje się głównie w celu redukcji guzów oraz jako leczenie paliatywne. Postacie agresywne chłoniaków T-komórkowych leczy się z zastosowaniem chemio- i radioterapii; z powodu złych wyników leczenia należy rozważyć przeszczep szpiku. Chłoniaki B-komórkowe mają najczęściej przebieg łagodny i leczy się je za pomocą radioterapii.Cutaneous lymphomas present with the mature T-cell (> 70%) or the B-cell phenotype. Primary cutaneous lymphomas are those manifesting clinically in the skin before an eventual lymph node or organ involvement. The therapy of cutaneous lymphomas needs an interdisciplinary approach involving dermatology, oncology and haematology. In the present WHO-EORTC classification of cutaneous lymphomas there are 19 well-defined entities among which mycosis fungoides is the most prevalent. Mycosis fungoides is an indolent, chronic lymphoma, which should primarily be managed by skin-directed therapies (phototherapy, radiotherapy), sometimes in combination with interferon or bexarotene. In more advanced stages tumor debulking or palliation can be achieved by chemotherapy. Treatment of aggressive T-cell lymphomas is difficult and systemic multiagent chemotherapy and allogeneic bone marrow transplant have been used. Cutaneous B-cell lymphomas are in most cases indolent and can easily be managed by radiotherapy

Ligand-Independent Activation of the EGFR by Lipid Raft Disruption

Normal and immortalized keratinocytes demonstrate large aggregates of lipid rafts, detectable by membrane staining with fluorescently tagged cholera toxin (CTx). As lipid rafts are known to regulate the function of many surface receptors, we wished to investigate their impact on the EGFR in HaCaT cells. When rafts were disrupted by cholesterol sequestration with methyl-β-cyclodextrin (MβCD) or filipin III, EGFR rearranged into approximately micrometer large clusters outside the CTxbright raft aggregates. These clusters contained high concentrations of activated, tyrosine-phosphorylated EGFR exhibiting greatly reduced mobility in the fluorescence recovery after photobleaching experiments. EGFR activation led to the stimulation of extracellular signal-regulated kinase 2, the phosphorylated form of which translocated to the nucleus and stimulated growth of the MβCD-treated cells. Experiments with the specific antagonistic antibody proved that the activation of EGFR by lipid raft disruption occurred without the participation of the ligand. We hypothesize that cholesterol depletion leads to the release of EGFR from the damaged rafts into the small confined areas of the membrane, where the receptor molecules are likely to be spontaneously activated owing to a very high density and/or separation from the inhibitory factors remaining in the surrounding portions of the membrane

Ubiquitin-specific protease 2 decreases p53-dependent apoptosis in cutaneous T-cell lymphoma

Treatment of advanced cutaneous T-cell lymphomas (CTCL) is challenging because they are resistant to conventional chemotherapy. USP2 has been shown to promote resistance to chemotherapeutic agents in several cancer models. We show here USP2 is expressed in quiescent and activated T-cells and its expression is 50% lower in CTCL cell lines (MyLa2000, SeAx and Hut-78) than in normal T-cells. USP2 is expressed in neoplastic cells in early, plaque-stage mycosis fungoides (MF) and is downregulated in advanced tumor stages. Upon treatment with psoralen with UVA (PUVA) or a p53 activator, nutlin3a, USP2 expression is significantly increased in MyLa2000 (p53(wt/wt)), but not in SeAx (p53(mut)) or Hut-78 (p53−/−). USP2 knockdown decreases MyLa2000 cell viability after PUVA by 50% but not Hut-78, suggesting that the function of USP2 in CTCL cells is p53-dependent. Furthermore, USP2 knockdown results in a decreased Mdm2 expression and upregulation of p53. Taken together, our findings suggest that USP2 stabilizes Mdm2 which antagonizes pro-apoptotic activity of p53 and possibly contributes to therapeutic resistance in CTCL

Employment is maintained and sick days decreased in psoriasis/psoriatic arthritis patients with etanercept treatment

BACKGROUND: Psoriasis and psoriatic arthritis (PsA) impair quality of life, including reduction in employment or job duties. The PRESTA (Psoriasis Randomized Etanercept STudy in Patients with Psoriatic Arthritis) study, a randomized, double-blind, two-dose trial, examined the efficacy of etanercept treatment in patients with moderate-to-severe plaque psoriasis and PsA and the main results have been presented previously. This analysis examined employment status, job duties and sick days, pre-defined endpoints in PRESTA, among this patient population. METHODS: Participants (N = 752) were randomized to receive etanercept 50 mg twice weekly (BIW; n = 379) or 50 mg once weekly (QW; n = 373) for 12 weeks by subcutaneous injection. All participants then received open-label etanercept 50 mg QW for 12 additional weeks, while remaining blinded to the randomization. A pharmacoeconomic questionnaire was administered at baseline, week 12 and week 24 of treatment. The questionnaire included employment status and changing job responsibilities and sick time taken due to psoriasis or PsA. The statistical methods included analysis of covariance, t-test, Fisher's exact test and McNemar's test. Last-observation-carried-forward imputation was used for missing data. RESULTS: Employment was at least maintained from baseline to week 24 in both dose groups (56% [BIW/QW] and 60% [QW/QW] at baseline, 61% and 60%, respectively, at week 24). Among employed participants, the proportion of patients whose job responsibilities changed due to PsA decreased significantly from baseline to week 24 (17-23% to 5-8%; p < 0.01). Similar results were seen with job responsibility changes due to psoriasis (11-14% to 4%; p < 0.01). The number of monthly sick days also decreased from baseline to week 24 (2.4 days for both treatment groups to 0.7 (BIW/QW) and 1.1 (QW/QW); p </= 0.03 for each). No significant differences between the treatment groups were observed for any economic endpoint at any time point. CONCLUSIONS: For patients with moderate-to-severe plaque psoriasis and PsA, etanercept treatment resulted in reducing job responsibility changes due to disease and in reducing sick time. Effective treatment of psoriasis and PsA may reduce missed work days