Evangelia Papadavid

PLCG1 mutations in cutaneous T-cell lymphomas

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor κB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation.

Probiotics for the treatment or prevention of atopic dermatitis: a review of the evidence from randomized controlled trials.

Probiotics are defined as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. To synthesize the evidence for the effectiveness of probiotics in the treatment or prevention of atopic dermatitis (AD) in children, we reviewed the results of 13 relevant randomized (placebo)-controlled trials (RCTs), 10 of which evaluated probiotics as treatment and 3 for prevention of AD. The main outcome measure in 9 RCTs was the change in SCORAD (SCORing Atopic Dermatitis).Four RCTs suggested that there was a statistically significant decrease in SCORAD after probiotic administration to infants or children with AD for 1 or 2 months compared with that after placebo, while in two RCTs SCORAD was significantly reduced after treatment with lactobacilli only in children with IgE-associated AD. In four of these six RCTs, clinical improvement was associated with a change in some inflammatory markers. In three RCTs, the change in SCORAD was not statistically significant between probiotic- and placebo-treated children, although in one of these trials SCORAD was significantly lower after probiotic than with placebo treatment in food-sensitized children. In most RCTs, probiotics did not cause a statistically significant change in interferon-γ, interleukin-4, tumor necrosis factor-α, eosinophil cationic protein or transforming growth factor-β compared with placebo.Regarding the effectiveness of probiotics in the prevention of AD, in two RCTs, infants at high risk for atopy who received probiotics developed AD significantly less frequently during the first 2 years of life than infants who received placebo. In these studies, mothers were administered Lactobacillus rhamnosus GG with or without other probiotics perinatally, followed by treatment of the infants with the same probiotics for the first 6 months of life. However, in another trial, neither the frequency nor the severity of AD during the first year of life were significantly different between infants with atopic mothers who received L. acidophilus for the first 6 months of life compared with infants who received placebo.Probiotics, especially L. rhamnosus GG, seem to be effective for the prevention of AD. They were also found to reduce the severity of AD in approximately half of the RCTs evaluated, although they were not found to change significantly most of the inflammatory markers measured in the majority of the RCTs evaluated. More RCTs need to be conducted to elucidate whether probiotics are useful for the treatment or prevention of AD.

Guidelines on the use of extracorporeal photopheresis

After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model

PURPOSE Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

Lasers for facial rejuvenation: a review.

Background Different types of laser are used for resurfacing and collagen remodeling in cutaneous laser surgery.

The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sézary syndrome.

Summary Background There is evidence that a T‐helper (Th) 2 cytokine pattern dominates in the peripheral blood as well as in tissue of patients with Sézary syndrome (SS), and that the malignant clone is of Th2 phenotype. However, there are conflicting studies on the cytokine pattern in the peripheral blood in different stages of cutaneous T‐cell lymphoma (CTCL).

Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial.

IMPORTANCE Hidradenitis suppurativa (HS) is a common skin disorder in which excessive inflammation is believed to have an important role. There is no specific therapy for HS. OBJECTIVE To investigate the safety and efficacy of the anti-inflammatory biological therapy anakinra in HS. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled clinical trial with a 12-week treatment phase and a 12-week follow-up phase. The setting was Attikon University General Hospital, a tertiary care institution in Athens, Greece. Participants were 20 patients with Hurley stage II or III HS. The study and the analysis were conducted between March 1, 2012, and February 28, 2014. INTERVENTIONS Patients were randomized to receive injections from identical syringes containing placebo or anakinra subcutaneously once daily for 12 weeks. Peripheral blood mononuclear cells were isolated and stimulated for cytokine production before the beginning of treatment and at week 12 (the end of treatment) and week 24. MAIN OUTCOMES AND MEASURES The primary end point was the effect of anakinra on HS disease severity. Secondary end points were the time to a new exacerbation and the production of cytokines. RESULTS Among the 20 trial participants, 10 each were randomized to the group to receive anakinra or the placebo group. The mean (SD) ages were 42.8 (13.8) and 36 (11.3) years in the anakinra and placebo groups, respectively. The disease activity score was decreased at the end of treatment in 20% (2 of 10) of the placebo arm compared with 67% (6 of 9) of the anakinra arm (P = .04). Hidradenitis suppurativa clinical response at 12 weeks was achieved in 30% (3 of 10) of the placebo arm and in 78% (7 of 9) of the anakinra arm (P = .04). The production of interferon-γ by peripheral blood mononuclear cells in the anakinra arm was decreased, and the production of interleukin 22 was increased. The time to a new HS exacerbation was prolonged in the anakinra arm by log-rank test (log rank, 6.137; P = .01). No serious adverse events were reported. CONCLUSIONS AND RELEVANCE Anakinra has the potential to be an effective and well-tolerated treatment for HS. Inhibition of interleukin 1 is a promising treatment strategy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01558375.

Serum resistin: a biomarker of breast cancer in postmenopausal women? Association with clinicopathological characteristics, tumor markers, inflammatory and metabolic parameters.

OBJECTIVE Previous few studies have shown that resistin is significantly elevated in breast cancer (BC) patients. Therefore, we investigated whether serum resistin could be used as a potential diagnostic and prognostic tool for postmenopausal BC (PBC), taking into account clinicopathological features, serum tumor markers, anthropometric, metabolic, and, for the first time, inflammatory parameters. METHODS Serum resistin, tumor markers (CA 15-3 and CEA), metabolic, anthropometric and inflammatory parameters (TNF-α, IL-6, hsCRP) were determined in 103 postmenopausal women with incident, pathologically confirmed, invasive BC, 103 controls matched on age and time of diagnosis, and 51 patients with benign breast lesions (BBL). RESULTS Mean serum resistin was significantly higher in cases than in controls and patients with BBL (p<0.001). In patients, resistin was significantly associated with tumor and inflammatory markers, cancer stage, tumor size, grade and lymph node invasion but not with anthropometric, metabolic parameters and hormone receptor status. Multivariable regression analysis revealed that serum IL-6 (p=0.02) and cancer stage (p=0.048) were the strongest determinants of serum resistin in cases adjusting for demographic, metabolic and clinicopathological features. Although resistins diagnostic performance was low based on ROC curve analysis [0.72, 95% CI: 0.64-0.79], it could, however, represent a BC biomarker reflecting advanced disease stage and inflammatory state. CONCLUSION Further prospective and longitudinal studies are needed to evaluate whether serum resistin could be used as a prognostic tool in BC monitoring and management. More research is essential to elucidate resistins ontological role in the association between obesity, representing a chronic low-grade subclinical inflammation, and PBC.

Frontal fibrosing alopecia: treatment with oral dutasteride and topical pimecrolimus

© 2008 The Authors JEADV 2009, 23, 570–620 Journal compilation

Could serum visfatin be a potential biomarker for postmenopausal breast cancer

OBJECTIVE Previous studies have shown that visfatin is significantly elevated in patients with gastric carcinoma and postmenopausal breast cancer (PBC). We thus explored whether serum visfatin could be used as a potential diagnostic and prognostic tool for PBC, taking into account clinicopathological features, serum tumor markers, anthropometric and metabolic parameters. METHODS Serum visfatin, tumor marker CA 15-3, carcinoembryonic antigen, metabolic and anthropometric parameters were determined in 103 postmenopausal women with pathologically confirmed, incident invasive breast cancer, 103 controls matched on age and time of diagnosis, and 51 patients with benign breast lesions (BBL). RESULTS Mean serum visfatin was significantly higher in cases than in controls and patients with BBL (p<0.001). In cases, visfatin was significantly associated with CA 15-3 (p=0.03), hormone-receptor status (p<0.001), lymph node invasion (p=0.06) but not with metabolic and anthropometric variables (p>0.05). Multivariable regression analysis revealed that absence of estrogen and progesterone receptors (ER-PR-) was the strongest significant determinant of serum visfatin (p<0.001) in cases adjusting for demographic, metabolic and clinicopathological features. Based upon receiver operator characteristic analysis, serum visfatin outperformed CA 15-3 only in discriminating between PBC cases with early cancer stage than those with late stage, and in differentiating particularly patients with ER-PR- breast tumors. CONCLUSION Further prospective and longitudinal studies are needed to determine whether serum visfatin could be used as a prognostic tool in the armamentarium of PBC monitoring and management in conjunction with other biomarkers.