Lieve Brochez

Serological markers for melanoma.

We present a review of current literature concerning the significance of serological markers in melanoma patients. Results for cytokines, cytokine receptors, cell adhesion molecules, S100 protein, melanoma inhibitory activity, tissue‐specific reverse transcription–polymerase chain reaction, neurone‐specific enolase, lipid‐bound sialic acid and melanin metabolites such as 5‐S‐cysteinyldopa and 6‐hydroxy‐5‐methoxyindole‐2‐carboxylic acid are discussed. For most of these substances, serum levels are more pronounced in the more advanced stages of disease. Therefore, these markers seem to have no place in the early detection of melanoma. On the other hand, sensitivity in the advanced stages of disease seems to be < 100%, compromising their use as a new staging procedure. Some markers show promising results as a possible prognostic factor in the early detection of disease progression or in the prediction of therapy outcome. If confirmed by further studies, this could direct future therapeutic strategies and could help to select patients who would benefit most from more aggressive (adjuvant) therapies. In addition, the study of some of these substances could add to the knowledge of tumour biology and immunology.

Quality of life and stigmatization profile in a cohort of vitiligo patients and effect of the use of camouflage.

Background: Few studies have paid attention to the effects of treatment interventions on the psychosocial consequences of vitiligo. Objectives: To quantify and analyse the psychosocial benefit of the use of camouflage in vitiligo patients. Patients and Methods: 78 vitiligo patients completed the Dermatology Life Quality Index (DLQI) and an adapted stigmatization questionnaire, and 62 of them completed the DLQI after at least a 1-month use of camouflage. Results: The initial mean overall DLQI score (n = 78) is 6.9 (SD 5.6). The mean global stigmatization score is 38%. Disease extent and disease severity are strong predictors of the DLQI (p < 0.0001). Vitiligo on the face/head/neck substantially affects the DLQI, independently of degree of involvement. The mean DLQI score before and after use of camouflage (n = 62) is 7.3 (SD 5.6) and 5.9 (SD 5.2; p = 0.006). Mainly the high-scoring items ‘feelings of embarrassment and self consciousness’ and ‘choice of clothing’ improve. Predictors of improvement are higher DLQI scores (p = 0.0005) and higher total severity scores (p = 0.03). Conclusions: Camouflage can be recommended, particularly in patients with higher DLQI scores or self-assessed disease severity. Patients with minor involvement of the face benefit from camouflage.

Inter-observer variation in the histopathological diagnosis of clinically suspicious pigmented skin lesions

When a biopsy is taken of a suspicious pigmented skin lesion, histological examination is expected to establish the definitive diagnosis. This study evaluated the inter‐observer variation of 20 pathologists in the histological diagnosis of a randomly selected set of suspicious pigmented skin lesions (PSLs), by comparing their diagnoses to a reference diagnosis. Overall sensitivity for melanoma was 87%, ranging from 55% to 100% between the observers. Sensitivity was significantly lower for thin (Breslow thickness <1 mm) than for thick melanomas (83% versus 97%, p=0.005). Overall melanoma specificity was 94%, ranging from 83% to 100% between observers. Dysplastic naevus was the most important source of false‐positive diagnoses, mainly in situ melanomas. Positive and negative predictive values in the given test set were 75% and 97%, respectively. In the case of melanoma, there was quite some variation in measured Breslow thickness. This would have led to a different therapeutic approach in 12% of the readings. Some of the variation seemed to be due to a different interpretation of the presence of a co‐existent naevus. In 9% (3/35) of the readings, participants did not agree on the presence of ulceration. These results reflect a tendency to overdiagnose mainly thin melanomas in general histopathological practice. They also demonstrate variation in the assessment of major prognostic factors of melanoma. Copyright

Acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts

Acute generalized exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction, most often provoked by drugs and acute infections. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. The clinical hallmark is the presence of multiple disseminated sterile pustules on an erythematous background, associated with fever and a massive neutrophilia and sometimes eosinophilia. The disease is characterised by an acute onset and a spontaneous resolution within 2 weeks. The involvement of drug-specific T cells in the pathomechanism can be confirmed by positive skin patch tests and lymphocyte transformation tests. In this review, we highlight the main clinical, pathophysiological and diagnostic aspects of this peculiar form of drug allergy.

Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression

Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival.

Cancer risk in immune-mediated inflammatory diseases (IMID)

Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.

Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients

BACKGROUND Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance. PATIENTS AND METHODS One hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry. RESULTS Cox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025). CONCLUSIONS This study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.

Clinical significance of Koebner phenomenon in vitiligo

Background  The clinical significance of Koebner phenomenon (KP) in vitiligo with respect to disease activity and course is still debatable. Recently, a new classification was introduced for the assessment of KP.

miR-145 overexpression suppresses the migration and invasion of metastatic melanoma cells

MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression which play important roles in tumorigenesis and cancer metastasis. Since they are often highly deregulated in various types of cancer, miRNAs may be effective treatment targets. miRNA profiling studies of melanoma have led to the identification of several tumor suppressor miRNAs. One of these include miR-145, although functional data proving its specific function are limited. Therefore, in this study, we examined the expression levels of miR-145 in three melanoma cell lines (BLM, FM3P and WM793). Additional gain-of-function experiments revealed that miR-145 exerts an anti-proliferative effect in the primary, non-invasive melanoma cell line, WM793, whereas cell migration and the invasive potential of metastatic melanoma cells was suppressed following transfection with miR-145 mimics. In order to investigate the mechanisms by which miR-145 exerts its invasion suppressor function, we examined the expression level of target genes [fascin homolog 1 (FSCN1), myosin‑Va (MYO5A and SOX9] and that of an indirect target (RAB27A) following the overexpression of miR-145. The results showed that SOX9, MYO5A and RAB27A were not involved in the biological effects caused by miR-145 mimics. Surprisingly, we discovered that miR-145 in melanoma, in contrast to many other tumor types, does not necessarily act via the target, FSCN1, since the downregulation of FSCN1 did not inhibit cell proliferation or migration but, on the contrary, increased cell invasion in two out of the three melanoma cell lines examined. Our in vitro data is in accordance with previously reported in vivo data describing the low expression of FSCN1 in malignant melanomas when compared to dysplastic nevi, suggesting that the expression of FSCN1 decreases as the formation and progression stage of melanoma advances. In conclusion, our data provide evidence that miR-145 is an invasion suppressor in metastatic melanoma cells. Despite the fact that it remains unclear which genes or pathways are regulated by miR-145 in melanoma, miR-145 may serve as a useful therapeutic agent in melanoma when re-expressed in situ.

EGFR in melanoma: clinical significance and potential therapeutic target

Background: The role of epidermal growth factor receptor (EGFR) has been established in a range of neoplasms. In melanoma, data on EGFR protein expression are conflicting. Fluorescence in situ hybridization (FISH) analysis for EGFR gene expression in melanoma showed EGFR gene amplification to be linked with worse prognosis. Cetuximab has been shown to suppress the formation of metastasis in mice.