[Brain metastases-Interdisciplinary approach towards a personalized treatment]. / Hirnmetastasen ­ interdisziplinär zu einer personalisierten Behandlung.

The incidence, treatment and prognosis of patients with brain metastases have substantially changed during the last decades. While the survival time after diagnosis of cerebral metastases was on average a maximum of 3-6 months only 10 years ago, the survival time could be significantly improved due to novel surgical, radiotherapeutic and systemic treatment modalities. Only a few years ago, the occurrence of brain metastases led to a withdrawal from systemic oncological treatment and the exclusion of drug therapy studies and to a purely palliatively oriented treatment in the sense of whole brain radiation therapy (WBRT) with or without surgery. The increasing availability of targeted and immunomodulatory drugs as well as adapted radio-oncological procedures enable increasingly more personalized treatment approaches. The aim of this review article is to demonstrate the progress and complexity of the treatment of brain metastases in the context of modern comprehensive interdisciplinary concepts.

Extended surgical safety margins and ulceration are associated with an improved prognosis in pleomorphic dermal sarcomas.

BACKGROUND: Pleomorphic dermal sarcomas (PDS) are frequent UV-induced sarcomas of the skin of intermediate grade malignant potential. Despite the fact that PDS have a noteworthy potential to recur (up to 28%) as well as to metastasize (up to 20%), there are no specific clinical guidelines with respect to follow-up these patients. Moreover, little is known about clinical, histological or molecular prognostic factors in PDS. OBJECTIVE: The aim of the present study was to identify risk factors to predict relapse in a large multicentre sample cohort of PDS which could aid to optimize personalized treatment recommendations regarding surgical safety margins and adjuvant radiotherapy. METHODS: Patients with a diagnosis of PDS were selected from nine European institutions based on the histopathologic criteria described by Fletcher. Clinicopathologic and follow-up data were collected and statistically analysed calculating univariate hazard ratios with 95% confidence intervals by use of the Cox proportional-hazards model and a significance level of P < 0.05. Patients with an incomplete excision of the tumour were excluded. RESULTS: Univariate Cox regression analysis of possible prognostic factors for progression-free survival (PFS) performed in 92 patients revealed that an excision margin of <2 cm is significantly associated with relapse of PDS [hazard ratio 4.478 (95% CI 1.536-13.055), P = 0.006]. Ulceration of the tumour was associated with a significantly better prognosis [0.396 (0.174-0.904), P = 0.028] whereas adjuvant radiotherapy did not reach statistical significance to improve prognosis in patients with PDS [0.775 (0.231-2.593), P = 0.679]. Gender, age, immunosuppression, intratumoural necrosis, tumour location, vertical thickness or horizontal diameter did not significantly influence PFS in PDS. CONCLUSION: We identified surgical safety margins of <2 cm and absence of ulceration as risk factors for relapse in patients with PDS. These findings may be implemented into both the primary treatment as well as the further monitoring of patients with PDS.

Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial.

BACKGROUND: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial. PATIENTS AND METHODS: Patients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR). RESULTS: Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08-2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96-1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms. CONCLUSION: In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.

How to reduce parental provision of unhealthy foods to 3- to 8-year-old children in the home environment? A systematic review utilizing the Behaviour Change Wheel framework.

BACKGROUND AND OBJECTIVE: The effectiveness of obesity prevention interventions to improve children's diet can be enhanced. Deconstructing past interventions can identify components with potential to change behaviour. This systematic review using the Behaviour Change Wheel aimed to examine the behaviour change content of interventions supporting parents of 3- to 8-year olds to reduce provision of unhealthy foods to children. METHODS: Ebscohost, Ovid, Scopus and Web of Science were searched. Eligible studies included controlled interventions with active parent involvement, at least one intervention strategy and outcome measure for unhealthy foods ≥3 months from baseline. Seventeen interventions were included describing 18 intervention arms. RESULTS: Interventions frequently targeted parents' reflective motivation (n = 17) and psychological capability (n = 15), through education (n = 15) or enablement (n = 15) intervention functions and service provision (n = 18) policy category. Only 24 of the 93 behaviour change techniques were used with an average of five techniques used per intervention. CONCLUSIONS: Existing interventions achieving small reductions in unhealthy food intake are homogenous in approach. There is potential to utilize untapped behaviour change techniques, through comprehensive intervention design and behavioural analysis guided by the Behaviour Change Wheel. Interventions targeting opportunity through persuasion, modelling or environmental restructuring, and using different policy categories are urgently needed to provide an evidence base to inform policy and practice.

Deletion of ADAM-9 in HGF/CDK4 mice impairs melanoma development and metastasis.

ADAM-9 is a metalloproteinase expressed in peritumoral areas by invading melanoma cells and by adjacent peritumoral stromal cells; however, its function in stromal and melanoma cells is not fully understood. To address this question in vivo in a spontaneous melanoma model, we deleted ADAM-9 in mice carrying the hepatocyte growth factor (Hgf) transgene and knock-in mutation Cdk4R24C/R24C, demonstrated to spontaneously develop melanoma. Spontaneous melanoma arose less frequently in ADAM-9-deleted mice than in controls. Similarly reduced tumor numbers (although with faster growth kinetics) were detected upon induction of melanoma with 7,12-dimethylbenz[a]anthracene (DMBA). However, more lesions were induced at early time points in the absence of ADAM-9. Increased initial and decreased late tumor numbers were paralleled by altered tumor cell proliferation, but not apoptosis or inflammation. Importantly, significantly reduced lung metastases were detected upon ADAM-9 deletion. Using in vitro assays to address this effect mechanistically, we detected reduced adhesion and transmigration of ADAM-9-silenced melanoma cells to/through the endothelium. This implies that ADAM-9 functionally and cell autonomously mediates extravasation of melanoma cells. In vitro and in vivo we demonstrated that the basement membrane (BM) component laminin ß3-chain is a direct substrate of ADAM-9, thus contributing to destabilization and disruption of the BM barrier during invasion. In in vitro invasion assays using human melanoma cells and skin equivalents, depletion of ADAM-9 resulted in decreased invasion of the BM, which remained almost completely intact, as shown by continuous staining for laminin ß3-chain. Importantly, supplying soluble ADAM-9 to the system reversed this effect. Taken together, our data show that melanoma derived ADAM-9 autonomously contributes to melanoma progression by modulating cell adhesion to the endothelium and altering BM integrity by proteolytically processing the laminin-ß3 chain. This newly described process and ADAM-9 itself may represent potential targets for anti-tumor therapies.

[Merkel cell carcinoma of the eyelid. An often unrecognized tumor entity : Clinical aspects and treatment strategies]. / Merkel-Zell-Karzinom des Augenlids ­ eine häufig verkannte Diagnose : Klinische Aspekte und Behandlungsmethoden.

Merkel cell carcinoma of the eyelid is an aggressive, highly malignant tumor of the skin. Totaling approximately 0.5 % of all tumors of the eyelid, it constitutes a relatively small group of lid tumors. Nevertheless Merkel cell carcinoma is of significance to the ophthalmologist. Because of its clinical presentation it can be easily confused as a chalazion, a hordeolum or the lesser aggressive basal cell carcinoma. This often leads to delayed treatment. In this article we describe clinical aspects, which aim to help the ophthalmologist suspect Merkel cell carcinoma earlier. Additionally we outline a diagnostic and therapeutic workup taking into consideration the special anatomy of the eyelid.

The fibronectin/α3ß1 integrin axis serves as molecular basis for keratinocyte invasion induced by ßHPV.

Organ-transplant-recipients exhibit cancerization of the skin from which multiple human papillomavirus (HPV)-positive squamous cell carcinomas (SCCs) arise. However, the molecular basis for HPV-induced invasion of skin keratinocytes is not known. We generated a transgenic mouse model expressing the E7 oncoprotein of HPV8 in the murine epidermis under the control of the keratin-14 promoter and showed that E7 is carcinogenic in mice. We further showed that both, the E7-expressing keratinocyte and mesenchymal components of the extracellular matrix as critical in eliciting the invasive behavior. E7 expression in basal keratinocytes, grown on fibronectin, led to epithelial-mesenchymal transition mediated by a cadherin switch. E7-positive keratinocytes displayed enhanced EDA-fibronectin expression and secretion and stimulated dermal fibroblasts to express EDA-fibronectin. Deposition of fibronectin was also detected in the peritumoral stroma of HPV8-positive skin SCC. When grown on fibronectin, E7-positive keratinocytes, in particular stem cell-like cells, exhibited increased cell surface levels of the α3-integrin chain. Functional blocking confirmed α3 as a critical molecule sufficient to induce E7-mediated invasion. This mechanistic link is further supported by expression of an E7-mutant, impaired in targeting α3 to the cell surface. These findings highlight the importance of epithelial-extracellular matrix interaction required for keratinocyte invasion and provide further mechanistic evidence for a role of HPV in skin carcinogenesis.

[Tumorogenesis and skin tumours in the elderly]. / Tumorigenese und Hauttumoren im Alter.

More than 1.5 million people were diagnosed with skin cancer in 2012 in Germany-of which 318,000 were malignant melanoma. The number of malignant skin tumours has increased by 60% since 2005. Epithelial skin cancers are even more common. Since 2012, 1.3 million diagnoses have been documented. This incidence represents an increase of 79% within 7 years. The number of skin cancer patients treated in German hospitals has also increased. In 2014, 99,613 patients were treated as inpatients with the diagnosis of skin cancer; in 2000 there were 57,147 patients. This was the largest growth rate among all cancer treatments in hospitalised patients. The continuously changing age pyramid leads to an expected further growth of the incidence of skin tumours. In parallel the development of molecular knowledge in tumorigenesis is also rapid. A series of cell-specific mutations have been described in recent years for various skin tumours. Mutations are found mainly in genes engaging their translation products at key positions in regulatory cell metabolism or cell division. These include oncogenes, which have greatly increased activity due to targeted mutations or tumor suppressor genes and act under physiological conditions as negative regulators that are inactivated by mutations. These findings have led to the development of a series of new promising compounds for the treatment of skin tumours.

[Adjuvant therapy and interdisciplinary follow-up care of conjunctival melanoma]. / Adjuvante Therapie und interdisziplinäre Nachsorge des Bindehautmelanoms.

BACKGROUND: Despite microscopically controlled tumor excision, malignant melanomas of the conjunctiva have a propensity for local recurrence, lymphatic spread and distant metastases. OBJECTIVES: This review outlines the options of adjuvant therapy as well as the structure of interdisciplinary follow-up care for patients with conjunctival melanoma. METHODS: The study provides a PubMed literature review and own clinical results. RESULTS: In conjunctival melanoma complete tumor excision using a minimal touch technique should always be combined with adjuvant therapy, such as cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy. For locally circumscribed lesions of the bulbar conjunctiva adjuvant brachytherapy can be supplemented and for non-bulbar, extensive, diffuse or multilocular tumor growth, complementary adjuvant topical mitomycin C therapy or proton radiotherapy can be used. Novel adjuvant approaches include topical interferon alpha-2b immunotherapy, topical vascular endothelial growth factor (VEGF) inhibitors or in cases of BRAF mutations personalized therapy using selective BRAF inhibitors or in combination with mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK), MAPK/ERK (MEK) inhibitors. All patients should be integrated into an interdisciplinary follow-up care program including quarter yearly checkups in the first 5 years and psycho-oncological healthcare. CONCLUSION: Following microscopically controlled tumor excision, adjuvant treatment using cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy as well as interdisciplinary follow-up care are mandatory for the modern management of patients with conjunctival melanoma.

Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a neuroendocrine cancer of the skin postulated to originate through Merkel cell polyomavirus (MCPyV) oncogenesis and/or by mutations in molecules implicated in the regulation of cell growth and survival. Despite the fact that MCPvV is detected more broadly within the population, only a part of the infected people also develop MCC. It is thus conceivable that together, virus and for example mutations, are necessary for disease development. However, apart from a correlation between MCPyV positivity or mutations and MCC development, less is known about the association of these factors with progressive disease. OBJECTIVES: To analyze MCPyV positivity, load and integration in MCC as well as presence of mutations in PDGFRα and TP53 genes and correlate these with clinical features and disease progression to identify features with prognostic value for clinical progression. METHODS: This is a study on a MCC population group of 64 patients. MCPyV positivity, load and integration in parallel to mutations in the PDGFRα and TP53 were analyzed on genomic DNA from MCC specimens. In addition, expression of PDGFRα, survivin and p53 proteins was analyzed by immunodetection in tissues specimens. All these parameters were analyzed as function of patient's disease progression status. RESULTS: 83% of MCCs were positive for the MCPyV and among these 36% also displayed virus-T integration. Viral load ranged from 0.006 to 943 viral DNA copies/ß-globin gene and was highest in patients with progressive disease. We detected more than one mutation within the PDGFRα gene and identified two new SNPs in 36% of MCC patients, whereas no mutations were found in TP53 gene. Survivin was expressed in 78% of specimens. We could not correlate either mutations in PDGFR or expression of PDGFR, p53 and surviving either to the disease progression or to the MCPyV positivity. CONCLUSIONS: In conclusion, our data indicate that the viral positivity when associated with high viral load, correlates with poor disease outcome. Frequent mutations in the PDGFRα gene and high survivin expression were found in MCC independent of the viral positivity. These data suggest that these three factors independently contribute to Merkel cell carcinoma development and that only the viral load can be used as indicator of disease progression in virus positive patients.

[Merkel cell carcinoma]. / Merkel-Zell-Karzinom.

Merkel cell carcinoma is a rare aggressive malignant neuroendocrine skin tumor, which can metastasize to lymph nodes early and often shows local recurrence. The prognosis depends on tumor size and disease stage. The majority of recurrences appear during the first 2 years after the primary diagnosis. The 5-year survival rate for primary tumor < 2 cm is 66-75 % and for primary tumors > 2 cm is 50-60 %. With lymph node metastases the 5-year survival rate is 42-52 %, while with distant metastases it drops to 17-12 %. Extensive staging inclusive sentinel lymph node biopsy is essential to assess the risk for distant metastasis and to allow the best recommendations for therapy. After surgical treatment with adequate safety margin, subsequent adjuvant radiation therapy of the tumor region and lymphatic draining basin is recommended to reduce the risk of local recurrence and lymphatic spread.

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine.

BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.

Two cases of lupus vulgaris in childhood and review of the clinical challenges.

BACKGROUND: Lupus vulgaris (LV) is the most common form of cutaneous tuberculosis (TB) in Europe, nevertheless the overall incidence is low. It constitutes about 1.5% of all extra-pulmonary cases worldwide. A slight raise in TB incidence rates among children was recently registered in Germany, which can be explained by the increased immigration. PATIENTS AND METHODS: We present 2 cases of immigrated children who were diagnosed with Lupus vulagris, both clinically and histopathologically. Although the symptoms and the duration of the skin lesions were very different, both patients had a non-healing skin ulceration.In our cases cultures of the skin biopsy were positive for Mycobacterium tuberculosis and the lesions showed marked improvement in response to antituberculous treatment. In the first patient, it took 6 years between occurrence of skin lesions and final diagnosis. The second patient had an extracutaneous focus, namely abdominal TB. CONCLUSION: We report our experience and emphasize on recent advances in the diagnosis and treatment of paediatric skin TB.

Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential.

Expression of the EMT-inducing transcription factor Snail is enhanced in different human cancers. To investigate the in vivo role of Snail during progression of epithelial cancer, we used a mouse model with skin-specific overexpression of Snail. Snail transgenic mice spontaneously developed distinct histological subtypes of skin cancer, such as basal cell carcinoma, squamous cell carcinoma and sebaceous gland carcinoma. Development of sebaceous gland carcinomas strongly correlated with the direct and complete repression of Blimp-1, a central regulator of sebocyte homeostasis. Snail expression in keratinocyte stem cells significantly promotes their proliferation associated with an activated FoxM1 gene expression signature, resulting in a larger pool of Mts24-marked progenitor cells. Furthermore, primary keratinocytes expressing Snail showed increased survival and strong resistance to genotoxic stress. Snail expression in a skin-specific p53-null background resulted in accelerated formation of spontaneous tumours and enhanced metastasis. Our data demonstrate that in vivo expression of Snail results in de novo epithelial carcinogenesis by allowing enhanced survival, expansion of the cancer stem cell pool with accumulated DNA damage, a block in terminal differentiation and increased proliferation rates of tumour-initiating cells.

The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas.

The incidence of skin cancer is increasing worldwide and cutaneous squamous cell carcinomas (SCCs) are associated with considerable morbidity and mortality, particularly in immunosuppressed individuals ('carcinomatous catastrophy'). Yet, molecular mechanisms are still insufficiently understood. Besides ultraviolet (UV)-indicative mutations, chromosomal aberrations are prominent. As telomeres are essential in preserving chromosome integrity, and telomere erosion as well as aberrant spatial telomere distribution contribute to genomic instability, we first established telomere length profiles across the whole tissue and identified normal skin (10/30) harboring discrete epidermal sites (stem cell territories) of evenly short telomeres. Precancerous actinic keratoses (AKs) (17) and SCCs (27) expressed two telomere phenotypes: (i) tissue-wide evenly short to intermediate and (ii) longer and tissue-wide heterogeneous telomere lengths, suggesting two modes of initiation, with one likely to originate in the epidermal stem cells. Although tumor histotype, location, patient gender or age failed to distinguish the two SCC telomere phenotypes, as did telomerase activity, we found a trend for a higher degree of aberrant p53 and cyclin D1 expression with long/heterogeneous telomeres. In addition, we established an association for the short/homogeneous telomeres with a simpler and the heterogeneous telomeres with a more complex karyotype correlating also with distinct chromosomal changes. SCCs (13) from renal transplant recipients displayed the same telomere dichotomy, suggesting that both telomere subtypes contribute to 'carcinomatous catastrophy' under immunosuppression by selecting for a common set (3, 9p and 17q) and subtype-specific aberrations (e.g., 6p gain, 13q loss). As a second mechanism of telomere-dependent genomic instability, we investigated changes in telomere distribution with its most severe form of telomeric aggregates (TAs). We identified a telomere length-independent but progression-dependent increase in cells with small telomere associations in AKs (17/17) and additional TAs in SCCs (24/32), basal cell carcinomas (30/31) and malignant melanomas (15/15), and provide evidence for a reactive oxygen species-dependent mechanism in this UV-induced telomere organization-dependent genomic instability.

Assessment of clinical parameters associated with mutational status in metastatic malignant melanoma: a single-centre investigation of 141 patients.

BACKGROUND: Inhibitors of the mutated, constitutively activated BRAF protein have shown efficacy in the treatment of metastatic melanoma in clinical trials. Mutation analysis especially of the BRAF, NRAS and KIT genes is essential to identify patients suitable for targeted therapies and has been introduced into routine patient care. OBJECTIVES: To correlate mutational status with clinical parameters including age, skin type, number of melanocytic naevi, primary tumour location, chronic sun damage and exposure to ultraviolet (UV) irradiation. The overall aim was to define subgroups with an increased or decreased likelihood of gene mutations. Additionally, the impact of activating BRAF mutations on clinical course was investigated. METHODS: In a single-centre, retrospective approach, mutation analysis was performed on patients with metastatic malignant melanoma. Clinical parameters were correlated with molecular findings. The total sun-burden score was assessed using a validated standardized questionnaire. RESULTS: The analysis included 141 patients with metastatic melanoma. Forty-four per cent of patients had activating BRAF mutations and were significantly younger than patients with wild-type BRAF or with NRAS mutations. KIT mutations were detected in only 3% of the patients. BRAF-mutated melanomas developed preferentially in intermittently sun-exposed areas of the body, and patients had significantly more melanocytic naevi. Once patients had progressed into stage IV disease, survival times were identical for those with BRAF-mutated and BRAF wild-type tumours. CONCLUSIONS: Mutations of the BRAF gene are correlated with younger age, a higher number of melanocytic naevi and a tumour location in intermittently UV-exposed skin. Signs of chronic photodamage are not indicative of mutational status. Patients with metastatic melanoma with BRAF mutations showed a nonsignificant tendency to progress later to stage IV disease, but once metastases were present the prognosis was identical to that with BRAF wild-type tumours.

[Personalized therapy concepts for malignant melanoma]. / Personalisierte Therapiekonzepte beim malignen Melanom.

Metastatic melanoma is commonly regarded as one of the most difficult tumor entities to treat. Up to 2011 no systemic therapy had been able to achieve a prolongation of overall survival in controlled randomized trials. Cytotoxic chemotherapy resulted in objective remission in only a small subgroup of patients. The growing insight into the molecular pathology and the discovery of frequent mutations made it possible to define melanoma subgroups suitable for targeted therapies. In approximately 50% of melanomas activating mutations of the BRAF gene were identified and can be treated with specific inhibitors. Further mutations which can be approached by targeted therapies are found on the c-Kit and NRAS genes. Another promising approach is immunotherapy aimed to activate cytotoxic T cells. A monoclonal antibody directed against CTLA-4 was approved after convincing results in clinical trials and antibodies against PD-1 or PD-L1 are currently under clinical investigation. Through these achievements life prolonging therapies are available for melanoma patients for the first time.

Successful Treatment of a Panniculitis-Like Primary Cutaneous T-Cell Lymphoma of the α/ß Type with Bexarotene.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) of the α/ß type is a rare subtype of non-Hodgkin's lymphoma of the skin. Although these tumors usually run an indolent course, disease-related morbidity is often severe. Clinical findings include subcutaneous tumors located on the extremities or trunk, often accompanied by systemic symptoms like fever or fatigue. Due to the low incidence of SPTL, no standardized therapy has been defined so far and there is currently no curative therapy available for this type of non-Hodgkin's lymphoma. By sharing our experience with bexarotene therapy, we present a safe and potentially improved treatment for patients with SPTL. In the case presented, bexarotene was able to induce remission even after recurrence of disease.