Dirk Schadendorf

Publications of Dirk Schadendorf

• Side effects of systemic oncological therapies in dermatology.

  Authors: Lisa Zimmer, Julia Vaubel, Elisabeth Livingstone, Dirk Schadendorf

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 05/2012;

  The discovery of specific gene mutations, termed "driver mutations", in different tumors has brought personalized medicine into the focus of cancer treatment. Targeted treatment agents generally areThe discovery of specific gene mutations, termed "driver mutations", in different tumors has brought personalized medicine into the focus of cancer treatment. Targeted treatment agents generally are administered orally and have a tolerable adverse event profile; they have become widely used in both inpatient and outpatient settings. The approval of the selective BRAF inhibitor vemurafenib (Zelboraf®) as first-line therapy of metastatic melanoma in Europe in February 2012 as well as the increasing use of MEK inhibitors within clinical trials confronts dermatologists and oncologists with a new spectrum of side effects. Knowledge of these possible adverse events and their management will be crucial for optimized patient care. This article offers an overview of the most important adverse events of currently employed dermato-oncologic therapeutic agents.

• Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis.

  Authors: Benjamin Weide, Henning Zelba, Evelyna Derhovanessian, Annette Pflugfelder, Thomas K Eigentler, Anna Maria Di Giacomo, Michele Maio, Erik H J G Aarntzen, I Jolanda M de Vries, Antje Sucker, Dirk Schadendorf, Petra Büttner, Claus Garbe, Graham Pawelec

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 04/2012;

  PURPOSETo analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. PATIENTS AND METHODSWePURPOSETo analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. PATIENTS AND METHODSWe examined 84 patients with follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen-reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation.ResultsIn cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan-A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months. CONCLUSIONThe presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.

• Current advances and perspectives in the treatment of advanced melanoma.

  Authors: Elisabeth Livingstone, Lisa Zimmer, Julia Vaubel, Dirk Schadendorf

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 03/2012;

  Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellentMelanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.

• Panniculitis With Arthralgia in Patients With Melanoma Treated With Selective BRAF Inhibitors and Its Management.

  Authors: Lisa Zimmer, Elisabeth Livingstone, Uwe Hillen, Stephanie Dömkes, Arne Becker, Dirk Schadendorf

  Archives of dermatology. 01/2012;

  BACKGROUND: Painful lobular panniculitis appears to be a novel cutaneous adverse effect of selective BRAF inhibitors. Observation We report the clinical course and management in 2 women withBACKGROUND: Painful lobular panniculitis appears to be a novel cutaneous adverse effect of selective BRAF inhibitors. Observation We report the clinical course and management in 2 women with metastatic melanomas harboring the BRAF(V600E) mutation, who developed panniculitis with arthralgia during therapy with selective oral BRAF inhibitors. Panniculitis with arthralgia was the acute presenting adverse effect in both patients. Painful, red, nodular lesions were located on the upper and lower extremities. Biopsy specimens of the nodules showed a mild, predominantly lobular neutrophilic panniculitis. Analgesic and anti-inflammatory treatment improved panniculitis and arthralgia in both cases. It was also necessary to reduce the BRAF inhibitor dose in 1 patient. CONCLUSIONS: During therapy with selective BRAF inhibitors, panniculitis with arthralgia represents a new adverse effect that can require dose reduction. In case of this adverse effect, treatment with nonsteroidal anti-inflammatory drugs, such as etoricoxib, should be initiated early to keep patients on treatment and to avoid drug discontinuation and tumor progression.

• Fluoreszenz-Markierung mittels Indocyanin-Grün bei der Sentinel-Lymphknoten-Exstirpation in der Dermatoonkologie.

  Authors: Ingo Stoffels, Hannah von der Stück, Christian Boy, Thorsten Pöppel, Nina Körber, Maren Weindorf, Joachim Dissemond, Dirk Schadendorf, Joachim Klode

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 01/2012; 10(1):51-8.

• pHH3 Immunostaining Improves Interobserver Agreement of Mitotic Index in Thin Melanomas.

  Authors: Tobias T Schimming, Florian Grabellus, Mathias Roner, Sonali Pechlivanis, Antje Sucker, Nicola Bielefeld, Iris Moll, Dirk Schadendorf, Uwe Hillen

  The American Journal of dermatopathology. 12/2011;

  According to the seventh edition of the American Joint Committee on Cancer guidelines, the TNM staging category in thin cutaneous melanomas depends on the mitotic rate (MR). In this study, we analyzeAccording to the seventh edition of the American Joint Committee on Cancer guidelines, the TNM staging category in thin cutaneous melanomas depends on the mitotic rate (MR). In this study, we analyze the interobserver agreement of the MR in a series of 92 thin cutaneous melanomas. Serial sections of the tumors were either stained with hematoxylin and eosin or immunohistochemically stained with pHH3, an antibody for phosphohistone H3, and analyzed by 4 observers. Determination of MR with pHH3 immunostaining resulted in higher sensitivity in counting mitosis for all observers. Moreover, interobserver agreement was higher with pHH3. Immunostaining with pHH3 is a sensitive method to detect mitosis in thin cutaneous melanomas, with good reproducibility of MR between independent observers. Further studies are needed to find out if higher sensitivity in the detection of mitosis by pHH3 immunostaining has additional prognostic relevance.

• Integrin genes and susceptibility to human melanoma.

  Authors: Romina E Lenci, P Sivaramakrishna Rachakonda, Andriy V Kubarenko, Alexander N R Weber, Andreas Brandt, Andreas Gast, Antje Sucker, Kari Hemminki, Dirk Schadendorf, Rajiv Kumar

  Mutagenesis. 12/2011;

  Integrins are transmembrane adhesion molecules that mediate cell-cell and cell-extracellular matrix attachment. Integrins regulate cell growth, proliferation, migration and apoptosis and as aIntegrins are transmembrane adhesion molecules that mediate cell-cell and cell-extracellular matrix attachment. Integrins regulate cell growth, proliferation, migration and apoptosis and as a consequence, can have a potential role in tumour progression and metastasis. In this study, we investigated 19 non-synonymous variants in the coding region of the human integrin genes representing 3 beta subunits and 13 alpha subunits, for their potential role in melanoma susceptibility and survival. The variants were selected on the basis of probable functional relevance and theoretical predictions. Our data showed that no genetic variant was significantly associated with survival. However, the variants in ITGA10 and ITGA6 genes showed association with decreased risk, and variants in ITGA2, ITGAE and ITGAM were associated with increased risk of melanoma. The haplotype analysis revealed association of CA haplotype of ITGAE and TAC haplotype of ITGAX with the risk modulation. A prediction analysis of functional effect, homology modelling and multiple sequence alignments of integrin sequences from different species supported our data for linkage of variants in the ITGA2 and ITGAE genes with susceptibility. The amino acid changes in each of these integrin proteins could affect intramolecularly and/or the interaction of the heterodimers. Our experimental data indicated a possible role for some of the variant alleles and/or haplotypes of the integrin genes in melanoma susceptibility, which is augmented by the theoretical analysis performed.

• Prospective evaluation of supportive care with or without CVD chemotherapy as a second-line treatment in advanced melanoma by patient's choice: a multicentre Dermatologic Cooperative Oncology Group trial.

  Authors: Maja A Hofmann, Axel Hauschild, Peter Mohr, Claus Garbe, Michael Weichenthal, Uwe Trefzer, Ulrike Drecoll, Wolfgang Tilgen, Dirk Schadendorf, Martin Kaatz, Jens Ulrich

  Melanoma research. 12/2011; 21(6):516-23.

  This prospective, nonrandomized multicentre, phase III study compared best supportive care (BSC) alone with cisplatin, vindesine and dacabazine-based (CVD) chemotherapy and BSC in patients withThis prospective, nonrandomized multicentre, phase III study compared best supportive care (BSC) alone with cisplatin, vindesine and dacabazine-based (CVD) chemotherapy and BSC in patients with advanced melanoma. A total of 117 pretreated patients with metastatic melanoma were evaluated, 34 patients in arm A (BSC) and 83 in arm B (BSC and CVD). Primary endpoint was overall survival and secondary endpoints were disease control rate and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30). Owing to sparse recruitment of patients for randomization, the protocol has been changed based on patients' choice. Baseline characteristics were imbalanced with respect to the Karnofsky Performance Index (P=0.001), the existence of brain metastases (P=0.035) and earlier application of chemoimmunotherapy (P=0.038). Disease control was observed in 8.8% of patients in arm A and in 28.9% of patients in arm B (P=0.028). Median overall survival time was 137 days in arm A and 229 days in arm B (P=0.014). Multivariate analyses could not ascribe this prognostic benefit to CVD treatment. No significant difference in the quality of life could be found. This study could not detect clear survival benefits for polychemotherapy with CVD compared with BSC alone in patients with advanced metastatic melanoma. Interestingly, having the choice of chemotherapy or BSC alone in a second-line situation, more than 70% of patients chose polychemotherapy.

• Indocyanine green fluorescence-guided sentinel lymph node biopsy in dermato-oncology.

  Authors: Ingo Stoffels, Hannah von der Stück, Christian Boy, Thorsten Pöppel, Nina Körber, Maren Weindorf, Joachim Dissemond, Dirk Schadendorf, Joachim Klode

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 11/2011; 10(1):51-7.

  Sentinel lymph node biopsy (SLNB) for cutaneous malignancies usually carried out with radioactive nanocolloids (Tc-99m). The SLNE is controversially discussed internationally. This is especiallySentinel lymph node biopsy (SLNB) for cutaneous malignancies usually carried out with radioactive nanocolloids (Tc-99m). The SLNE is controversially discussed internationally. This is especially given to the high false-negative rate up to 44 %. An alternative could be the fluorescent dye indocyanine green (ICG). We investigated the advantage of intraoperative fluorescence detection of lymphatic vessels and SLN with a Near-Infrared (NIR) camera in comparison to conventional methods using preoperative lymphoscintigraphy and SPECT/CT in 22 patients with malignant melanoma. A total of 61 SLNs were removed in 22 operative procedures. In 7 SLN (10.3 %; 7/68) the histopathological assessment could demonstrate a metasta-tic involvement. 11 additional SLN (19.1 %) in 8 patients were only identified using the fluorescent labeling. Two of these additional SLN (9.1 %; 2/22) showed metastatic involvement. The ICG fluorescence-guided SLNB is an innovative imaging technique for dermato-oncology, reliable and providing additional information in the detection of SLN. Therefore SLNB with fluorescence-dye is an attractive option with intraoperative real-time lymphoscintigraphy to improve the detection of SLN in cutaneous malignancies and potential reduction of the false negative rate in SLN.

• Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D.

  Authors: Anja Heinemann, Fang Zhao, Sonali Pechlivanis, Jürgen Eberle, Alexander Steinle, Sven Diederichs, Dirk Schadendorf, Annette Paschen

  Cancer research. 11/2011; 72(2):460-71.

  Malignant cells express ligands for the natural killer cell immunoreceptor NKG2D, which sensitizes to early recognition and elimination by cytotoxic lymphocytes and provides an innate barrier againstMalignant cells express ligands for the natural killer cell immunoreceptor NKG2D, which sensitizes to early recognition and elimination by cytotoxic lymphocytes and provides an innate barrier against tumor development. However, the mechanisms that control NKG2D ligand (NKG2DL) expression in tumor cells remain unknown. We recently identified the NKG2DL ULBP2 as strong prognostic marker in human malignant melanoma. Here, we provide evidence that the tumor-suppressive microRNAs (miRNA) miR-34a and miR-34c control ULBP2 expression. Reporter gene analyses revealed that both miRNAs directly targeted the 3'-untranslated region of ULBP2 mRNA and that levels of miR-34a inversely correlated with expression of ULBP2 surface molecules. Accordingly, treatment of cancer cells with miRNA inhibitors led to upregulation of ULBP2, whereas miR-34 mimics led to downregulation of ULBP2, diminishing tumor cell recognition by NK cells. Treatment with the small molecule inhibitor Nutlin-3a also decreased ULBP2 levels in a p53-dependent manner, which was due to a p53-mediated increase in cellular miR-34 levels. Taken together, our study shows that tumor-suppressive miR-34a and miR-34c act as ULBP2 repressors. These findings also implicate p53 in ULBP2 regulation, emphasizing the role of the specific NKG2DL in tumor immune surveillance.

• RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors.

  Authors: Patrick A Oberholzer, Damien Kee, Piotr Dziunycz, Antje Sucker, Nyam Kamsukom, Robert Jones, Christine Roden, Clinton J Chalk, Kristin Ardlie, Emanuele Palescandolo, Adriano Piris, Laura E MacConaill, Caroline Robert, Günther F L Hofbauer, Grant A McArthur, Dirk Schadendorf, Levi A Garraway

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2011; 30(3):316-21.

  RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promoteRAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1%; immunosuppression, 18.9%; and spontaneous, 17.6%; P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.

• Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991.

  Authors: Alexander M M Eggermont, Stefan Suciu, Alessandro Testori, Wim H Kruit, Jeremy Marsden, Cornelis J Punt, Mario Santinami, François Salès, Dirk Schadendorf, Poulam Patel, Reinhard Dummer, Caroline Robert, Ulrich Keilholz, Antoine Yver, Alan Spatz

  European journal of cancer (Oxford, England : 1990). 11/2011; 48(2):218-25.

  Adjuvant interferon has modest activity in melanoma patients at high risk for relapse. Patient selection is important; stage and ulceration of the primary tumour are key prognostic factors. In thisAdjuvant interferon has modest activity in melanoma patients at high risk for relapse. Patient selection is important; stage and ulceration of the primary tumour are key prognostic factors. In this post hoc meta-analysis of European Organisation for Research and Treatment of Cancer (EORTC) trials 18952 (intermediate doses of interferon α-2b [IFN] versus observation in stage IIb-III patients) and 18991 (pegylated [PEG]-IFN versus observation in stage III patients), the predictive value of ulceration on the efficacy of IFN/PEG-IFN with regard to relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) was assessed in the overall population and in subgroups stratified by stage (IIb and III-N1 [microscopic nodal disease] and III-N2 [macroscopic nodal disease]). In the overall population, the comparison of IFN/PEG-IFN versus observation for RFS, DMFS and OS yielded estimated hazard ratios (HR) of 0.85 (p = 0.004), 0.89 (p = 0.04) and 0.94 (p = 0.36), respectively. The impact of treatment was greater in the ulceration group (n = 849) compared with the non-ulceration group (n = 1336) for RFS (test for interaction: p = 0.02), DMFS (p < 0.001) and OS (p < 0.001). The greatest risk reductions were observed in patients with ulceration and stage IIb/III-N1, with estimated HR for RFS, DMFS, and OS of 0.69 (p = 0.003), 0.59 (p < 0.0001) and 0.58 (p < 0.0001), respectively. The efficacy of IFN/PEG-IFN was lower in stage III-N2 patients with ulceration and uniformly absent in patients without ulceration. There was consistency between the data of both trials. This meta-analysis of the EORTC 18952 and 18991 trials indicated that both tumour stage and ulceration were predictive factors for the efficacy of adjuvant IFN/PEG-IFN therapy.

• Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.

  Authors: Christiane Meyer, Alexandra Sevko, Marcel Ramacher, Alexandr V Bazhin, Christine S Falk, Wolfram Osen, Ivan Borrello, Masashi Kato, Dirk Schadendorf, Michal Baniyash, Viktor Umansky

  Proceedings of the National Academy of Sciences of the United States of America. 10/2011; 108(41):17111-6.

  Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated withTumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

• Nodöse Scabies: Hypersensitivitätsreaktion oder Infektion?

  Authors: Johanna Christina Czeschik, Lisa Huptas, Dirk Schadendorf, Uwe Hillen

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 10/2011; 9(10):840-1.

• Mucosal melanomas of the head and neck: new aspects of the clinical outcome, molecular pathology, and treatment with c-kit inhibitors.

  Authors: Giorgios Papaspyrou, Claus Garbe, Dirk Schadendorf, Jochen A Werner, Axel Hauschild, Friederike Egberts

  Melanoma research. 09/2011; 21(6):475-82.

  Approximately 50% of mucosal melanomas affect the head and neck region representing approximately 9% of all malignant head and neck tumors. The pathogenesis of this disease is unknown. MucosalApproximately 50% of mucosal melanomas affect the head and neck region representing approximately 9% of all malignant head and neck tumors. The pathogenesis of this disease is unknown. Mucosal melanomas are characterized by an aggressive biological behavior, leading to a 5-year survival rate of less than 25%. Data for this review were identified by searches of Medline, Current Contents, PubMed, and references from relevant articles using the terms 'mucosal melanoma,' 'head and neck melanoma,' 'c-kit mutation in melanoma,' and 'c-kit inhibitors'. Therapy aims for the complete surgical excision of the primary tumor, whereas sentinel node biopsy is not established and present data do not support the addition of radiotherapy. Mutilating operations of larger tumors should be avoided, as they do not inhibit the frequent development of distant metastasis. C-kit mutations and amplifications are found in approximately 15-30% of mucosal and acral-lentiginous melanomas. Therefore, the use of so-called targeted therapies addressing molecular structures in mucosal melanomas seem to represent new promising treatment tools. In this study, we review the literature regarding epidemiology, molecular pathology, and therapy of mucosal melanomas of the head and neck emphasizing c-kit protein inhibiting treatment modalities for tumors carrying c-kit mutations.

• Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma.

  Authors: Khelifa Arab, Laura T Smith, Andreas Gast, Dieter Weichenhan, Joseph Po-Hsien Huang, Rainer Claus, Thomas Hielscher, Allan V Espinosa, Matthew D Ringel, Carl D Morrison, Dirk Schadendorf, Rajiv Kumar, Christoph Plass

  Carcinogenesis. 07/2011; 32(10):1467-73.

  Metastatic melanoma is a fatal disease due to the lack of successful therapies and biomarkers for early detection and its incidence has been increasing. Genetic studies have defined recurrentMetastatic melanoma is a fatal disease due to the lack of successful therapies and biomarkers for early detection and its incidence has been increasing. Genetic studies have defined recurrent chromosomal aberrations, suggesting the location of either tumor suppressor genes or oncogenes. Transcription factor 21 (TCF21) belongs to the class A of the basic helix-loop-helix family with reported functions in early lung and kidney development as well as tumor suppressor function in the malignancies of the lung and head and neck. In this study, we combined quantitative DNA methylation analysis in patient biopsies and in their derived cell lines to demonstrate that TCF21 expression is downregulated in metastatic melanoma by promoter hypermethylation and TCF21 promoter DNA methylation is correlated with decreased survival in metastatic skin melanoma patients. In addition, the chromosomal location of TCF21 on 6q23-q24 coincides with the location of a postulated metastasis suppressor in melanoma. Functionally, TCF21 binds the promoter of the melanoma metastasis-suppressing gene, KiSS1, and enhances its gene expression through interaction with E12, a TCF3 isoform and with TCF12. Loss of TCF21 expression results in loss of KISS1 expression through loss of direct interaction of TCF21 at the KISS1 promoter. Finally, overexpression of TCF21 inhibits motility of C8161 melanoma cells. These data suggest that epigenetic downregulation of TCF21 is functionally involved in melanoma progression and that it may serve as a biomarker for aggressive tumor behavior.

• Nodular scabies: hypersensitivity reaction or infection?

  Authors: Johanna Christina Czeschik, Lisa Huptas, Dirk Schadendorf, Uwe Hillen

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 07/2011; 9(10):840-1.

• Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032).

  Authors: Poulam M Patel, Stefan Suciu, Laurent Mortier, Wim H Kruit, Caroline Robert, Dirk Schadendorf, Uwe Trefzer, Cornelis J A Punt, Reinhard Dummer, Neville Davidson, Juergen Becker, Robert Conry, John A Thompson, Wen-Jen Hwu, Kristel Engelen, Sanjiv S Agarwala, Ulrich Keilholz, Alexander M M Eggermont, Alain Spatz

  European journal of cancer (Oxford, England : 1990). 07/2011; 47(10):1476-83.

  To compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. A total of 859 patients wereTo compare the efficacy of an extended schedule escalated dose of temozolomide versus standard dose dacarbazine in a large population of patients with stage IV melanoma. A total of 859 patients were randomised to receive oral temozolomide at 150 mg/m(2)/day for seven consecutive days every 2 weeks or dacarbazine, administered as an intravenous infusion at 1000 mg/m(2)/day on day 1 every 3 weeks. The primary endpoint was overall survival (OS), using an intent-to-treat principle. EudraCT number 2004-000654-23 NCI registration number NCT00005052. Median OS was 9.1 months in the temozolomide arm and 9.4 months in the dacarbazine arm, with a hazard ratio (HR) of 1.00 (95%confidence interval [CI]: 0.86, 1.17; P=0.99). Median progression-free survival (PFS) was 2.3 months in the temozolomide arm and 2.2 months in the dacarbazine arm, with a HR of 0.92 (95%CI: 0.80, 1.06; P=0.27). In patients with measurable disease, overall response rate was higher in the temozolomide arm than in the dacarbazine arm (14.5% versus 9.8%, respectively), but the median duration of response was longer for dacarbazine. The extended schedule, escalated dose temozolomide arm showed more toxicity than the standard dose, single agent dacarbazine arm. The most common non-haematological treatment emergent adverse events reported in both treatment arms were nausea, fatigue and vomiting and constipation. Extended schedule escalated dose Temozolomide (7 days on 7 days off) is feasible and has an acceptable safety profile, but does not improve OS and PFS in metastatic melanoma when compared to standard dose dacarbazine.

• Behavioural conditioning as the mediator of placebo responses in the immune system.

  Authors: Sabine Vits, Elvir Cesko, Paul Enck, Uwe Hillen, Dirk Schadendorf, Manfred Schedlowski

  Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 06/2011; 366(1572):1799-807.

  Current placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response. Behaviourally conditioned changes in peripheral immune functions have beenCurrent placebo research postulates that conditioning processes are one of the major mechanisms of the placebo response. Behaviourally conditioned changes in peripheral immune functions have been demonstrated in experimental animals, healthy subjects and patients. The physiological mechanisms responsible for this 'learned immune response' are not yet fully understood, but some relevant afferent and efferent pathways in the communication between the brain and the peripheral immune system have been identified. In addition, possible benefits and applicability in clinical settings have been demonstrated where behaviourally conditioned immunosuppression attenuated the exacerbation of autoimmune diseases, prolonged allograft survival and affected allergic responses. Here, we summarize data describing the mechanisms and the potential clinical benefit of behaviourally conditioned immune functions, with particular focus on learned placebo effects on allergic reactions.

• Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

  Authors: Paul B Chapman, Axel Hauschild, Caroline Robert, John B Haanen, Paolo Ascierto, James Larkin, Reinhard Dummer, Claus Garbe, Alessandro Testori, Michele Maio [......] John M Kirkwood, Alexander M M Eggermont, Brigitte Dreno, Keith Nolop, Jiang Li, Betty Nelson, Jeannie Hou, Richard J Lee, Keith T Flaherty, Grant A McArthur

  The New England journal of medicine. 06/2011; 364(26):2507-16.

  Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. WePhase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).