Reinhard Dummer

Publications (255)1413.13 Total impact

• Article: Brief S2k guidelines - Cutaneous lymphomas.

  Rudolf Stadler, Chalid Assaf, Claus-Detlev Klemke, Dorothee Nashan, Michael Weichenthal, Reinhard Dummer, Wolfram Sterry
  Journal der Deutschen Dermatologischen Gesellschaft 06/2013; 11 Suppl 3:19-28. · 1.47 Impact Factor
• Article: S2k kurzleitlinie - kutane lymphome.

  Rudolf Stadler, Chalid Assaf, Claus-Detlev Klemke, Dorothee Nashan, Michael Weichenthal, Reinhard Dummer, Wolfram Sterry
  Journal der Deutschen Dermatologischen Gesellschaft 06/2013; 11 Suppl 3:20-30. · 1.47 Impact Factor
• Article: Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study.

  Caroline Robert, Reinhard Dummer, Ralf Gutzmer, Paul Lorigan, Kevin B Kim, Marta Nyakas, Ana Arance, Gabriella Liszkay, Dirk Schadendorf, Mireille Cantarini, Stuart Spencer, Mark R Middleton
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  ABSTRACT: BACKGROUND: Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. METHODS: This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. FINDINGS: Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2-15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6-14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67-1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47-0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9-5·9) versus 3·0 months (2·8-4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). INTERPRETATION: Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. FUNDING: AstraZeneca.
  The lancet oncology 05/2013; · 14.47 Impact Factor
• Article: Basal cell carcinoma: a paradigm for targeted therapies.

  Jil Dreier, Lea Felderer, Marjam Barysch, Sima Rozati, Reinhard Dummer
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  ABSTRACT: Introduction: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012. Areas covered: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials. Expert opinion: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary.
  Expert Opinion on Pharmacotherapy 05/2013; · 3.20 Impact Factor
• Article: Hypoxia contributes to melanoma heterogeneity by triggering HIF1α-dependent phenotype switching.

  Daniel S Widmer, Keith S Hoek, Phil F Cheng, Ossia M Eichhoff, Thomas Biedermann, Marieke I G Raaijmakers, Silvio Hemmi, Reinhard Dummer, Mitchell P Levesque
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  ABSTRACT: We have previously reported a model for melanoma progression in which oscillation between melanoma cell phenotypes characterized by invasion or proliferation is fundamental to tumor heterogeneity and disease progression ADDIN EN.CITE ADDIN EN.CITE.DATA (Hoek et al., 2006). In this study we examine the possible role of hypoxia as one of the microenvironmental influences driving metastatic progression by promoting a switch from a proliferative to an invasive phenotype. Immunohistochemistry on primary human cutaneous melanoma biopsies showed intratumoral heterogeneity for cells expressing melanocytic markers, and a loss of these markers correlated to hypoxic regions. Furthermore, we show that the down-regulation of melanocytic markers is dependent on HIF1α, a known regulator of the hypoxic response. In vitro invasion assays showed that a hypoxic environment increases the invasiveness of proliferative melanoma cell cultures in a HIF1α-dependent manner. In contrast, invasive phenotype melanoma cells showed no increase in invasive potential upon exposure to hypoxia. Thus, exposure of proliferative melanoma cells to hypoxic microenvironments is sufficient, in a HIF1α-dependent manner, to down-regulate melanocytic marker expression and increase their invasive potential.Journal of Investigative Dermatology accepted article preview online, 8 March 2013; doi:10.1038/jid.2013.115.
  Journal of Investigative Dermatology 03/2013; · 6.31 Impact Factor
• Article: Aldara activates TLR7-independent immune defence.

  Anne Walter, Matthias Schäfer, Virginia Cecconi, Claudia Matter, Mirjana Urosevic-Maiwald, Benedetta Belloni, Nicola Schönewolf, Reinhard Dummer, Wilhelm Bloch, Sabine Werner, Hans-Dietmar Beer, Alexander Knuth, Maries van den Broek
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  ABSTRACT: Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.
  Nature Communications 03/2013; 4:1560. · 7.40 Impact Factor
• Article: MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study.

  Paolo A Ascierto, Dirk Schadendorf, Carola Berking, Sanjiv S Agarwala, Carla Ml van Herpen, Paola Queirolo, Christian U Blank, Axel Hauschild, J Thaddeus Beck, Annie St-Pierre, Faiz Niazi, Simon Wandel, Malte Peters, Angela Zubel, Reinhard Dummer
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  ABSTRACT: Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma. In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. Novartis Pharmaceuticals.
  The lancet oncology 03/2013; 14(3):249-56. · 14.47 Impact Factor
• Article: Dermatofibrosarcoma Protuberans in Childhood Treated with Slow Mohs Micrographic Surgery.

  Marjam J Barysch, Lisa Weibel, Kathrin Neuhaus, Ulrike Subotic, Leo Schärer, Davide Donghi, Juerg Hafner, Ralph Braun, Severin Läuchli, Reinhard Dummer, Clemens Schiestl
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  ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) in childhood is a rare tumor with high recurrence rates. Wide local excision can result in disfiguring mutilation, whereas Mohs micrographic surgery (MMS) reduces surgical margins. MMS in children is not performed routinely, as the required infrastructures such as a histopathology lab in close proximity to the operating room is often lacking. We retrospectively reviewed children diagnosed with DFSP treated at our hospital over 2 years. We recorded surgical treatment details, including margins, duration of inpatient stay, outcome, follow-up, and molecular genetic tumor tissue analysis. Four children with a median age of 6.8 years (range 6.0-8.8 years) were identified who had a diagnostic delay of a median of 2.5 years (range 0.5-4.0 years); all underwent complete tumor excision using the slow MMS technique using vacuum-assisted closure systems between repeated excisions and before wound closure. The median maximal safety margins were 1.5 cm (range 1.0-3.0 cm). By using vacuum-assisted closure systems, no dressing changes were needed, pain was limited, and full mobility was maintained in all children. The median total time in the hospital was 11 days (range 10-14 days). No relapses occurred during a median follow-up of 25.8 months (range 11.3-32.6 months). Collagen 1A1/platelet-derived growth factor B (COL1A1/PDGFB) translocation on chromosomes 17 and 22 was detected in all three analyzable specimens. Lesions suspected of being DFSP warrant prompt histologic evaluation; interdisciplinary management is mandatory in particular for children. Micrographic surgery allows smaller surgical margins than wide excision and should be considered as the treatment of choice in children with DFSP. The interim usage of vacuum-assisted closure systems increases patient comfort. Translocations in the COL1A1/PDGFB gene imply susceptibility to targeted treatment modalities for therapy-resistant cases.
  Pediatric Dermatology 02/2013; · 1.07 Impact Factor
• Article: Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: Detailed safety analysis from a phase 3 trial in patients with advanced melanoma.

  Jeffrey S Weber, Reinhard Dummer, Veerle de Pril, Celeste Lebbé, F Stephen Hodi
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  ABSTRACT: BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010-20). Ipilimumab produced a characteristic spectrum of immune-related adverse events (irAEs) of special interest, consistent with its immune-based mechanism of action. METHODS: In MDX010-20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy. RESULTS: Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks. CONCLUSIONS: Most ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Cancer 2013;. © 2013 American Cancer Society.
  Cancer 02/2013; · 4.77 Impact Factor
• Article: Melanoma immunotherapy: historical precedents, recent successes and future prospects.

  Marieke Ig Raaijmakers, Sima Rozati, Simone M Goldinger, Daniel S Widmer, Reinhard Dummer, Mitchell P Levesque
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  ABSTRACT: The idea of cancer immunotherapy has been around for more than a century; however, the first immunotherapeutic ipilimumab, an anti-CTLA-4 antibody, has only recently been approved by the US FDA for melanoma. With an increasing understanding of the immune response, it is expected that more therapies will follow. This review aims to provide a general overview of immunotherapy in melanoma. We first explain the development of cancer immunotherapy more than a century ago and the general opinions about it over time. This is followed by a general overview of the immune reaction in order to give insight into the possible targets for therapy. Finally, we will discuss the current therapies for melanoma, their shortcomings and why it is important to develop patient stratification criteria. We conclude with an overview of recent discoveries and possible future therapies.
  Immunotherapy 02/2013; 5(2):169-82. · 1.85 Impact Factor
• Source

  Available from: Dirk Schadendorf

  Article: The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network

  Caroline J. Voskens, Simone M. Goldinger, Carmen Loquai, Caroline Robert, Katharina C. Kaehler, Carola Berking, Tanja Bergmann, Clemens L. Bockmeyer, Thomas Eigentler, Michael Fluck, [......], Beatrice Schuler-Thurner, Uwe Trefzer, Jens Ulrich, Julia Vaubel, Roger von Moos, Patrik Weder, Tabea Wilhelm, Daniela Göppner, Reinhard Dummer, Lucie M. Heinzerling
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  ABSTRACT: Background Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases
  PLoS ONE 01/2013; 8(1):e53745. · 4.09 Impact Factor
• Source

  Available from: Martin Mcmahon

  Article: Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.

  Meghna Das Thakur, Fernando Salangsang, Allison S Landman, William R Sellers, Nancy K Pryer, Mitchell P Levesque, Reinhard Dummer, Martin McMahon, Darrin D Stuart
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  ABSTRACT: Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)→MEK→ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.
  Nature 01/2013; · 36.28 Impact Factor
• Source

  Available from: Christian Praetorius

  Dataset: Supplementary data

  Keith S Hoek, Natalie C Schlegel, Ossia M Eichhoff, Daniel S Widmer, Christian Praetorius, Steingrimur O Einarsson, Sigridur Valgeirsdottir, Kristin Bergsteinsdottir, Alexander Schepsky, Reinhard Dummer, Eirikur Steingrimsson
• Article: RASopathic Skin Eruptions during Vemurafenib Therapy.

  Jeannine D Rinderknecht, Simone M Goldinger, Sima Rozati, Jivko Kamarashev, Katrin Kerl, Lars E French, Reinhard Dummer, Benedetta Belloni
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  ABSTRACT: Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions. Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders. Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type). Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.
  PLoS ONE 01/2013; 8(3):e58721. · 4.09 Impact Factor
• Source

  Available from: Thomas Eigentler

  Article: Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases

  Heike Niessner, Andrea Forschner, Bernhard Klumpp, Jürgen B Honegger, Maria Witte, Antje Bornemann, Reinhard Dummer, Annemarie Adam, Jürgen Bauer, Ghazaleh Tabatabai, [......], Ulrike Leiter, Cornelia Mauch, Alexander Roesch, Benjamin Weide, Thomas Eigentler, Dirk Schadendorf, Claus Garbe, Dagmar Kulms, Leticia Quintanilla-Martinez, Friedegund Meier
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  ABSTRACT: Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.
  Cancer Medicine. 12/2012;
• Article: Real-life Experience With Pegylated Interferon and Conventional Interferon in Adjuvant Melanoma Therapy.

  Sima Rozati, Lukas Naef, Mitchell P Levesque, Lars E French, Reinhard Dummer
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  ABSTRACT: Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 µg flat dose peg-IFN, which is commonly referred to as "low-dose," actually represents a higher dose of IFN, which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance.
  Journal of immunotherapy (Hagerstown, Md.: 1997) 11/2012; · 3.20 Impact Factor
• Article: Spindle-cell variant of primary cutaneous follicle center lymphoma spreading to the hepatobiliary tree, mimicking Klatskin tumor.

  Sima Rozati, Katrin Kerl, Werner Kempf, Marianne Tinguely, Dieter R Zimmermann, Reinhard Dummer, Antonio Cozzio
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  ABSTRACT: Primary cutaneous follicle center lymphoma (pcFCL) is an indolent type of primary cutaneous B-cell lymphoma (pcBCL) rarely disseminating to other organs. PcBCL with spindle-cell morphology has been described as a rare variant of pcFCL but the prognosis data of this variant is sparse. We report a rare case of spindle-cell pcFCL with CD20(+) , CD79a(+) , CD3(+) , Bcl-6(+) , Mum-1(-) and CD10(-) tumor cells that infiltrated the hepatic hilum, mimicking a Klatskin tumor. On the basis of the sparse published data on spindle-cell morphology of pcBCL, this growth pattern should elicit awareness of an increased risk of systemic involvement in the otherwise indolent pcFCL.
  Journal of Cutaneous Pathology 11/2012; · 1.56 Impact Factor
• Source

  Available from: Blanca Espinet

  Dataset: Salgado et al, JID 2010, Commentary to Salgado et al

  Maarten H Vermeer, Reinhard Dummer, Maria B Karpova, Blanca Espinet, Pablo L Ortiz-Romero, Marta Herrera, Marie C Zipser, Vicen|[ccedil]| Romagosa, Cornelis P Tensen, Javier Suela, [......], Roc|[iacute]|o Salgado, Juan C Cigudosa, Teresa Estrach, Octavio Servitje, Francesc Sol|[eacute, Carlos Barranco, Ramon M Pujol, Marta Salido, Fernando Gallardo, Sergio Serrano
• Article: Will PAXgene substitute formalin? A morphological and molecular comparative study using a new fixative system.

  Benedetta Belloni, Chiara Lambertini, Paolo Nuciforo, Jay Phillips, Eric Bruening, Stephane Wong, Reinhard Dummer
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  ABSTRACT: Formalin fixation and paraffin embedding present the standard procedures for conserving clinical tissues for histological analysis. However, molecular analysis is impaired by the cross linking properties of formalin. The PAXgene tissue system (PreAnalytix, Switzerland) is a new formalin-free tissue collection device. AIMS: In this study we aimed to evaluate this new tissue preservation technique in comparison with formalin fixation and fresh frozen tissue samples. METHODS: 12 melanoma biopsy samples were divided and fixed simultaneously with formalin, PAXgene or fresh frozen in liquid nitrogen and analysed with regard to morphology, immunohistochemistry, DNA and RNA content and quality. Markers of melanocytic differentiation and tumour cell proliferation were used. RESULTS: Morphology was well preserved in PAXPE samples. However, 5 out of 11 immunohistochemical markers showed significantly lower overall staining and staining intensity with PAXPE tissues in comparison with formalin-fixed, paraffin-embedded (FFPE). Increasing membrane permeability through adding a detergent did proportionally increase staining intensity in PAXPE samples. Amplification of different mRNA amplicons showed a direct relationship with the size of the amplicon with greater template integrity observed in PAXPE samples. Sequencing and mutational analysis of DNA samples were comparable for all the different fixation methods, while the level of DNA fragmentation seemed to be lower in PAXPE compared with FFPE tissues. CONCLUSIONS: The switch from formalin to PAXgene fixation would require a re-evaluation of immunohistochemical markers and staining procedures originally developed for FFPE tissues. Our data demonstrate that PAXPE fixation offers some advantages concerning molecular analysis. However, these advantages would not justify substituting formalin fixation in any routine pathology laboratory.
  Journal of clinical pathology 11/2012; · 2.43 Impact Factor
• Article: Prospective International Multicenter Phase II Trial of Intravenous Pegylated Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012.

  Reinhard Dummer, Pietro Quaglino, Jürgen C Becker, Baktiar Hasan, Matthias Karrasch, Sean Whittaker, Stephen Morris, Michael Weichenthal, Rudolf Stadler, Martine Bagot, Antonio Cozzio, Maria G Bernengo, Robert Knobler
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  ABSTRACT: PURPOSEMycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF. PATIENTS AND METHODS Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m(2) on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR). RESULTS: three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively. CONCLUSIONPLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.
  Journal of Clinical Oncology 10/2012; · 18.37 Impact Factor