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A variety of therapeutic agents are currently available for the systemic treatment of metastatic renal cell carcinoma (mRCC). It was only when targeted treatment was developed in the past decade that a significant improvement was achieved in tumour therapy. This also led to the development of sequential treatment for mRCC.7 molecular targeted agents are available today (axitinib, bevacizumab/ IFNα, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus). Due to the individualisation of treatment it remains a challenge to choose the most appropriate drug in a given setting, with the choice being based on the knowledge of the relevant clinical data as well as individual patient parameters.During the recent past, efforts have been made to test different inhibitors or combinations without a major breakthrough. Instead, the development of novel specific immunotherapeutic approaches now heralds the next level of treatment in mRCC. The first significant trial results will be expected this year, and further trials for optimisation of treatment are warranted., (© Georg Thieme Verlag KG Stuttgart · New York.)

Graft-versus-host-disease (GvHD) is despite improvement in transplantation medicine the major cause for morbidity and mortality after allogeneic stem cell transplantation. We describe a patient with chronic cutaneous GvHD who developed massive skin ulcerations after changing the immunosuppressive therapy to a mammalian target of rapamycin (mTOR)-inhibitor.

LAM is one of the rare lung diseases. Approximately 200-400 female patients are to be expected in Germany. Only rare reports exist describing a male LAM patient. LAM exists in two forms: a spontaneous mosaic mutation (S-LAM) and a germ line mutation resulting in a combination of pulmonary and systemic symptoms called tuberous sclerosis (TSC-LAM). Although the influence of estrogen is not yet entirely recognized, pregnancy and estrogen containing anticonception will worsen the course of the disease. Ten year prognosis of the disease is well over 80% but variability is large. Rapid progression exists.The clinical picture of S-LAM is dominated by pneumothorax, chylous pleural effusions, dyspnoea upon exertion. (HR) CT demonstrates the easily recognizable and characteristic cystic transformation of the parenchyma. The cellular sequels of the disease involve constant activation of the mTORC1 complex with protein synthesis, proliferation, enzymatic parenchymal transformation, improved cellular survival and metastasis into the lungs most likely from an extrapulmonary source. Following extensive research on the pathologic activation of the mTORC1 pathway, an initial way of halting progression has been found in using mTORC1 inhibitors (Sirolimus, Everolimus). Complimentary strategies are currently investigated in order to improve the therapeutic effect. These measures will improve LAM prognosis in the future. Therapy resistant LAM is a valid indication for lung transplantation., (Georg Thieme Verlag KG Stuttgart · New York.)

Iatrogenic Kaposi sarcomas (KS) in organ transplant recipients are often treated by switching immunosuppressive therapy to an mTOR inhibitor, such as sirolimus or everolimus, as these have immunosuppressive as well as anti-tumor effects. We report on an 80-year-old male patient who developed a disseminated cutaneous KS during therapy with prednisone and azathioprine for myasthenia gravis. After discontinuation of azathioprine therapy and despite continuing therapy with cortisone, the KS progressed and autoantibody levels against the nicotinic acetylcholine receptor increased. During the administration of everolimus, a long-term near-complete remission of KS and a decrease in autoantibodies took place. This case study illustrates that even in non-organ transplant patients with iatrogenic KS, switching to immunosuppressive therapy using an mTOR inhibitor can be beneficial.

Prolonged fever of unknown origin together with night sweats in the elderly requires a systematic search for malignant and infectious foci. Here we present a case of fever of unknown origin which ultimately led us to the diagnosis of everolimus-induced fever. After changing the immunosuppressive regime it resolved rapidly.

Background: Since 2006 in Germany six different target drugs for therapy in metastatic renal cell cancer (mRCC) have been used. Comparative studies for the application with the same indication are absent, and the order of potential sequential therapy is up to now unclear. The aim of the study was to collect data on therapy decisions in Germany regarding mRCC in the age of "targeted therapy". At the same time the study addressed the central question of sequencing of the different therapy options. In addition, the data of this study were to be compared to a study already published in 2008., Patients and Methods: In 2010, four groups of doctors specialized in the therapy of patients with mRCC were asked for their behaviour in the first-, second- and third-line or sequential therapy. Those questioned included urologists in private practice (n=40), oncologists in private practice (n=40), hospital urologists (n=35) and hospital oncologists (n=35). Further the reasons for a therapy decision should be stated or weighted., Results: Altogether 92% of all patients with mRCC were treated. Urologists in private practice treat only 30% of their patients themselves. The earlier used immune therapies (IFN, IL-2) no longer play a role. Sunitinib is used most often in first-line therapy by urologists in private practice (50.4%) and oncologists in private practice (47.1%). In second- and third-line therapy everolimus is used by urologists in private practice (27.1%, 26.3%) and sorafenib (28.6%) or everolimus (26.4%) by oncologists in private practice. Hospital oncologists use primarily sunitinib (56.1%), in second-line sorafenib (45.5%) and in third-line above all everolimus (19.4%). Hospital urologists use sunitinib most often for first-line therapy (57.6%) and sorafenib for second-line treatment (37.3%), while in third-line therapy temsirolimus (49.6%) and also everolimus (30.4%) were used., Conclusions: The therapy of mRCC is determined very strongly by the substances sunitinib and sorafenib. The mTOR inhibitors have recently been increasingly included in the second- and third-line therapy. With the introduction of the new targeted therapies, the treatment of these special patients is performed less by urologists and increasingly more by oncologists. This trend is strengthened in comparison to the DGFIT study from 2008.

With the introduction of targeted drug therapies, a paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards to replace the use of cytokines as standard therapy. Recently, these substances have been complemented by everolimus and pazopanib. An interdisciplinary consensus conference was held to discuss which criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2009 conference provided the basis for the 2010 meeting. The results of the 2010 conference are presented as short theses., (© Georg Thieme Verlag KG Stuttgart ˙ New York.)

With the introduction of targeted therapies, a -paradigm shift for the treatment of metastatic renal cell carcinoma has taken place. The use of cytokines as the long-standing standard therapy has declined. New compounds like sunitinib, -sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards. Since mid-2009, these substances have been complemented by everolimus. An interdisciplinary consensus conference was held to discuss what criteria to consider when using these drugs (treatment sequence) and what questions remain unanswered based on the current study situation (open questions). Results from the 2008 conference provided the basis for the 2009 meeting. The results of the 2009 conference are presented as short theses., (Copyright Georg Thieme Verlag Stuttgart . New York.)

Introduction: Until recently, the standard therapy for metastatic renal cell carcinoma (mRCC) in Germany consisted of interleukin-2 (IL-2), interferon-alfa (IFN) as single agents or in combination, with or without chemotherapy. Since 2005, new drugs (target drugs) in the therapy for mRCC are available. The aim of this study was to analyse the current therapy standard in Germany., Methods: By representative telephone interviews (GFK-Nürnberg by order of DGFIT) the following colleagues were contacted A: urologists in private practice (n = 40), B: oncologists in private practice (n = 40), C: hospital urologists (n = 35) and D: hospital oncologists (n = 35). Screening criteria were 1) responsibility for therapy in mRCC; 2) therapy of at least 10 patients with mRCC per year., Results: Patients/year: A: n = 19, B: n = 17, C: n = 43, D: n = 21. 98% of patients with mRCC were treated: A: the most frequent therapy was sunitinib (43%, 42%, 33% as first-, second-, third-line), B: the most frequent therapy was sunitinib (45% as first-line, 37% as second-line), the most frequent third-line therapy was sorafenib (35%); C: the most frequent therapy were sorafenib and sunitinib (first-line 26% vs. 27%, second-line 46% vs. 42%), in third-line therapy additionally temsirolimus 24%; D: primary sorafenib and sunitinib (first-line 33% vs. 40%, second-line 46% vs. 42%), in third-line therapy additionally temsirolimus 23%. Immunotherapy (IL-2, IFN with or without chemotherapy) in mRCC plays in Germany for the second- and third-line therapy in A-D no major role (less than 10%). Otherwise, for first-line therapy immunotherapy has some relevance: A: 25%, B: 37%, C: 33%, D: 16%. The most important criteria for therapy decision making in A-D were: efficacy, toxicity, drug approval status., Conclusions: Most patients with mRCC in Germany were seen by hospital urologists. Sunitinib (in first-line) and sorafenib (in second-line) are currently the most frequent prescribed drugs in mRCC. Temsirolimus is used mostly for third-line therapy (followed by sunitinib/sorafenib). Treatment of mRCC in Germany is increasingly being performed by oncologists., (Georg Thieme Verlag Stuttgart New York.)

Targeted therapies have fundamentally altered the therapy of metastatic renal cell carcinoma (mRCC). Sunitinib today is an internationally recommended reference standard in first-line therapy; other drugs such as Temsirolimus, Everolimus, Bevacizumab (in combination with Interferon-alpha) and Sorafenib are part of the therapeutic arsenal. Practitioners thus have now more and better therapeutic options at hand, leading to a significantly improved prognosis for mRCC patients. Numerous ongoing research activities aim at the improvement of the benefits of the new compounds in the metastatic situation or application earlier in the course of the disease. Key aspects of future development in RCC are the optimization of the current therapy options by developing new targeted therapies, the search for the best combinations and sequences including the role of nephrectomy and the assessment in the adjuvant or neo-adjuvant setting. The following contribution provides an overview of ongoing studies, thus giving insight into the future therapy of RCC., (Copyright 2010 S. Karger AG, Basel.)

The treatment objective in the metastatic situation is to delay progression while maintaining the best possible quality of life. Since several targeted therapies with different modes of action already exist, sequence therapy is increasingly being considered. Current data regarding sequential treatment is still insufficient and several approaches are being tested in ongoing clinical studies. Based on current data, guidelines, and the therapeutic algorithms supported by national and international professional associations, the German Cancer Society's interdisciplinary task force on renal cell carcinoma (RCC) recommends the following approach: since the efficacy of cytokines is very limited after a previous cytokine-based therapy has failed, Sorafenib or Sunitinib are the treatment of choice. Treatment with other targeted substances is recommended after first-line therapy has failed as a number of retrospective studies have documented relevant activity. Everolimus currently is the treatment of first choice when VEGF-directed therapy has failed. Based on the results of phase II studies, other tyrosine kinase inhibitors can alternatively be applied., (Copyright 2010 S. Karger AG, Basel.)

Several molecular therapies have recently become available in first-line therapy of metastatic renal cell carcinoma (mRCC), thus marginalizing cytocine-based therapy. The primary aim of treatment in this situation is to delay progression with an increase in long-term life expectancy along with enhanced quality of life. At present, three new substances are available: Sunitinib, Temsirolimus, and - in combination with Interferon-alpha - Bevacizumab. To date, sufficient data is at hand for all drugs, which has resulted in a consolidation of therapeutic strategy. Selecting the best therapy is highly relevant in everyday practice, depending, among other things, on clinical evidence, guidelines, and the respective approval status. The prognostic score according to Motzer (MSKCC) plays a major role. It covers three prognostically relevant risk groups which are important for the preferential application of the new substances. Current recommendations suggest the application of Sunitinib and Bevacizumab plus Interferon-alpha for good and medium prognoses, with Sunitinib being regarded to be one therapy of first choice. It is the most frequently applied substance for this indication in Germany. The efficacy of Temsirolimus has been documented for patients with poor prognosis and it has been approved for this indication only. Hence, the mTor inhibitor should be the standard for this group of patients., (Copyright 2010 S. Karger AG, Basel.)

With the introduction of targeted therapies, a paradigm shift for the treatment of metastatic renal cell cancer has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards. An interdisciplinary consensus conference was held to discuss treatment sequences and open questions. Results from the 2007 conference provided the basis for the 2008 meeting. The results of the 2008 conference are presented as short theses.

Unlabelled: A 67-year-old man who had been heart transplanted ten years before was admitted to our hospital because of diarrhea. During his stay he developed a severe lingual and facial angioedema. After excluding hereditary angioedema caused by a deficiency in functional C1 esterase inhibitor we focused on adverse effects of his drugs. The medication was composed of Aspirin, Enalapril, Diltiazem, Everolimus, Mycophenolate Mofetil, Bisoprolol, Pravastatin, Esomeprazol and Allopurinol. The angioedema disappeared with anti-allergic treatment. The administration of the suspected trigger enalapril was stopped. However weeks later the patient was admitted again with angioedema. Due to missing urticaria Aspirin was unlikely the causer. The only new drug the patient had been medicated with was Everolimus for 30 days. We assumed a link between the angioedema and Everolimus. Consequently we changed the immunosuppressive regime. After stopping Everolimus no angioedema occurred., Conclusion: Everolimus is a potential trigger of angioedema.

The introduction of targeted therapy in metastatic renal cancer patients provides a whole array of individual therapeutic options. The basis for this treatment is the inactivation of the von Hippel-Lindau tumor suppressor gene, resulting in high expression of pro-angiogenic growth factors, e.g. vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). This provides the rationale for targeting these pathways in clear cell renal cell carcinomas by small molecule inhibitors. This article gives a review on clinical trials with sunitinib, sorafenib, and temsirolimus in patients with advanced renal cell carcinoma and shows how promising treatments can emerge from an understanding of the molecular genetics and signaling pathways of tumors. However, a predictive marker, e.g. specific mutations associated with drug-resistant or responsive tumors, has not yet been identified and is paramount for the future.

Once surgical options have been exhausted, systemic therapy is indicated for metastasizing renal cell carcinoma. Until recently this was carried out using mainly immunotherapeutic concepts with unsatisfactory results. Since the majority of clear cell renal cell carcinomas are well vascularised, angiogenetic inhibition offered an alternative therapy goal. To date, four substances have been approved to control angiogenesis in the therapy of renal cell carcinoma: sunitinib, sorafenib, temsirolimus, as well as a combination of bevacizumab and interferon alpha. Other substances, such as everolimus, pazopanib and axitinib, are currently the subject of clinical trials. Initial data on tolerance and efficacy was presented at this years annual conference of the American Society of Clinical Oncology (ASCO). This article examines current therapy options and ASCO data and discusses future trends.

Therapeutic approaches based solely on cytokine are meanwhile no longer recommended without restrictions as the primary therapy for metastatic renal cancer due to the reduced clinical response and the promising available data regarding molecular therapy. Several randomized controlled studies have been performed since the introduction of the so-called targeted therapies for metastatic renal cancer. Substantial data relevant for drug approval are available for the multikinase inhibitors sorafenib (Nexavar) and sunitinib (Sutent), the mTOR inhibitor temsirolimus (Torisel), and the monoclonal antibody bevacizumab (Avastin) in combination with interferon-alpha. Sunitinib, temsirolimus, and bevacizumab are approved for first-line treatment, whereas sorafenib was approved for second-line treatment in Germany.Clinical trials are currently investigating the questions of optimal timing, value of neoadjuvant or adjuvant treatment, form, and sequence of the molecular targeted therapy. Experimental investigations for a better understanding of signaling pathways will preferably allow preselecting patients for an individualized therapy in metastatic renal cell cancer (RCC). The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding"targeted" therapeutics during the treatment of metastatic RCC.

This Macro-Micro-Dermatology-contribution with the theme innovative drugs and drug reactions illustrates two new observations of practical interest: 1. Follicular eruption after Everolimus and 2. Atrophy of sebaceous glands after Sirolimus.

The use of drugeluting stents (DES) has tackled the "Achilles' heel" of percutaneous coronary interventions (PCI) like no innovation before: the restenosis following initially successful PCI of de novo stenoses. Today, with DES, the pivotal clinical parameter TVF (target vessel failure) is in the upper single- digit range for "standard" lesions and 16% for long lesions. Numerous studies have assessed the effects of various antiproliferative and antiinflammatory substances, like Sirolimus, Tacrolimus, Everolimus, ABT-578, Biolimus, Paclitaxel, QP2 as well as of other drugs, like Dexamethasone, 17-beta-Estradiol, Batimastat, Actinomycin-D, Methotrexat, Angiopeptin, Tyrosinkinase inhibitors, Vincristin, Mitomycin, Cyclosporin, and also the C-myc antisense technology (Resten-NG, AVI-4126). At the time of this analysis, four DES are CE-certified and commercially available in Europe: The Cypher stent, releasing Sirolimus from a polymer (Cordis, J&J), the Taxus stent, releasing Paclitaxel from a polymer (Boston-Scientific), the V-Flex stent, releasing Paclitaxel without a polymer (Cook) and the Dexamet stent, releasing Dexamethasone from a PC coating (Abbott). Since more DES will be CE-certified soon, an increasing challenge vexes interventional cardiologists and health care providers: Which DES should be chosen for routine patient care?A prerequisite for assessing the efficacy of DES are randomized, controlled trials. Registries, even with strong monitoring, are limited by the known restrictions, comparing data to historical controls. At the time of this analysis, only three drugs had proven their efficacy in 13 randomized studies in 5669 patients: Paclitaxel, Sirolimus and Everolimus, with 3815 patients in Paclitaxel studies, 1748 patients in Sirolimus studies and 106 patients in Everolimus studies. For further analysis, it makes sense to divide the primary endpoints into non-clinical and clinical endpoints. Non-clinical primary endpoints are usually angiographic parameters, like the percentage of DS (diameter stenosis, ASPECT, ELUTES), the instent LLL (late lumen loss, RAVEL, FUTURE-II), the in-stent MLD (minimal lumen diameter, E-SIRIUS, C-SIRIUS) or, like in TAXUS-II, the IVUS-determined percentage of volume obstruction. Clinical primary endpoints were either MACE (major adverse cardiac events, TAXUS-I, FUTUREI), TVF (target vessel failure, DELIVER-I, SIRIUS) or TVR (target vessel revascularization, TAXUS-IV und TAXUS-VI). As ASPECT, ELUTES and DELIVER-I have shown, even a statistically significant effect on an angiographic primary endpoint does not necessarily translate into a significant clinical effect, which is completely absent in some such cases. Since it is not the goal of PCI to improve angiographic parameters but rather to improve patients' outcome, the choice of DES for routine treatment should be based on the results of randomized controlled studies with a clinical primary endpoint at an appropriate time interval. At the present time, these criteria have been met by only the Cypher and the Taxus stents.