Prognostic Parameters for the Primary Care of Melanoma Patients: What Is Really Risky in Melanoma?

Due to intensified research in recent years, the understanding of the molecular mechanisms involved in the development of melanoma has dramatically improved. The discovery of specific, causal mutations such as BRAF or KIT oncogenes not only renders a targeted and thus more effective therapeutic approach possible, but also gives rise to a new genetic-based classification. Targeting just a few out of several potential mutations, BRAF-Inhibitors such as PLX 4032 achieved already tremendous results in the therapy of metastatic melanoma. Up to now, the correlation of clinical, histomorphologic, and genetic features is, however, not understood. Even more, is it not well known precisely what kind of molecular changes predispose the primary melanoma for metastasis. The identification of morphological surrogates and prognostic parameters in tumors with such genetic alteration seems therefore crucial when differentiating and classifying this heterogeneous tumor entity in more detail and thus facilitates the stratification of prognosis as well as therapy. This review summarizes the current understanding of carcinogenesis and gives a detailed overview of known morphologic and potentially future genetic prognostic parameters in malignant melanoma

Basal Cell Carcinoma: From the Molecular Understanding of the Pathogenesis to Targeted Therapy of Progressive Disease

Due to intensified research over the past decade, the Hedgehog (HH) pathway has been identified as a pivotal defect implicated in roughly 25% of all cancers. As one of the most frequent cancer worldwide, the development of Basal cell carcinoma (BCC) due to activation of the HH pathway has been convincingly demonstrated. Thus the discovery of this central tumor-promoting signalling pathway has not only revolutionized the understanding of BCC carcinogenesis but has also enabled the development of a completely novel therapeutic approach. Targeting just a few of several potential mutations, HH inhibitors such as GDC-0449 achieved already the first promising results in metastatic or locally advanced BCC. This paper summarizes the current understanding of BCC carcinogenesis and describes the current “mechanism-based” therapeutic strategies

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

Human primary aldosteronism (PA) can be caused by mutations in several ion channel genes but mouse models replicating this condition are lacking. We now show that almost all known PA-associated CLCN2 mutations markedly increase ClC-2 chloride currents and generate knock-in mice expressing a constitutively open ClC-2 Cl(−) channel as mouse model for PA. The Clcn2(op) allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca(2+) concentration. Clcn2(op) mice display typical features of human PA, including high serum aldosterone in the presence of low renin activity, marked hypertension and hypokalemia. These symptoms are more pronounced in homozygous Clcn2(op/op) than in heterozygous Clcn2+/op mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2(+/op) zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2(op) mice are a valuable model to study the pathological mechanisms underlying this disease

Cellular basis of ClC-2 Cl(-) channel-related brain and testis pathologies

The ClC-2 chloride channel is expressed in the plasma membrane of almost all mammalian cells. Mutations that cause the loss of ClC-2 function lead to retinal and testicular degeneration and leukodystrophy, whereas gain of function mutations cause hyper­aldosteronism. Leukodystrophy is also observed with a loss of GlialCAM, a cell adhesion molecule which binds to ClC-2 in glia. GlialCAM changes the localization of ClC-2 and opens the channel by altering its gating. We now used cell-type specific deletion of ClC-2 in mice to show that retinal and testicular degeneration depend on a loss of ClC-2 in retinal pigment epithelial cells and Sertoli cells, respectively, whereas leukodystrophy was fully developed only when ClC-2 was disrupted in both astrocytes and oligodendrocytes. The leukodystrophy of Glialcam(-/-) mice could not be rescued by crosses with Clcn2(op/op) mice in which a mutation mimics the ‘opening’ of ClC-2 by GlialCAM. These data indicate that GlialCAM-induced changes in biophysical properties of ClC-2 are irrelevant for GLIALCAM-related leukodystrophy. Taken together, our findings suggest that the pathology caused by Clcn2 disruption results from disturbed extracellular ion homeostasis and identifies the cells involved in this process

The price of tumor control

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. 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 in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

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 in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Aufbau eines Prüfstands zur Erprobung von Online- Messungen von Seilspannungen im Antrieb eines chirurgischen Instruments zur Verbesserung der Regelbarkeit des Systems

Diese Abschlussarbeit stellt Möglichkeiten zur Erfassung von Seilspannungen in einem Instrument für die minimal invasive Roboter Chirurgie vor. Die zu entwickelnde Sensorik soll in ein bereits vorhandenes Instrument integriert werden können, um die Regelung des Instruments während des Einsatzes bei Operationen zu verbessern. Das Instrument, genannt MICA, ist auf einem Leichtbau-Roboterarm (MIRO) montiert, welcher frei am Operationstisch befestigt werden kann. Es werden mögliche Erfassungsmethoden auf Basis von physikalischen Wirkprinzipien aufgezeigt und mit Hilfe von festgelegten Kriterien bewertet. Die beste Variante wird mit Hilfe eines Prüfaufbaus verifiziert und auf ihre Eignung getestet. Abschließend werden mögliche Veränderungen im Aufbau des Instruments aufgezeigt, um die Erfassung der Seilspannungen zu verbessern