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Solitare Hamangiome im Kindesalter konnen bei ungunstiger Lokalisation oder rascher Wachstumstendenz ein Problem darstellen, auch wenn es sich per se um eine gutartige Gefasproliferation handelt. Da es im Einzelfall nicht vorhersehbar ist, ob sich ein Hamangiom spontan zuruckbildet oder aber zu einer grosflachigeren, meist auch hinsichtlich der Tiefenausdehnung progredienten Lasion weiterentwickelt, ist jedes kindliche Hamangiom individuell zu betrachten. In diesem Zusammenhang kann es von groser Bedeutung sein, diagnostische Methoden zu entwickeln, die eine Differenzierung der Hamangiome in Korrelation mit dem klinischen Befund und der Lokalisation der Lasion erlauben, und dass damit verbunden die individuell richtige Behandlungsstrategie festgelegt wird. Bei der Behandlung solitarer kleinerer planer bis planotuberoser Hamangiome sollte eine nebenwirkungsarme und effektive Lokaltherapie der systemischen Therapie mit s‑Blockern (Propranolol) vorgezogen werden. Neben der Kryokontakttherapie ist vor allem die Therapie mit dem gepulsten Farbstofflaser (595 nm) hierbei auch heute noch Mittel der Wahl. Ziel vorliegender Arbeit war es, in mehreren Einzelfallen den klinischen Befund mit einer sonographischen Untersuchung und Befunderhebung zu korrelieren. Es wurden im Rahmen der Sprechstunde fur Lasertherapie Kinder mit jeweils einem planen/planotuberosen Hamangiom an unterschiedlichen Lokalisationen ausgewahlt. Alle ausgewahlten Hamangiome zeigten eine sehr rasche Wachstumstendenz und/oder befanden sich an ungunstiger Lokalisation und wurden daher als behandlungsbedurftig eingestuft. Als Indikator fur die rasche Grosenzunahme wurde bei allen Hamangiomen vor Beginn oder wahrend der Lasertherapie eine sonographische Befunderhebung durchgefuhrt (MyLab 70 von Esaote, 18 MHz) und anschliesend mehrmalig mit dem gepulsten Farbstofflaser (PDL, V‑Beam, Perfecta, Candela, 585 nm) behandelt. Drei der ausgewahlten Hamangiome sprachen nur masig auf die mehrmalige Lasertherapie an, daher wurde der klinische Befund hier wiederholt durch eine sonographische Untersuchung in Beziehung gesetzt und dadurch das weitere Prozedere festgelegt. Bei einem Kind befand sich das Hamangiom sehr nah an der noch offenen vorderen Fontanelle, sodass wir hier die Durchfuhrung einer Therapie mit dem Farbstofflaser nicht empfehlen konnten. Bei Fallbeispielen liesen sich der klinische Aspekt und sonographische Befund in Bezug auf das Ansprechen/Nichtansprechen der Hamangiome auf die Therapie mit dem gepulsten Farbstofflaser sehr gut korrelieren. Der Erfolg der Lasertherapie problematischer kindlicher Hamangiome kann mittels Ultraschalluntersuchung vor Beginn der Behandlung besser eingeschatzt bzw. wahrend der Behandlungszeit intermittierend als prognostischer Indikator des Behandlungserfolgs der Lasertherapie gewertet werden. Dabei korreliert eine fruhzeitige Behandlung der Hamangiome mit dem gepulsten Farbstofflaser, d. h. im Initialstadium, besonders bei ungunstiger Lokalisation, mit dem Behandlungserfolg.

Background Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. Methods To analyze the therapeutic effects of sGARP, adult NOD/Scidγc−/− (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP. Results In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45+ cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-β receptor pathway, mice additionally received anti-TGF-β receptor II (TGF-βRII) antibodies. Blocking the signaling of TGF-β through TGF-βRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation. Conclusion Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases.

Introduction Sacroiliac joint (SIJ) pain affects older adults with a prevalence of up to 20% among patients with chronic low back pain. While pain medication, joint blocks and denervation procedures achieve pain relief in most patients, some cases fail to improve. Our goal was to determine the effectiveness of SIJ peripheral nerve stimulation in patients with severe conservative therapy–refractory SIJ pain. Materials and Methods Here we present 12 patients with severe conservative therapy–refractory pain receiving an SIJ peripheral nerve stimulation. Patient satisfaction, pain, and quality of life were evaluated by means of the International Patient Satisfaction Index (IPSI), visual analog scale (VAS), and Oswestry Disability Index 2.0 (ODI) using standard questionnaires. For stimulation we placed an eight-pole peripheral nerve electrode parallel to the SIJ. Results Two weeks postoperatively, our patients reported an average ODI reduction from 57% to 32% and VAS from 9 to 2.1. IPSI was 1.1. After six months, the therapy was rated as effective in seven out of eight patients reporting at that period. The average ODI was low at 34% (p = 0.0006), while the VAS index rose to 3.8 (p < 0.0001) and IPSI to 1.9. Twelve months after stimulation, six out of seven patients considered their treatment a success with an average ODI of 21% (p < 0.0005), VAS 1.7 (p < 0.0001), and IPSI 1.3. Conclusions We conclude that SIJ stimulation is a promising therapeutic strategy in the treatment of intractable SIJ pain. Further studies are required to determine the precise target group and long-term effect of this novel treatment method.

AimsThe chemokine receptor CXCR7 is found on glioma cells and glioma-associated vessels and dependent upon its localisation on tumour or endothelial cells the CXCR7 receptor can mediate glioma cell invasion and tumour angiogenesis. Its expression predicts survival in several types of cancers.MethodsWe immunohistochemically studied the expression of CXCR7 and its ligand SDF1α in a cohort of 354 human patients with glioma. In an in vivo glioma model, we studied the effect of selective CXCR7 inhibition on mean vascular density.ResultsHere we show that expression of either mutant isocitrate dehydrogenase (IDH) 1 or podoplanin (PDPN), two proteins present in basically non-overlapping glioma populations, predicts the prognostic significance of CXCR7. Specifically, expression of CXCR7 on endothelial cells in IDH1 mutant cases predicted poor outcome. Surprisingly, in PDPN expressing gliomas, one of the marker genes for the recently identified mesenchymal subgroup, expression of CXCR7 predicts diminished prognosis on tumour cells and better prognosis on endothelial cells.ConclusionsSince CXCR7 is expressed on migrating cells our data suggest that, although ubiquitously present, angiogenesis and invasion are outcome-relevant events in specific glioma subgroups, providing a potentially important tool for targeted therapy assignment.

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3(+) Treg cell subpopulation that was unable to control the maturation of IRF4(+)PD-L2(+) dendritic cells required for the development of TH2 responses in vivo.

Melanoma is the most dangerous form of skin cancer with a growing incidence over the last decades. Fourty percent of all melanomas harbor a mutation in the signaling adaptor BRAF (V600E) that results in ERK hyperactivity as an oncogenic driver. In these cases, treatment with the BRAFV600E inhibitors Vemurafenib (VEM) or Dabrafenib (DAB) coapplied with the MEK1/2 inhibitors Cobimetinib (COB) or Trametinib (TRA) can result in long-term suppression of tumor growth. Besides direct suppression of ERK activity, these inhibitors have been reported to also modulate tumor immune responses, and exert pro-inflammatory side effects such as fever and rash in some patients. Here we asked for potential effects of BRAFV600E inhibitors on dendritic cells (DC) which are essential for the induction of adaptive anti-tumor responses. Both splenic and bone marrow-derived (BM) mouse dendritic cells (DC) up-regulated costimulator expression (CD80, CD86) in response to DAB but not VEM treatment. Moreover, DAB and to lesser extent VEM enhanced IL-1β (interleukin 1 beta) release by splenic DC, and by LPS-stimulated BMDC. We demonstrate that DAB and VEM activated the NLRC4/Caspase-1 inflammasome. At high concentration, DAB also induced inflammasome activation independent of Caspase-1. TRA and COB elevated MHCII expression on BMDC, and modulated the LPS-induced cytokine pattern. Immunomodulatory activity of DAB and VEM was also observed in human monocyte-derived DC, and DAB induced IL-1β in human primary DC. Altogether, our study shows that BRAFV600E inhibitors upregulate IL-1β release by mouse and human DC which may affect the DC-mediated course of anti-tumor immune responses.

The B16F10 murine melanoma cell line displays a low expression of MHC class I molecules favoring immune evasion and metastases in immunocompetent C57 BL/6 wild-type mice. Here, we generated metastases to the liver, an organ that is skewed towards immune tolerance, by intrasplenic injection of B16F10 cells in syngeneic C57 BL/6 compared to allogeneic Balb/c mice. Surprisingly, Balb/c mice, which usually display a pronounced M2 macrophage and Th2 T cell polarization, were ∼3 times more susceptible to metastasis than C57 BL/6 mice, despite a much higher M1 and Th1 T cell immune response. The anti-metastatic advantage of C57 BL/6 mice could be attributed to a more potent NK-cell mediated cytotoxicity against B16F10 cells. Our findings highlight the role of NK cells in innate anti-tumor immunity in the context of the liver – particularly against highly aggressive MHC I-deficient cancer cells. Moreover, the B16F10 model of melanoma liver metastasis is suited for developing novel therapies targeting innate NK cell related immunity in liver metastases and liver cancer.

Myeloid cells are the most abundant cells in the tumor microenvironment (TME). The tumor recruits and modulates endogenous myeloid cells to tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC) and neutrophils (TAN), to sustain an immunosuppressive environment. Pathologically overexpressed mediators produced by cancer cells like granulocyte-macrophage colony-stimulating- and vascular endothelial growth factor induce myelopoiesis in the bone marrow. Excess of myeloid cells in the blood, periphery and tumor has been associated with tumor burden. In cancer, myeloid cells are kept at an immature state of differentiation to be diverted to an immunosuppressive phenotype. Here, we review human myeloid cells in the TME and the mechanisms for sustaining the hallmarks of cancer. Simultaneously, we provide an introduction into current and novel therapeutic approaches to redirect myeloid cells from a cancer promoting to a rather inflammatory, cancer inhibiting phenotype. In addition, the role of platelets for tumor promotion is discussed.

Dynamic stabilization devices were developed to reduce spinal hypermobility while preserving a certain degree of physiological motion. Our goal was to assess radiographic and clinical outcomes of patients treated with surgical decompression and stabilization with the LimiflexTM implant. We investigated the effect of LimiFlex implantation on post-operative translation and angulation in 36 patients with spinal stenosis and degenerative spondylolisthesis Meyerding Grade I treated with decompression and dynamic stabilization. Significant improvements following lumbar decompression were observed. The average Oswestry Disability Index (ODI) score fell from 45.9 Pre-operatively to 29.6 at dismissal and 26.5 at first follow up. The average visual analog scale (VAS) score fell from 7 Pre-operatively to 3 at dismissal and 3 at follow up. Pre-operatively the median translation within the operated segment was 2.0 mm. Post-operatively the translation was reduced to 0.7 mm (p=0.006, Student’s t-test). Pre-operatively the median rotation within the operated segment was 4.6°. Post-operatively the rotation was reduced to 3.5° (p=0.08, Student’s t-test). The re-operation rate was 6 out of 36 (16.7%). Here we provide evidence suggesting that the dynamic paraspinous stabilization implant LimiflexTM is well tolerated in patients with degenerative spondylolisthesis and lumbar spinal canal stenosis. Our data show that within 3 months after the operation it limits hypermobility in the operated segment. This might be well suited in cases such as spinal stenosis with Grade I degenerative spondylolisthesis, where instability at the operated segment is likely to happen, but a patient is not indicated for a spinal fusion.

BACKGROUND Recently, isocitrate dehydrogenase 1 (IDH1) was identified as a major participant in glioma pathogenesis. At present, the enzymatic activity of the protein has been the main topic in investigating its physiological function, but its signaling pathway allocation was unsuccessful. Interestingly, proteins regulated by phosphoinositide 3-kinase (PI3K)/Akt signaling, are among the top downregulated genes in gliomas associated with high percentage of IDH1 and IDH2 mutations. The aim of this study was to investigate a hypothetical relation between IDH1 and PI3K signaling. METHODS The presence of mutant IDH1 and markers for active PI3K/Akt signaling, present as phosphorylated Akt and podoplanin (PDPN), were investigated in a discovery cohort of 354 patients with glioma. In vitro experiments were used to confirm functional links. RESULTS This study shows an inverse correlation between mutant IDH1 and markers for active PI3K/Akt signaling. In support of a functional link between these molecules, in vitro expression of mutant IDH1 inhibited Akt phosphorylation in a 2-hydroxyglutarate–dependent manner. CONCLUSIONS This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling. Cancer 2014;120:2440–2447. © 2014 American Cancer Society.

Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-β (TGF-β). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4⁺ T cells. We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve CD4⁺ T cells into T effector cells. Exposure to sGARP induces Foxp3, decreases proliferation and represses interleukin (IL)-2 and interferon-γ production, resulting in differentiation of naïve T cells into induced Treg. This is associated with Smad2/3 phosphorylation and partially inhibited by blockade of TGF-β signaling. Furthermore, in the presence of the proinflammatory cytokines IL-6 and IL-23, sGARP facilitates the differentiation of naïve T cells into Th17 cells. More important, in a preclinical humanized mouse model of xenogeneic graft-versus-host disease (GVHD), sGARP prevents T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. These results demonstrate a crucial role of sGARP in modulation of peripheral tolerance and T effector cell function, opening the possibility to use sGARP as a potent immunomodulator of inflammatory diseases including transplant rejection, autoimmunity, and allergy.

Macrophages, myeloid-derived suppressor cells and tolerogenic dendritic cells are central players of a heterogeneous myeloid cell population, with the ability to suppress innate and adaptive immune responses and thus to promote tumor growth. Their influx and local proliferation are mainly induced by the cancers themselves, and their numbers in the tumor microenvironment and the peripheral blood correlate with decreased survival. Therapeutic targeting these innate immune cells, either aiming at their elimination or polarization toward tumor suppressive cells is an attractive novel approach to control tumor progression and block metastasis. We review the current understanding of cancer immunology including immune surveillance and immune editing in the context of these prominent innate suppressor cells, and their targetability by nanoparticular immunotherapy with small molecules or siRNA.

Aim: Evaluation of dextran-based nanoparticles (DNP) as a drug delivery system to target myeloid cells of the liver. Materials & methods: DNP were synthesized and optionally PEGylated. Their toxicity and cellular uptake were studied in vitro. Empty and siRNA-carrying DNP were tested in vivo with regard to biodistribution and cellular uptake. Results: In vitro, DNP were taken up by cells of the myeloid lineage without compromising their viability. In vivo, empty and siRNA-carrying DNP distributed to the liver where a single treatment addressed approximately 70% of macrophages and dendritic cells. Serum parameters indicated no in vivo toxicity. Conclusion: DNP are multifunctional liver-specific drug carriers which lack toxic side effects and may be utilized in clinical applications targeting liver macrophages.

Objective: Sacroiliac joint (SIJ) pain affects older adults with a prevalence of up to 36% among patients with chronic low back pain. While pain medication, joint blocks and denervation procedures achieve pain relief in most patients, some cases fail to improve. Recently we were able to show that[for full text, please go to the a.m. URL], 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role. In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-β dependent way, is also expressed on human primary melanoma. Interestingly, membrane bound GARP is shed from the surface of both, activated Treg and melanoma cells, and, in its soluble form (sGARP), not only induces peripheral Treg but also a tumor associated (M2) macrophage phenotype. Notably, proliferation of cytotoxic T cells and their effector function is inhibited in the presence of sGARP. GARP expression on Treg and melanoma cells is significantly decreased in the presence of agents such as IFN-α, thus explaining at least in part a novel mechanism of action of this adjuvant therapy. In conclusion, GARP in its soluble and membrane bound form contributes to peripheral tolerance in a multipronged way, potentiates the immunosuppressive tumor microenvironment and thus acts as a negative regulator in melanoma patients. Therefore, it may qualify as a promising target and a new checkpoint for cancer immunotherapy.

Several lines of evidence suggest nuclear factor of activated T-cells (NFAT) to control regulatory T cells: thymus-derived naturally occurring regulatory T cells (nTreg) depend on calcium signals, the Foxp3 gene harbors several NFAT binding sites, and the Foxp3 (Fork head box P3) protein interacts with NFAT. Therefore, we investigated the impact of NFAT on Foxp3 expression. Indeed, the generation of peripherally induced Treg (iTreg) by TGF-β was highly dependent on NFAT expression because the ability of CD4 + T cells to differentiate into iTreg diminished markedly with the number of NFAT family members missing. It can be concluded that the expression of Foxp3 in TGF-β–induced iTreg depends on the threshold value of NFAT rather than on an individual member present. This is specific for iTreg development, because frequency of nTreg remained unaltered in mice lacking NFAT1, NFAT2, or NFAT4 alone or in combination. Different from expectation, however, the function of both nTreg and iTreg was independent on robust NFAT levels, reflected by less nuclear NFAT in nTreg and iTreg. Accordingly, absence of one or two NFAT members did not alter suppressor activity in vitro or during colitis and transplantation in vivo. This scenario emphasizes an inhibition of high NFAT activity as treatment for autoimmune diseases and in transplantation, selectively targeting the proinflammatory conventional T cells, while keeping Treg functional.

Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors. Besides a number of Treg-associated molecules such as Foxp3, CTLA-4 or GARP, known to play critical roles in Treg differentiation, activation and function, the involvement of additional regulatory elements is suggested. Herein, kinase activities seem to play an important role in Treg fine tuning. Nevertheless, our knowledge regarding the complex intracellular signaling pathways controlling phenotype and function of Treg is still limited and based on single kinase cascades so far. To gain a more comprehensive insight into the pathways determining Treg function we performed kinome profiling using a phosphorylation-based kinome array in human Treg at different activation stages compared to Teff. Here we have determined intriguing quantitative differences in both populations. Resting and activated Treg showed an altered pattern of CD28-dependent kinases as well as of those involved in cell cycle progression. Additionally, significant up-regulation of distinct kinases such as EGFR or CK2 in activated Treg but not in Teff not only resemble data we obtained in previous studies in the murine system but also suggest that those specific molecular activation patterns can be used for definition of the activation and functional state of human Treg. Taken together, detailed investigation of kinome profiles opens the possibility to identify novel molecular mechanisms for a better understanding of Treg biology but also for development of effective immunotherapies against unwanted T cell responses in allergy, autoimmunity and cancer.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem–like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFβR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem–like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFβR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma. Cancer Res; 71(23); 7155–67. ©2011 AACR.

The kinetics of Ga-68-BZH3, a Ga-68-bombesin analog, was compared to molecular biological data obtained from gene arrays in seven patients with a recurrent glioma. The primary aim of this study was the correlation of receptor expression and tracer kinetics.Dynamic positron emission tomography studies were performed and the data were analyzed by a volume-of-interest technique using a two-tissue compartment model as well as a non-compartment model. Gene array data were obtained from gene array analysis of tumor tissue samples.The correlation analysis revealed a significant nonlinear correlation of r = 0.89 (p 0.03) for k1 and BB(2) (gastrin-releasing peptide receptor). BB(1) and BB(3) were not significantly correlated with k1. vb and k3 were not significantly correlated with the expression data of the receptors on the p 0.05 level.The parameter k1 is correlated with the expression of BB(2) based on gene array data. The quantitative analysis of the Ga-68-BZH3 kinetics can be used to predict the receptor expression of BB(2) in gliomas based on k1 of the compartment analysis. However, this study is limited to the expression data on the mRNA level and further studies are needed to assess the correlation of gene expression on the protein level.

Purpose:Dynamic PET studies with a 68Ga-Bombesin analog, the 68Ga-BZH3, were performed in patients with highly suspected recurrent gliomas to investigate the effect of the receptor scintigraphy on tumor grading. Furthermore, dynamic F-18 Fluorodeoxyglucose (FDG) studies were performed for comparison

Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population characterized by immunosuppressive activity. Elevated levels of MDSC in peripheral blood are found in inflammatory diseases as well as in malignant tumors where they are supposed to be major contributors to mechanisms of tumor-associated tolerance. We investigated the frequency and function of MDSC in peripheral blood of melanoma patients and observed an accumulation of CD11b(+) CD33(+) CD14(+) HLA-DR(low) MDSC in all stages of disease (I-IV), including early stage I patients. Disease progression and enhanced tumor burden did not result in a further increase in frequencies or change in phenotype of MDSC. By investigation of specific MDSC-associated cytokines in patients' sera, we found an accumulation of IL-8 in all stages of disease. T-cell proliferation assays revealed that MDSC critically contribute to suppressed antigen-specific T-cell reactivity and thus might explain the frequently observed transient effects of immunotherapeutic strategies in melanoma patients.

• regulatory T cells • tolerance • signal transduction • autoimmunity • allergies • cancer Summary Regulatory T cells (Tregs) are essential for induction and maintenance of immunological tolerance. They contribute to prevention of autoimmunity by control and modulation of immune responses. The prevalence of autoimmune diseases, chronic infections, cancer and allergies has markedly increased in the last decades. In additions the treatment of these disorders is often unsatisfactory so that improvements are needed. This has stimulated intensive research in the biology of Tregs. Recent studies revealed that naturally occurring CD4 + CD25 + Tregs (nTregs) and induced Tregs (iTregs) are critical for the control of inadequate immune reactions. In humans, various iTreg populations are generated to inhibit naive as well as activated effector T cells. Key molecules of signal transduction, essential for suppressor function of iTregs, have been identified and may be target molecules to modulate the activity of suppressor T cells with novel biologicals. Precise insight into the properties of Tregs may contribute to the development of innovative therapeutic approaches which directly affect Tregs in patients or use adoptive transfer of Tregs.

The current WHO classification of brain tumors defines gliomatosis cerebri (GC) as an extensively infiltrating astrocytic glioma involving at least three cerebral lobes. The relation of GC to diffuse astrocytomas and glioblastoma is uncertain. Due to malignant biological behavior, GC is allotted to WHO grade III. Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors WHO grades II and III and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas. Here, we examined the frequency of IDH1 mutations in 35 GC samples by direct sequencing, derived cleaved amplified polymorphic sequence analysis and immunohistochemistry. We identified IDH1 mutations in 10/24 (42%) cases, which also included a solid tumor portion (type 2 GC), but not in 11 “classical” cases without solid tumor mass (type 1 GC). TP53 mutations were revealed in two type 2 GC, but not in any type 1 GC, while combined chromosomal losses of 1p and 19q were not found at all. Our data suggest that GC consists of two histological/molecular subtypes, type 1 being clearly distinct from diffuse astrocytoma, and type 2 sharing features with diffuse astrocytoma.

Long-term administration of adjuvant temozolomide is common practice in many institutions, especially when treatment is well tolerated and stable disease is achieved. In this study, we evaluate the feasibility and efficacy of long-term temozolomide in patients with glioblastoma multiforme treated at a single institution. One hundred and fourteen patients with newly diagnosed glioblastoma were followed for the course of their disease. Treatment consisted of surgery [gross total resection (GTR) subtotal resection (STR) or biopsy] followed by radiotherapy and concomitant temozolomide. Adjuvant temozolomide was administered until evidence for progressive disease or serious side effects occurred. Follow-up was routinely performed every 3 months. One hundred and fourteen patients with glioblastoma multiforme received a median of 6 cycles of adjuvant first-line temozolomide (range 1–57). For patients with less than 6 cycles, chemotherapy was stopped in 60% for reasons other than progression, while only in 17% of patients receiving 6 or more (P

Dendritic cells (DC) are potent antigen-presenting cells capable to induce efficient antigen-specific T cell responses in vitro and in vivo. Herein, the maturation process is of great significance, as immature DC (iDC) are known to induce rather regulatory than effector T cell differentiation. This study was designed to characterize the role of the CD40-CD40L pathway for differentiation and function of human DC. Therefore, iDC were stimulated through CD40-CD40L interaction by transduction of DC with adenoviral vectors encoding for CD40L (Ad-CD40L). Resulting DC (CD40L-DC) were analysed concerning their phenotype, cytokine profile and T cell stimulatory capacity. Transduction induced a DC phenotype comparable to stimulation with proinflammatory cytokines as revealed by upregulation of CD83 and the costimulatory molecules CD80 and CD86. Additionally, Ad-CD40L-induced strong production of IL-12p70 not observed in cytokine-matured DC. Surprisingly, the T cell stimulatory capacity was markedly reduced in CD40L-DC. Furthermore, stimulation of CD8(+) T cells by peptide-loaded CD40L-DC resulted in a substantial reduction of antigen-specific IFN-gamma production. This phenomenon is due to an enhanced IL-10 production of CD40L-DC in DC-T cell coculture as well as a stabilization of the IL-10 receptor expression on activated T cells. These data demonstrate that DC stimulated through CD40-CD40L interaction differentiate into tolerogenic DC with immunomodulatory function.

Naturally occurring CD4(+) CD25(+) regulatory T-cell (Treg) activity is assumed to facilitate tumor development and progression. To elucidate the possible role of Tregs in the course of melanoma progression, we analysed the frequency of Tregs in the peripheral blood of patients at melanoma stages I-IV and in patients at melanoma stage IV that underwent dendritic cell (DC)-based immunotherapy. Using CD25, Foxp3, CD127 and HLA-DR as Treg associated markers, we observed increased Treg frequencies in patients at the late melanoma stage (stage IV) when compared to healthy donors. Accumulation of Tregs in patients with progressed melanoma correlated with a general reduction of T-cell responsiveness to the recall antigens tetanus toxoid and tuberculin-GT. However, DC-based immunotherapy not only restored antigen-specific immunity, but also decreased the frequency of Tregs in peripheral blood of patients with melanoma. These findings indicate that tumor progression in patients with melanoma result in general immunosuppression that is associated with Treg expansion in the periphery and can be overcome by DC-based vaccination.

Object Several approaches have been established for the treatment of intracranial hypertension; however, a considerable number of patients remain unresponsive to even aggressive therapeutic strategies. Lumbar CSF drainage has been contraindicated in the setting of increased intracranial pressure (ICP) because of possible cerebral herniation. The authors of this study investigated the efficacy and safety of controlled lumbar CSF drainage in patients suffering from intracranial hypertension following severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH). Methods The authors prospectively evaluated 100 patients—45 with TBI and 55 with SAH—having a mean age of 43.7 ± 15.7 years (mean ± SD) and suffering from refractory intracranial hypertension (ICP > 20 mm Hg). Intracranial pressure and cerebral perfusion pressure (CPP) before and after the initiation of lumbar CSF drainage as well as related complications were documented. Patient outcomes were assessed 6 months after injury. Results The application of lumbar CSF drainage led to a significant reduction in ICP from 32.7 ± 10.9 to 13.4 ± 5.9 mm Hg (p < 0.05) and an increase in CPP from 70.6 ± 18.2 to 86.2 ± 15.4 mm Hg (p < 0.05). Cerebral herniation with a lethal outcome occurred in 6% of patients. Thirty-six patients had a favorable outcome, 12 were severely disabled, 7 remained in a persistent vegetative state, and 45 died. Conclusions Lumbar drainage of CSF led to a significant and clinically relevant reduction in ICP. The risk of cerebral herniation can be minimized by performing lumbar drainage only in cases with discernible basal cisterns.

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alphabeta CD8(+) T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-gamma (IFN-gamma) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-gamma treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells.

Glioblastoma multiforme is the prototype of an angiogenic tumour. Under experimental conditions, anti-angiogenic therapy strategies lead to an increased invasion. Here we report on the pattern of tumour recurrence in glioblastoma patients treated with an anti-angiogenic chemotherapy.A total of 32 patients with glioblastoma multiforme and a residual tumour mass after operation were treated with a continuous low-dose chemotherapy with temozolomide and a COX-II inhibitor, a presumably anti-angiogenic therapy.While anti-tumour activity of this therapy regimen was excellent with a mean overall time to progression of 10.4 (+/-0.9) months and a mean overall survival of 17.8 (+/-1.5) months, an unusually high rate of distant recurrences was observed (62.5%).Patients treated with an anti-angiogenic chemotherapy experience distant recurrences at a higher rate than reported for conventional therapies. This may reflect an anti-angiogenic therapy-induced activation of glioma invasion confirming similar recently published experimental results.

Symptomatic intramedullary arachnoid cysts are rare, especially in children; these lesions are rarely described as a cause of spinal cord compression in this age group. The authors report on an 18-month-old boy who experienced a sudden loss of his ability to stand and walk due to a paraparesis. Magnetic resonance imaging of the spine exhibited a cystic intramedullary lesion at the level of T5–6. A hemilaminectomy was performed, and after myelotomy the cystic lesion was decompressed by fenestration to the subarachnoid space. The histopathological examination verified the diagnosis of an arachnoid cyst. In the postoperative course the boy experienced complete resolution of the initial paraparesis.

Despite as yet limited clinical effectiveness, dendritic cell (DC)-based immunotherapy remains a promising approach for the treatment of cancer, but requires further improvement in its immunostimulatory effectiveness. Potent anti-tumor immunity often depends on the induction of type 1 (T(H)1) immune responses. Therefore, we combined different DC maturation stimuli that are known to induce T(H)1 immunity [anti-CD40, interleukin (IL)-12, IL-18], with the aim to trigger a T(H)1 driven anti-tumor CTL response. When compared with untreated DC or DC treated with anti-CD40 alone, DC matured with anti-CD40 plus IL-12 and IL-18 expressed significantly more IFN-gamma and IL-12, induced enhanced CD8(+) T-cell proliferation, prolonged synaptic interaction with T cells and increased CD8(+) T-cell-mediated cytotoxicity. To analyse if these DC are able to induce efficient anti-tumor immunity, mice carrying a B16-OVA tumor were treated with tumor antigen (TA)-loaded DC that had been exposed to anti-CD40 or to anti-CD40 plus IL-12 and IL-18. Our data show that anti-CD40 plus IL-12 and IL-18 matured DC are superior to controls in retarding tumor growth. These data indicate that maturation of DC with anti-CD40 plus IL-12 and IL-18 potently stimulates the generation of an anti-tumor immune response and may lead to improved immunotherapeutic capacity of DC vaccination.