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The nasal decongestant oxymetazoline (OMZ) is frequently used in the topical treatment of rhinitis/sinusitis. As proinflammatory cytokines play a critical role in the development and maintenance of local inflammation, the aim of this study was to investigate the influence of OMZ on immune cells in order to diminish the mucosal infiltration of the nose. Peripheral blood mononuclear cells (PBMC) from buffy coats of healthy volunteers were isolated and stimulated in the presence or absence of OMZ. In addition, monocyte-derived dendritic cells (DC) were generated and different concentrations of OMZ were added. DC phenotype and their T-cell stimulatory properties were analysed. The vasoactive substance OMZ showed a concentration dependent inhibitory effect on T-cell activation as well as a dominant effect on T-cell stimulatory properties of DC. Low concentrations of OMZ inhibited the proliferation of polyclonally activated T cells. In addition, secretion of proinflammatory mediators such as the cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF alpha), IL-6 and IL-8 were inhibited in the presence of physiological doses of OMZ. Interestingly, the addition of IL-6 to DC-T-cell co-culture was able to completely restore T-cell proliferation. In conclusion, these findings indicate that the anti-inflammatory properties of OMZ are partially mediated by the inhibition of proinflammatory cytokines as well as reduced T-cell stimulatory capacity of DC resulting in a repressed stimulation of T cells. Therefore, the therapeutic benefit of OMZ can be explained in part by its immunomodulating effects in the topical treatment of nasal inflammation.

Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status.A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase-2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis.The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded.In patients with decreased general condition (KPS70), not eligible for standard treatment, anti-angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care.

Current models of emotion simulation propose that intentionally posing a facial expression can change one's subjective feelings, which in turn influences the processing of visual input. However, the underlying neural mechanism whereby one's facial emotion modulates the visual cortical responses to other's facial expressions remains unknown. To understand how one's facial expression affects visual processing, we measured participants' visual evoked potentials (VEPs) during a facial emotion judgment task of positive and neutral faces. To control for the effects of facial muscles on VEPs, we asked participants to smile (adopting an expression of happiness), to purse their lips (incompatible with smiling) or to pose with a neutral face, in separate blocks. Results showed that the smiling expression modulates face-specific visual processing components (N170/vertex positive potential) to watching other facial expressions. Specifically, when making a happy expression, neutral faces are processed similarly to happy faces. When making a neutral expression or pursing the lips, however, responses to neutral and happy face are significantly different. This effect was source localized within multisensory associative areas, angular gyrus, associative visual cortex and somatosensory cortex. We provide novel evidence that one's own emotional expression acts as a top-down influence modulating low-level neural encoding during facial perception.

A significant percentage of stage II melanoma patients (tumor thickness >1 mm) remain at risk of tumor recurrence after primary tumor excision. In this study, we used tumor antigen-pulsed dendritic cells as an adjuvant for immunization of these “high-risk” melanoma patients after resection of the primary tumor. A total of 13 patients were included and vaccinated 6 times every 14 days with autologous dendritic cells pulsed with a MelanA/MART-1 peptide in combination with a recall antigen. Antigen-specific immune responses were monitored before, during and up to 1 year after the last vaccination. The majority of patients exhibited increased recall antigen-specific CD4+ T cell responses upon vaccination. MelanA/MART-1-specific CD8+ T cells were expanded in 9/13 patients resulting in increased frequencies of memory cells in these patients. CD8+ T cells acquired the capacity to secrete IFN-γ, to proliferate in culture in response to the tumor antigen used for vaccination and postvaccine samples contained MelanA/MART-1-specific T cells that recognized also the natural MelanA/MART-1-antigen expressed by tumor cells. Moreover, vaccination induced a long-lived tumor antigen-specific DTH-reactivity in the majority of the patients, detectable even 12 months after the last immunization. These data demonstrate for the first time that vaccination with tumor antigen-pulsed dendritic cells in a clinically adjuvant setting induces strong and persistent antigen-specific T-cell responses in tumor-free stage II melanoma patients, suggesting that tumor protective T cell immunity can be achieved. © 2005 Wiley-Liss, Inc.

In recent years, vaccination strategies using antigen-presenting cells (APC) have been under investigation. Antigen delivery using genetic immunization through ex vivo transduction of dendritic cells (DC) is supposed to enhance the induction of antitumor responses in humans by activating a broad range of peptide-specific CD8+ T cells. In this study, we compared the potential of adenoviral (Ad)-transduced versus peptide-pulsed DC to induce melanoma-antigen (Ag)-specific T-cell responses in vitro. Whereas gp100-peptide-pulsed DC induced long-lasting specific CD8+ T-cell responses against single peptides, Ad-transduced DC induced broad and strong, specific immunity against various peptides of the gp100-Ag. Surprisingly, several restimulations led to decreasing gp100-specific and in parallel to increasing anti-adenoviral T-cell responses. Nevertheless, those anti-adenoviral T-cell responses provided an "adjuvant" effect by inducing an early release of high amounts of IL-2/IFN-gamma, therewith enhancing CTL induction in the initiation phase. Based on these data, we suggest a prime/boost vaccination strategy in melanoma patients--combining the use of Ad-DC and peptide-pulsed DC--to obtain efficient and long-term antitumor T-cell responses.

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-α is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF-α and deliver it into various cancer cell lines and dendritic cells. Half-maximal effective concentration (EC50 ) for loaded TNF-α is reduced by more than two orders of magnitude. Particle stability and premature cargo release are assessed with enzyme-linked immunosorbent assay. TNF-α-loaded particles are stable for up to 5 d in medium. Tumor cells are grown in vitro as 3D fluorescent ubiquitination-based cell cycle indicator spheroids that mimic in vivo tumor architecture and microenvironment, allowing real-time cell cycle imaging. DMSN penetrate these spheroids, release TNF-α from its pores, preferentially affect cells in S/G2/M phase, and induce cell death in a time- and dose-dependent manner. In conclusion, DMSN encapsulation is demonstrated, which is a promising approach to enhance delivery and efficacy of antitumor drugs, while minimizing adverse side effects.

e17566 Background: Sentinel Lymph Node Biopsy (SLNB) is the standard procedure for malignant melanoma with a thicknes above 1mm. However, the benefits of this procedure have recently been questioned because of a high number of false negative findings. The aim of our study was to investigate the number of early recurrence in patients with negative SLNB. Methods: All patients with malignant melanoma of the head and neck region who underwent SLNB between 2010 and 2016 in our department were included and data reviewed retrospectively. Recurrence in the same cervical lymph node region of the previously extirpated sentinel lymph node (SLN) within one year was defined as primary false-negative. Results: Allover 101 patients were investigated (mean age 62.48 years (±17.66; 73.3% ♂, 26.7% ♀). Most frequent location of the primary melanoma were the cheeks and ears (each 18.8%), followed by the hair bearing region (13.9%). Superficial Spreading Melanoma and Nodular Melanoma were the most frequently seen subtypes (each 23.8%), followed by Lentigo maligna Melanoma (19.8%). Median thickness of all patients was 2.5mm (min: 0.15 – max: 10.0 mm). In average 3 SLN were removed during operation (min: 1 – max 16). In 79.2% of the cases the SLN was negative. 13% showed one metastasis, 5.2% showed two and 1.6% three metastases. Positive findings in the SLN were significantly correlated with T-classification. Ulceration and tumor thickness showed significant tendencies in Χ2-Test and Mann-Whitney-Test. Out of the patients with negative SLN 13.1% had at least one metastasis in a cervical lymph node of the same region within one year. Mean duration until recurrence was 6.5 months. 75.0% of the metastases in our study were diagnosed within this period. 62.5% of the patients with secondary positive SLN had a tumor of intermediate thickness (between 1mm and 4mm). Conclusions: With 13.1 % secondary positive SLN this study shows that SLNB has a high rate of false-negative findings. However, SLNB has lower complication rates compared to traditional lymph node extirpation. This study shows that patients with negative SLN especially with intermediate tumor thickness should be controlled by ultrasound or computer tomography in short intervals.

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.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.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.This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling.

The involvement of nitric oxide (NO) in cerebral blood flow (CBF) stimulation by acetazolamide was studied in anaesthetised, mechanically ventilated Wistar rats. CBF was monitored by laser Doppler scanning. Acetazolamide induced a long-lasting significant rCBF-increase. Application of N G -Nitro- l -arginine (L-NNA), an inhibitor of all NO synthetases (NOS), prevented CBF stimulation by acetazolamide. Continuous infusion of the exogenous NO donor SIN-1 (3-morpholinosydnonimine) suppressed L-NNA induced increases of mean arterial blood pressure without effect on rCBF in comparison to baseline. Additional acetazolamide injection then again caused a significant increase of rCBF in spite of NOS-inhibition. We thus conclude that NO is involved in acetazolamide-induced CBF stimulation. The mere continuous presence of NO is sufficient to re-establish the acetazolamide-response in spite of NOS-inhibition. These data suggest that NO acts rather as a modulator than as a mediator of the acetazolamide-induced CBF response.

A subpopulation of peripheral human CD4(+)CD25(+) T cells that expresses CD45RO, histocompatibility leukocyte antigen DR, and intracellular cytotoxic T lymphocyte-associated antigen (CTLA) 4 does not expand after stimulation and markedly suppresses the expansion of conventional T cells in a contact-dependent manner. After activation, CD4(+)CD25(+) T cells express CTLA-4 on the surface detectable for several weeks. These cells show a G1/G0 cell cycle arrest and no production of interleukin (IL)-2, IL-4, or interferon (IFN)-gamma on either protein or mRNA levels. The anergic state of CD4(+)CD25(+) T cells is not reversible by the addition of anti-CD28, anti-CTLA-4, anti-transforming growth factor beta, or anti-IL-10 antibody. However, the refractory state of CD4(+)CD25(+) T cells was partially reversible by the addition of IL-2 or IL-4. These data demonstrate that human blood contains a resident T cell population with potent regulatory properties.

Dendritic cells (DCs) elicit potent anti-tumoral T-cell responses in vitro and in vivo. However, different types of DC have yet to be compared for their capacity to induce anti-tumor responses in vivo at different developmental stages. Herein, we correlated the efficiencies of different types of monocyte-derived DC as vaccines on the resulting anti-tumor immune responses in vivo. Immature and mature DCs were separately pulsed with a peptide derived from tyrosinase, MelanA/MART-1 or MAGE-1 and a recall antigen. Both DC populations were injected every 2 weeks in different lymph nodes of the same patient. Immune responses were monitored before, during and after vaccination. Mature DCs induced increased recall antigen-specific CD4(+) T-cell responses in 7/8 patients, while immature DCs did so in only 3/8. Expansion of peptide-specific IFN-gamma-producing CD8(+) T cells was observed in 5/7 patients vaccinated with mature DCs but in only 1/7 using immature DCs. However, these functional data did not correlate with the tetramer staining. Herein, immature DCs also showed expansion of peptide-specific T cells. In 2/4 patients vaccinated with mature DCs, we observed induction of peptide-specific cytotoxic T cells, as monitored by chromium-release assays, whereas immature DCs failed to induce peptide-specific cytotoxic T cells in the same patients. Instead, FCS-cultured immature DCs induced FCS-specific IgE responses in 1 patient. Our data demonstrate that this novel vaccination protocol is an efficient approach to compare different immunization strategies within the same patient. Thus, our data define FCS-free cultured mature DCs as superior inducers of T-cell responses in melanoma patients.

Background. Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. Methods. This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. Results. Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4 –41.4 mo) and a median OS of 46.9 months (range, 21.2–49.2 mo) for this subgroup. c-KITexpression in vascular endothelial cells (n ¼ 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/ dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. Conclusion. Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS.ClinicalTrials.gov Identifier: NCT00535379.

Translaminar approaches have been described for lumbar disc herniations which are displaced cranially or laterally into the neuroforamen. This technique provides the advantages of a minimally invasive approach with regard to postoperative instability or partial facet joint resection and avoids a medial arthrectomy. We describe this technique for the first time as an option for a caudally sequestrated disc herniation via a transaxillar sequesterotomy.

TGF- β is a highly pleiotropic cytokine and a well-known suppressor of inflammatory T cells. Dysregulation in TGF- β function is associated with multiple pathological phenomenons including tumor cell growth, fibrosis and autoimmunity. GARP (glycoprotein A repetitions predominant) is an activation maker on human regulatory T cells (Treg) which is known to modulate the bioavailability of TGF- β . To address the cell-independent regulatory capacity of GARP we generated a soluble GARP protein (sGARP). Interestingly, T cells cultured in presence of sGARP showed SMAD2/3 phosphorylation similar to TGF- β treated T cells. In addition, sGARP function was inhibited by blockade of TGF- β -signaling, suggesting that sGARP activity is at least in part dependent on TGF- β . To investigate the potential role of GARP as an immunomodulator of T cell function we analyzed the effect of sGARP on the activation and differentiation process of human CD4+ T cells. Exposure to sGARP induced Foxp3, decreased proliferation and repressed IL-2 and IFN-o production of naive T cells resulting in their differentiation into induced Treg. In contrast, in presence of IL-6 and IL-23, sGARP promoted the differentiation into Th17 cells. More importantly, in a pre-clinical humanized mouse model of xenogeneic graft-versus-host disease sGARP prevented T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. Taken together, our results indicate a modulating role for GARP in peripheral T cell tolerance and open the possibility to use sGARP as an immune modifier in treatment of inflammatory disorders such as autoimmune and allergic diseases.

Sinus thrombosis is an acute life-threatening disease. While cavernous sinus thrombosis secondary to facial infections is described in the literature, it is uncommon. The key clinical characteristics are a facial infection, headache, chemosis and edema of the eyelid. The main differential diagnostic consideration is meningoencephalitis. Early diagnosis by angiography, magnetic resonance imaging and examination of CSF is important as treatment should be initiated as soon as possible in order to decrease morbidity and mortality. The mainstays of therapy are heparinization and appropriate intravenous antibiotic therapy.

Objective To report extremely rare cases of ligamentum flavum hematomas in the cervical and thoracic spine. Only six cases of thoracic ligamentum flavum hematomas and three cases of cervical ligamentum flavum hematomas have been reported so far. Methods Two patients presented with tetraparesis and one patient presented with radicular pain and paresthesias in the T3 dermatome. MRI was performed in two patients, which showed a posterior intraspinal mass, continuous with the ligamentum flavum. The mass was moderately hypointense on T2-weighted images and hyperintense on T1-weighted images with no contrast enhancement. The third patient underwent cervical myelography because of a cardiac pacemaker. The myelography showed an intraspinal posterior mass with compression of the dural sac at C3/C4. Results All patients underwent a hemilaminectomy to resect the ligamentum flavum hematoma and recovered completely afterwords, and did not experience a recurrence during follow-up of at least 2 years. Conclusion This case series shows rare cases of ligamentum flavum hematomas in the cervical and thoracic spine. Surgery achieved complete recovery of the preoperative symptoms in all patients within days.

Objective: The chemokine receptor CXCR7 and its ligand SDF-1a are expressed on both glioma cells and tumor-associated vessels. Both molecules have been linked to cancer angiogenesis and tumor cell migration where CXCR7 is expressed on the migrating cells and SDF-1a acts as a chemoattractant. Currently[for full text, please go to the a.m. URL], 64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

APG101 is a glycosylated fusion protein consisting of the extracellular domain of human CD95 (APO-1/Fas) and the Fc domain of human IgG1. Administration of APG101 blocks the interaction between CD95 and its cognate ligand CD95L, thereby inhibiting various pathways involved in e.g. proliferation, migration, differentiation and apoptosis induction. The safety and tolerability of ascending single doses of intravenously applied APG101 was examined in a randomized, double-blind, placebo-controlled, mono-centre "first in man" dose escalation study in 34 healthy male volunteers. Pharmacokinetics and pharmacodynamics were also assessed. The maximum serum concentration of 460 tg/ml was achieved following 1 h infusion of the highest dose of 20 mg/kg. The systemic clearance was low (0.4 to 0.5 ml/h kg). Mean terminal elimination half-life was 12 to 15 days. Two patients suffering from malignant glioma received APG101 intravenously under compassionate use conditions. They received doses ranging from 5 mg to 600 mg APG101. No adverse events and no clinical significant changes in laboratory parameters related to APG101 were reported. The presence of anti-drug-antibodies (ADA) was investigated and revealed no detectable levels of ADA. Overall, single ascending doses of APG101 up to 20 mg/kg body weight (bw) administered as infusion over 1 h were considered as safe and well tolerated in healthy volunteers. After the application of multiple doses of 400 mg in two glioma patients, steady state for APG101 seemed to be reached. These results support further clinical evaluation of APG101 at a dose of 400 mg per week: in glioblastoma patients. (C) 2012 Elsevier B.V. All rights reserved.

BACKGROUND AND AIMS OF THE STUDY The diagnosis and treatment of low-grade gliomas (LGG) are multimodal. Today, there is no defined standard in diagnosis and treatment. Controversies are, in general, about a "wait-and-see" strategy, diagnostic workup, surgical intervention, postoperative imaging, adjuvant treatment, and follow-up. The aim of this study is to gain an overview about management strategies of high-volume German neurosurgical departments treating these patients. MATERIAL AND METHODS A questionnaire including diagnostic, preoperative, perioperative, and postoperative parameters and 5 cases with magnetic resonance imaging data with questions to various treatment options in these patients was sent to all 34 German neurosurgical departments at university hospitals. RESULTS In total, 24 questionnaires were returned and analysed. Centres were divided into those who generally practice a "wait-and-see" strategy vs. those who do not or only in highly selected cases. Statistical analyses were performed with Fisher test and Chi (2)-test. Interestingly, 50% of all centres routinely follow a "wait-and-see" strategy. CONCLUSION Although the management of patients with LGG is complex and a simple questionnaire will not be able to define a standard in diagnosis and treatment, this study offers an overview on strategies at high-volume academic centres dealing with these patients. There is consensus to resect superficially located lobar and circumscribed low-grade lesions. However, the differences between centres become apparent with increasing complexity of the lesions.

Dendritic cells (DC) are professional antigen-presenting cells defined by their ability to transport incoming infectious signals from the periphery to T cell areas in lymphoid organs and by their unique properties to induce primary T cell activation. As sentinels of immunity DC play a critical role in the initiation of immune responses. Thus, they are key targets in antigen-specific immunotherapeutic strategies for cancer. However, beside this essential immunostimulatory function in the immune system, DC also play an important role in the maintenance of peripheral tolerance. Dependent on subtype and mode of activation, tissue resident immature DC differentiate into immunostimulatory or immunosuppressive antigen-presenting cells with a strong capacity to activate or to inhibit T cell responses, respectively. This review summarizes our current knowledge about the complex interaction between DC and T cells considering both--immunity and tolerance--as well as the possibilities to use this knowledge for development of novel diagnostic and immunotherapeutic strategies to treat immune-imbalanced human diseases such as cancer, allergy, and autoimmunity.

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.The study consisted of 15 patients with histologically confirmed recurrent gliomas. Dynamic PET scans using ⁶⁸Ga-BZH₃ and FDG were obtained on 2 different days within 1 week. Multivariate analysis was used for the evaluation of the kinetic data. Standardized uptake values were calculated and a compartment (2-tissue) as well as a noncompartment model was used for data evaluation of both tracers.The evaluation includes 6 patients with a WHO II, 6 patients with a WHO III, and 3 patients with a WHO IV recurrent gliomas. Of the 15 patients, 10 patients demonstrated an increased ⁶⁸Ga-BZH₃ uptake visually, 3 of them with a WHO II, 4 with a WHO III, and 3 with a WHO IV tumor. Of the 15 patients, 6 patients revealed an enhanced FDG metabolism visually, 3 of them with a WHO II, and 3 with a WHO III. None of the 3 patients with WHO IV tumor demonstrated an enhanced FDG-uptake. Discriminant analysis based on a combination of FDG influx and binding potential of ⁶⁸Ga-BZH₃ best discriminated between low- and high-grade gliomas with a correct classification rate of 100%.⁶⁸Ga-BZH₃ seems to be helpful in patients with recurrent gliomas for the differentiation between low- and high-grade gliomas. Overall, the quantitative evaluation was superior to the visual analysis and the parameters of the ⁶⁸Ga-BZH₃ kinetics were more helpful than those of FDG for the differentiation between low- and high-grade gliomas.

Prolonged administration of temozolomide is widely used in patients with glioblastoma; whereas the treatment of anaplastic glioma differs between neurooncological centres. The safety, feasibility and efficacy of prolonged temozolomide administration in patients with anaplastic gliomas was evaluated.Forty-two patients with primary, recurrent or secondary anaplastic glioma were retrospectively analysed for the course of their disease. Treatment mostly consisted of surgery, followed by radiotherapy with concomitant and adjuvant temozolomide. In five patients with recurrence of primary anaplastic glioma, chemotherapy was initiated without previous surgery. Temozolomide was administered until evidence of tumour recurrence, appearance of serious side-effects or patients' wish to finish chemotherapy.The median overall survival (OS) was 39 months with a median cycle number of 7.5 (1-42). Treatment with temozolomide was stopped in 12 patients due to side-effects in general, whereas in only three patients (7.1%) treatment had to be discontinued due to haematological side-effects. There was no evidence of treatment related infections or grade IV toxicity. Extent of surgery had a significant influence on OS in anaplastic gliomas, the number of adjuvant temozolomide cycles showed a positive influence as well on time to progression (TTP) and OS.Prolonged administration of adjuvant temozolomide is safe and can be favorable for patients with anaplastic gliomas.

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 naïve 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.

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.

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.

Translaminar approaches have been described for lumbar disc herniations which are displaced cranially or laterally into the neuroforamen. This technique provides the advantages of a minimally invasive approach with regard to postoperative instability or partial facet joint resection and avoids a medial arthrectomy. We describe this technique for the first time as an option for a caudally sequestrated disc herniation via a transaxillar sequesterotomy.

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m(2) twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-L-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8-12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.

Gliomatosis cerebri is a rare primary cerebral tumour entity characterized by diffuse infiltrative growth patterns representing a WHO grade III malignancy. The prognosis is dismal and therapeutical options are still controversial. In contrast to other high-grade gliomas, angiogenesis is thought to be absent in gliomatosis cerebri.Despite this assumption, histopathological analyses of samples of six patients with gliomatosis cerebri were performed and surprisingly there was angiogenic activity with expression of vascular endothelial growth factor and cyclooxygenase 2. It was therefore decided to administer continuous low-dose chemotherapy with temozolomide and celecoxib for antiangiogenic treatment in the four patients that were in good clinical condition following external radiotherapy.In all patients, treatment was well tolerated and MRI follow-up showed no tumour progression for at least six months. One patient died due to pulmonary embolism 9 months after diagnosis; another patient survived 15 months after diagnosis with progressive disease in the last follow-up MRI before death. Two other patients at the present time are still in a stable clinical condition without signs of tumour progression in MRI (12 and 18 months).From our initial experience in a small number of patients with gliomatosis cerebri with signs of angiogenic activity, we conclude that low-dose chemotherapy might provide a promising approach for treatment of these patients and that overexpression of angiogenic factors such as VEGF or COX-2 seems to be more frequent than hitherto reported.

Glioblastoma multiforme is the most common and most malignant primary brain tumour. Prognosis after diagnosis remains poor despite recent advances in adjuvant therapy. Treatment of choice is gross surgical resection and combined radio-chemotherapy with temozolomide as chemotherapeutic agent. Experimental continuous low-dose chemotherapy with temozolomide in combination with a cyclooxygenase-2 inhibitor has shown encouraging effects on progression-free survival and overall survival in patients, but leads to a high proportion of distant recurrences. Here, we describe extreme far-distant metastases along the neural axis of glioblastoma multiforme in four patients receiving metronomic antiangiogenic chemotherapy and review the literature to discuss possible mechanisms.

Recent experimental work suggests that circulating endothelial progenitor cells (cEPCs) are recruited to the angiogenic vascular system of malignant gliomas. Consequently, the level of cEPCs has been proposed as a novel biomarker for the diagnosis and monitoring of these lesions. The aim of the present study was to examine the level of cEPCs and the level of EPC mobilizing mediators in the blood of patients with malignant gliomas. The authors were also interested in whether a correlation could be observed between the level of cEPCs and the extent of glioma angiogenesis determined by conventional methods.Peripheral blood mononuclear cells from the whole blood of 12 patients with malignant gliomas (all glioblastomas multiforme [GBMs]), 10 with metastases to the brain, and 10 healthy volunteers were isolated using Ficoll density gradient centrifugation. The number of cEPCs was quantified by fluorescence-activated cell sorting analysis using antibodies against CD34, CD133, and VEGFR-2. Serum concentrations of VEGF and granulocyte-macrophage colony-stimulating factor (GM-CSF) were determined using the enzyme-linked immunosorbent assay. Histological analysis of tumor blood vessel density was performed by CD34 immunohistochemical staining.The number of cEPCs was significantly higher in patients with GBMs than in those with metastases (p0.04) or in the healthy volunteers (p0.004). The serum VEGF concentrations in patients with GBMs and metastases were significantly higher than in the healthy volunteers (p0.0001). Similar findings were observed for concentrations of GM-CSF. In addition, the patients in the GBM group with higher levels of cEPCs had significantly higher tumor blood vessel densities (1.71 +/- 1.17% of total area) compared with patients who had low levels of cEPCs (0.62 +/- 0.28% of total area; p0.02).Endothelial progenitor cells are increasingly mobilized in patients with malignant gliomas, and their levels correlate with tumor angiogenic activity. Therefore, the authors' results suggest that cEPCs may have the potential to serve as a novel biomarker for the identification of patients who would benefit from antiangiogenic therapy for GBM.

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.

Tolerogenic dendritic cells (DC) play an important role in maintaining peripheral T cell tolerance in steady-state conditions through induction of anergic, IL-10-producing T cells with suppressive properties. ICOS, an activation-induced member of the CD28 family on T cells, is involved in the induction of IL-10, which itself could contribute to induction of anergy and development of suppressive T cells. Therefore, we analyzed the functional role of ICOS in the differentiation process of human CD4+ T cells upon their interaction with tolerogenic DC. We compared the functional properties of CD4+ T cells from healthy volunteers and ICOS-deficient patients after stimulation with tolerogenic DC. We report that induction of T cell anergy and suppressive capacity is completely blocked after knockdown of ICOS expression in T cells as well as after blocking of ICOS-ICOS ligand interaction in DC/T cell cocultures. Moreover, CD4+ T cells from ICOS-deficient patients were completely resistant to anergy induction and differentiation into suppressive T cells even after supplementation of IL-10. Furthermore, ICOS/ICOS ligand interaction stabilizes IL-10R expression on T cells and thus renders them sensitive to IL-10 effects. Taken together, these results indicate a crucial role for ICOS in the induction of peripheral tolerance maintained by tolerogenic DC mediated mostly via an IL-10-independent mechanism.

Treatment of gliomas is multimodal. Magnetic resonance imaging (MRI) in the posttreatment course is of limited value due to therapy-induced changes. In low-grade gliomas (LGG) malignant transformation is of special interest. Our patients and methods were as follows: In nine consecutive patients with LGG we examined the role of bombesin labelled with gallium-68 ((68)Ga-bombesin) studied with positron emission tomography (PET), in addition to fluoro-18-fluorodeoxyglucose ((18)F-FDG) in the differential diagnosis of tumour recurrence versus malignant transformation. We used (68)Ga-bombesin combined with (18)F-FDG-PET in these patients with suspicious new contrast enhancement at the original tumour site or resection cavity in MRI. Eight patients were operated. In one patient, tumour recurrence was most likely as shown by the PET findings and chemotherapy was administered. Our results have shown that in this last mentioned patient after the follow-up period, MRI contrast enhancement was definitively regressive. In the operated patients the tumour was graded as glioblastoma multiforme, gliosarcoma and WHO grade III tumour. In two patients histological grading confirmed the PET findings without malignant transformation. In all of the 9 patients the combination of (68)Ga-bombesin and (18)F-FDG-PET predicted correctly malignant transformation or recurrence of the initial tumour grade which shows that (68)Ga-bombesin-PET can provide additional important information to detect a malignant transformation. In conclusion it is crucial for the patient to differentiate the nature of the new lesion in order to endorse an aggressive or non-aggressive treatment.

Thrombocytosis, which is defined as a platelet count greater than 400 platelets/nl, has been found to be an independent predictor of shorter survival in various tumors. Release of growth factors from tumors has been proposed to increase platelet counts. Preoperative platelet counts and other clinical and hematological parameters were reviewed from the records of 153 patients diagnosed between 1999 and 2004 with histologically confirmed glioblastoma in order to evaluate the prognostic significance of preoperative thrombocytosis in these patients. The relationship between thrombocytosis and survival was initially analyzed in all patients regardless of further therapy. Univariate log-rank tests showed that the median survival time of 29 patients with preoperative thrombocytosis (19%) was significantly shorter (4 months; 95% confidence interval [95% CI], 3-6 months) compared to 124 patients with normal platelet counts (11 months; 95% CI, 8-13 months; p = 0.0006). Multivariate analysis (Cox proportional hazards model) confirmed preoperative platelet count, age, prothrombin time, and activated partial thromboplastin time to be prognostic factors of survival (all p < 0.05). In a subset of patients (only operated patients with radiation therapy with or without additional chemotherapy), survival was likewise significantly shorter when preoperative thrombocytosis was diagnosed (6 months; 95% CI, 4-12 months) compared to patients with normal platelet count (13 months; 95% CI, 11-15 months; p = 0.0359). In multivariate analysis, age, platelet count, preoperative prothrombin time, and degree of tumor resection retained significance as prognostic factors of survival (all p < 0.05). The results of our study demonstrate preoperative thrombocytosis to be a prognostic factor associated with shorter survival time in patients with glioblastoma.

Dendritic cells (DC) are professional antigen-presenting cells in the immune system which are able to induce primary T-cell responses. Because of their central role in the initiation of immune responses, DC are an important tool for tumor-antigen-specific immunotherapy of cancer. DC vaccination using tumor-antigen-loaded DC has led to tumor regression in individual advanced-stage cancer patients. However, there is a discrepancy between strong and antigen-specific T cell responses in vaccinated cancer patients detectable ex vivo and only weak clinical responses. In most cases the immune system of advanced stage IV cancer patients allows only a temporary anti-tumor response and increasing evidence exists that active suppressive mechanisms of the immune system as well as of the tumor itself ultimately prevent "autoaggressive" immune reactions against the tumor. Active counter-regulation of effector T cells by tumor-antigen-specific regulatory T-cell (Treg) populations play a central role in limiting the efficacy of the vaccines. Nevertheless, recent studies have shown that DC,additionally activated byToll-Like-receptor ligands (TLRL) can neutralize these suppressive effects of Treg and facilitate the induction of long-lasting effector T cell responses even in the presence of activated Treg. These studies open a new way for "conditioning" of DC by TLRL and might significantly enhance the efficiency of DC-based melanoma vaccines in the future.

Aims and background We retrospectively analyzed the impact of different adjuvant chemotherapy regimens in a group of patients treated for glioblastoma compared to patients receiving only postoperative radiotherapy. Material and methods Eighty-six consecutive patients underwent radiotherapy between January 2000 and December 2003: 52 patients received radiotherapy alone, 17 patients radiochemotherapy with low-dose temozolomide (20 mg/m2) + cyclooxygenase-2-inhibitors (200 mg), 6 patients radiochemotherapy with high-dose temozolomide (50 mg/m2). Eleven patients, with unfavorable prognostic factors, were treated with imatinib and 55/2.5 Gy. Results The groups treated with high- and low-dose temozolomide showed the longest overall survival (median, 21 months and 17 months, respectively). Median overall survival was 9 months for radiation alone and 4 months for the imatinibtreated group. The same positive trend of temozolomide on prolonged overall survival was confirmed when only patients submitted to maximally radical resection or patients with KPS >70 were considered. Differences in progression-free survival were not statistically significant. Conclusions Patients treated with adjuvant temozolomide either inside or outside of study protocols had survival times similar to other reports or randomized studies. The absence of a significant influence of temozolomide on progression-free survival could depend on the unavoidable drawbacks and biases of retrospective investigations or on the definition of relapse used. The unsatisfactory results of radiotherapy plus imatinib may have been due to a high prevalence of unfavorable prognostic factors in the respective patients. The ongoing controlled trial will further define the efficacy of adjuvant/concomitant imatinib.

The prognosis of malignant gliomas is still dismal despite aggressive treatment attempts. Thus, alternative therapy strategies are needed. Malignant gliomas are upon the best vascularized tumors in humans and their proliferation is hallmarked by a distinct proliferative vascular component. Hence it seems to be a logical consequence to apply anti-angiogenic treatment strategies to malignant gliomas. These treatment strategies have shown promising effects in animal models and some experimental clinical studies. This review gives a short introduction into the molecules involved in angiogenesis of malignat gliomas, it provides an overview of the latest experimental developments of glioma angiogenesis inhibition and discusses the results of clinical anti-angiogenic trials in patients with high grade glioma. Additionally the problem of monitoring the treatment success of an anti-angiogenic therapy is addressed.