Low FoxG1 and high Olig-2 labelling indices define a prognostically favourable subset in isocitrate dehydrogenase (IDH)-mutant gliomas.

AIMS: Previous data suggest that expression of transcription factors FoxG1 and Olig-2 can separate hotspot histone H3 family member 3A (H3F3A)-mutant tumours in paediatric glioma. We evaluated their prognostic potential and feasibility for identifying H3F3A-mutant tumours among IDH-mutant/wild-type gliomas. METHODS: Immunohistochemistry of FoxG1/Olig-2 and α-thalassaemia/mental-retardation-syndrome-X-linked gene (ATRX) in 471 cases of diffuse gliomas and molecular determination of IDH, H3F3A, MGMT and 1p/19 codeletion status. RESULTS: Mean percentage of FoxG1-positive tumour cells increased from 17% in WHO grade II to over 21% in grade III to 37% in grade IV tumours, whereas mean Olig-2 indices decreased from 29% to 28% to 17% respectively. FoxG1 indices were similar in astrocytic and oligodendroglial tumours, whereas Olig-2 indices were increased in oligodendrogliomas compared to astrocytic tumours (n = 451, P < 0.0001). FoxG1-positive nuclei were significantly reduced in IDH and H3F3A K27-mutant tumours, whereas Olig-2-positive nuclei were significantly reduced in IDH-wild-type and H3F3A G34-mutant tumours. Among IDH-mutant tumours, mean Olig-2 index was significantly higher in 1p/19q codeleted tumours (mean: 43%) compared to IDH-mutant tumours with ATRX loss (mean: 23%, P < 0.0001). A significantly better outcome was first suggested for FoxG1low tumours (n = 212, log rank P = 0.0132) and Olig-2high tumours (n = 203, log-rank P = 0.0011) based on classification and regression tree determined cutoffs, but this was not confirmed by multivariate analysis including IDH mutation, WHO grade, ATRX status and age. CONCLUSIONS: While the combined FoxG1/Olig-2 profile may discriminate H3F3A K27- and G34-mutant tumours and define a prognostically favourable subset in IDH-mutant gliomas, our data show that labelling indices of these transcription factors overlap with adult IDH-mutant and wild-type tumour classes.

Effect of the FXa inhibitors Rivaroxaban and Apixaban on platelet activation in patients with atrial fibrillation.

Rivaroxaban and Apixaban, increasingly used for stroke prevention in non-valvular atrial fibrillation (AF), might impact platelet reactivity directly or indirectly. By inhibition of Factor Xa (FXa) they preclude not only generation of relevant thrombin amounts but also block signalling of FXa via protease activated receptors. However, weather FXa-inhibition affects platelet haemostasis remains incompletely known. One hundred and twenty-eight patients with AF on chronic anticoagulation with either Rivaroxaban or Apixaban for at least 4 weeks were included in the study. In a time course group (25 on Rivaroxaban, 13 on Apixaban) venous blood samples were taken before NOAC medication intake in the morning as well as 2 and 6 h afterwards. In 90 patients (Rivaroxaban n = 73, Apixaban n = 17) blood samples were drawn during left atrial RFA procedures before as well as 10 and 60 min after the first heparin application (RFA group). Platelet reactivity analyzed by whole blood aggregometry (Multiplate Analyzer, Roche) in response to ADP, Collagen, TRAP and ASPI (arachidonic acid) was not altered by Rivaroxaban or Apixaban neither in the time course nor in the RFA group. Moreover, soluble P-selectin, Thrombospondin, von Willebrand Factor and beta thromboglobulin plasma levels, measured by ELISA, showed no statistically significant changes in both clinical settings for either FXa-inhibitor. The present study fails to demonstrate any significant changes on platelet reactivity in patients with AF under chronic Rivaroxaban or Apixaban medication, neither for trough or peak levels nor in case of a haemostatic activation in vivo as depicted by RFA procedures.

Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: chemical synthesis, mechanistic studies, and effectiveness in vivo.

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

[New ESH/ESC guidelines on arterial hypertension : what is new and what indications remain for renal denervation?]. / Neue ESH/ESC-Leitlinien für die arterielle Hypertonie : Was ist neu, und welche Indikation bleibt für die renale Denervierung?

Arterial hypertension is one of the most common diseases in the western world and one of the most important risk factors for other cardiovascular diseases. Despite widespread therapeutic options, there is still a large proportion of patients with uncontrolled hypertension. The new European guidelines on hypertension give clear lines of action for diagnosis and treatment sorted into appropriate evidence levels based on current scientific data. Such evidence is still unclear for renal denervation so that no clear recommendations can be given.

Circulating tissue factor and microparticles are not increased in patients with deep vein thrombosis.

BACKGROUND: Circulating tissue factor (TF) is associated with inflammation and may contribute to thrombotic events. Aim of this study was to analyze circulating TF activity and proinflammatory cytokines in patients with deep venous thrombosis. PATIENTS AND METHODS: Forty-eight patients with deep vein thrombosis and 45 control subjects were included. Venous blood samples were obtained at diagnosis for analysis of TF activity, TF antigen, prothrombin fragment F1 + 2, microparticles (expressing phosphatidylserine and supporting FXa generation), Interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and tumor-necrosis-factor-alpha (TNF). RESULTS: TF antigen, activity and microparticles were similar in both groups: In contrast, a significant increase in plasma IL-6, IL-8 and F1 + 2 levels was found in thrombosis. This increase in IL-6 and IL-8 as well as F1 + 2 was not correlated with the extent of thrombosis, predisposing factors or onset of symptoms. CONCLUSIONS: Circulating TF and microparticles are not elevated in deep venous thrombosis. The increase in IL-6, IL-8 and F1 + 2 during thrombosis was not proportional to the extent or predisposing risk factors.

[Multifocal manifestation of Rosai-Dorfman disease. A rare case of purely extranodal sinus histiocytosis in the elderly]. / Multifokale Manifestation einer Rosai-Dorfman-Erkrankung. Seltene, rein extranodale Sinushistiozytose im Erwachsenenalter.

Rosai-Dorfman disease belongs to the group of childhood histiocytoses and was initially described as sinus histiocytosis with massive lymphadenopathy. Its rare purely extranodal manifestation is primarily found in the head and neck region. An atypical primary manifestation in an elderly patient with multifocal extranodal disease is described, and this pathological entity is reviewed. Specific difficulties concerning differential diagnostic aspects as well as individually appropriate treatment strategies are discussed.

[Traumatic optic neuropathy: a review of the literature in the light of personal experiences]. / Die traumatische Optikusneuropathie: Aktuelle Literaturübersicht im Spiegel eigener Erfahrungen.

BACKGROUND: Therapy of traumatic optic neuropathy (TON) is still discussed controversially. Studies of medical treatment and surgical decompression of the nerve could not find any correlation between therapy and result. Today's knowledge of the treatment in TON is to be analyzed by the latest results in the literature, supplemented by personal experiences with our own patients, who underwent a combination of corticosteroids and surgical decompression. METHODS: The study group consisted of 9 patients at the age of 13-58 years. 8 patients suffered from a cranial trauma, 1 patient had sinus surgery, which resulted in an indirect damage of the optic nerve. Pretherapeutically, 5 patients had residual vision, 4 patients were blind. A fracture line through the optic canal in the CT-scan was seen in 6 cases. Decompression was performed within 24 hours in 3 cases; in the worst 3 cases it took up to 8 days. In 8 patients the intervention was performed via an endonasal, microscopic-endoscopic approach, once it was done transfacially. Simultaneously, high-dose corticosteroids were administered. RESULTS: All patients with a residual vision before therapy showed an improvement of their visual acuity: In the best case visual acuity changed from perception of light to 0.8. All patients with posttraumatic blindness remained blind after therapy. CONCLUSION: A surgical decompression may be considered in patients with residual vision. Referring to the latest data in the literature endonasal, microscopic-endoscopic decompression is then to be combined with simultaneous application of high-dose corticosteroids. In our opinion, a mere wait-and-see strategy completely without any treatment can hardly be recommended.

A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.

Tissue factor (TF), the protease receptor initiating the coagulation system, functions in vascular development, angiogenesis, and tumor cell metastasis by poorly defined molecular mechanisms. We demonstrate that immobilized ligands for TF specifically support cell adhesion, migration, spreading, and intracellular signaling, which are not inhibited by RGD peptides. Two-hybrid screening identified actin-binding protein 280 (ABP-280) as ligand for the TF cytoplasmic domain. Extracellular ligation of TF is necessary for ABP-280 binding. ABP-280 recruitment to TF adhesion contacts is associated with reorganization of actin filaments, but cytoskeletal adaptor molecules typically found in integrin-mediated focal contacts are not associated with TF. Chimeric molecules of the TF cytoplasmic domain and an unrelated extracellular domain support cell spreading and migration, demonstrating that the extracellular domain of TF is not involved in the recruitment of accessory molecules that influence adhesive functions. Replacement of TF's cytoplasmic Ser residues with Asp to mimic phosphorylation enhances the interaction with ABP-280, whereas Ala mutations abolish coprecipitation of ABP-280 with immobilized TF cytoplasmic domain, and severely reduce cell spreading. The specific interaction of the TF cytoplasmic domain with ABP-280 provides a molecular pathway by which TF supports tumor cell metastasis and vascular remodeling.

[Surgical complications of paranasal sinus surgery. Topographical classification and therapeutic management]. / Komplikationen der Nasennebenhöhlen-Chirurgie. Topographische Einteilung und therapeutisches Management.

Surgery of the paranasal sinuses is one of the most frequently performed surgical interventions in otorhinolaryngology today. The potential for surgical complications with damage to paranasal structures in the close vicinity (orbit, endocranium, vital arteries) is still significant despite very elaborate, minimally invasive endoscopic and microscopic techniques. Reviewing the wide range of surgical complications of paranasal sinus surgery in a systematic and topographical fashion, elucidated by typical clinical case reports, we discuss the therapeutic management of such surgical sequelae. In addition, medicolegal aspects of informed patient consent as well as general recommendations to possibly avoid such complications are given.

[Intramuscular lipoma. A differential diagnosis of great prognostic relevance]. / Das intramuskuläre Lipom. Eine Differenzialdiagnose mit grosser prognostischer Bedeutung.

Lipomata of the head and neck mostly present as cosmetically disturbing, superficial lesions lying within the subcutaneous tissue such that they can be easily removed by minor surgical interventions. In cases of deeply extended, lipomatous tumors, as reported here regarding two exemplary cases, physicians should always take into account that they might have to deal with infiltrative, intramuscular lipomata or even malignant neoplasms, especially if concomitant functional disorders are observed. Even though such tumors are rare in the head and the neck, preoperative planning must anticipate these possible pathological entities. At any stage, modification of the surgical procedure should be possible according to the intraoperative findings, as these tumors are prone to recurrence after incomplete resection. The actual diagnosis with infiltration of the surrounding tissue cannot be sufficiently made either by adequate imaging techniques or by preoperative fine-needle cytology but only by histological workup of the resected, tumorous tissue.

[Atypical gout tophi for differential diagnosis of head and neck tumors : case report and review of the literature]. / Atypische Gichttophi als Differenzialdiagnose von HNO-Tumoren : Fallbericht und Literaturübersicht.

Gout is a mostly hereditary metabolic disease and is considered a disease of affluence. The disease is promoted by a purine-rich diet and shows an intermittent course of inflammatory joint manifestations and periods free of symptoms. The pathognomonic sign of the disease is an acute and very painful monarthritis with typical local deposits of uric acid, so-called gout tophi. No or inadequate treatment leads to the chronic form of gouty arthritis characterized more by joint destruction than by persistent pain. In head and neck gout tophi are seen as nodular lesions along the outer helical edges of the auricle. A case report of gout manifestation in the infratemporal fossa, deriving from the temporomandibular joint, with arrosion of the bony skull base demonstrates gout as a relevant disease for the ENT clinician. Potential diagnostic difficulties as well as recommendations for a therapeutic regimen of gouty lesions in such critical localizations will be reviewed.

Current trends in multiple myeloma management.

Treatment of multiple myeloma, a B-cell cancer, is usually palliative, however, as a result of intensive clinical research there are numerous new treatment options available today. The present review summarizes non-transplant treatment options for multiple myeloma on the basis of available publications. Treatment with new substances, such as immunomodulatory agents, farnesyl transferase inhibitors and apoptosis stimulators, and their mechanisms of action are discussed. In addition to this systematic review of the available evidence on multiple myeloma therapy we have also summarized current recommendations from national and international organizations on aspects of the treatment of multiple myeloma. This should enable readers to see different points of view at a glance and, hopefully, will provide a basis for translation of the available evidence into the best possible therapy.

Cost-effectiveness of oral clodronate compared with oral ibandronate, intravenous zoledronate or intravenous pamidronate in breast cancer patients.

This study aimed to identify the effects of different bisphosphonates in reducing skeletal-related events, and to determine whether there are any differences in their cost-effectiveness, taking into account their efficacy, safety profile and administration routes. A systematic literature search of databases, such as PubMed and the Cochrane Controlled Trials Register, supplemented by the latest congress abstracts from meetings of the European Hematology Association and the American Society of Clinical Oncology was conducted up to November 2006. Important references in reviews published by peer-reviewed journals were also taken into consideration. Our base-case cost-effectiveness analysis for Germany and the UK showed cost savings for oral clodronate therapy compared with other bisphosphonate therapies. In Germany, costs per patient of treatment with oral clodronate were euro1092.38, euro2360.40 and euro2500.29 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively. The UK results were similar, the costs per patient of treatment with oral clodronate being euro841.79, euro2989.99 and euro3669.19 less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively.

[Surgical therapy in Menière's disease. Historical development and today's state of the art]. / Die chirurgische Therapie des M. Menière. Historische Entwicklung und heutiger Stand.

After P. Menière's first description of the typical symptoms in 1861 it took more than 40 years before the first otosurgical procedures were performed to cure Menière's disease. Various surgical methods were established during the twentieth century, which still are employed in the treatment of intractable Menière's disease, especially saccotomy and vestibular neurectomy but also intoxication of the labyrinth by intratympanic application of gentamicin. Despite the good results of such therapeutic regimens the basic pathological mechanism is still not fully understood. Since the description of an endolymphatic hydrops by Hallpike und Cairns in 1938 as a typical feature, there have been some observations of a possible infectious, allergic and autoimmunological (co)pathogenesis without enough proof to explain the disease in every case. This article aims to present the current scientific data, diagnostics and therapy of Menière's disease with special emphasis on surgical treatment options.

The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue.

Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold-organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified. In this study, we demonstrate that the incorporation of a specific antioxidant phenol fragment can counterbalance the pro-oxidative potential of the Au containing complex molecule. The electrochemical studies of AuPPh3SR (1, R= 3,5-di-tert-butyl-4-hydroxyphenyl) and its precursors AuPPh3Cl (2) and RSH (3) showed that complex 1 and phenol 3 efficiently scavenged the radicals (as detected by cyclic voltammetry) whereas 2 had no effect. Compound 1 inhibited TrxR in vitro with IC50 0.57 ± 0.15 µM, a value one order of magnitude bigger than the potency reported for auranofin. Compound 1 (5 mg kg-1 daily gavage for 14 days) caused a decrease in ex vivo spontaneous and ascorbate-induced lipid peroxidation in the homogenates of rat lung, heart muscle, spleen, liver, kidneys, testicles and brain as assessed by the thiobarbituric acid reactive substances. Importantly, in animals fed with 1, no discernible general toxicity was registered suggesting that this compound is well tolerated. Our results provide evidence for an efficient synthetic route to obtain gold containing anti-inflammatory drug candidates with balanced pro/anti-oxidative properties.

The anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban or rivaroxaban.

PURPOSE: Measuring the anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban and rivaroxaban is challenging, since the activated coagulation time (ACT) does not seem to reflect the true anticoagulant activity of these drugs. We therefore evaluated coagulation properties of apixaban and rivaroxaban during RFA by different coagulation assays to better monitor periprocedural hemostasis. METHODS: The study included 90 patients (61 ± 12 years) with atrial fibrillation who underwent RFA procedures. Patients received 20 mg rivaroxaban (n = 73) once or 5 mg apixaban (n = 17) twice daily 4 weeks prior to the procedure. During RFA, unfractionated heparin i.v. was given to maintain an ACT of 250-300 s. Blood samples were taken before and 10, 60, and 360 min after heparin administration. RESULTS: Heparin displayed a lower anti-Xa activity in rivaroxaban-treated patients compared to apixaban-treated patients. In contrast, D-dimer and prothrombin fragment F1+2 plasma levels indicated a higher activation of the coagulation cascade in apixaban/heparin than in rivaroxaban/heparin patients. This discordant coagulative state measured in vitro had no clinical impact in terms of bleeding or thromboembolic complications. CONCLUSION: We found different biochemical responses to rivaroxaban/heparin and apixaban/heparin during RFA. Precaution is necessary when monitoring periprocedural hemostasis in DOAC patients to avoid mismanagement.

[Tissue factor in acute coronary syndromes]. / Tissue-Faktor im akuten Koronarsyndrom.

Rupture of an atherosclerotic plaque with subsequent thrombosis and myocardial ischemia is the patho-physiological mechanism in acute coronary syndromes. Tissue factor (TF) as the main initiator of the extrinsic coagulation cascade plays a central role in the pathogenesis of acute coronary syndromes. The extent of the thrombotic process is modulated by local vascular TF of the ruptured plaque as well as by circulating TF. In addition, TF alters signaling pathways and, thereby, contributes to inflammatory reactions and vascular remodeling. This review addresses current concepts of the role of TF in acute coronary syndromes and discusses potential consequences and therapeutic approaches.

Cobaltoceniumethynyl gold(I) as an unusual heterodinuclear bioorganometallic fragment to study the biological properties of alkynyl gold complexes.

A cobaltoceniumethynyl gold(i) complex with a triphenylphosphane ligand triggered efficient cytotoxic effects in cancer cells in contrast to a derivative with two cobaltocenium moieties. The complex effectively inhibited the enzyme thioredoxin reductase (TrxR) suggesting this enzyme as a possible biological target. The cellular uptake of both metal fragments of the active complex was studied by atomic absorption spectroscopy and indicated a high biological stability of the complex.