Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Quantitative Agreement between Electron-Optical Phase Images of WSe_{2} and Simulations Based on Electrostatic Potentials that Include Bonding Effects.

The quantitative analysis of electron-optical phase images recorded using off-axis electron holography often relies on the use of computer simulations of electron propagation through a sample. However, simulations that make use of the independent atom approximation are known to overestimate experimental phase shifts by approximately 10%, as they neglect bonding effects. Here, we compare experimental and simulated phase images for few-layer WSe_{2}. We show that a combination of pseudopotentials and all-electron density functional theory calculations can be used to obtain accurate mean electron phases, as well as improved atomic-resolution spatial distribution of the electron phase. The comparison demonstrates a perfect contrast match between experimental and simulated atomic-resolution phase images for a sample of precisely known thickness. The low computational cost of this approach makes it suitable for the analysis of large electronic systems, including defects, substitutional atoms, and material interfaces.

[Therapeutic options for brain metastases]. / Optionen für die Behandlung von Hirnmetastasen.

Brain metastases are common in cancer patients, especially in lung cancer, breast cancer and melanoma and represent a therapeutic challenge. Established local therapeutic procedures include neurosurgical resection, stereotactic irradiation and whole brain radiotherapy; however, for selected patients novel targeted therapies with documented activity against brain metastases are emerging. These include v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, the anticytotoxic T lymphocyte-associated protein 4 (CTL4A) antibodies ipilimumab in melanoma, HER2 antagonists in breast cancer and epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer. Therefore, the modern management of patients with brain metastases should be performed in an interdisciplinary setting and under consideration of relevant molecular markers to facilitate optimal patient outcome.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Bevacizumab can induce reactivity to VEGF-C and -D in human brain and tumour derived endothelial cells.

Though clinical trials demonstrated effectiveness of the anti-VEGF antibody bevacizumab (Avastin) in adjuvant therapies for some solid tumours, there are rather few experimental data about cellular effects of bevacizumab on tumour cells and tumour associated endothelial cells. Recent reports demonstrate resistance mechanisms and secondary re-angiogenesis after a transient normalization of tumour vessels. Therefore we investigated the influence of bevacizumab on human glioma cells and human brain derived as well as tumour derived endothelial cells focussing on the role of VEGF-C and -D as potential alternative pro-angiogenic factors. Bevacizumab treatment showed no influence on proliferation after short term exposure (1-5 days) but slowed down endothelial cell proliferation by 25-30% after 14 days treatment. There was no significant induction of apoptosis after short or long term exposure. Tube formation capabilities were significantly impaired by bevacizumab with a continuing effect after 14 days of treatment even after omitting the antibody. VEGF-C and -D had no effect on endothelial cells in untreated or short term treatment groups. However, cells developed responsiveness to these factors in terms of increased proliferation and tube formation after 14 days bevacizumab treatment. Furthermore, bevacizumab induced expression of VEGF-C and -D in glioma cells. Treatment with bevacizumab may induce alterations in human brain and tumour endothelial cells leading to escape mechanisms from anti-VEGF therapy. VEGF-C and -D thus might act as alternative pro-angiogenic factors during anti-VEGF therapy.

[Examination of the painful wrist]. / Diagnostik des schmerzhaften Handgelenks.

The anatomy of the wrist is complex. Mechanical, neurological or systemic causes are responsible for a painful wrist. In many cases a specific diagnosis can already be made by taking a precise medical history. Physical examination includes inspection, palpation of landmarks and a dynamic examination in regard to joint regions. Plane X-Ray examinations are the basic tools in diagnostic imaging. Additional radiographic adjustments, ultrasound-, MRI- and CT-examinations may lead to more detailed information in special cases. A diagnostic arthroscopy is accomplished, if a pathological cause for wrist-pain with non-invasive methods cannot be found.

[Examination of the painful wrist]. / Diagnostik des schmerzhaften Handgelenks.

The anatomy of the wrist is complex. Mechanical, neurological or systemic causes are responsible for a painful wrist. In many cases a specific diagnosis can already be made by taking a precise medical history. Physical examination includes inspection, palpation of landmarks and a dynamic examination in regard to joint regions. Plane X-Ray examinations are the basic tools in diagnostic imaging. Additional radiographic adjustments, ultrasound-, MRI- and CT-examinations may lead to more detailed information in special cases. A diagnostic arthroscopy is accomplished, if a pathological cause for wrist-pain with non-invasive methods cannot be found.

Amino acid substitution (Ile194----Thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands. Support for a multicentric origin.

Studies on the molecular biology of lipoprotein lipase (LPL) deficiency have been facilitated by the availability of LPL gene probes and the recent characterization of gene mutations underlying human LPL deficiency. Typically, missense mutations have predominated and show a preferential localization to exons 4 and 5. This distribution supports earlier studies attributing functional significance to residues encoded by these exons. We now report a further missense mutation within exon 5 of the LPL gene in three unrelated patients. Amplification of individual exons by the polymerase chain reaction and direct sequencing revealed a T----C transition at codon 194 of the LPL cDNA which results in a substitution of threonine for isoleucine at this residue. The catalytic abnormality induced by this mutation was confirmed through in vitro mutagenesis studies in COS-1 cells. Transfection with a LPL cDNA containing the codon 194 transition resulted in the synthesis and secretion of a catalytically defective protein. The Thr194 substitution was associated with two different DNA haplotypes, consistent with a multicentric origin for this mutation.

Reversible dementia and corresponding CSF alterations due to intraspinal lumbosacral metastasis of a prostate carcinoma.

We report, for the first time, how intraspinal carcinoma metastasis can cause reversible dementia accompanied by distinct cerebrospinal fluid (CSF) alterations. A 73-year-old male patient who suffered from rapidly progressive dementia and gait disturbance showed marked abnormalities of CSF tau protein, amyloid beta(1-42), and prostate-specific antigen. A lumbosacral, intraspinal metastasis from a prostate carcinoma was found, and after microsurgical removal, CSF alterations normalized and the clinical symptoms regressed. This case illustrates how malignant tumors can disturb brain function via indirect mechanisms.

Topological similarities in TGF-beta 2, PDGF-BB and NGF define a superfamily of polypeptide growth factors.

BACKGROUND: The development of functional diversity through gene duplication and subsequent divergent evolution can give rise to proteins that have little or no sequence similarity, but retain similar topologies. RESULTS: The crystal structures of nerve growth factor, transforming growth factor-beta 2 and platelet-derived growth factor-BB show that all three are based on a cystine-knot plus beta-strands topology. There is very little sequence identity between the three proteins and the relationship between the structures had not been deduced from sequence comparisons. Each growth factor is usually active as a dimer; each exists as a dimer in the crystal, but the relative orientations of the protomers are different in each case. CONCLUSION: The structural motif of disulphide bonds and hydrogen-bonded beta-strands unexpectedly found in these three growth factors acts as a stable framework for elaboration of loops of low sequence similarity that contain the specificity for receptor interaction.

Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex.

BACKGROUND: Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-gamma (IFN-gamma) signals through a multimeric receptor complex consisting of two different but structurally related transmembrane chains: the high-affinity receptor-binding subunit (IFN-gammaRalpha) and a species-specific accessory factor (AF-1 or IFN-gammaRbeta). In the signaling complex, the two receptors probably interact with one another through their extracellular domains. Understanding the atomic interactions of signaling complexes enhances the ability to control and alter cell signaling and also provides a greater understanding of basic biochemical processes. RESULTS: The crystal structure of the complex of human IFN-gamma with the soluble, glycosylated extracellular part of IFN-gammaRalpha has been determined at 2.9 A resolution using multiwavelength anomalous diffraction methods. In addition to the expected 2:1 complex, the crystal structure reveals the presence of a third receptor molecule not directly associated with the IFN-gamma dimer. Two distinct intermolecular contacts, involving the edge strands of the C-terminal domains, are observed between this extra receptor and the 2:1 receptor-ligand complex thereby forming a 3:1 complex. CONCLUSIONS: The observed interactions in the 2:1 complex of the high-affinity cell-surface receptor with the IFN-gamma cytokine are similar to those seen in a previously reported structure where the receptor chains were not glycosylated. The formation of beta-sheet packing interactions between pairs of IFN-gammaRalpha receptors in these crystals suggests a possible model for receptor oligomerization of Ralpha and the structurally homologous Rbeta receptors in the fully active IFN-gamma signaling complex.

Structural and functional insights into the AmtB/Mep/Rh protein family.

X-ray crystallography revealed a similar architecture of the ammonium transport protein AmtB from Escherichia coli and the homologous protein Amt-1 from Archaeoglobus fulgidus. Furthermore, the atomic structures suggest that the proteins conduct ammonia (NH3) rather than ammonium ions (NH4+). These findings indicate that the more than 350 members of the ammonium transporter/methylamine permease/Rhesus (Amt/Mep/Rh) protein family found in archaea, bacteria, fungi, plants and animals are ammonia-conducting channels rather than ammonium ion transporters. The essential part of these proteins is the narrow hydrophobic ammonia-conducting pore with two highly conserved histidine residues located in the middle of the pore. A specific ammonium ion binding site is found at the extracellular entry site of E. coli AmtB. E. coli AmtB and its regulator GlnK form an effective ammonium sensory system that couples intracellular gene regulation by the nitrogen control system to external changes in ammonium availability. Based on structural and functional analysis of various mutants, two conserved histidine residues were found to be essential for substrate conductance also in the functional eukaryotic ammonium transporters. The next big challenge in the field surely is to determine the atomic structure of Rh proteins.

[Differential Diagnoses of Trigger Thumb]. / Differenzialdiagnosen des Pollex rigidus.

Trigger thumb is one of the most common hand pathologies in toddlers. Its differential diagnoses are thumb-in-palm deformity, hyperflexible thumb, thumb hypoplasia, and congenital stiffness of the distal interphalangeal joint of the thumb. This article describes typical clinical signs of these different diseases in order to enable surgeons to make the correct diagnosis leading to the right treatment.

[Epiphyseal Bar Resection for Correction of Clinodactyly]. / Resektion der atypischen Wachstumsfuge zur Korrektur der Klinodaktylie.

BACKGROUND: Clinodactyly is a digital angulation in the radio-ulnar plane. Mostly it is seen on the little finger. The middle phalanx typically has a triangular or trapezoid shape (delta phalanx), resulting in radial deviation of the distal phalanx. Resection of the longitudinal epiphyseal bracket (physiolysis) with fat graft interposition is a possible surgical technique, which uses children's growth potential to correct the axial deviation. AIM: The purpose of our study was to review the degree of correction at least 2 years postoperatively and after an average of 5 years postoperatively, and to find out if children´s age influences the results. PATIENTS AND METHODS: 23 children (43 little fingers) underwent physiolysis and were retrospectively analyzed after a median follow-up of 5 years (2.1-7.9 years). The active range of motion of the little finger's MP, PIP and DIP joints and finger-palm-distance were measured. Lateral deviation was determined by using standardized radiographs and subsequently compared with preoperative values. Patients were divided into 2 subgroups: younger than 3 years (16 fingers, group A), older than 3 years (27 fingers, group B). The achieved correction of the lateral deviation was compared between both groups. RESULTS: All patients showed full active range of motion in all joints of treated fingers. Finger-palm-distance was 0 cm. No complications occurred. The mean preoperative deviation of all patients was 37°±11, which improved after surgery by 17°±11 (i. e. 44.0%±23.1 of initial findings). Group A demonstrated a mean preoperative lateral deviation of 40°±9, and group B a mean deviation of 36°±12. In both groups we saw a similar improvement (group A mean: 17°±10, group B mean: 17°±11). In group A there was a wider dispersion of postoperative results. In the age group 7 to 10, the results of individual cases show the large variability of the corrective potential. X-rays revealed the following incidental findings after surgery: a premature fusion of the proximal radial epiphyseal plates in 2 fingers and a sinuous-shaped proximal radial epiphyseal plate in 12 other fingers. CONCLUSION: Resection of the longitudinal epiphyseal bracket with fat graft interposition is a technically simple and effective treatment option for clinodactyly, particularly in children of 3 to 6 years of age.

[Distraction Osteogenesis is an Effective Method to Lengthen Digits in Congenital Malformations]. / Die Kallusdistraktion ist eine effektive Methode zur Fingerverlängerung bei angeborenen Fehlbildungen.

PURPOSE: The aim of this study was to investigate the feasible amount of lengthening by distraction osteogenesis in congenital hand deficiencies. PATIENTS AND METHODS: A total of 60 patients (1.6-17.8 years) underwent lengthening of 71 bones between 1994 and 2014. Bone lengthening was performed on 46 metacarpals and 25 phalanges. Mostly the first (n=30) and the fifth (n=21) rays were lengthened. Bone lengthening was performed to treat primarily symbrachydactyly (b=32) and amniotic band syndrome (n=10). To analyze the amount of lengthening preoperative radiographs and radiographs taken while removing the external fixator were compared. The charts were reviewed regarding age at surgery, duration of lengthening, duration of bony consolidation, complication, etc. RESULTS: The average of metacarpal distraction was 18.4 mm=73% lengthening with respect to the preoperative length; the average of phalange distraction was 14.0 mm=77% of the preoperative length. In both, metacarpals and phalanges, a lengthening of > 100% of the preoperative bone length was possible. In target length was reached in 89% of the procedures. The average time for consolidation was 6.1 (1-20) days/mm lengthening. The external fixator was in use on average for 140 (50-346) days. After removing of the external fixator an axial K-wire was used to stabilize the callus in 9 procedure, and an iliac bone craft plus axial K-wire in 11 procedures. The rate of complications was 30% (early consolidation, deviation, joint dislocation, pin infection, tendon dislocation). All complications could be treated without with acceptable results. CONCLUSION: Metacarpal and phalangeal distraction lengthening is an effective but demanding technique for ray reconstruction in congenital malformations of the hand. It is possible to lengthen a bone by more than 100%. Complications are common, but in most cases easy to handle.

Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects.

UNLABELLED: ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis. BACKGROUND: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. MATERIALS AND METHODS: Sixteen healthy male or female volunteers with a mean age of 26 ± 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti-activated factor X assay and liquid chromatography-mass spectrometry. MAIN RESULTS: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 ± 25 nmol L(-1) vs. 106 ± 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. CONCLUSIONS: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.

Aspects of the mechanism of action of local anesthetics on the sarcoplasmic reticulum of skeletal muscle.

1. The effect was studied of local anesthetics (tetracaine, dibucaine, procaine and xylocaine) on the forward and the backward reactions of the calcium pump of skeletal muscle sarcoplasmic reticulum. 2. The inhibition of the rate of calcium uptake, the rate of calcium-dependent ATP splitting and the rate of calcium-dependent ATP-ADP phosphate exchange by sarcoplasmic reticulum in the presence of the above drugs is at least partially due to the inhibition of the phosphoprotein formation from ATP. 3. The rate of the ADP-induced calcium release from sarcoplasmic reticulum and the rate of ATP synthesis driven by the calcium efflux are inhibited on account of a reduction of the phosphoprotein formation by orthophosphate. 4. The phosphorylation of calcium transport ATPase by either ATP or orthophosphate is diminished by the local anesthetics owing to a reduction in the apparent calcium affinity of sarcoplasmic reticulum emmbranes on the outside and on the inside, respectively. 5. The drug-induced calcium efflux from calcium-preloaded sarcoplasmic reticulum vesicles, a reaction not requiring ADP, is probably not mediated by calcium transport ATPase.

Crystallization of complexes of EcoRV endonuclease with cognate and non-cognate DNA fragments.

Complexes of the type II restriction endonuclease EcoRV with a variety of short, selfcomplementary deoxyoligonucleotides have been crystallized. The best crystals diffract to about 2.7 A resolution and consist of 1:1 complexes between endonuclease dimers and duplexes of the cognate decamer GGGATATCCC containing the hexameric RV recognition sequence GATATC. Crystals with the non-cognate DNA octamer duplexes CGAGCTCG and CGAATTCG diffract to 3.0 and 3.5 A resolution, respectively, and contain two DNA duplexes per enzyme dimer.