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.

[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.

[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.

[Mid-term outcome after implantation of a pyrocarbon endoprosthesis in patients with degenerative arthritis]. / Mittelfristige Ergebnisse nach Implantation einer Pyrocarbonprothese bei Fingermittelgelenksarthrose.

AIM: The aim of this study was to make a mid-term evaluation of an unconstrained pyrocarbon prosthesis (Ascension®) in the treatment of idiopathic degenerative arthritis of the proximal interphalangeal joint of the hand. METHOD: 13 implants (10 patients) were clinically and radiologically studied after a follow-up period of 71 months (range: 48-92 months). RESULTS: The average ROM was 52° (± 27°STD). A luxation of the components did not occur and all implants are still in-situ. However, X-ray examination was unremarkable in only six fingers. In seven patients significant radiolucent lines (≥ 1 mm) were detected. Three prosthesis demonstrated axial subsidence and in one patient a loosening of the proximal component with axial rotation was observed. CONCLUSION: The results of this study show a high complication rate after an average of 6 years after implantation. Radiolucent lines in half of the cases may be explained by a lack of osteointegration of the prosthesis. The average ROM differs significantly from patient to patient, which has to be taken into account when discussing different treatment options.

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.

TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma.

Bone marrow-derived human mesenchymal stem cells (hMSCs) have become valuable candidates for cell-based therapeutical applications including neuroregenerative and anti-tumor strategies. Yet, the molecular mechanisms that control hMSC trans-differentiation to neural cells and hMSC tropism toward glioma remain unclear. Here, we demonstrate that hMSCs incubated with 50 ng/ml tumor necrosis factor alpha (TNF-α) acquired astroglial cell morphology without affecting proliferation, which was increased at 5 ng/ml. TNF-α (50 ng/ml) upregulated expression of numerous genes important for neural cell growth and function including LIF (leukemia inhibitory factor), BMP2 (bone morphogenetic protein 2), SOX2 (SRY box 2), and GFAP (glial fibrillary acidic protein), whereas NES (human nestin) transcription ceased suggesting a premature neural phenotype in TNF-α-differentiated hMSCs. Studies on intracellular mitogen-activated protein kinase (MAPK) signaling revealed that inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity abolished the TNF-α-mediated regulation of neural genes in hMSCs. In addition, TNF-α significantly enhanced expression of the chemokine receptor CXCR4 (CXC motive chemokine receptor 4), which facilitated the chemotactic invasiveness of hMSCs toward stromal cell-derived factor 1 (SDF-1) alpha. TNF-α-pretreated hMSCs not only exhibited an increased ability to infiltrate glioma cell spheroids dependent on matrix metalloproteinase activity in vitro, but they also showed a potentiated tropism toward intracranial malignant gliomas in an in vivo mouse model. Taken together, our results provide evidence that culture-expansion of hMSCs in the presence of TNF-α triggers neural gene expression and functional capacities, which could improve the use of hMSCs in the treatment of neurological disorders including malignant gliomas.

[Mid-term results after scaphoid excision and four-corner wrist arthrodesis using K-wires for advanced carpal collapse]. / Mittelfristige Ergebnisse nach Skaphoidresektion und mediokarpaler Teilarthrodese unter Verwendung von K-Drähten bei fortgeschrittenem karpalen Kollaps.

AIM: Successful four-corner fusion after scaphoid excision provides pain relief und preserves an acceptable movability of the wrist. However, this treatment option for advanced carpal collapse is not without complications, such as malunion, hardware impingement or incomplete correction of lunate extension. K-wires, staples, Herbert screws or, recently, locking plates are all possible fixation techniques after scaphoid excision. Only a few studies including mid-term results using K-wires are available. The aim of our study was to evaluate clinical and radiological mid-term results after scaphoid excision and four-corner arthrodesis using K-wires for stage II and III scapholunate and scaphoid non-union advanced collapse. METHOD: Twelve wrists of 11 patients (4/SNAC II degrees, 3/SNAC III degrees, 0/SLAC II degrees, 5/SLAC III degrees) were treated operatively by scaphoid excision and four-corner arthrodesis. Four K-wires were used for osteosynthesis. After an average follow-up of 60.25 months, reexamination included subjective, objective and radiological values. Clinical examinations covered wrist motion, grip strength and pinch strength. These parameters were compared with preoperatively collected data and values of the unaffected side. The DASH score (disabilities of the arm, shoulder and hand), Cooney score and the visual analogue scale (VAS 0-10) were analysed. Radiographic assessment of consolidation was verified by conventional X-rays. The carpal height was compared to the preoperative value by assessing the Youm index. RESULTS: All patients were satisfied, pain relief was reported and displayed on VAS from 7.4 (5-10) to 1.4 (0-5). The mean flexion-extension arc of 76.3 +/- 28.8 degrees (59.7% of the opposite wrist), preoperatively 75 +/- 17.3 degrees, was documented. The average total arc of ulnar and radial deviation was 37.5 +/- 9.2 degrees (51% of the opposite wrist). The preoperative value was 33.5 +/- 9.8 degrees. Further clinical evaluation yielded a mean grip strength of 39.3 kp (89.5% of the anaffected side) and pinch strength of 7.6 kp (81.7%). Total DASH score and Cooney score averaged 15 and 74.17 points, respectively. Osseus consolidation was observed radiologically in all patients already after 6 weeks. The Youm index decreased from 0.55 +/- 0.054 to 0.51 +/- 0.057. The radiolunate joint space remained unaltered in height. There were no infections. Except for wire removal, no additional surgery was necessary. CONCLUSION: Scaphoid excision and four-corner arthrodesis for advanced collapse of the wrist enjoy great satisfaction by the patients, with a high degree of pain reduction. This method shows persistent strength and movability in mid-term-results. Compared to alternative fixation techniques, the use of K-wires is a low-risk and low-cost treatment option, although removal of the K-wires is commonly necessary.

[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.

Cerebellar leukoencephalopathy: most likely histiocytosis-related.

BACKGROUND: Histiocytosis, both Langerhans and non-Langerhans cell type, can be associated with cerebellar white matter abnormalities, thought to be paraneoplastic. The associated clinical picture consists of ataxia, spasticity, and cognitive decline. Hormonal dysfunction is frequent. MRI shows cerebellar white matter abnormalities, as well as brainstem and basal ganglia abnormalities. This so-called "neurodegenerative syndrome" may occur years before or during manifest histiocytosis and also years after cure. We discovered similar MRI abnormalities in 13 patients and wondered whether they could have the same syndrome. METHODS: We reviewed the clinical and laboratory information of these 13 patients and evaluated their brain MRIs. Seven patients underwent spinal cord MRI. RESULTS: All patients were isolated cases; 10 were male. They had signs of cerebellar and pyramidal dysfunction, behavioral problems, and cognitive decline. MRI showed abnormalities of the cerebellar white matter, brainstem, basal ganglia, and, to a lesser extent, cerebral white matter. Three patients had spinal cord lesions. Three patients had laboratory evidence of hormonal dysfunction. No evidence was found of an underlying metabolic defect. In two patients biopsy of nodular brain lesions revealed histiocytic infiltrates. CONCLUSIONS: Considering the striking clinical and MRI similarities between our patients and the patients with this neurodegenerative syndrome in the context of proven histiocytosis, it is likely that they share the same paraneoplastic syndrome, although we cannot exclude a genetic disorder with certainty. The fact that we found histiocytic lesions in two patients substantiates our conclusion. Patients with cerebellar white matter abnormalities should be monitored for histiocytosis.

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.

[Complexities of "reversible posterior leukoencephalopathy syndrome"]. / "Reversibles posteriores Leukenzephalopathiesyndrom": Eine unglückliche Begriffsprägung für eine komplexe Erkrankung.

We report a case of reversible posterior leukoencephalopathy syndrome in a 50-year-old patient with severe untreated hypertension. Recent advances in magnetic resonance imaging (especially diffusion-weighted imaging) allow new pathopysiological insight: it was found that the resulting vasogenic edema was restricted neither to the posterior vascular territories nor to white matter. The apparent diffusion coefficient helps to differentiate between reversible vasogenic edema and cytotoxic edema, the latter indicating irreversible neuronal death.

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.