Topotecan-vincristine-doxorubicin in stage 4 high risk neuroblastoma patients failing to achieve a complete metastatic response to rapid COJEC : a SIOPEN study

Purpose : Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with <= three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([I-123] mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. Materials and Methods : Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m(2)/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m(2), and doxorubicin, 45 mg/m(2). Results : Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with <= 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). Conclusion : TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials

Conserved Ising Model on the Human Connectome

Dynamical models implemented on the large scale architecture of the human brain may shed light on how function arises from the underlying structure. This is the case notably for simple abstract models, such as the Ising model. We compare the spin correlations of the Ising model and the empirical functional brain correlations, both at the single link level and at the modular level, and show that their match increases at the modular level in anesthesia, in line with recent results and theories. Moreover, we show that at the peak of the specific heat (the \it{critical state}) the spin correlations are minimally shaped by the underlying structural network, explaining how the best match between structure and function is obtained at the onset of criticality, as previously observed. These findings confirm that brain dynamics under anesthesia shows a departure from criticality and could open the way to novel perspectives when the conserved magnetization is interpreted in terms of an homeostatic principle imposed to neural activity

Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain

peer reviewedAlthough disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [18F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following

Outcome Prediction of Consciousness Disorders in the Acute Stage Based on a Complementary Motor Behavioural Tool.

Attaining an accurate diagnosis in the acute phase for severely brain-damaged patients presenting Disorders of Consciousness (DOC) is crucial for prognostic validity; such a diagnosis determines further medical management, in terms of therapeutic choices and end-of-life decisions. However, DOC evaluation based on validated scales, such as the Revised Coma Recovery Scale (CRS-R), can lead to an underestimation of consciousness and to frequent misdiagnoses particularly in cases of cognitive motor dissociation due to other aetiologies. The purpose of this study is to determine the clinical signs that lead to a more accurate consciousness assessment allowing more reliable outcome prediction. From the Unit of Acute Neurorehabilitation (University Hospital, Lausanne, Switzerland) between 2011 and 2014, we enrolled 33 DOC patients with a DOC diagnosis according to the CRS-R that had been established within 28 days of brain damage. The first CRS-R assessment established the initial diagnosis of Unresponsive Wakefulness Syndrome (UWS) in 20 patients and a Minimally Consciousness State (MCS) in the remaining13 patients. We clinically evaluated the patients over time using the CRS-R scale and concurrently from the beginning with complementary clinical items of a new observational Motor Behaviour Tool (MBT). Primary endpoint was outcome at unit discharge distinguishing two main classes of patients (DOC patients having emerged from DOC and those remaining in DOC) and 6 subclasses detailing the outcome of UWS and MCS patients, respectively. Based on CRS-R and MBT scores assessed separately and jointly, statistical testing was performed in the acute phase using a non-parametric Mann-Whitney U test; longitudinal CRS-R data were modelled with a Generalized Linear Model. Fifty-five per cent of the UWS patients and 77% of the MCS patients had emerged from DOC. First, statistical prediction of the first CRS-R scores did not permit outcome differentiation between classes; longitudinal regression modelling of the CRS-R data identified distinct outcome evolution, but not earlier than 19 days. Second, the MBT yielded a significant outcome predictability in the acute phase (p&lt;0.02, sensitivity&gt;0.81). Third, a statistical comparison of the CRS-R subscales weighted by MBT became significantly predictive for DOC outcome (p&lt;0.02). The association of MBT and CRS-R scoring improves significantly the evaluation of consciousness and the predictability of outcome in the acute phase. Subtle motor behaviour assessment provides accurate insight into the amount and the content of consciousness even in the case of cognitive motor dissociation

Complexity of multi-dimensional spontaneous EEG decreases during propofol induced general anaesthesia

Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct ‘flavours’ of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia

Burgmeester Alfons Pieters (2)

He had excavated approximately 15 cms towards the initial signal and 5 cms in depth when he came to a rock, he then continued to excavate down when the uncontrolled detonation occurred

SUpporting well-being through PEeR-Befriending (SUPERB) trial: an exploration of fidelity in peer-befriending for people with aphasia

Assessing the evolution of severely brain-injured patients with disorders of consciousness (DOC) with current tools like the Glasgow Outcome Scale-Extended (GOS-E) remains a challenge. At the bedside, the most reliable diagnostic tool is currently the Coma Recovery Scale-Revised. The CRS-R distinguishes patients with unresponsive wakefulness syndrome (UWS) from patients in minimally conscious state (MCS) and patients who have emerged from MCS (EMCS). This international multi-centric study aims to validate a phone outcome questionnaire (POQ) based on the CRS-R and compare it to the CRS-R performed at the bedside and to the GOS-E which evaluates the level of disability and assigns patient’s in outcomes categories. The POQ will allow clinicians to probe the evolution of patient’s state of consciousness based on caregivers feedback. This research project is part of the International Brain Injury Association, Disorders of Consciousness-Special Interest Group (DOCSIG) and DOCMA consortium

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al