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

Comparison of the Full Outline of UnResponsiveness and Glasgow Liege Scale/Glasgow Coma Scale in an Intensive Care Unit Population.

peer reviewedBACKGROUND: The Full Outline of UnResponsiveness (FOUR) has been proposed as an alternative for the Glasgow Coma Scale (GCS)/Glasgow Liege Scale (GLS) in the evaluation of consciousness in severely brain-damaged patients. We compared the FOUR and GLS/GCS in intensive care unit patients who were admitted in a comatose state. METHODS: FOUR and GLS evaluations were performed in randomized order in 176 acutely (<1 month) brain-damaged patients. GLS scores were transformed in GCS scores by removing the GLS brainstem component. Inter-rater agreement was assessed in 20% of the studied population (N = 35). A logistic regression analysis adjusted for age, and etiology was performed to assess the link between the studied scores and the outcome 3 months after injury (N = 136). RESULTS: GLS/GCS verbal component was scored 1 in 146 patients, among these 131 were intubated. We found that the inter-rater reliability was good for the FOUR score, the GLS/GCS. FOUR, GLS/GCS total scores predicted functional outcome with and without adjustment for age and etiology. 71 patients were considered as being in a vegetative/unresponsive state based on the GLS/GCS. The FOUR score identified 8 of these 71 patients as being minimally conscious given that these patients showed visual pursuit. CONCLUSIONS: The FOUR score is a valid tool with good inter-rater reliability that is comparable to the GLS/GCS in predicting outcome. It offers the advantage to be performable in intubated patients and to identify non-verbal signs of consciousness by assessing visual pursuit, and hence minimal signs of consciousness (11% in this study), not assessed by GLS/GCS scales

Cildb: a knowledgebase for centrosomes and cilia

Ciliopathies, pleiotropic diseases provoked by defects in the structure or function of cilia or flagella, reflect the multiple roles of cilia during development, in stem cells, in somatic organs and germ cells. High throughput studies have revealed several hundred proteins that are involved in the composition, function or biogenesis of cilia. The corresponding genes are potential candidates for orphan ciliopathies. To study ciliary genes, model organisms are used in which particular questions on motility, sensory or developmental functions can be approached by genetics. In the course of high throughput studies of cilia in Paramecium tetraurelia, we were confronted with the problem of comparing our results with those obtained in other model organisms. We therefore developed a novel knowledgebase, Cildb, that integrates ciliary data from heterogeneous sources. Cildb links orthology relationships among 18 species to high throughput ciliary studies, and to OMIM data on human hereditary diseases. The web interface of Cildb comprises three tools, BioMart for complex queries, BLAST for sequence homology searches and GBrowse for browsing the human genome in relation to OMIM information for human diseases. Cildb can be used for interspecies comparisons, building candidate ciliary proteomes in any species, or identifying candidate ciliopathy genes

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

Visual fixation in the vegetative state: an observational case series PET study

BACKGROUND: Assessment of visual fixation is commonly used in the clinical examination of patients with disorders of consciousness. However, different international guidelines seem to disagree whether fixation is compatible with the diagnosis of the vegetative state (i.e., represents "automatic" subcortical processing) or is a sufficient sign of consciousness and higher order cortical processing. METHODS: We here studied cerebral metabolism in ten patients with chronic post-anoxic encephalopathy and 39 age-matched healthy controls. Five patients were in a vegetative state (without fixation) and five presented visual fixation but otherwise showed all criteria typical of the vegetative state. Patients were matched for age, etiology and time since insult and were followed by repeated Coma Recovery Scale-Revised (CRS-R) assessments for at least 1 year. Sustained visual fixation was considered as present when the eyes refixated a moving target for more than 2 seconds as defined by CRS-R criteria. RESULTS: Patients without fixation showed metabolic dysfunction in a widespread fronto-parietal cortical network (with only sparing of the brainstem and cerebellum) which was not different from the brain function seen in patients with visual fixation. Cortico-cortical functional connectivity with visual cortex showed no difference between both patient groups. Recovery rates did not differ between patients without or with fixation (none of the patients showed good outcome). CONCLUSIONS: Our findings suggest that sustained visual fixation in (non-traumatic) disorders of consciousness does not necessarily reflect consciousness and higher order cortical brain function

Minimally conscious state “plus”: diagnostic criteria and relation to functional recovery

peer reviewedBackground: We investigated the relationship between three language-dependent behaviors (i.e., command-following, intelligible verbalization, and intentional communication) and the functional status of patients with disorders of consciousness (DoC). We hypothesized that patients in minimally conscious state (MCS) who retain behavioral evidence of preserved language function would have similar levels of functional disability, while patients who lack these behaviors would demonstrate significantly greater disability. We reasoned that these results could then be used to establish empirically-based diagnostic criteria for MCS+. Methods: In this retrospective cohort study we included rehabilitation inpatients diagnosed with DoC following severe-acquired brain injury (MCS = 57; vegetative state/unresponsive wakefulness syndrome [VS/UWS] = 63); women: 46; mean age: 47 ± 19 years; traumatic etiology: 68; time post-injury: 40 ± 23 days). We compared the scores of the Disability Rating Scale score (DRS) at time of transition from VS/UWS to MCS or from MCS– to MCS+, and at discharge between groups. Results: Level of disability on the DRS was similar in patients with any combination of the three language-related behaviors. MCS patients with no behavioral evidence of language function (i.e., MCS–) were more functionally impaired than patients with MCS+ at time of transition and at discharge. Conclusions: Command-following, intelligible verbalization, and intentional communication are not associated with different levels of functional disability. Thus, the MCS+ syndrome can be diagnosed based on the presence of any one of these language-related behaviors. Patients in MCS+ may evidence less functional disability compared to those in MCS who fail to demonstrate language function (i.e., MCS–). © 2019, Springer-Verlag GmbH Germany, part of Springer Nature

Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome

BACKGROUND: Some patients awaken from coma (that is, open the eyes) but remain unresponsive (that is, only showing reflex movements without response to command). This syndrome has been coined vegetative state. We here present a new name for this challenging neurological condition: unresponsive wakefulness syndrome (abbreviated UWS). DISCUSSION: Many clinicians feel uncomfortable when referring to patients as vegetative. Indeed, to most of the lay public and media vegetative state has a pejorative connotation and seems inappropriately to refer to these patients as being vegetable-like. Some political and religious groups have hence felt the need to emphasize these vulnerable patients' rights as human beings. Moreover, since its first description over 35 years ago, an increasing number of functional neuroimaging and cognitive evoked potential studies have shown that physicians should be cautious to make strong claims about awareness in some patients without behavioral responses to command. Given these concerns regarding the negative associations intrinsic to the term vegetative state as well as the diagnostic errors and their potential effect on the treatment and care for these patients (who sometimes never recover behavioral signs of consciousness but often recover to what was recently coined a minimally conscious state) we here propose to replace the name. CONCLUSION: Since after 35 years the medical community has been unsuccessful in changing the pejorative image associated with the words vegetative state, we think it would be better to change the term itself. We here offer physicians the possibility to refer to this condition as unresponsive wakefulness syndrome or UWS. As this neutral descriptive term indicates, it refers to patients showing a number of clinical signs (hence syndrome) of unresponsiveness (that is, without response to commands) in the presence of wakefulness (that is, eye opening)

Disruption in structural–functional network repertoire and time-resolved subcortical fronto-temporoparietal connectivity in disorders of consciousness

Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace (GNW) and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, the prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, that is so-called eigenmodes, was supplemented as potential markers. By analysing time-resolved functional connectivity from functional MRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and subcortical fronto-temporoparietal network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the GNW theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness