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Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults
Background
Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults.
Methods
10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria.
Results
No clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation.
Conclusion
Although the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas.
Trial Registration
Current Controlled Trials ISRCTN45828668
Journal Article
Thiamine Status in Humans and Content of Phosphorylated Thiamine Derivatives in Biopsies and Cultured Cells
Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines.
Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ∼60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines.
The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation.
Journal Article
Water Constraints and Flood-Recession Agriculture in the Senegal River Valley
Flood recession farming practiced in flood-prone areas and on the banks of rivers and lakes in arid or semi-arid environments essentially depends on the soil water stock after the flood has receded. During these last few decades, this coveted agriculture is increasingly challenged by severe water constraints, due to increased hydrological hazards and development projects aimed at controlling floods. These challenges are difficult to anticipate, and are the subject of a great deal of uncertainty regarding the sustainability of development projects in the concerned areas. In this study, recent hydraulic data of the Senegal River were analyzed to understand the constraints related to the river management in flood-prone areas. Satellite imagery analysis techniques were used to estimate flooded areas and establish relationships with the river regime. Agricultural practices implemented by farmers were also analyzed to evaluate the resilience of this cropping system to the risk of water stress. The results confirmed many constraints of different importance related to the objectives assigned to the management of dams under multiple water use context. It clearly came out that the water resource management rules relegate flood-recession agriculture to the lowest priorities. In addition, there are safety issues related to unexpected effects of flooding on the water structures and in the nearby inhabited localities of flood-prone areas. Knowing some characteristics of the flooding and of the river’s levels and their relationships can be useful within the framework of an organized climate service that would help farmers and communities to better anticipate constraints.
Journal Article
NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury
Background
A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has demonstrated rapid re-expression of CSPGs at and around the lesion site. The pharmacological digestion of CSPGs in such lesion models results in substantially enhanced axonal regeneration and a significant functional recovery. The potential therapeutic relevance of interfering with CSPG expression or function following experimental injuries seems clear, however, the spatio-temporal pattern of expression of individual members of the CSPG family following human spinal cord injury is only poorly defined. In the present correlative investigation, the expression pattern of CSPG family members NG2, neurocan, versican and phosphacan was studied in the human spinal cord.
Methods
An immunohistochemical investigation in
post mortem
samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having \"complete\" injuries and presented lesions of the maceration type.
Results
In sections from control spinal cord, NG2 immunoreactivity was restricted to stellate-shaped cells corresponding to oligodendrocyte precursor cells. The distribution patterns of phosphacan, neurocan and versican in control human spinal cord parenchyma were similar, with a fine reticular pattern being observed in white matter (but also located in gray matter for phosphacan). Neurocan staining was also associated with blood vessel walls. Furthermore, phosphacan, neurocan and versican were present in the myelin sheaths of ventral and dorsal nerve roots axons. After human SCI, NG2 and phosphacan were both detected in the evolving astroglial scar. Neurocan and versican were detected exclusively in the lesion epicentre, being associated with infiltrating Schwann cells in the myelin sheaths of invading peripheral nerve fibres from lesioned dorsal roots.
Conclusion
NG2 and phosphacan were both present in the evolving astroglial scar and, therefore, might play an important role in the blockade of successful CNS regeneration. Neurocan and versican, however, were located at the lesion epicentre, associated with Schwann cell myelin on regenerating peripheral nerve fibres, a distribution that was unlikely to contribute to failed CNS axon regeneration. The present data points to the importance of such correlative investigations for demonstrating the clinical relevance of experimental data.
Journal Article
INTRASELLAR ARACHNOID CYSTS
Abstract
OBJECTIVE
To evaluate the clinical, endocrinological, and radiological presentation of nine cases of surgically verified intrasellar arachnoid cysts and to discuss the physiopathological mechanisms of formation of these cysts.
METHODS
Among 1540 patients presenting with pituitary lesions, nine presented with an intrasellar arachnoid cyst. Their charts were retrospectively reviewed.
RESULTS
Presenting symptoms included headache (n = 2), visual symptoms (n = 3), menstrual irregularities (n = 2), rapid weight gain (n = 1), vertigo (n = 1), and/or confusion (n = 1). Two cysts were discovered incidentally. T1-weighted magnetic resonance imaging scans showed an intrasellar cystic lesion in all cases, with a huge suprasellar extension in six cases. The cyst was of the same intensity as the cerebrospinal fluid (CSF) in only two patients. A transsphenoidal approach allowed the transdural aspiration of fluid and injection of a water-soluble contrast agent under mild pressure. In three patients, the contrast infiltrated along the pituitary stalk toward the subarachnoid spaces; in the other patients, it remained in the intrasellar compartment. Cyst membranes were removed as completely as possible with fenestration toward the subarachnoid spaces in communicating cysts. In spite of tight packing of the sella and sphenoid sinus, CSF fistulae requiring reoperation developed in two patients.
CONCLUSION
The clinical picture of an intrasellar arachnoid cyst resembles that of a nonfunctional pituitary adenoma. Magnetic resonance imaging scans typically show a cystic intrasellar lesion with suprasellar extension, containing isointense or, more often, hyperintense fluid on T1-weighted sequences. In spite of the risk of CSF fistulae, the preferred surgical approach is transsphenoidal. A physiopathological mechanism is proposed according to anatomic variations of the sellar diaphragma allowing penetration of subarachnoid spaces into the sellar compartment and their enlargement by a ball-valve mechanism.
Journal Article
Intraoperative magnetic resonance imaging versus standard neuronavigation for the neurosurgical treatment of glioblastoma: A randomized controlled trial
Background: Although the added value of increasing extent of glioblastoma resection is still debated, multiple technologies can assist neurosurgeons in attempting to achieve this goal. Intraoperative magnetic resonance imaging (iMRI) might be helpful in this context, but to date only one randomized trial exists. Methods: We included 14 adults with a supratentorial tumor suspect for glioblastoma and an indication for gross total resection in this randomized controlled trial of which the interim analysis is presented here. Participants were assigned to either ultra-low-field strength iMRI-guided surgery (0.15 Tesla) or to conventional neuronavigation-guided surgery (cNN). Primary endpoint was residual tumor volume (RTV) percentage. Secondary endpoints were clinical performance, health-related quality of life (HRQOL) and survival. Results: Median RTV in the cNN group is 6.5% with an interquartile range of 2.5-14.75%. Median RTV in the iMRI group is 13% with an interquartile range of 3.75-27.75%. A Mann-Whitney test showed no statistically significant difference between these groups (P = 0.28). Median survival in the cNN group is 472 days, with an interquartile range of 244-619 days. Median survival in the iMRI group is 396 days, with an interquartile range of 191-599 days (P = 0.81). Clinical performance did not differ either. For HRQOL only descriptive statistics were applied due to a limited sample size. Conclusion: This interim analysis of a randomized trial on iMRI-guided glioblastoma resection compared with cNN-guided glioblastoma resection does not show an advantage with respect to extent of resection, clinical performance, and survival for the iMRI group. Ultra-low-field strength iMRI does not seem to be cost-effective compared with cNN, although the lack of a valid endpoint for neurosurgical studies evaluating extent of glioblastoma resection is a limitation of our study and previous volumetry-based studies on this topic.
Journal Article
Law, Public Offers and Restructurings
French rules governing public offers have been amended frequently, sometimes reflecting the legislator’s desire to encourage such transactions and sometimes reflecting a distrust of them. In the latter case, this is notably due to the restructurings that they can entail.In view of these risks, the law of 29 March 2014 attempted to tighten the restrictions on restructurings contemplated in the context of takeover bids by increasing the powers of the board and of the works council. However, the actual scope of these new provisions needs to be qualified with regard to the restrictions they introduce. Conversely, foreign investment procedures, which may result in the investor having to give a certain number of commitments, appear to take on a much more important role in these transactions.A distinction must be made between voluntary takeover bids on the one hand and mandatory bids and buyout offers on the other, as the rules governing them provide for different approaches to restructurings, in particular with regard to the AMF’s discretion either to grant exemptions or to impose the filing of an offer. In order to limit so-called financial takeover bids, initiated notably by investment funds, France has opted for a high threshold, of 95%, triggering a squeeze-out. JEL Codes: G18, K22, L5.
Journal Article
Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): A Prospective Longitudinal Observational Study
BACKGROUND:Current classification of traumatic brain injury (TBI) is suboptimal, and management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies.
OBJECTIVE:To improve characterization and classification of TBI and to identify best clinical care, using comparative effectiveness research approaches.
METHODS:This multicenter, longitudinal, prospective, observational study in 22 countries across Europe and Israel will collect detailed data from 5400 consenting patients, presenting within 24 hours of injury, with a clinical diagnosis of TBI and an indication for computed tomography. Broader registry-level data collection in approximately 20 000 patients will assess generalizability. Cross sectional comprehensive outcome assessments, including quality of life and neuropsychological testing, will be performed at 6 months. Longitudinal assessments will continue up to 24 months post TBI in patient subsets. Advanced neuroimaging and genomic and biomarker data will be used to improve characterization, and analyses will include neuroinformatics approaches to address variations in process and clinical care. Results will be integrated with living systematic reviews in a process of knowledge transfer. The study initiation was from October to December 2014, and the recruitment period was for 18 to 24 months.
EXPECTED OUTCOMES:Collaborative European NeuroTrauma Effectiveness Research in TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research.
DISCUSSION:Comparative effectiveness research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care, and outcome to support optimal personalized patient management.
Journal Article