Survival of breast cancer patients with meningeal carcinomatosis treated by intrathecal thiotepa.

Treatment of breast cancer meningeal carcinomatosis (MC) relies on intrathecal chemotherapy. Thiotepa is one of the few drugs approved in this setting, although no large cohort has been reported. The aim of our retrospective study is to describe survival and prognostic factors of breast cancer patients treated by intrathecal thiotepa. A search in the electronic database of the Institut Curie was performed and retrieved the patients diagnosed with breast cancer MC from 2000 to 2012 and who received at least one intrathecal injection of thiotepa. The standard regimen was intrathecal thiotepa (10 mg) and methylprednisolone (40 mg), repeated every other week. Clinical data were retrieved from the computerized medical file of each patient. Sixty-six patients have been treated with intrathecal thiotepa either as first line or second line of treatment for breast cancer MC. The median overall survival was 4.5 months (range 0.1-50). There was no significant survival difference between patients treated as first or second line. In multivariate analysis, main adverse prognostic factors at diagnosis were performance status >2 (p = 0.001, RR = 3.4, 95 % CI 1.6-7.2) and history of more than 3 previous systemic chemotherapy lines (p = 0.002, RR = 2.90, 95 % CI 1.50-5.65). After start of the treatment, high primary tumor grade, elevated Cyfra 21-1 levels in the cerebrospinal fluid, and lack of clinical improvement were also independent adverse prognostic factors in multivariate analysis. This is the largest retrospective cohort of breast cancer MC treated by intrathecal thiotepa ever reported. The median overall survival was short but some patients clearly benefited from this treatment, even used as second line.

PHLDA2 is an imprinted gene in cattle.

Genomic imprinting is an epigenetic non-Mendelian phenomenon found predominantly in placental mammals. Imprinted genes display differential expression in the offspring depending on whether the gene is maternally or paternally inherited. Currently, some 100 imprinted genes have been reported in mammals, and while some of these genes are imprinted across most mammalian species, others have been shown to be imprinted in only a few species. The PHLDA2 gene that codes for a pleckstrin homology-like domain, family A (member 2), protein has to date been shown to be a maternally expressed imprinted gene in humans, mice and pigs. Genes subject to imprinting can have major effects on mammalian growth, development and disease. For instance, disruption of imprinted genes can lead to aberrant growth syndromes in cloned domestic mammals, and it has been demonstrated that PHLDA2 mRNA expression levels are aberrant in the placenta of somatic clones of cattle. In this study, we demonstrate that PHLDA2 is expressed across a range of cattle foetal tissues and stages and provide the first evidence that PHLDA2 is a monoallelically expressed imprinted gene in cattle foetal tissues, and also in the bovine placenta.

CT-guided infiltration of greater occipital nerve for refractory craniofacial pain syndromes other than occipital neuralgia.

PURPOSE: The purpose of this study was to evaluate the effectiveness of computed tomography (CT)-guided infiltration of greater occipital nerve (GON) for the treatment of refractory craniofacial pain syndromes other than occipital neuralgia. MATERIALS AND METHODS: Fifty-six patients suffering from refractory craniofacial pain syndromes were included between 2011 and 2017. There were 33 women and 23 men with a mean age of 50.7 years±13.1 (SD) (range: 27-74 years). CT-guided infiltration was performed at the intermediate site of the GON with local anesthetics and cortivazol. Twenty-six (26/56; 46%) patients suffered from chronic migraine, 14 (14/56; 25%) from trigeminal neuralgia and 16 (16/56; 29%) from cluster headaches. Clinical success at 1, 3, and 6 months was defined by a decrease of at least 50% of pain as assessed using visual analog scale (VAS). RESULTS: Mean overall VAS score before infiltration was 8.7±1.3 (SD) (range: 6 - 10). Mean overall VAS scores after infiltration were 2.3±3 (SD) (range: 0 - 10) (P<0.01) at one month, 3.5±3.3 (SD) (range: 0 - 10) (P<0.01) at three months and 7.6±1.3 (SD) (range: 1-10) (P<0.01) at six months. After infiltration, clinical success was achieved in 44 patients (44/56; 78.5%) at 1 month, 37 patients (37/56; 66%) at 3 months and 13 patients (13/56; 23%) at 6 months. Clinical success according to the clinical presentation were as follows: 88% (23/26) at one month, 73% (19/26) at 3 months, and 23% (6/26) at 6 months in patients with chronic migraine, 81% (13/16), 69% (11/16) and 31% (5/16) in those with cluster headaches and 57% (8/14), 50% (7/14) and 14% (2/14) in those with trigeminal neuralgia. No major complications due to CT-guided GON infiltration were reported in any patient. CONCLUSION: CT-guided infiltration at the intermediate site of the GON appears as an effective treatment of craniofacial pain syndromes especially in patients with chronic migraine and those with cluster headaches.

Clinical outcome in children with chronic recurrent multifocal osteomyelitis.

OBJECTIVE: To determine the clinical outcome of children with chronic recurrent multifocal osteomyelitis (CRMO). METHODS: We retrospectively reviewed clinical, biological and radiological data of children with CRMO at five French paediatric centres. Outcome data were obtained through review of hospital charts and questionnaires sent to all patients to assess disease activity and educational and vocational achievement. RESULTS: Forty patients were assessed (34 females and 6 males) with a median age at diagnosis of 11.5 yrs (range 2-17). Median number of initial bony lesions was 2 at onset, and 3.5 over disease course. Median time since diagnosis was 3.5 yrs (range 0.5-15) and median duration of active disease 2.7 yrs (range 0.5-13.5). Nine (22.5%) patients had psychological or physical sequelae. Twenty-nine children (72.5%) responded to the questionnaire. Twenty-six had no physical disability as judged by the HAQ 0-1, two had moderate disability (HAQ: 1-2) and one had severe disability (HAQ: 2-3). Seventeen patients (58.6%) had active disease at follow-up (after 6 months to 15 yrs since diagnosis) and continued to have pain (median value of visual analogue scale: 10/100). CRMO had interfered with patient's education in two cases. CONCLUSIONS: Clinical outcome of children with CRMO is generally good, but a sizeable proportion of patients have active disease at follow-up, and a minority of patients can have a severe and prolonged disease course despite intensive treatments. Further studies are required to determine predictive factors for severe disease.

The biokinetics and radiotoxicology of curium: a comparison with americium.

The human and animal data on the biokinetics of (242)Cm and (244)Cm are reviewed and shown to be very similar to those for (241)Am. Liver and skeleton are the main organs of deposition and the retention of curium in the skeleton is very prolonged in all the species examined. Retention of both curium and americium in the liver appears to be species-dependent, being relatively rapidly removed from the liver of rats, and probably humans, but being tenaciously retained in dogs and some other species. The radiotoxicity of curium is also reviewed and it is shown that, as with (241)Am, lung and bone tumour induction are the major hazards from inhaled and systemically deposited (244)Cm. The use of chelating agents for the treatment of accidental contamination of the human body with (242,244)Cm is also discussed.

Development of a database: DACTARI for a radiotoxic element ranking methodology.

Dosimetric impact studies aim at evaluating potential radiological effects of chronic or acute releases from nuclear facilities. A methodology for ranking radionuclides (RN) in terms of their health-related impact on the human population was first developed at CEA with specific criteria for each RN that could be applied to a variety of situations. It is based, in particular, on applying physico-chemical criteria to the complete RN inventory (present in the release or in the source term) and on applying norms related to radiation protection and chemical toxicology. The initial step consisted in identifying and collecting data necessary to apply the methodology, with reference to a previous database of long-lived radionuclides (LLRN, with half-lives ranging from 30 to 10(14) y) containing 95 radionuclides. The initial results have allowed us to identify missing data and revealed the need to complete the study for both toxic and radiotoxic aspects. This led us to the next step, developing a specific database, DAtabase for Chemical Toxicity and Radiotoxicity Assessment of RadIonuclides (DACTARI), to collect data on chemical toxicity and radiotoxicity, including acute or chronic toxicity, the chemical form of the compounds, the contamination route (ingestion, inhalation), lethal doses, target organs, intestinal and maternal-foetal transfer, drinking water guidelines and the mutagenic and carcinogenic properties.

6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury.

Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis.

[Role of visual analysis of first-pass contrast-enhanced MRI in reperfused myocardial infarction]. / Intérêt de l'IRM de perfusion avec analyse visuelle a la phase aiguë de l'infarctus du myocarde reperfusé.

The aim of this work is to evaluate the relationship between improvement of regional myocardial function and visual analysis of contrast-enhanced (CE) MRI in patients after acute myocardial infarction. MRI was performed on 19 patients 1 and 11 weeks after a reperfused acute myocardial infarction. Perfusion data (first-pass images [FPI] and delayed CE images) were acquired after an intravenous bolus of gadolinium-DTPA and visually analyzed using a 17 segment model. Each segment was then classified in 3 groups, according to the presence or absence of FPI and CE patterns at baseline study: group 0: normal-appearing segments; group 1: segments with delayed hyper-enhancement but no early hypo-enhancement; group 2: segments with early hypoenhancement. Relative Wall thickening (RWT) was analyzed in each segment and its improvement evaluated in each group. Between first MRI and follow-up study, a significant improvement of RWT occurred in group 1 (mean +/- SD) [from 43.43 +/- 26.59% to 76.71 +/- 47.38%; p = 0.001] but not in group 2 (from 32.73 +/- 25.58% to 39.57 +/- 30.57%; p = NS). In group 0, RWT despite normal value at baseline study exhibited a significant improvement at follow-up (from 65.23 +/- 46.52% to 79.73 +/- 48.46%; p = 0.0015). In conclusion, the combined analysis of early and delayed perfusion abnormalities in MRI in the week following myocardial infarction can predict myocardial viability and allows in the future an evaluation of the efficacy of perfusion therapy.

On the difficulty to communicate with fMRI-based protocols used to identify covert awareness.

Assessment of awareness in patients with disorders of consciousness such as patients in a vegetative state (unresponsive wakefulness syndrome, UWS) and patients in a minimally conscious state (MCS) remains difficult, with a high rate of misdiagnosis (around 40%). While patients with UWS have no awareness, patients with MCS have partial preservation of conscious awareness. To improve the assessment of awareness in these patients, recent functional neuroimaging protocols have been developed. However, does the complexity of realizing and interpreting these functional magnetic resonance imaging (fMRI) investigation protocols, which are currently carried out by only a few specialist teams, permit generalizable use in clinical routine? In this study, 32 healthy volunteers, by definition perfectly conscious and able to efficiently communicate, performed the protocol proposed by Monti et al. in 2010. Four methods (comprising the method proposed by Monti et al., a mean squared error-based method, a correlation-based method, and a support vector machine-based method) were tested for correctly and accurately interpreting the communication task. Firstly, the different instructions for the localizer and the communication tasks had no effect on activations. Secondly, 25% of participants (8/32) did not provide the expected patterns of activations during fMRI tasks (four for each imagery task). However, this did not necessarily prevent the classification methods from correctly guessing the answers during the communication task. Conversely, these classification methods may fail to detect the correct answers even though participants activated the expected brain areas. None of the four methods produced 100% correct detection during the communication phases. The correlation-based method obtained the best results with an error rate of 4.2%. The results of this study demonstrate that fMRI-based communication paradigms may not be robust enough to reliably detect awareness in all aware patients. There is still a need to develop new statistical and analytical methods before considering their generalization in clinical routine.

[Overall treatment time assessment of radiotherapy delivered in a curative intent: A prospective study]. / Respect de l'étalement de la radiothérapie à visée curative : étude prospective.

PURPOSE: To assess the overall treatment time of radiotherapy delivered with curative intent in a cohort of 185 consecutive patients and the causes of this possible delay. If delay, to propose corrective actions. MATERIALS AND METHODS: We report a single-center prospective study including all consecutive patients receiving a radiation therapy with curative intent, from 1st December 2013 to 28th February 2014, on the three linear accelerators of the radiotherapy department. For each fraction missed, the causes of non-completion were prospectively collected. This analysis took into account the following parameters: age, sex, occupation, transport type and duration, tumour localization, radiation dose, concomitant chemotherapy, hospitalization, type of linear accelerator. RESULTS: One hundred and fifty-five patients were included in the study (183 evaluable, two did not complete treatment). The overall treatment time was respected for 31 patients (17%). It was lengthened on 4.6 days (d) (0-29 d; median: 3d). The mean number of delayed fractions was 3.4 (0-17; median: 2). The reasons of delay were: breakdown 32.2%; maintenance 29.3%; holiday 11%; treatment toxicity 9.4%; inadequate planning 8.6%; other disease 3.9%; treatment refusal 2.1%; unspecified personal reasons 1.5%; refusal to wait 0.8%; transportation 0.3%; error of communication 0.3%; other 0.6%. Two parameters had a significant impact on the overall treatment time: the type of linear accelerator in relation to breakdown occurrence (P<0.001) and transportation duration (more or less than 40 min, P=0.022). One hundred and thirty-eight patients (75%) and 79 patients (43%) were treated on one or more than two Saturdays. Treatment on Saturday significantly reduced the overall treatment time (median, 1.9 d; P<0.001). CONCLUSION: The overall treatment time was globally respected excluding break down and maintenance. Their impact on the overall treatment time is minimized by the systematic opening of the department on Saturdays.

Substitute or complement? Defining the relative place of EEG and fMRI in the detection of voluntary brain reactions.

To improve the assessment of awareness in patients with disorders of consciousness, recent protocols using functional Magnetic Resonance Imaging (fMRI) have been developed, and led some specialized coma centers to use this method on a routine basis. Recently, promising results have also been observed with electroencephalography (EEG), a less expensive and widely available technique. However, since the spatiotemporal nature of the recorded signal differs between both EEG and fMRI, the question of whether one method could substitute or should complement the other method is a matter of debate. In this study, we compared the neural processes of two well-known EEG and fMRI mental imagery protocols to define the relative place of each method in the assessment of awareness. A group of 20 healthy volunteers performed both EEG and fMRI command-following and communication tasks. Distinct command following was found with both EEG and fMRI for five subjects, only with fMRI for 12 subjects, and only with EEG for one subject. In the communication task, neither EEG nor fMRI alone gave satisfactory results and no reliable communication could be established in approximately 1/3rd of the participants. If fMRI showed the best performance to detect volitional reactions in mental imagery tasks, our results provide evidence that the use of EEG must not be underestimated since a better detection was found with this method for at least one subject. More than being used as a substitute, EEG should complement fMRI to improve the detection of sign of awareness, and to reduce the risks of misjudgments.

Binding of (+)-PN 200-110 to rat pituitaries and to normal and adenomatous human pituitaries.

Endocrine cells possess voltage-sensitive Ca2+ channels involved in the modulation of hormonal secretion. Using the dihydropyridine, (+)-PN 200-110, we have investigated the binding characteristics of this ligand to pituitary membrane Ca2+ channels from normal rat, normal and adenomatous human pituitaries. [3H]PN 200-110 binds specifically to rat pituitary membranes to one class of sites (Kd = 0.41 +/- 0.10 mM; Bmax = 39 +/- 1.3 fmol/mg protein). At 37 degrees C, equilibrium is reached in 45 min and half-life of the binding is 13 min. No significant changes were observed for either the Kd or Bmax values between normal rat and human pituitaries or between the different types of adenomas (GH- and PRL-secreting and non-secreting). As the secretory activity of the pituitary adenomas, involving Ca2+ mobilization, varies from one adenoma to another, our results could indicate that, if there is a modified regulation of Ca2+ entry in the adenomas, it may not be related to a varying number of calcium channels, at least the channels labeled by the dihydropyridine (+)-PN 200-110.

[Early study of myocardial perfusion with MRI in revascularized infarcts]. / Etude précoce de la perfusion myocardique par IRM des infarctus revascularisés.

The aim of this work is to study the regional myocardial perfusion by MRI early after revascularised myocardial infarction and to compare it with regional function. This prospective work has included 15 patients with acute first myocardial infarction that was precociously revascularised. A myocardial MRI was performed between D2 and D10 after myocardial infarction. The regional myocardial thickening was evaluated from cine-MRI sequences. For the study of myocardial perfusion, the first pass of the contrast agent was analysed from curves of the signal evolution versus time. The signal enhancement on late images acquired 10 minutes after the perfusion of the contrast agent was also evaluated. Among 384 studied myocardial segments, those with a normal gadolinium first pass curve had a relative thickening of 46 +/- 38%. The segments with a severely reduced first pass kinetic have a markedly reduced relative thickening (14 +/- 20%) in relation with myocardial hypoperfusion. The myocardial enhancement is frequently seen in the infarct territory and appears related to a reduced regional contractility. The myocardium is enhanced on late images in 12% of the normally perfused segments. These segments have a mildly reduced wall thickening (3.36 +/- 2.84 mm vs 4.42 +/- 2.83 mm). The segmental contractility in a reperfused myocardial infarction appears to depend both on the myocardial perfusion which reflects the microvascularisation and on the myocardial enhancement which is linked to myocardial structural alterations. MRI appears to be an adequate method to evaluate these abnormalities and allows an easy assessment of the no-reflow phenomenon, if present.

[Magnetic resonance imaging early after acute myocardial infarction. A visual analysis of myocardial perfusion based on a 17 segment model]. / Imagerie par résonance magnétique en postinfarctus immédiat. Analyse visuelle de la perfusion myocardique sur un modèle à 17 segments.

Magnetic resonance imaging allows an accurate calculation of the left ventricular ejection fraction and left ventricular volumes. Additionally, it makes possible to assess myocardial perfusion after gadolinium chelate injection. Late after the injection, the presence of a myocardial hyper-enhancement can be visualized. The present study has used the 17 segment standardized nomenclature for tomographic imaging of the heart as recommended for all cardiac imaging modalities. Sixty nine patients were studied after a revascularised myocardial infarction. All patients had Timi grade 3 flow in the infarct-related artery after therapy. Regional and global function was studied using cine MR short axis slices. The gadolinium chelate first pass was scored using a 5 level scale reflecting the transmural extent of the segmental myocardial enhancement. The delayed enhancement due to gadolinium accumulation in the myocardium 10 min post injection was scored in the same manner. Left ventricular ejection fraction was 51 +/- 13%. Segmental thickening parameters (systolic thickness, absolute thickening and relative thickening) appeared statistically related to the hypoperfusion and delayed enhancement scores. Absolute myocardial thickening varied from 4.8 +/- 2.7 mm in the myocardial segments free of any delayed enhancement to 2.4 +/- 2.1 mm in segments presenting with a transmural extent of the delayed hyper-enhancement. Scores obtained after gadolinium injection were also well correlated with the global left ventricular function (r = 0.65, p < 0.01 for late enhancement). Magnetic resonance imaging of the heart allows a precise characterisation of revascularised myocardium which makes this technique very attractive for evaluating the treatments designed to improve myocardial microperfusion.

An EWOD-based microfluidic chip for single-cell isolation, mRNA purification and subsequent multiplex qPCR.

Single cell analysis circumvents the need to average data from large populations by observing each cell individually, thus enabling the analysis of cell-to-cell variability. The ability to work on this scale presents many new opportunities for the life sciences and biomedical applications. Microfluidics has become a tool of choice for such studies and electrowetting on dielectric (EWOD) technology is well adapted for samples with reduced size and biological studies at the single cell level. In the present manuscript, for the first time, we present an integrated and automated system based on EWOD that can process the complete workflow on a single device, from the isolation of a single cell to mRNA purification and gene expression analysis.

Time course of odorant- and trigeminal-induced activation in the human brain: an event-related functional magnetic resonance imaging study.

It is well known that most odorants stimulate the trigeminal system but the time course of the brain regions activated by these chemical stimulations remains poorly documented, especially regarding the trigeminal system. This functional magnetic resonance imaging (fMRI) study compares brain activations resulting from the contrast between two odorant conditions (one bimodal odor and one relatively pure olfactory stimulant) according to the duration of the stimulation (i.e. one inhalation, or three or six successive inhalations). The results show striking differences in the main brain regions activated according to these durations. The caudate nucleus and the orbitofrontal cortex are only involved in short-duration stimulations, and the posterior insular cortex and post-central gyrus (SI) are only activated by long duration stimulations. Different regions of the frontal, temporal and occipital lobe are activated depending on the duration but mainly during medium-duration stimulations. These results expand on the findings of previous studies and contribute to the description of temporal networks in trigeminal perception.

[Scanning electron microscopy study of the effect of steel and tungsten carbide burs on dental tissues]. / Etude en microscopie électronique à balayage de l'effet des fraises en acier et en carbure de tungstène sur les tissus dentaires.

The effects of steel and tungsten carbide burs have been studied under the scanning electron microscope on human enamel and dentin during preparation of mesio-occluso-distal cavities in vitro with cutting speeds varying from 5 000 to 120 000 r.p.m. All the cavities presented clean and regular walls. However, the final quality of the cavity borders, and in particular the cavo-surface angles of the box walls, was directly related to the speed and rotation direction of the bur. The cavo-surface angles at the gingival planes showed in all cases fractures of the superficial prisms. The cutting character displayed in dentine surfaces were mainly dependent on the orientation of the tubules in relation to the surface of the cavity preparation and the degree of sclerosed dentine. The cavities prepared in the absence of water and air showed the presence of tissue debris nd cracks; their number increased with increasing rotational speed.

[Effect of the action of rotary diamond instruments on the enamel and dentine. Scanning electron microscopic study]. / Effets de l'action d'instruments rotatifs diamantés sur l'émail et la dentine. Etude en microscopie électronique á balayage.

Mesio-occluso-distal cavities were prepared "in vitro" on human teeth using cylindrical diamond instruments of fine granulometry and operating at high and very high speeds. The surface states obtained on enamel and dentine were examined with scanning electron microscopy. The striae produced by these instruments appeared as well marked straight ridges and depressions the depths of which were higher than those produced by steel and tungsten carbide burs. Along cavo-surface angles, superficial prism fractures and/or border irregularities were visible, especially in relation to the cutting plane orientation versus the prism axes. A highly adhering smear layer on enamel walls was observed. The rotational direction of the diamond instruments did not appear to affect the quality of the cavo-surface box angles as it did for steel and tungsten carbide burs.

Oxygen monitoring in supercritical carbon dioxide using a fibre optic sensor.

Investigations of enzymatic reactions in supercritical CO(2) are often hindered by the high pressure involved in these processes, making reaction monitoring extremely difficult. This paper describes the implementation of a fiber optic based oxygen sensor into a high pressure reactor for supercritical carbon dioxide. The sensor is pressure resistant, working in supercritical carbon dioxide and reusable after depressurisation. The sensor signal is found to be affected by pressure changes, but stable at constant pressure. Oxygen concentration in supercritical CO(2) is monitored using the disproportionation of hydrogen peroxide as a simple oxygen producing reaction.