CAR T-cell-associated neurotoxicity: A comprehensive review.

Chimeric antigen receptor T-cell (CAR T-cell) therapies have emerged as a promising treatment modality for several malignancies, particularly haematological malignancies, by inducing robust antitumour responses. However, CAR T-cell therapies are associated with a spectrum of adverse events, including neurological complications. We here provide a review of neurological adverse events observed in patients undergoing CAR T-cell therapy, focusing on their incidence, clinical manifestations, underlying mechanisms and potential management strategies.

[Assessment of lower urinary tract symptoms as part of falls screening : Knowledge and practice of health care workers involved in the management of older people]. / Évaluation des symptômes du bas appareil urinaire lors du dépistage du risque de chute : connaissances et pratiques des soignants impliqués dans la prise en charge des personnes âgées.

INTRODUCTION: Falling is a public health problem that could be prevented by screening at-risk populations. Several tools exist, some of which assess lower urinary tract symptoms (LUTS). Our aim was to examine knowledge and practice regarding the assessment of LUTS when screening for fall risk in older people. MATERIALS AND METHODS: The knowledge and practices of geriatric caregivers regarding falls risk screening were surveyed by an online self-administered questionnaire, consisting of 6 to 29 questions depending on the responses. A descriptive analysis of the responses was performed. RESULTS: Of 120 caregivers approached, 71 responded to the questionnaire (92% female, median age 44 years [40.5-50.7]). Most respondents were nurses (58%). 51 were aware of at least one fall risk screening tool, and 23 felt they assessed at least one LUTS. The 3 most known tools were the Timed up and go test (n=16), the unipodal stance time (n=10) and the Morse scale (n=8). 33 used fall risk screening tools, and 15 felt they assessed at least one SBAU. The 3 most used tools were the Timed up and go test (n=6), the STRATIFY scale (n=5) and the Morse scale (n=4). CONCLUSION: Most fall risk screening tools known or used by caregivers involved in the care of the older adult do not assess LUTS.

Predictive factors of human cytomegalovirus reactivation in newly diagnosed glioblastoma patients treated with chemoradiotherapy.

The human cytomegalovirus (HCMV) is a ubiquitous herpes virus which infects 40 to 99% of the population. HCMV reactivation may occur in the context of immunosuppression and can induce significant morbidities. Several cases of HCMV infections or HCMV reactivation have thus been reported in glioblastoma (GBM) patients treated with radio(chemo)therapy. With the aim to identify the main risk factors associated with HCMV reactivation, we reviewed all patients treated for a newly diagnosed GBM in our institution from October 2013 to December 2015. Age, sex, Karnofsky performance status (KPS), absolute lymphocyte count (ALC), serological HCMV status, and steroid doses were recorded at the start and 1 month after the end of radiotherapy (RT). Within the 103 patients analyzed, 34 patients (33%) had an initial negative serology for HCMV, and none of them developed a seroconversion after treatment. Among patients with positive HCMV IgG (n = 69), 16 patients (23%) developed a viremia at one point during treatment. Age (> 60 years), steroid intake, and ALC (< 1500/mm3) before RT were correlated with HCMV reactivation. HCMV viremia was associated with neurological decline 1 month after chemoradiotherapy but progression-free survival was not impacted. A shorter overall survival was seen in these patients when compared with the others, but this could be biased by the older age in this subgroup. HCMV reactivation needs to be sought in case of a neurological decline during RT especially in older patients treated with steroids and low lymphocytes counts.

Contribution of the neuropsychological assessment in concussion.

INTRODUCTION: The neuropsychological assessment is a cornerstone in the care management of concussion or mild traumatic injury. OBJECTIVE: To present the different stages of an exhaustive neuropsychological assessment exploring cognitive and behavioral domains. METHOD: Description of the value of the main tests available for behavioral and cognitive assessment. The choice of tests is based on the clinical experience and expertise of the authors. RESULTS: Questionnaires are mainly used to explore the behavioral sequelae (depression, anxiety or fatigue) and the impact of these potential difficulties in daily life. Four cognitive abilities could be impaired by concussion: attention, memory, visuospatial functions and executive functions. These abilities could be explored with "paper and pencil" tests or with computerized test batteries. While cognitive sequelae in the context of a moderate or a severe traumatic brain injury are consolidated, in the context of concussion, neuropsychological sequelae tend to resolve in a short time. As a consequence, several neuropsychological assessments could be conducting in a short period involving some methodological considerations. Moreover, as concussion could be reported in a Whiplash injury from a car crash with forensic consequences, it is crucial to propose tests to be sure that the weak performance obtained into the neuropsychological assessment is not explained by poor effort and/or malingering. DISCUSSION/CONCLUSION: This article revises these aspects of a neuropsychological assessment in the specific context of concussion.

Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature.

Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related disorders. We here review the literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3.8% with anti-CTLA4 antibodies, 6.1% with anti-PD1 antibodies, and 12.0% with the combination of both. The clinical spectrum of neurological disorders was highly heterogeneous. Most of these nAEs were grade 1-2 and consisted of non-specific symptoms such as headache (55%). The incidence of high grade nAEs was below 1% for all types of treatment. Headaches, encephalopathies and meningitis were the most commonly reported (21%, 19% and 15%, respectively). Among the 27 case reports, the most common nAEs were encephalopathies, meningoradiculoneuritis, Guillain-Barré like syndromes and myasthenic syndromes. The median time of nAEs onset was 6 weeks. In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-Barré syndrome.

Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma.

BACKGROUND AND PURPOSE: Despite surgery, radiotherapy (RT) and temozolomide (TMZ), the prognosis of glioblastoma (GBM) patients remains dismal. Normally prescribed with the aim to lower blood pressure, angiotensin-II (Ang-II) inhibitors were reported to reduce angiogenesis and tumour growth in several tumour models including one glioma. Thus whether treatment with Ang-II inhibitors could be associated with a better clinical outcome in GBM patients was investigated. METHODS: A series of 81 consecutive patients, homogeneously treated with RT and TMZ for a newly diagnosed, supratentorial GBM, were analysed. The objective of this retrospective study was to assess the impact of angiotensin-converting enzyme inhibitors (ACEIs) and Ang-II receptor 1 blockers (ARBs) on functional independence, progression-free survival (PFS) and overall survival (OS). RESULTS: Amongst the 81 GBM patients analysed, 26 were already treated for high blood pressure (seven with ACEIs and 19 with ARBs). The number of patients who remained functionally independent at 6 months after RT was higher in the group of patients treated with Ang-II inhibitors compared to the other patients (85% vs. 56%, P = 0.01). In patients treated with Ang-II inhibitors, PFS was 8.7 months (vs. 7.2 months in the other patients) and OS was 16.7 months (vs. 12.9 months). The use of Ang-II inhibitors was a significant prognostic factor for both PFS (P = 0.04) and OS (P = 0.04) in multivariate analysis. CONCLUSION: Treatment with Ang-II inhibitors in combination with RT and TMZ might improve clinical outcome in GBMs. Prospective trials are needed to test this hypothesis.

[Supportive care, cognition and quality of life in brain metastases]. / Soins de support, cognition, qualité de vie et métastases cérébrales.

Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper.

A comprehensive study of thiol reduction gene expression under stress conditions in Arabidopsis thaliana.

Thiol reduction proteins are key regulators of the redox state of the cell, managing development and stress response programs. In plants, thiol reduction proteins, namely thioredoxin (TRX), glutaredoxin (GRX), and their respective reducers glutathione reductase (GR) and thioredoxin reductase (TR), are organized in complex multigene families. In order to decipher the function of the different proteins, it is necessary to have a clear picture of their respective expression profiles. By collecting information from gene expression databases, we have performed a comprehensive in silico study of the expression of all members of different classes of thiol reduction genes (TRX, GRX) in Arabidopsis thaliana. Tissue expression profiles and response to many biotic and abiotic stress conditions have been studied systematically. Altogether, the significance of our data is discussed with respect to published biochemical and genetic studies.

PreFix™ external fixator used to treat a floating shoulder injury caused by gunshot wound.

Open fractures of the shoulder are extremely rare, and their treatment is a major challenge for surgeons. Only cases encountered in military settings have been reported thus far. Such fractures are often the result of ballistic trauma, which causes extensive damage to both bony and soft tissues. Since these injuries are associated with a high risk of infection and the presence of comminuted fractures, external fixation is necessary for repair. Use of external fixators and revascularization techniques has reduced the number of cases requiring shoulder amputation or disarticulation. Injury to the proximal extremity of the humerus, acromion, and clavicle further complicates the treatment. No published studies have described the assembly of external fixators for fractures in the scapular region with significant bone loss. In addition, no cases have been described in civilian settings. However, with an increase in urban violence and the traffic of illegal arms, civilian surgeons are now encountering an increasing number of patients with these injuries. In this report, we not only present a rare case of floating shoulder injury in a civilian setting but also provide an overview of the existing treatment strategies for this type of trauma, with special focus on the use of external fixators in elective shoulder arthrodesis and on military cases.

Steroid-sparing effects of angiotensin-II inhibitors in glioblastoma patients.

BACKGROUND: The standard of care in patients with glioblastoma (GBM) relies on surgical resection, radiation therapy (RT), and temozolomide. Steroids are required in almost all patients to reduce peritumoral edema, but are associated with numerous side effects. Vascular endothelial growth factor (VEGF) is a key driver of peritumoral edema and angiogenesis in human GBM. Recently, angiotensin-II inhibitors were reported to reduce VEGF secretion and tumor growth in some animal models. METHODS: To investigate whether angiotensin-II inhibitors might have a similar effect in humans and before undertaking a prospective study, we retrospectively investigated a series of 87 consecutive, newly diagnosed GBM patients, treated in a single center. Amongst these patients, 29 (33%) were already treated before RT for high blood pressure (HBP), 18 of them (21%) with an angiotensin-II inhibitor. In all patients, performance status, surgical procedures, and steroid dosages were documented. RESULTS: Patients treated with angiotensin-II inhibitors, but not other antihypertensive drugs, required half of the steroids of the other patients during radiotherapy (P = 0.005 in multivariate analysis, considering other antihypertensive treatments, surgical resection, and performance status). This effect of angiotensin-II inhibitors was also significant at the beginning of radiotherapy (P = 0.03 in multivariate analysis). Treatment with angiotensin-II inhibitors had no effect on survival (16.2 vs. 17.9 months for the treated and the non-treated group, respectively, P = 0.77). CONCLUSION: Angiotensin-II inhibitors might display significant steroid-sparing effects in brain tumor patients. Given the morbidity associated with steroids, this finding might have important practical consequences in these patients and warrants a randomized study.

Cognitive function and 99mTc-ECD brain SPECT are significantly correlated in patients with primary Sjogren syndrome: a case-control study.

OBJECTIVES: To assess subclinical central nervous system (CNS) involvement in primary Sjögren syndrome (pSS), by comparing standard brain MRI, in-depth neuropsychological testing and (99m)Tc-ECD brain single-photon emission computed tomography (SPECT) of patients with pSS with matched controls. METHODS: 10 women (<55 years old), with pSS defined using European-American criteria, presence of anti-SSA and/or anti-SSB antibodies and no history of neurological involvement were prospectively investigated, and compared with 10 age- and sex-matched controls. All subjects underwent, within 1 month, brain MRI, neuropsychological testing, including overall evaluation and focal cognitive function assessment, and (99m)Tc-ECD brain SPECT. RESULTS: (99m)Tc-ECD brain SPECT abnormalities were significantly more common in patients with pSS (10/10) than controls (2/10; p<0.05). Cognitive dysfunctions, mainly expressed as executive and visuospatial disorders, were also significantly more common in patients with pSS (8/10) than controls (0/10; p<0.01). Notably, between-group comparisons enabled a significant correlation to be established between neuropsychological assessment and (99m)Tc-ECD brain SPECT abnormalities in patients with pSS (r(s) = 0.49, p<0.01). MRI abnormalities in patients and controls did not differ significantly. CONCLUSIONS: Neuropsychological testing and (99m)Tc-ECD brain SPECT seem to be the most sensitive tools to detect subclinical CNS dysfunction in pSS. The strong correlation between cortical hypoperfusion in (99m)Tc-ECD brain SPECT and cognitive dysfunction suggests an organic aetiology of CNS dysfunction in pSS. These data should be confirmed in a larger study.

[Atypical progressive multifocal leukoencephalopathy (PML) in a patient with pulmonary sarcoidosis]. / Leucoencéphalopathie multifocale progressive atypique chez un patient atteint de sarcoïdose médiastinopulmonaire.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of central nervous system due to the JC virus. PML generally occurs in immunocompromised hosts and has a fatal outcome. OBSERVATION: We report a case of an atypical PML in a patient with pulmonary sarcoidosis: MRI showed multifocal and punctate contrast enhancements. The diagnostic was made by brain biopsy. CONCLUSION: The pathophysiology of this association is probably related to the immunodepression induced by sarcoidosis.

Impact of storage induced outgassing organic contamination on laser induced damage of silica optics at 351 nm.

The impact of storage conditions on laser induced damage density at 351 nm on bare fused polished silica samples has been studied. Intentionally outgassing of polypropylene pieces on silica samples was done. We evidenced an important increase of laser induced damage density on contaminated samples demonstrating that storage could limit optics lifetime performances. Atomic Force Microscopy (AFM) and Gas Chromatography -Mass Spectrometry (GC-MS) have been used to identify the potential causes of this effect. It shows that a small quantity of organic contamination deposited on silica surface is responsible for this degradation. Various hypotheses are proposed to explain the damage mechanism. The more likely hypothesis is a coupling between surface defects of optics and organic contaminants.

[Hemispheric specialisation versus inter-hemispheric communication]. / Spécialisation hémisphérique versus coopération inter-hémisphérique.

The first part of this article covers the main discoveries that led to the concept of hemispheric specialisation, from Egyptian antiquity to present times, through the pivotal XIXth century period that saw the attribution of specific cognitive functions to the left and right hemispheres. Next, this dichotomous conception of cerebral function, attributing a given process to a hemisphere and hypothesising callosal transmission, is discussed in the light of recent studies on language comprehension. Present day knowledge suggesting an alternative to the structuralist view of hemispheric specialisation in the form of dynamic, complementary sharing of labour, and of cooperation through transcortical neural networks, is then considered. Finally, the role of the corpus callosum in interhemispheric communication is briefly covered. An emphasis is placed on the diversity of this structure that is at the origin of highly different functions (fibre size, homotopic vs heterotopic connections). Ultimately, we contrast the view of a corpus callosum serving as an information transmitting channel with that of a fibre tract co-activating the non-engaged hemisphere and preparing it for potential stimulation. In this manner, the corpus callosum minimises disparities in the distribution of attention between the two hemispheres.

[Intracranial localization revealing Hodgkin's disease]. / Lésion intracrânienne révélatrice d'une maladie de Hodgkin.

The central nervous system's (CNS) involvement is uncommon in Hodgkin's disease (HD) and usually occurs in patients with relapsing disease many years after the initial diagnosis. An isolated involvement of the CNS is extremely rare and therefore, difficult to diagnosis. We report the case of a 27-year-old woman with seizure and a left cerebrodural mass on the cerebral imaging; secondarily, she developed cervical lymph node swelling; histological examination of the node revealed HD of the nodular sclerosis type. The dural lesion resolved after chemotherapy for HD.

[Listeria monocytogenes encephalitis revealed by left progressive hemiparesis]. / Hémiparésie d'installation progressive révélant une encéphalite à listéria monocytogènes.

INTRODUCTION: Central nervous system listeriosis is a diagnostic and therapeutic challenge for the clinician. CASE REPORT: We report the case of a 66-year-old woman who was admitted for a left progressive hemiparesis associated with headaches. She was treated for one year by immunosuppressive drugs for vulgaris pemphigus. At the time of admission, examination revealed left hemiparesis without fever, and a computed tomography brain scan demonstrated a focal lesion in the right frontal lobe. Blood analyses were normal. Two days after, she suddenly developed fever (40 degrees C), and aggravation of her motor deficit followed by partial motor seizures. The cerebrospinal fluid was normal. Treatment with amoxicillin (3g IV q6h), cefotaxim, gentamycin (120mg IV q12h) and aciclovir was started empirically. The brain MRI without gadolinium displayed infiltrative lesions in the right hemisphere and in the mildbrain. The blood culture grew Listeria monocytogenes. The antimicrobial regimen was changed to amoxicillin for seven weeks and gentamicin for the first ten days. Four days after beginning the antimicrobial regimen, the brain MRI with gadolinium displayed several abscesses measuring less than one cm diameter. The clinical and imaging outcome excellent. CONCLUSION: Meningitis is by far the most central nervous system listeriosis. In our patient, the diagnosis of listeria monocytogenes encephalitis was established on the basis of positive blood cultures, as such patients do not have sterile cerebrospinal fluid.

Multielemental speciation of trace elements in estuarine waters with automated on-site UV photolysis and resin chelation coupled to inductively coupled plasma mass spectrometry.

An integrated approach for the accurate determination of total, labile and organically bound dissolved trace metal concentration in the field is presented. Two independent automated platforms consisting of an ultraviolet (UV) on-line unit and a chelation/preconcentration/matrix elimination module were specifically developed to process samples on-site to avoid sample storage prior to inductively coupled plasma mass spectrometry (ICP-MS) analysis. The speciation scheme allowed simultaneous discrimination between labile and organic stable dissolved species of seven trace elements including Cd, Cu, Mn, Ni, Pb, U and Zn, using only 5ml of sample with detection limits ranging between 0.6ngl(-1) for Cd and 33ngl(-1) for Ni. The influence of UV photolysis on organic matter and its associated metal complexes was investigated by fluorescence spectroscopy and validated against natural samples spiked with humic substances standards. The chelation/preconcentration/matrix elimination procedure was validated against an artificial seawater spiked sample and two certified reference materials (SLRS-4 and CASS-4) to ensure homogenous performance across freshwater, estuarine and seawater samples. The speciation scheme was applied to two natural freshwater and seawater samples collected in the Adour Estuary (Southwestern, France) and processed in the field. The results indicated that the organic complexation levels were high and unchanged for Cu in both samples, whereas different signatures were observed for Cd, Mn, Ni, Pb, U and Zn, suggesting organic ligands of different origin and/or their transformation/alteration along estuarine water mixing.

Conformational analysis and crystal structure of {[1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidin-4yl]methyl}[(5-methylpyridin-2-yl)methyl]amine, fumaric acid salt.

{[1-(3-Chloro-4-fluorobenzoyl)-4-fluoropiperidin-4yl]methyl}[(5-methylpyridin-2-yl)methyl]amine, fumaric acid salt (C(20)H(22)ClF(2)N(3)O, C(4)H(4)O(4)) (1) was synthesized and characterized by the complete (1)H, (13)C and (19)F NMR analyses. The conformation of the piperidin ring, in the solution state, was particularly studied from the coupling constants determined by recording a double-quantum filtered COSY experiment in phase-sensitive mode. (1)H NMR line-shape analysis was used, at temperatures varying between -5 and +60 degrees C, to determine the enthalpy of activation of the rotational barrier around the CN bond. Compound 1 crystallizes in the triclinic space group P1 with a=8.517(3) Angstrom, b=12.384(2) Angstrom, c=12.472(3) Angstrom, alpha=70.88(2) degrees, beta=82.04(2) degrees, gamma=83.58(2) degrees. The results strongly indicate that the solid and solution conformations are similar. Thermal stability and phases transitions were investigated by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore polymorphism screening was studied from recrystallization of 1 performed in seven solvents and by slurry conversion in water. The X-ray powder diffraction (XRPD) and differential scanning calorimetry results suggested that 1 crystallizes into one crystalline form which melts at 157 degrees C (DeltaH=132 J g(-1)).

Grafted self-assembled monolayers derived from naturally occurring phenolic lipids.

Self-assembled monolayers grafted onto silicon surfaces were obtained from the hydrosilylation products by trialcoxysilanes of naturally occurring phenolic lipid allyl ethers. The as-obtained materials were characterized by various physical and physicochemical methods. Thus, contact angles of water drops showed that they possess very high hydrophobicity. Their excellent regularity was corroborated by AFM microscopy. The frequencies of the stretching CH2 infrared modes indicate the presence of alkyl chains mainly in the trans/trans conformation. Additionally, optical ellipsometry and quartz microbalance measurements enabled us to estimate the thickness of the films. The results, as a whole, are in good agreement with the formation of densely packed monolayers.