Benoît Bihin

SPECT/CT lymphoscintigraphy of sentinel node(s) for superselective prophylactic irradiation of the neck in cN0 head and neck cancer patients: A prospective phase I feasibility study

BackgroundClinically node negative HNSCC patients have a risk ranging between 18 and 45% of occult metastases, making prophylactic irradiation mandatory. Selective irradiation of nodal target volume based on international guidelines is practice. Anyway, about half the tumours lying in an anatomical subsite known to potentially drain bilaterally effectively do so, leading to unnecessary large volume irradiation. Moreover, 15% of the tumours show drainage outside of predicted basin, increasing the risk for potential geographical misses. Three-dimensional SPECT/CT lymphoscintigraphy (LS) of sentinel node(s) may help to individualize nodal target volume selection. This prospective phase I study explores its feasibility and the dosimetric impact.MethodsTen cN0 HNSCC patients eligible for definitive radiotherapy were imaged with SPECT/CT after 99mTc nanocolloid injection around the tumour. The neck levels containing up to four hottest nodes were identified and selected for prophylactic irradiation (CTVn-LS) by volumetric modulated arc therapy. A comparative virtual planning was performed with volumes selected according to international guidelines (CTVn-IG).ResultsMigration was observed in all patients (one with gamma probe only). 2.9 sentinel nodes were detected per patient on average. In some patients, accurate localization was difficult when not using thermoplastic mask for SPECT/CT. CTVn-LS was totally encompassed by CTVn-IG in all patients but one (unpredicted drainage in retropharyngeal level). On average, CTVn-LS and related planning target volumes were two times smaller than IG ones. This led to significant dose decrease in identified organs at risk as well as remaining volume at risk.ConclusionsSPECT/CT LS is a promising tool to individualize prophylactic node CTV in cN0 HNSCC patients eligible for definitive radiotherapy. Oncological safety must be confirmed by ongoing phase II study.

Optic Neuritis Associated or Not with TNF Antagonists in Patients with Inflammatory Bowel Disease

BACKGROUND AND AIMS Acute optic neuritis [ON] is an inflammatory condition affecting the optic nerve. Clinicians should suspect optic neuritis in cases of painful and rapidly progressive loss of central visual field. This condition may be associated with a multitude of diseases, and mostly with multiple sclerosis [MS] where it may present as an initial symptom. The literature reports that optic neuritis and MS occur in patients with inflammatory bowel disease [IBD] before and after the era of anti-tumour necrosis factor-α [TNFα] drugs. At the present moment, there is little consensus for managing this complication, currently treated with corticosteroids and discontinuation of the causative agents. METHODS We collected cases through a retrospective multicentre European Crohns and Colitis Organisation CONFER [COllaborative Network For Exceptionally Rare case reports] project. We also performed a comprehensive retrospective search of the available literature on this topic. RESULTS We report herein 12 new cases of ON, including 10 under anti-TNF therapy, collected through the CONFER project. We also compare characteristics of ON associated or not with anti-TNFα agents. CONCLUSIONS The exceptional and current observation of distant family history of MS in 17% of our patients who developed ON, despite the small number and the lack of a control arm, might be an important signal that should be taken into account in our therapeutic strategies in the future.

Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes

Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes. Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization by lipid droplet‐associated proteins as well as lipolytic enzymes have been identified. Increasing energy expenditure by inducing a mild uncoupling of mitochondria in adipocytes might represent a putative interesting anti‐obesity strategy as it reduces the adipose tissue triacylglycerol content (limiting alterations caused by cell hypertrophy) by stimulating lipolysis through yet unknown mechanisms, limiting the adverse effects of adipocyte hypertrophy. Herein, the molecular mechanisms involved in lipolysis induced by a mild uncoupling of mitochondria in white 3T3‐L1 adipocytes were characterized. Mitochondrial uncoupling‐induced lipolysis was found to be independent from canonical pathways that involve lipolytic enzymes such as HSL and ATGL. Finally, enhanced lipolysis in response to mitochondrial uncoupling relies on a form of autophagy as lipid droplets are captured by endolysosomal vesicles. This new mechanism of triacylglycerol breakdown in adipocytes exposed to mild uncoupling provides new insights on the biology of adipocytes dealing with mitochondria forced to dissipate energy.

Myeloperoxidase-Oxidized LDLs Enhance an Anti-Inflammatory M2 and Antioxidant Phenotype in Murine Macrophages

Macrophages and oxidized LDLs play a key role in atherogenesis but their heterogeneity has been neglected up to now. Macrophages are prone to polarization and subsets of polarized macrophages have been described in atheromas. LDLs can be oxidized not only chemically by copper (Ox-LDLs) but also enzymatically by myeloperoxidase (MpOx-LDLs) resulting in oxidized LDLs poor in lipid peroxides. The effects of physiologically relevant myeloperoxidase-oxidized LDLs on macrophage polarization or on polarized macrophages remain largely unknown. In this study, the effects of LDLs on macrophage polarization were investigated by monitoring the expression of M1 and M2 genes following stimulation with native LDLs, Ox-LDLs, or MpOx-LDLs in RAW 264.7 cells. Except for MRC1, which is induced only by Ox-LDLs, MpOx-LDLs induced an overexpression of most of the selected marker genes at the mRNA level. MpOx-LDLs also modulate marker gene expression in polarized macrophages favoring notably anti-inflammatory Arg1 expression in M2 cells and also in the other phenotypes. Noteworthy, MpOx-LDLs were the most efficient to accumulate lipids intracellularly in (un)polarized macrophages whatever the phenotype. These data were largely confirmed in murine bone marrow-derived macrophages. Our data suggest that MpOx-LDLs were the most efficient to accumulate within cells and to enhance an anti-inflammatory and antioxidant phenotype in M2 cells and also in the other macrophage phenotypes.

Which algorithm diagnoses invasive pulmonary aspergillosis best in ICU patients with COPD

Invasive pulmonary aspergillosis (IPA) is a potentially lethal opportunistic infection, mainly affecting immunocompromised patients, particularly those with prolonged neutropenia [1]. Several reports have shown that Aspergillus spp. can also cause IPA in patients with a priori less severe immune dysfunction, such as those in intensive care units (ICUs) [2–5] or with chronic obstructive pulmonary disease (COPD) [5–8]. In these patients, diagnosis of IPA remains a challenge, because the reference diagnostic criteria (defined by the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG)) were developed for research in high-risk patients and not specifically for patients in the ICU or patients with COPD [9]. Two alternative algorithms have been proposed for this setting: the COPD algorithm for patients with COPD [6] and the Clinical algorithm for patients in the ICU [10]. In ICU COPD patients, the Clinical algorithm seems to be more useful to diagnose IPA than the COPD or EORTC/MSG ones http://ow.ly/N2TN30e6Zur

Application of a clot-based assay to measure the procoagulant activity of stored allogeneic red blood cell concentrates.

BACKGROUND Thrombotic effects are possible complications of red blood cell transfusion. The generation and accumulation of procoagulant red blood cell extracellular vesicles during storage may play an important role in these thrombotic effects. The objective of this study was to assess the value of a simple phospholipid-dependent clot-based assay (STA®-Procoag-PPL) to estimate the procoagulant activity of stored red blood cells and changes in this activity during storage of the blood component. MATERIALS AND METHODS Extracellular vesicles from 12 red blood cell concentrates were isolated at 13 storage time-points and characterised by quantitative and functional methods: the degree of haemolysis (direct spectrophotometry), the quantification and determination of cellular origin (flow cytometry) and the procoagulant activity (thrombin generation and STA®-Procoag-PPL assays) were assessed. RESULTS The mean clotting time of extracellular vesicles isolated from red blood cell concentrates decreased from 117.2±3.6 sec on the day of collection to 33.8±1.3 sec at the end of the storage period. This illustrates the phospholipid-dependent procoagulant activity of these extracellular vesicles, as confirmed by thrombin generation. Results of the peak of thrombin and the STA®-Procoag-PPL were well correlated (partial r=-0.41. p<0.001). In parallel, an exponential increase of the number of red blood cell-derived extracellular vesicles from 1,779/μL to 218,451/μL was observed. DISCUSSION The STA®-Procoag-PPL is a potentially useful technique for assessing the procoagulant activity of a red blood cell concentrate.

Assessment of a computed tomography guided injection technique of the lumbo-sacral disc in sheep.

OBJECTIVES Recent data indicate that degeneration of intervertebral discs occurs naturally in sheep, with a higher prevalence at the level of the lumbo-sacral disc. The objective of this ex vivo study was to evaluate a computed tomography (CT) guided method of injection into the ovine lumbo-sacral disc. METHODS Six euthanatized sheep were used for identification of the approach plane, the optimal direction of the needle and the mean distance from skin to disc. Dissection after injection of coloured ink was used to determine the anatomical structures that were penetrated. In seven other animals, all spines were assessed beforehand by CT and magnetic resonance imaging to determine whether disc pathology was present. The final position of the needle was assessed by CT to determine the accuracy of the technique. Contrast agent was injected to identify any problems associated with administration of liquid into the disc. RESULTS The CT guided injection technique was easy to perform and enabled adequate positioning of the needle into all (n = 7) lumbo-sacral discs. Distance between the skin and the disc ranged between 12 and 17 cm. No organ, vascular or nervous structure was penetrated and the needle path remained intramuscular without penetration of the peritoneal cavity. Contrast medium leaked out through three degenerate discs. CLINICAL SIGNIFICANCE The current study described a consistently safe and accurate CT guided injection technique to the lumbo-sacral disc for future in vivo experimental studies that will use sheep as animal model for human intervertebral disc disease disease.

Effect of a single dose of retigabine in cortical excitability parameters: A cross-over, double-blind placebo-controlled TMS study.

BACKGROUND Antiepileptic drugs (AEDs) decrease the occurrence of epileptic seizures and modulate cortical excitability through several mechanisms that likely interact. The modulation of brain excitability by AEDs is believed to reflect their antiepileptic action(s) and could be used as a surrogate marker of their efficacy. Transcranial magnetic stimulation (TMS) is one of the best noninvasive methods to study cortical excitability in human subjects. Specific TMS parameters can be used to quantify the various mechanisms of action of AEDs. A new AED called retigabine increases potassium efflux by changing the conformation of KCNQ 2-5 potassium channels, which leads to neuronal hyperpolarisation and a decrease in excitability. HYPOTHESIS The purpose of this study is to investigate the effect of retigabine on cortical excitability. Based on the known mechanisms of action of retigabine, we hypothesized that the oral intake of retigabine would increase the resting motor threshold (RMT). METHODS Fifteen healthy individuals participated in a placebo-controlled, double-blind, randomised, clinical trial (RCT). The primary outcome measure was the RMT quantified before and after oral intake of retigabine. Several secondary TMS outcome measures were acquired. RESULTS The mean RMT, active motor threshold (AMT) and intensity to obtain a 1mV peak-to-peak amplitude potential (SI1mV) were significantly increased after retigabine intake compared to placebo (RMT: P=0.039; AMT: P=0.014; SI1mV: P=0.019). No significant differences were found for short-interval intracortical inhibition/intracortical facilitation (SICI/ICF), long-interval intracortical inhibition (LICI) or short-interval intracortical facilitation (SICF). CONCLUSION A single dose of retigabine increased the RMT, AMT and S1mV in healthy individuals. No modulating intracortical facilitation or inhibition was observed. This study provides the first in vivo demonstration of the modulating effects of retigabine on the excitability of the human brain, and the results are consistent with the data showing that retigabine hyperpolarizes neurons mainly by increasing potassium conductance.

Long-term stability of ketamine hydrochloride 50mg/ml injection in 3ml syringes.

INTRODUCTION Ketamine hydrochloride (Ketalar(®)) injection is often used as a general anesthetic agent. It is particularly suited to short-term interventions. It can also be used as an inducer of anesthesia before the administration of other anesthetic agents. The aim of this study was to evaluate the stability of ketamine hydrochloride in 3ml polypropylene syringes after storage for up to 180days at room temperature. METHOD Syringes containing ketamine hydrochloride (50mg/ml) were prepared and stored at room temperature (25°C) for 180days. The concentrations were measured by validated ultra-performance liquid chromatography-diode array detection at 0, 7, 14, 28, 60, 84, 112, 140 and 180days. A degradation test was performed to evaluate the specificity of the analysis. At each time point, the pH, color and visible particles of each solution were also assessed. RESULTS Degradation tests proved no interfering peaks with ketamine. All solutions were physically stable during the storage. The lower confidence limit of the concentration for these solutions remains superior to 90% of the initial concentration at this date as recommended by the Food and Drug Administration (FDA) until 180days (100%±2%). CONCLUSION Solutions of ketamine (50mg/ml) were chemically stable for 180days in polypropylene syringes with storage at room temperature and could be prepared in advance by a centralized intravenous admixture service.

Spousal Caregiving is Associated With an Increased Risk of Frailty: A Case-Control Study

BackgroundEvidence suggests that providing care for a disabled elderly person may have implications for the caregiver’s own health (decreased immunity, hypertension, and depression).ObjectiveExplore if older spousal caregivers are at greater risks of frailty compared to older people without a load of care.DesignCase-control study.SettingParticipants were assessed at home in Wallonia, Belgium.ParticipantsCases: community-dwelling spousal caregivers of older patients, recruited mainly by the geriatric outpatient clinic.Controlspeople living at home with an independent spouse at the functional and cognitive level matched for age, gender and comorbidities.MeasurementsMini nutritional assessment-short form (MNA-SF), short physical performance battery (SPPB), frailty phenotype (Fried), geriatric depression scale (GDS-15), clock drawing test, sleep quality, and medications. The multivariable analysis used a conditional logistic regression.ResultsAmong 79 caregivers, 42 were women; mean age and Charlson comorbidity index were 79.4±5.3 and 4.0±1.2, respectively. Among care-receivers (mean age 81.4±5.2), 82% had cognitive impairment. Caregiving was associated with a risk of frailty (Odd Ratio (OR) 6.66; 95% confidence interval (CI) 2.20-20.16), the consumption of antidepressants (OR 4.74; 95% CI 1.32 -17.01), shorter nights of sleep (OR 3.53; 95% CI 1.37-9.13) and more difficulties maintaining a social network (OR 5.25; 95% CI 1.68-16.40).ConclusionsSpousal caregivers were at an increased risk of being frail, having shorter nights of sleep, taking antidepressants and having difficulties maintaining their social network, compared to non-caregiver controls. Older spousal caregivers deserve the full attention of professionals to prevent functional decline and anticipate a care breakdown.