Establishing the utility of multi-platform liquid biopsy by integrating the CSF methylome and proteome in CNS tumours.

BACKGROUND: Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, it is increasingly recognized that multi-omic molecular approaches are a powerful avenue through which to understand complex and heterogeneous disease biology. We hypothesize that merging these two promising frontiers of cancer research will improve the discriminatory capacity of current models and allow for improved clinical utility. METHODS: We have compiled a cohort of patients with glioblastoma, brain metastasis, and primary central nervous system lymphoma. Cell-free methylated DNA immunoprecipitation (cfMeDIP) and shotgun proteomic profiling was obtained from the cerebrospinal fluid (CSF) of each patient and used to build tumour-specific classifiers. RESULTS: We show that the DNA methylation and protein profiles of cerebrospinal fluid can be integrated to fully discriminate lymphoma from its diagnostic counterparts with perfect AUC of 1 (95% confidence interval 1-1) and 100% specificity, significantly outperforming single-platform classifiers. CONCLUSIONS: We present the most specific and accurate CNS lymphoma classifier to date and demonstrates the synergistic capability of multi-platform liquid biopsies. This has far-reaching translational utility for patients with newly diagnosed intra-axial brain tumours.

Endothelium-independent vasorelaxant activity of Trachyspermum ammi essential oil on rat aorta.

Several pharmacological activities of the essential oil of Trachyspermum ammi seeds (TAEO) have been previously studied. These include antitussive, antihypertensive, and antispasmodic effects. However, its action on isolated aorta has not yet been studied. This study was aimed to investigate the vasorelaxant activity of TAEO and characterize its mechanism of action. Extraction of TAEO was performed using Clevenger-type apparatus with the final content of 4.5% (v/w). To evaluate some probable mechanisms of action of TAEO, the action isometric tension was then measured in the aortic rings from Wistar rats which were precontracted with phenylephrine (PHE) (1 µM) or KCl (60 mM). The major constituents of TAEO included Thymol (38.1%), gamma-terpinene (33.3%), and p-cymene (23.1%), as was analyzed by GC-MS. The cumulative concentrations of TAEO reduced precontraction caused by PHE and KCl (p < 0.05) significantly, which was dose dependent. The vasorelaxation caused by TAEO was not influenced in the presence of methylene blue and L-NAME in the endothelium-intact and denuded aorta ring. The inhibitory effect of TAEO on the aortic rings precontracted with KCl and PHE was considerably reduced by nifedipine. These findings hypothesized that the vasorelaxation caused by TAEO is completely endothelium independent and the extracellular Ca2+ influx was also inhibited by TAEO.

Quantification and comparison of neurosurgical approaches in the preclinical setting: literature review.

There is a growing awareness of the need for evidence-based surgery and of the issues that are specific to research in surgery. Well-conducted anatomical studies can represent the first, preclinical step for evidence-based surgical innovation and evaluation. In the last two decades, various reports have quantified and compared neurosurgical approaches in the anatomy laboratory using different methods and technology. The aim of this study was to critically review these papers. A PubMed and Scopus search was performed to select articles that quantified and compared different neurosurgical approaches in the preclinical setting. The basic characteristics that anatomically define a surgical approach were defined. Each study was analyzed for measured features and quantification method and technique. Ninety-nine papers, published from 1990 to 2013, were included in this review. A heterogeneous use of terms to define the features of a surgical approach was evident. Different methods to study these features have been reported; they are generally based on quantification of distances, angles, and areas. Measuring tools have evolved from the simple ruler to frameless stereotactic devices. The reported methods have each specific advantages and limits; a common limitation is the lack of 3D visualization and surgical volume quantification. There is a need for a uniform nomenclature in anatomical studies. Frameless stereotactic devices provide a powerful tool for anatomical studies. Volume quantification and 3D visualization of the surgical approach is not provided with most available methods.

Correlation between Cranial Nerve Microstructural Characteristics and Vestibular Schwannoma Tumor Volume.

BACKGROUND AND PURPOSE: Vestibular schwannomas are common cerebellopontine angle tumors arising from the vestibulocochlear nerve and can result in cranial nerve dysfunction. Conventional MR imaging does not provide information that could correlate with cranial nerve compression symptoms of hearing loss or imbalance. We used multitensor tractography to evaluate the relationship between the WM microstructural properties of cranial nerves and tumor volume in a cohort of patients with vestibular schwannomas. MATERIALS AND METHODS: A retrospective study was performed in 258 patients with vestibular schwannomas treated at the Gamma Knife clinic at Toronto Western Hospital between 2014 and 2018. 3T MR images were analyzed in 160 surgically naïve patients with unilateral vestibular schwannomas. Multitensor tractography was used to extract DTI-derived metrics (fractional anisotropy and radial, axial, and mean diffusivities of the bilateral facial and vestibulocochlear nerves [cranial nerves VII/VIII]). ROIs were placed in the transition between cisternal and intracanalicular segments, and images were analyzed using the eXtended Streamline Tractography reconstruction method. Diffusion metrics were correlated with 3D tumor volume derived from the Gamma Knife clinic. RESULTS: DTI analyses revealed significantly higher fractional anisotropy values and a reduction in axial diffusivity, radial diffusivity, and mean diffusivity (all P < .001) within the affected cranial nerves VII and VIII compared with unaffected side. All specific diffusivities (axial, radial, and mean diffusivity) demonstrated an inverse correlation with tumor volume (axial, radial, and mean diffusivity, P < .01). CONCLUSIONS: Multitensor tractography allows the quantification of cranial nerve VII and VIII WM microstructural alterations in patients with vestibular schwannomas. Our findings support the hypothesis that tumor volume may cause microstructural alterations of the affected cranial nerves VII and VIII. This type of advanced imaging may represent a possible avenue to correlate diffusivities with cranial nerve function.

Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study.

Vaginal bleeding during aplasia can induce transfusion support, infection and discomfort. Oral and intramuscular hormonotherapy can be toxic and/or difficult to manage (mucositis). This single-center pilot study evaluated the efficacy and safety of leuprorelin (L) in preventing heavy vaginal bleeding in 20 nonmenopausal women with leukemia, lymphoma or myeloma and foreseable therapy-induced thrombocytopenia. Until platelet recovery, patients received subcutaneous injections of L, with concomitant nomegestrol acetate (NA) during the first 35 days to prevent flare-up. Median age was 33 years (18-48). Platelet nadir was < 20 x 10(9)/l in 17 patients; 103 L injections were performed (median per patient: 4 [1-14]). No moderate or severe adverse event was related to hormonal therapy. Seventeen patients did not experience any clinically or therapeutically relevant bleeding. Eleven spottings and 8 metrorrhagias (mean duration: 3 days) occurred in 11 patients, requiring enhanced NA in 3 cases (baseline platelet count was < 20 x 10(9)/l in 1 pt, premature termination of NA [the single platelet transfusion for metrorrhagia] in 1 pt, and endometrial hyperplasia (EH) in the third). In patients without EH, only 5 spottings were observed after the third injection, without neither clinical nor therapeutic impact (63 injections). In conclusion, leuprorelin administration is safe and effective in preventing vaginal bleeding. The sustained-release form and subcutaneous administration offer quality of life advantages.

Endoscopic sphenoid sinus drainage in Lemierre syndrome.

Lemierre syndrome is a rare condition arising from an invasive oropharyngeal infection, which leads to septic thrombophlebitis of the internal jugular vein and multi-organ septic embolization. Intracranial complications are rare but serious, including subdural empyema, cavernous sinus thrombosis, and internal carotid artery aneurysms. We report a patient with Lemierre syndrome with multiple intracranial complications despite aggressive antimicrobial therapy. The patient eventually required transsphenoidal endoscopic drainage of the sphenoid sinus to help eradicate the infectious source. We postulate that in patients with Lemierre syndrome with evidence of infection in the paranasal sinuses, endoscopic sinus drainage can be an adjunct to antimicrobial therapy in achieving infection control.

Assessment of functional and structural connectivity between motor cortex and thalamus using fMRI and DWI.

Connectivity evaluations have been performed in a noninvasive manner by examining resting state fMRI alongside diffusion-weighted images (DWI). The spatial structures of coherent spontaneous BOLD fluctuations provided the most convincing preliminary evidence that the BOLD signal was predominantly of neuronal origin rather than non-neuronal, artifactual noise. In this study we have shown that in thalamocortical network, the results of functional connectivity analysis and DWI correspond well with each other, thereby providing cross-validation of the two techniques. We have used the resting state fMRI data of 3 subjects with 10 minute resting state functional images via a 3T Siemens scanner. we used cross correlation for functional analysis and reported thalamocortical results with p value=0.01 and cluster size=100, Then showed corresponding tracts connecting premotor cortex and thalamus. In addition, both techniques correspond well to histological delineation and invasive tract tracing, which provides a 'gold standard' validation of the two techniques. The degree of structural connectivity has been shown to correlate with the strength of functional connectivity, thereby providing a potentially straightforward structural explanation for many of the changes in functional connectivity in disease states.

Directed differential connectivity graph of interictal epileptiform discharges.

In this paper, we study temporal couplings between interictal events of spatially remote regions in order to localize the leading epileptic regions from intracerebral EEG (iEEG). We aim to assess whether quantitative epileptic graph analysis during interictal period may be helpful to predict the seizure onset zone of ictal iEEG. Using wavelet transform, cross-correlation coefficient, and multiple hypothesis test, we propose a differential connectivity graph (DCG) to represent the connections that change significantly between epileptic and nonepileptic states as defined by the interictal events. Postprocessings based on mutual information and multiobjective optimization are proposed to localize the leading epileptic regions through DCG. The suggested approach is applied on iEEG recordings of five patients suffering from focal epilepsy. Quantitative comparisons of the proposed epileptic regions within ictal onset zones detected by visual inspection and using electrically stimulated seizures, reveal good performance of the present method.

Comparison of five directed graph measures for identification of leading interictal epileptic regions.

Directed graphs (digraphs) derived from interictal periods of intracerebral EEG (iEEG) recordings can be used to estimate the leading interictal epileptic regions for presurgery evaluations. For this purpose, quantification of the emittance contribution of each node to the rest of digraph is important. However, the usual digraph measures are not very well suited for this quantification. Here, we compare the efficiency of recently introduced local information (LI) measure and a new measure called total global efficiency with classical measures like global efficiency, local efficiency and node degree. For evaluation, the estimated leading interictal epileptic regions based on five measures are compared with seizure onset zones obtained by visual inspection of epileptologists for five patients. The comparison revealed the superior performance of the LI measure. We showed efficiency of different digraph measures for the purpose of source and sink node identification.

An endemic focus of visceral leishmaniasis in Meshkin-Shahr, east Azerbaijan province, north-west part of Iran and IFA serological survey of the disease in this area.

The incidence of visceral leishmaniasis has being increased in Iran during the recent decade. Since 1980, more than 200 cases have been diagnosed from East Azerbaijan province, mostly, from Meshkin-Shahr area. It seems, that kala-azar has being endemic in this area for a long time. The majority (86%) of kala-azar cases were found among children up to 4 years. The sex incidence ratio of males/females was 1.27/1. In IFA serological survey, sero-positive rate in females was higher than males. However, geometric mean of leishmanial antibody titers in males was, slightly, more than females. These serological findings indicate that females are exposed to the infection at least as much as males. The cross-sectional IFA serological survey, relatively reflected the kala-azar status among different studied groups with various incidences of the disease in Meshkin-Shahr area. IFAT showed also a good efficiency in the assessment of the treatment in the treated kala-azar patients.