Nearly all stroke neuroprotection modalities, including selective intra-arterial cooling (SI-AC), have failed to be translated from bench to bed side. Potentially overlooked reasons may be biological ...gaps, inadequate attention to reperfusion states and mismatched attention to neurological benefits. To advance stroke translation, we describe a novel thrombus-based stroke model in adult rhesus macaques. Intra-arterial thrombolysis with tissue plasminogen activator leads to three clinically relevant outcomes – complete, partial, and no recanalization based on digital subtraction angiography. We also find reperfusion as a prerequisite for SI-AC-induced benefits, in which models with complete or partial reperfusion exhibit significantly reduced infarct volumes, mitigated neurological deficits, improved upper limb motor dysfunction in both acute and chronic stages; however, no further neuroprotection is observed in those without reperfusion. In summary, we discover reperfusion as a crucial regulator of SI-AC-induced neuroprotection and provide insights of long-term functional benefits in behavior and imaging levels. Our findings could be important not only for the translational prerequisite and potential molecular targets, but also for this thrombus-thrombolysis model in monkeys as a powerful tool for further translational stroke studies.
Vertebrobasilar dolichoectasia (VBD) is a rare type of cerebrovascular disorder with high rates of morbidity and mortality. Due to the distinct pathological characteristics that fragmented internal ...elastic lamina and multiple dissections, VBD is difficult to treat and cured. Stent-assisted coil embolization is one of the main treatment modalities for such lesions. However, the duration of healing remained questionable, and there were no effective measures for evaluating endothelial coverage. Before complete endothelial coverage, the discontinuation of antiplatelet therapy may lead to fatal in-stent thrombosis; however, continued antiplatelet therapy could also result in bleeding complications. Thus, we present an autopsy case of late in-stent thrombosis due to the discontinuation of antiplatelet therapy and systematically review the literature to provide a reference for endovascular treatment and antiplatelet regimen of VBD.
Early reperfusion is increasingly prioritized in ischemic stroke care, but outcomes remain suboptimal. Therefore, there is an urgent need to find neuroprotective approaches that can be combined with ...reperfusion to maximize efficacy. Here, the neuroprotective mechanisms behind therapeutic hypothermia were evaluated in a monkey model of ischemic stroke. Focal ischemia was induced in adult rhesus monkeys by placing autologous clots in the middle cerebral artery. Monkeys were treated with tissue plasminogen activator (t-PA) alone or t-PA plus selective intra-arterial cooling (SI-AC). Serial MRI scans and functional deficit were evaluated after ischemia. Histopathology and immunohistochemistry analysis were performed after the final MRI scan. t-PA plus SI-AC treatment led to a higher rate of MRI tissue rescue, and significantly improved neurologic deficits and daily activity scores compared with t-PA alone. In peri-infarct areas, higher fractional anisotropy values and greater fiber numbers were observed in models receiving t-PA plus SI-AC. Histological findings indicated that myelin damage, spheroids, and spongiosis were significantly ameliorated in models receiving SI-AC treatment. White matter integrity was also improved by SI-AC based on immunochemical staining. Our study demonstrates that SI-AC can be effectively combined with t-PA to improve both structural and functional recovery in a monkey model of focal ischemia. These findings provide proof-of-concept that it may be feasible to add neuroprotective agents as adjunctive treatments to reperfusion therapy for stroke.
Background and Aim: Mutations in isocitrate dehydrogenase (IDH), co-deletion of 1p and 19q, loss or expression of the transcription regulator ATRX, and mutations in telomerase reverse transcriptase ...(TERT) gene promoters are intimately linked with diffuse gliomas. We further explored the roles of the key molecules in adulthood diffuse gliomas and their prognosis. Materials and Methods: A total of 413 patients who underwent primary surgery between 2009 and 2015 at Xuanwu Hospital, Beijing, China, were included in this observational study. All specimens from the patients were fixed in 10% neutral buffered formalin and embedded in paraffin. The mutational status of IDH1/2 and the TERT promoter was determined using polymerase chain reaction-based direct sequencing. The assay for the 1p and 19q co-deletion was conducted using fluorescence in situ hybridization. Overall- and progression-free survival was calculated using the Kaplan-Meier method and the log-rank test. The study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University, China (approval No. 2019004) on May 22, 2019. Results: We found that tumors characterized by multiple lesions were predominantly free of IDH mutations (P < 0.001). Gliomas with IDH mutations arose more often in the frontal and insular lobes than in the other lobes (P < 0.001). Rates of IDH mutations were higher in patients who had seizures or were without discomfort than in those who had other clinical symptoms (P = 0.0003). Of 119 patients with complete molecular information according to the 2016 World Health Organization classification of central nervous system tumors, 5 had oligoastrocytomas that had multiple genotypes - IDH1 mutation, loss of ATRX expression, and 1p/19q co-deletion - but lacked TERT promoter mutations. Patients with seizures or without discomfort who had IDH mutations had better outcomes than did other patients (P < 0.001). Patients whose tumors had IDH and TERT promoter mutations had a better prognosis than did other patients (P < 0.001). Among patients whose tumors had wild-type IDH, those with loss of ATRX survived longer than did others (P = 0.005). Conclusions: The status of both ATRX and the TERT promoter can indicate the prognosis in patients with IDH wild-type gliomas. The diagnosis that is based on clinical symptoms, histologic findings, and molecular analysis should be implemented as the diagnostic standard for patients with oligoastrocytomas.
The BRAF p.V600E mutation is the most common genetic alteration in ganglioglioma (GG). Herein, we collected a consecutive series of 30 GG specimens from Xuanwu Hospital in order to corroborate the ...genetic landscape and genotype–phenotype correlation of this enigmatic and often difficult‐to‐classify epilepsy‐associated brain tumor entity. All specimens with histopathologically confirmed lesions were submitted to targeted next‐generation sequencing using a panel of 131 genes. Genetic alterations in three cases with histologically distinct tumor components, that is, GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), or an oligodendroglioma (ODG)‐like tumor component, were separately studied. A mean post‐surgical follow‐up time‐period of 23 months was available in 24 patients. Seventy seven percent of GG in our series can be explained by genetic alterations, with BRAF p.V600E mutations being most prevalent (n = 20). Three additional cases showed KRAS p.Q22R and KRAS p.G13R, IRS2 copy number gain (CNG) and a KIAA1549‐BRAF fusion. When genetically studying different histopathology patterns from the same tumor we identified composite features with BRAF p.V600E plus CDKN2A/B homozygous deletion in a GG with PXA features, IRS2 CNG in a GG with DNT features, and a BRAF p.V600E plus CNG of chromosome 7 in a GG with ODG‐like features. Follow‐up revealed no malignant tumor progression but nine patients had seizure recurrence. Eight of these nine GG were immunoreactive for CD34, six patients were male, five were BRAF wildtype, and atypical histopathology features were encountered in four patients, that is, ki‐67 proliferation index above 5% or with PXA component. Our results strongly point to activation of the MAP kinase pathway in the vast majority of GG and their molecular‐genetic differentiation from the cohort of low‐grade pediatric type diffuse glioma remains, however, to be further clarified. In addition, histopathologically distinct tumor components accumulated different genetic alterations suggesting collision or composite glio‐neuronal GG variants.
Our results strongly point to activation of the MAP kinase pathway in the vast majority of ganglioglioma (GG).
Composite genetic alterations were found in cases with histologically distinct tumor components firstly, i.e. GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor, or an oligodendroglioma‐like tumor.
Seizure recurrence is inclined to ganglioglioma with atypical histopathology features (i.e. GG containing a ki‐67 proliferation index above 5% or GG with PXA component).
Aims
Focal cortical dysplasia (FCD) is a major cause of drug‐resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and ...brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype–phenotype association of 20 patients with histopathologically confirmed FCDIIb using next generation sequencing (NGS) of paired blood–brain samples.
Methods
Clinical and neuropathological data were retrospectively reviewed from the hospital archive. The NGS panel included 11 mTOR‐pathway‐related genes with maximum coverage of 2000×. The detected variants were validated by digital droplet PCR.
Results
Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR‐wildtype FCDIIb suggested a profound genotype–phenotype association characterised by (1) a non‐temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032 ± 1.859 cm3 vs 1.110 ± 0.856 cm3, p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm2 vs 31.64 ± 30.56 BC/mm2, p = 0.099) and dysmorphic neurons (48.72 ± 19.47DN/mm2 vs 15.28 ± 13.95DN/mm2, p = 0.000) and (4) a positive correlation between VAF and the lesion volume (r = 0.802, p = 0.017).
Conclusions
Our study identified frequent MTOR mutations in the cell‐rich FCDIIb phenotype, clinically characterised by a non‐temporal location and large lesion volume. Comprehensive genotype–phenotype associations will help us further explore and define the broad spectrum of FCD lesions to make more targeted therapies available in the realm of epileptology.
Targeted hybrid capture next generation sequencing of a panel including 11 mTOR‐pathway related genes identified pathogenic somatic MTOR variants in 10/20 FCDIIb patients, all of which revealed a profound clinical and pathological phenotype characterised by (1) a non‐temporal lobe lesion on MRI, (2) a large lesion volume, (3) abundant balloon cells and dysmorphic neurons visible in the resected brain sample and (4) variant allele frequency (VAF) correlated with the extent of the epileptogenic zone.
To explore the disease manifestations and radiological characteristics of patients with meningeal carcinomatosis (MC) combined with myelopathy.
The detailed medical information of patients who ...suffered from MC with myelopathy in record system were collected and reviewed.
In these patients, five cases were male and two cases were female. The age was from fifteen to fifty-seven years. In the course of disease, tumor cells were discovered in cerebrospinal fluid of three patients and in biopsy samples of four patients. Cerebrospinal fluid (CSF) test results showed white blood cell counts increased in seven patients, protein increased in six patients and glucose reduced in five patients. In addition, MRI revealed that the white matter abnormalities showed in all cases and pia mater was enhanced in four patients, meningeal enhanced was observed in three patients. All patients were given appropriate therapy during hospitalization. Follow-up result showed that all patients passed away two to five months after diagnosis.
MC causes spinal membrane, spinal nerve root to be involved besides, also can produce the matter of myelopathy. Early detection of intramedullary lesion is conducive to strengthening the awareness of the diagnosis of MC.
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Over decades, nearly all attempts to translate the benefits of therapeutic hypothermia in stroke models of lower-order species to stroke patients have failed. Potentially overlooked ...reasons may be biological gaps between different species and the mismatched initiation of therapeutic hypothermia in translational studies. Here, we introduce a novel strategy of selective therapeutic hypothermia in a non-human primate ischemia-reperfusion model, in which autologous blood was cooled ex vivo and the cool blood transfusion was administered at the middle cerebral artery just after the onset of reperfusion. Cold autologous blood cooled the targeted brain rapidly to below 34 °C while the rectal temperature remained around 36 °C with the assistance of a heat blanket during a 2-h hypothermic process. Therapeutic hypothermia or extracorporeal-circulation related complications were not observed. Cold autologous blood treatment reduced infarct sizes, preserved white matter integrity, and improved functional outcomes. Together, our results suggest that therapeutic hypothermia, induced by cold autologous blood transfusion, was achieved in a feasible, swift, and safe way in a non-human primate model of stroke. More importantly, this novel hypothermic approach conferred neuroprotection in a clinically relevant model of ischemic stroke due to reduced brain damage and improved neurofunction. This study reveals an underappreciated potential for this novel hypothermic modality for acute ischemic stroke in the era of effective reperfusion.
Gliosarcoma, which is regarded as a variant of glioblastoma, is a rare malignant neoplasm of the central nervous system. Both its sarcomatous component and glial component are reported to share ...significant clinical and genetic similarities. However, gliosarcomas are considered to be characterised by a lack of the
V600E mutation. Here, we report two cases of gliosarcoma harbouring the
V600E mutation, of which one case appears to have arisen de novo, while the other likely arose from ganglioglioma. Interestingly, the
V600E mutation was detected only in the glial component in the first case, but was present in both the glial and the sarcomatous components in the recurrent gliosarcoma. Furthermore, the different mutation state of
V600E in our two cases suggests that the malignant transformation of gliosarcoma might have different underlying genetic alterations and mechanisms in de novo versus recurrent gliosarcoma.
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•Volume-based morphometry analysis can help in detecting FCD lesions individually.•The sensitivity and specificity of the MorphoBox was 93.9% and 79.6%, respectively.•Atrophic regions ...are more likely than hypertrophic ones to represent FCD lesions.
Surgical resection is the most effective treatment for focal cortical dysplasia (FCD). However, many patients with FCD have unremarkable or even negative findings on conventional magnetic resonance imaging (MRI). In this study, we explored the brain volume abnormalities of FCD patients at the individual level using an experimental volume-based morphometry algorithm and further estimated whether the volume abnormalities can help in the detection of FCD lesions.
Sixteen patients with histologically-proven FCD lesions were retrospectively studied. Among them, eight patients had no visible abnormalities on routine MRI, three had abnormalities which partly matched the location of the surgical resection regions, and two did not match. For each patient, cerebral high-resolution T1-weighted magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images were segmented into 45 structures, according to a brain anatomy template, and the volume of each structure was compared with an age- and gender-matched normal population at the individual level, based on a MorphoBox prototype. A Receiver Operating Characteristics (ROC) curve was used to evaluate the performance of the prototype in patients. To find the most appropriate threshold value for localizing the epileptogenic zones, deviations from the normative ranges of each resulting volume estimate were assessed by z-scores.
Volume abnormalities including atrophic and hypertrophic volumes could be found in all the patients. Epileptogenic zones were found in brain structures with an abnormal volume in 87.5% (14/16) of patients. In 71.4% of patients (10/14), these zones were fully located in regions with an atrophic volume. This suggests that FCD lesions are more likely to be in regions with an atrophic volume than in those with a hypertrophic volume. When the best cut-off z-score value was –3.0, the sensitivity, specificity, and ROC area under the curve of the volume estimates were 93.9%, 79.6%, and 0.89, respectively.
Volume abnormalities can assist in the diagnosis of epileptogenic zones at the individual level in FCD patients with negative or positive findings on conventional MR images. Atrophic regions are more likely than hypertrophic ones to represent epileptogenic zones. Volume-based morphometry based on a MorphoBox prototype has potential to assist a careful scrutiny by radiologists with target in atrophic regions in patients who are initially deemed to be MR-negative, further trying to increase the detection rate of FCD.
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