Type I atlanto-occipital dislocation complicated by non-communicating hydrocephalus - A case report.

Hydrocephalus, an extremely rare complication of craniocervical junction injuries, is postulated to result from compression of the fourth ventricular cerebrospinal fluid (CSF) outlets by fractured and displaced bone fragments, a swollen upper spinal cord or adhesions formed after a traumatic subarachnoid haemorrhage. We present the case of a 21-year-old woman for whom an injury to the cervical spine complicated by a type I atlanto-occipital dislocation contributed to the development of non-communicating hydrocephalus. The hydrocephalus was probably a consequence of impaired CSF circulation at the fourth ventricular outlets (the foramina of Luschka and Magendie), caused by post-haemorrhagic adhesions formed after severe injury to the craniocervical junction.

External validation of the Chicago Chiari Outcome Scale in adults with Chiari malformation type I.

OBJECTIVE: The Chicago Chiari Outcome Scale (CCOS) serves as a standardized clinical outcome evaluation tool among patients with Chiari malformation type I (CM-I). While the reliability of this scale has been proven for pediatric patients, the literature lacks CCOS validation when used solely in adults. Therefore, this study aimed to determine the validity of the CCOS in an external cohort of adult patients. METHODS: The authors retrospectively analyzed the medical records of symptomatic patients with CM-I who underwent posterior fossa decompression between 2010 and 2018 in six neurosurgical departments. Each patient was clinically assessed at the latest available follow-up. Gestalt outcome was determined as improved, unchanged, or worsened compared with the preoperative clinical state. Additionally, the CCOS score was calculated for each patient based on the detailed clinical data. To verify the ability of the CCOS to determine clinical improvement, the area under the receiver operating characteristic (AUROC) curve was evaluated. A logistic regression analysis using all four components of the CCOS (pain symptoms, nonpain symptoms, functionality, and complications) was performed to establish predictors of the improved outcome. RESULTS: Seventy-five individuals with a mean age of 42 ± 15.32 years were included in the study. The mean follow-up duration was 52 ± 33.83 months. Considering gestalt outcome evaluation, 41 patients (54.7%) were classified as improved, 24 (32%) as unchanged, and 10 (13.3%) as worsened. All patients with a CCOS score of 14 or higher improved, while all those with a CCOS score of 8 or lower worsened. The AUROC was 0.986, suggesting almost perfect accuracy of the CCOS in delineating clinical improvement. A CCOS score of 13 showed high sensitivity (0.93) and specificity (0.97) for identifying patients with clinical improvement. Additionally, a meaningful correlation was found between higher CCOS scores in each component and better outcomes. Patient stratification by total CCOS score showed that those categorized as improved, unchanged, and worsened scored prevalently between 13 and 16 points, 10 and 12 points, and 4 and 9 points, respectively. CONCLUSIONS: In this adult cohort, the CCOS was found to be almost perfectly accurate in reflecting postoperative clinical improvement. Moreover, all four CCOS components (pain symptoms, nonpain symptoms, functionality, and complications) significantly correlated with patient clinical outcomes.

Preservation of the Hypoxic Transcriptome in Glioblastoma Patient-Derived Cell Lines Maintained at Lowered Oxygen Tension.

Despite numerous efforts aiming to characterise glioblastoma pathology (GBM) and discover new therapeutic strategies, GBM remains one of the most challenging tumours to treat. Here we propose the optimisation of in vitro culturing of GBM patient-derived cells, namely the establishment of GBM-derived cultures and their maintenance at oxygen tension mimicking oxygenation conditions occurring within the tumour. To globally analyse cell states, we performed the transcriptome analysis of GBM patient-derived cells kept as spheroids in serum-free conditions at the reduced oxygen tension (5% O2), cells cultured at atmospheric oxygen (20% O2), and parental tumour. Immune cells present in the tumour were depleted, resulting in the decreased expression of the immune system and inflammation-related genes. The expression of genes promoting cell proliferation and DNA repair was higher in GBM cell cultures when compared to the relevant tumour sample. However, lowering oxygen tension to 5% did not affect the proliferation rate and expression of cell cycle and DNA repair genes in GBM cell cultures. Culturing GBM cells at 5% oxygen was sufficient to increase the expression of specific stemness markers, particularly the PROM1 gene, without affecting neural cell differentiation markers. GBM spheroids cultured at 5% oxygen expressed higher levels of hypoxia-inducible genes, including those encoding glycolytic enzymes and pro-angiogenic factors. The genes up-regulated in cells cultured at 5% oxygen had higher expression in parental GBMs compared to that observed in 20% cell cultures, suggesting the preservation of the hypoxic component of GBM transcriptome at 5% oxygen and its loss in standard culture conditions. Evaluation of expression of those genes in The Cancer Genome Atlas dataset comprising samples of normal brain tissue, lower-grade gliomas and GBMs indicated the expression pattern of the indicated genes was specific for GBM. Moreover, GBM cells cultured at 5% oxygen were more resistant to temozolomide, the chemotherapeutic used in GBM therapy. The presented comparison of GBM cultures maintained at high and low oxygen tension together with analysis of tumour transcriptome indicates that lowering oxygen tension during cell culture may more allegedly reproduce tumour cell behaviour within GBM than standard culture conditions (e.g., atmospheric oxygen tension). Low oxygen culture conditions should be considered as a more appropriate model for further studies on glioblastoma pathology and therapy.

Glioblastoma: Pitfalls and Opportunities of Immunotherapeutic Combinations.

Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumour in adults. It has extremely poor prognosis since the current standard of care, comprising of gross total resection and temozolomide (TMZ) chemoradiotherapy, prolongs survival, but does not provide a durable response. To a certain extent, this is due to GBM's heterogeneous, hostile and cold tumour microenvironment (TME) and the unique ability of GBM to overcome the host's immune responses. Therefore, there is an urgent need to develop more effective therapeutic approaches. This review provides critical insights from completed and ongoing clinical studies investigating novel immunotherapy strategies for GBM patients, ranging from the use of immune checkpoint inhibitors in different settings of GBM treatment to novel combinatorial therapies. In particular, we discuss how treatment regimens based on single antigen peptide vaccines evolved into fully personalised, polyvalent cell-based vaccines, CAR-T cell, and viral or gene therapies. Furthermore, the results of the most influential clinical trials and a selection of innovative preclinical studies aimed at activating the immunologically cold GBM microenvironment are reviewed.

Triggering anti-GBM immune response with EGFR-mediated photoimmunotherapy.

BACKGROUND: Surgical resection followed by chemo-radiation postpones glioblastoma (GBM) progression and extends patient survival, but these tumours eventually recur. Multimodal treatment plans combining intraoperative techniques that maximise tumour excision with therapies aiming to remodel the immunologically cold GBM microenvironment could improve patients' outcomes. Herein, we report that targeted photoimmunotherapy (PIT) not only helps to define tumour location and margins but additionally promotes activation of anti-GBM T cell response. METHODS: EGFR-specific affibody molecule (ZEGFR:03115) was conjugated to IR700. The response to ZEGFR:03115-IR700-PIT was investigated in vitro and in vivo in GBM cell lines and xenograft model. To determine the tumour-specific immune response post-PIT, a syngeneic GBM model was used. RESULTS: In vitro findings confirmed the ability of ZEGFR:03115-IR700 to produce reactive oxygen species upon light irradiation. ZEGFR:03115-IR700-PIT promoted immunogenic cell death that triggered the release of damage-associated molecular patterns (DAMPs) (calreticulin, ATP, HSP70/90, and HMGB1) into the medium, leading to dendritic cell maturation. In vivo, therapeutic response to light-activated conjugate was observed in brain tumours as early as 1 h post-irradiation. Staining of the brain sections showed reduced cell proliferation, tumour necrosis, and microhaemorrhage within PIT-treated tumours that corroborated MRI T2*w acquisitions. Additionally, enhanced immunological response post-PIT resulted in the attraction and activation of T cells in mice bearing murine GBM brain tumours. CONCLUSIONS: Our data underline the potential of ZEGFR:03115-IR700 to accurately visualise EGFR-positive brain tumours and to destroy tumour cells post-conjugate irradiation turning an immunosuppressive tumour environment into an immune-vulnerable one.

Alternative Definitions of Cerebral Aneurysm Morphologic Parameters Have an Impact on Rupture Risk Determination.

BACKGROUND: A discrepancy between definitions of morphologic parameters describing cerebral aneurysms across studies leads to conflicting results concerning performances of these factors and threshold values for rupture status prediction. The aim of the study was to evaluate how various definitions of morphologic parameters may influence the prediction of the risk for aneurysm rupture. METHODS: A total of 425 intracranial aneurysms were reviewed. Analyzed factors included demographic and clinical parameters, aneurysm maximal height (Hmax), dome length (Dlength), dome width (Dwidth), dome maximal diameter (Dmax) and dome minimal diameter (Dmin), neck length (Nlength), neck width (Nwidth), and neck maximal diameter (Nmax) and neck minimal diameter (Nmin). Alternative definitions of aspect ratio (AR), bottleneck factor (BNF), and height-to-width ratio (HW) were used. Univariate and multivariate analysis were performed to identify predictors for aneurysm rupture. RESULTS: Hmax, AR defined as Hmax/Nwidth and Hmax/Nmin, BNF definitions using Nwidth and Nmin, and selected definitions of HW (Hmax/Dlength and Hmax/Dmin) were indicated as potential predictors for rupture. Aneurysm location was found to be a confounding factor with statistical significance. AR defined as Hmax/Nwidth and Hmax/Nmin were the best performers (P < 0.001; area under the curve, 0.64). In multivariate analysis, AR defined as Hmax/Nwidth and aneurysm location with significantly higher risk for rupture of anterior communicating artery aneurysms were independent predictors for subarachnoid hemorrhage. CONCLUSIONS: Different definitions of aneurysm parameters affect various rupture risk determination. AR defined as Hmax/Nwidth and aneurysm location with significantly higher rupture risk of anterior communicating artery aneurysms are independent predictors for aneurysm rupture.

Endovascular treatment of complex intracranial aneurysms.

PURPOSE: Complex intracranial aneurysms (CIA) are heterogenous group of intracranial vascular malformations. Due to its giant size, difficult location, broad neck, branches arising from the aneurysm, wall structure, calcification, presence of intraluminal thrombus or previous treatments it requires more careful approach. The aim of this study was to evaluate endovascular treatment results of CIA in our Department. MATERIAL AND METHODS: In order to differentiate CIA from all the aneurysms, treated endovascularly in years 2008-2014, authors proposed their own qualification criteria. Additionally, subgroup of patients with CIA with simultaneous subarachnoid haemorrhage (SAH) was divided. Clinical outcomes of patients were assessed with Glasgow Outcome Scale (GOS), while radiological outcomes were assessed with Montreal Scale. Aneurysm localization, incidence of aborted procedures, intraoperative complications were also evaluated. RESULTS: Internal carotid artery was the most common localization in both CIA and non-complex (nCIA) groups. Incidence of aborted procedures was significantly higher in CIA group than in nCIA (25% vs. 7%; p < 0.01). CIA group had worse Montreal scores then nCIA group (1.90 vs. 1.49; p < 0.01). Clinical outcome in GOS scale in patients with SAH and CIA was significantly worse than in SAH and nCIA (2.86 vs. 4.06; p = 0.04). CONCLUSIONS: To conclude, proposed criteria of CIA should be taken into consideration during diagnosis and qualification to invasive treatment. Classifying aneurysm as CIA is related to greater possibility of aborting endovascular procedure due to technical difficulties.