Ventricular Space Research Articles

Impact of Subarachnoid Hemorrhage on Human Glymphatic Function: A Time-Evolution Magnetic Resonance Imaging Study.

Subarachnoid hemorrhage (SAH) is associated with significant mortality and morbidity. The impact of SAH on human glymphatic function remains unknown. This prospective, controlled study investigated whether human glymphatic function is altered after SAH, how it differs over time, and possible underlying mechanisms. Glymphatic enrichment was examined by intrathecal contrast-enhanced magnetic resonance imaging (MRI, glymphatic MRI), utilizing the MRI contrast agent gadobutrol (Gadovist, Bayer AG, GE; 0.50 mmol) as a cerebrospinal fluid (CSF) tracer. The distribution of the tracer in the brain and the subarachnoid and ventricular CSF spaces was assessed using standardized multi-phase MRI T1 sequences, and between-group differences in percentage change of standardized T1 signal unit ratios over time were analyzed by linear mixed models. The study comprised 27 patients with SAH (19 female/8 male; 59.3±10.2 years) who were examined <3 months (n=5), 3 to 6 months (n=10), 6 to 12 months (n=5), or >12 months (n=7) after bleed. A sex- and age-matched control group of 22 individuals (15 female/7 male; 55.5±10.5 years) underwent the same glymphatic MRI protocol but had no neurological or CSF disease. The patients with SAH showed a marked impairment of glymphatic enrichment throughout the brain (particularly addressing the cerebral cortex and subcortical white matter), especially after 24 hours. The glymphatic impairment was accompanied by redistribution of CSF tracer from subarachnoid spaces toward ventricles. These alterations were most pronounced after 3 to 6 months and less after 12 months, though with interindividual variation. CSF tracer transport within perivascular subarachnoid spaces was impaired and coincided with impaired glymphatic enrichment. Human glymphatic function is severely impaired by SAH, particularly shortly after the event. Glymphatic failure is associated with redistribution of CSF from subarachnoid spaces toward ventricles. SAH-related impairment of fluid transport within perivascular subarachnoid spaces may contribute to reduced glymphatic influx. Since patient groups are small, care should be made when concluding about the impact of time on glymphatic function.

Abstract B071: Identifying the clinical utility of CSF as a source of liquid biopsy in pediatric brain tumors

Abstract Pediatric tumors of the central nervous system (CNS) are a leading cause of cancer-related childhood mortality. Along with imaging, it is essential to molecularly characterize tumor tissue for the diagnosis, treatment, and prognosis of these cancers. Biopsies of deeply-seeded lesions may not be possible or may carry significant risks. On the other hand, liquid biopsy, using cerebral spinal fluid (CSF), provides a minimally invasive alternative to identify and monitor tumor DNA at crucial time points, from diagnosis to follow-up. This allows for molecular diagnosis, identification of therapeutic targets, monitoring response to therapy, and early detection of recurrence or progression. The aim of our study was to assess the practicality and usefulness of liquid biopsies in a diverse group of CNS tumor patients. We used a combination of methods, including a targeted hybridization capture panel and low-pass whole genome sequencing (LP-WGS) based on the sample characteristics. We analyzed a total of 243 CSF samples from patients with CNS tumors including: low-grade glioma (LGG; N=57), high-grade glioma (HGG; N=53), medulloblastoma (MB; N=40), germinoma (CNS-GCT; N=29), and no prior biopsy (N=42). We found somatic mutations in 88% of CSF samples from HGG and 67% from LGG with known tumor DNA variants and sufficient sequencing quality. It's important to note that in LGG patients, samples collected from lumbar puncture were positive only in disseminated cases, while a higher positivity rate was found in cases where CSF was collected from ventricular spaces. Moreover, we observed positive copy number alterations (CNA) in CSF samples collected from HGG, embryonal tumors, and CNS-GCT patients at the time of diagnosis and follow-up with a sensitivity of 64%. Within our sample cohort that had an unknown or query tumor due to no prior biopsy, we were able to detect diagnostic, targetable mutations and/or a positive CNA profile in 30% of cases. This supports the utility of liquid biopsy as a diagnostic tool in in CNS lesions. This tool may also assist in monitoring for relapse in high-grade tumors. For example, in a case study, we were able to detect recurrent MB by indication of a positive CNA profile in keeping with the primary tumor CNV, six years post-surgical resection. In CNS- GCT patients, we found that LP-WGS was highly sensitive at diagnosis as we have observed similar CNV in both CSF and tumor DNA. In summary, the utility of our liquid biopsy platform in the context of CNS cancers is an impactful tool that can aid clinicians in diagnosis, treatment and monitoring disease in a minimally invasive manner. Citation Format: Liana Nobre, Mansuba Rana, Yoshiko Nakano, Ian Burns, Robert Siddaway, Richard Yuditskiy, Cyril Li, Andrew Bondoc, Anthony Liu, Uri Taboori, Cynthia Hawkins. Identifying the clinical utility of CSF as a source of liquid biopsy in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B071.

BIOM-48. UTILITY OF CIRCULATING TUMOR DNA (CTDNA) FROM CEREBROSPINAL FLUID (CSF) FOR PROGNOSIS OF PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA

Abstract High-grade gliomas (HGGs) are the most aggressive primary brain tumors, and molecular characterization is vital for their diagnosis and treatment. Due to their location, tumor sampling is often challenging. Therefore, developing minimally invasive diagnostic methods is urgently needed. Here we report that circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) can identify key genomic alterations and track clonal evolution in HGGs. Detection of CSF ctDNA correlates with leptomeningeal disease and overall survival, indicating its potential for integration into clinical decision-making. Our study includes 313 samples from 253 patients with recurrent glioma treated at MSKCC who underwent CSF collection using the MSK-IMPACT targeted sequencing assay. 37% of genomic alterations were detected using our less stringent variant calling criteria and Gaussian Mixture Model to call copy number events. CSF ctDNA positivity was determined by the presence of at least one oncogenic disease-defining alteration or any shared alteration with the tumor. We found 212 CSF ctDNA positive (68%) and 101 CSF ctDNA negative (32%) samples. CSF ctDNA positivity was the highest amongst histone mutant tumors (96%). We noticed 44% of alterations shared between the tumor and the CSF, additionally, we noted considerable tumor evolution particularly within the growth signaling pathways (e.g. PDGFRA). Our cohort demonstrated that patients with positive CSF ctDNA had a significantly shorter overall survival compared to those who were CSF ctDNA negative (4.83 months vs 14.14 months, HR 2.4, p &amp;lt; 0.001). Radiographic findings such as enhancing disease and contact of the tumor with the ventricular space were positively associated with CSF ctDNA positivity. Additionally, CSF ctDNA was associated with positive cytology in 12/12 cases (100%). With our improved pipeline, we hypothesize CSF ctDNA may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study.

CSF flow measurement in the mesencephalic aqueduct using 2D cine phase-contrast MRI in dogs with communicating internal hydrocephalus, ventriculomegaly, and physiologic ventricular spaces.

Brachycephalic dogs are overrepresented with ventricular enlargement. Cerebrospinal fluid (CSF) flow dynamics are not completely understood. MRI techniques have been used for the visualization of CSF dynamics including phase-contrast imaging. This study aimed to determine a causality between CSF flow and ventriculomegaly or hydrocephalus and to compare CSF flow dynamics among dogs with ventriculomegaly, internal hydrocephalus, and physiologic ventricles. A total of 51 client-owned dogs were included in the study. Magnetic resonance imaging (MRI)-based FLASH sequences and phase-contrast images of the brain were obtained, and the ROI was placed at the level of the mesencephalic aqueduct. ECG monitoring was performed parallel to MRI acquisition. Evaluation of flow diagrams and processing of phase-contrast images were performed using commercially available software (Argus VA80A, Siemens AG Healthcare Sector, Erlangen, Germany). Dogs were divided into three groups: Group 1 consisted of brachycephalic dogs with ventriculomegaly (group 1A) or internal hydrocephalus (group 1B), group 2 consisted of brachycephalic dogs with normal ventricles, and group 3 consisted of meso- to dolichocephalic dogs with normal ventricles. Group 1 had a higher median Vrost (4.32 cm/s; CI: 2.94-6.33 cm/s) and Vcaud (-6.1 cm/s, CI: 3.99-9.33 cm/s) than group 2 (Vrost: 1.99 cm/s; CI 1.43-2.78 cm/s; Vcaud: 2.91 cm/s, CI: 2.01-4.21 cm/s; p = 0.008; p = 0.03) and group 3 (Vrost:1.85 cm/s, CI: 1.31-2.60 cm/s; Vcaud - 2.46 cm/s, CI 1.68-3.58 cm/s; p = 0.01; p = 0.02). The median Volcaud of group 1 (-0.23 mL/min, CI: 0.13-0.42 mL/min) was higher than that of group 2 (-0.09 mL/min, CI: 0.05 mL/min and 0.15 mL/min) (p = 0.03). Groups 1A and 1B did not differ in Vcaud, Vrost, Volcaud, and Volrost. Group 1A and 1B showed a higher median Vrost (4.01 cm/s, CI: 2.30-7.05 cm/s; 5.94 cm/s, CI: 2.16-7.88 cm/s) than group 2 (1.85 cm/s, CI: 1.24-2.80 cm/s.) (p = 0.03; p = 0.004). Increased CSF flow velocities in rostral and caudal directions are present in dogs with ventriculomegaly and internal hydrocephalus compared to normal controls.

Technical note: durable resolution of hydrocephalus after ultrasound-guided percutaneous fenestration of giant suprasellar arachnoid cyst in a neonate

Arachnoid cysts are relatively common, but rarely require intervention. While most arachnoid cysts in typical middle or posterior cranial fossa locations are seldom symptomatic, suprasellar cysts may become symptomatic due to the potential for ventricular outflow obstruction and hydrocephalus. Typical standard of care for the treatment of these lesions is endoscopic fenestration with third ventriculostomy, or the placement of ventriculoperitoneal or cystoperitoneal shunts. The surgical and anaesthetic risks of traditional interventions may be higher in the early neonatal period, including leak of cerebrospinal fluid, infection, and premature failure of ventriculostomy or shunts. This note describes a novel bedside ultrasound-guided technique to percutaneously fenestrate large suprasellar arachnoid cysts under local anaesthesia. The technique involves insertion of a 25-g spinal needle until contact with the membrane of the arachnoid cyst medially, followed by a lateral sweeping to widely incise/fenestrate the lesion into the ventricular space under continuous ultrasound visualisation. This note describes an example case which demonstrates durable radiological and clinical improvement after 2 years of follow-up. This may represent a management option to temporise, or perhaps definitively manage suprasellar arachnoid cysts in the neonatal period.

Cerebroventricular deformation and vector mapping, a topographic visualizer for surgical interventions in pediatric hydrocephalus.

Hydrocephalus is a challenging neurosurgical condition due to nonspecific symptoms and complex brain-fluid pressure dynamics. Typically, the assessment of hydrocephalus in children requires radiographic or invasive pressure monitoring. There is usually a qualitative focus on the ventricular spaces even though stress and shear forces extend across the brain. Here, the authors present an MRI-based vector approach for voxelwise brain and ventricular deformation visualization and analysis. Twenty pediatric patients (mean age 7.7 years, range 6 months-18 years; 14 males) with acute, newly diagnosed hydrocephalus requiring surgical intervention for symptomatic relief were randomly identified after retrospective chart review. Selection criteria included acquisition of both pre- and posttherapy paired 3D T1-weighted volumetric MRI (3D T1-MRI) performed on 3T MRI systems. Both pre- and posttherapy 3D T1-MRI pairs were aligned using image registration, and subsequently, voxelwise nonlinear transformations were performed to derive two exemplary visualizations of compliance: 1) a whole-brain vector map projecting the resulting deformation field on baseline axial imaging; and 2) a 3D heat map projecting the volumetric changes along ventricular boundaries and the brain periphery. The patients underwent the following interventions for treatment of hydrocephalus: endoscopic third ventriculostomy (n = 6); external ventricular drain placement and/or tumor resection (n = 10); or ventriculoperitoneal shunt placement (n = 4). The mean time between pre- and postoperative imaging was 36.5 days. Following intervention, the ventricular volumes decreased significantly (mean pre- and posttherapy volumes of 151.9 cm3 and 82.0 cm3, respectively; p < 0.001, paired t-test). The largest degree of deformation vector changes occurred along the lateral ventricular spaces, relative to the genu and splenium. There was a significant correlation between change in deformation vector magnitudes within the cortical layer and age (p = 0.011, Pearson), as well as between the ventricle size and age (p = 0.014, Pearson), suggesting higher compliance among infants and younger children. This study highlights an approach for deformation analysis and vector mapping that may serve as a topographic visualizer for therapeutic interventions in patients with hydrocephalus. A future study that correlates the degree of cerebroventricular deformation or compliance with intracranial pressures could clarify the potential role of this technique in noninvasive pressure monitoring or in cases of noncompliant ventricles.

Capillary connections between sensory circumventricular organs and adjacent parenchyma enable local volume transmission.

Among contributors to diffusible signaling are portal systems which join two capillary beds through connecting veins (Dorland 2020). Portal systems allow diffusible signals to be transported in high concentrations directly from one capillary bed to the other without dilution in the systemic circulation. Two portal systems have been identified in the brain. The first was discovered almost a century ago and connects the median eminence to the anterior pituitary gland (Popa & Fielding 1930). The second was discovered a few years ago, and links the suprachiasmatic nucleus to the organum vasculosum of the lamina terminalis, a sensory circumventricular organ (CVO) (Yao et al. 2021). Sensory CVOs bear neuronal receptors for sensing signals in the fluid milieu (McKinley et al. 2003). They line the surface of brain ventricles and bear fenestrated capillaries, thereby lacking blood brain barriers. It is not known whether the other sensory CVOs, namely the subfornical organ (SFO), and area postrema (AP) form portal neurovascular connections with nearby parenchymal tissue. This has been difficult to establish as the structures lie at the midline and protrude into the ventricular space. To preserve the integrity of the vasculature of CVOs and their adjacent neuropil, we combined iDISCO clearing and light-sheet microscopy to acquire volumetric images of blood vessels. The results indicate that there is a portal pathway linking the capillary vessels of the SFO and the posterior septal nuclei, namely the septofimbrial nucleus and the triangular nucleus of the septum. Unlike the latter arrangement, the AP and the nucleus of the solitary tract share their capillary beds. Taken together, the results reveal that all three sensory circumventricular organs bear specialized capillary connections to adjacent neuropil, providing a direct route for diffusible signals to travel from their source to their targets.

First-trimester ultrasound of the cerebral lateral ventricles in fetuses with open spina bifida: a retrospective cohort study

Beyond 18 weeks of gestation, an increased size of the fetal lateral ventricles is reported in most fetuses with open spina bifida. In the first trimester of pregnancy, the definition of ventriculomegaly is based on the ratio of the size of the choroid plexus to the size of the ventricular space or the entire fetal head. However, contrary to what is observed from the midtrimester of pregnancy, in most fetuses with open spina bifida at 11 to 13 weeks of gestation, the amount of fluid in the ventricular system seems to be reduced rather than increased. This study aimed to compare the biometry of the lateral ventricles at 11 0/7 to 13 6/7 weeks of gestation between normal fetuses and those with confirmed open spina bifida. This was a retrospective cohort study that included all cases of isolated open spina bifida detected at 11 0/7 to 13 6/7 weeks of gestation over a period of 5 years and a group of structurally normal fetuses attending at our center over a period of 1 year for the aneuploidy screening as controls. Transventricular axial views of the fetal brain obtained from cases and controls were extracted from the archive for post hoc measurement of cerebral ventricles. The choroid plexus-to-lateral ventricle length ratio, sum of the choroid plexus-to-lateral ventricle area ratio, choroid plexus area-to-fetal head area ratio, and mean choroid plexus length-to-occipitofrontal diameter ratio were calculated for both groups. The measurements obtained from the 2 groups were compared, and the association between each parameter and open spina bifida was investigated. A total of 10 fetuses with open spina bifida were compared with 358 controls. Compared with controls, fetuses with open spina bifida showed a significantly smaller size of the cerebral ventricle measurements, as expressed by larger values of choroid plexus-to-lateral ventricle area ratio (0.49 vs 0.72, respectively; P<.001), choroid plexus-to-lateral ventricle length ratio (0.70 vs 0.79, respectively; P<.001), choroid plexus area-to-fetal head area ratio (0.28 vs 0.33, respectively; P=.006), and choroid plexus length-to-occipitofrontal diameter ratio (0.52 vs 0.60, respectively; P<.001). The choroid plexus-to-lateral ventricle area ratio was found to be the most accurate predictor of open spina bifida, with an area under the curve of 0.88, a sensitivity of 90%, and a specificity of 82%. At 11 0/7 to 13 6/7 weeks of gestation, open spina bifida is consistently associated with a reduced amount of fluid in the lateral cerebral ventricles of the fetus, as expressed by a significantly increased choroid plexus-to-lateral ventricle length ratio, choroid plexus-to-lateral ventricle area ratio, choroid plexus area-to-fetal head area ratio, and choroid plexus length-to-occipitofrontal diameter ratio.

Cardioprotective effects of native herb-derived cardiac tonic on infarct size in a mouse model of experimental myocardial infarction

Cardiac remodeling is a significant issue involving molecular, cellular, and interstitial changes that affect the size, mass, integrity, and function of the heart following a myocardial infarction (MI). We hypothesized that therapy with mixed herbal extracts has a protective effect in mouse models of MI. The underlying mechanisms are thought to be protective against left ventricular (LV) remodeling through reduced collagen deposition. We therefore studied the effects of mixed herbal extracts commonly used in various ways in the belief that they have beneficial effects on cardiac disease. MI was induced by left anterior descending (LAD) coronary artery ligation in switch albino mice. Ethanol extracts of herbs Arjuna bark, oleander leaves, ginseng root, garlic, cardamom seeds and oregano leaves were prepared by ethanol extraction and rotary evaporation technique of dried herbs and then mixed the extracts to make a therapeutic cocktail. The mixture is then administered orally by lavage for 28 days. At the end of 28 days cardiac tissues were harvested and stored for histopathology analysis and assessment of SOD levels. Survival curve data over a period of 28 days showed significant (P&lt;0.05) differences between groups and mortality was reduced in the herbal extract treated group. Heart mass especially ventricular and atrial space and ratio of ​​infarct to total heart area revealed better improvement in treated group compared to untreated group. Histopathological studies showed that the myocardium of the herbal extract treated group had fewer collagen fibers than the non-treated group. SOD activity levels were up-regulated in animals treated with herbal extracts indicating reduction of oxidative stress by herbal extract mixture. Hence, their effects reduce collagen deposition, reduce LV mass and prevent myocardial tissue damage, reduce structural changes and increase survival by their anti-stress effects. Mixed herbal tonic may provide a new therapeutic approach in ischemic cardiomyopathy and ischemic heart failure. Asian Australas. J. Biosci. Biotechnol. 2024, 9(2), 14-23

A novel preparation for histological analyses of intraventricular macrophages in the embryonic brain.

Microglia colonize the brain starting on embryonic day (E) 9.5 in mice, and their population increases with development. We have previously demonstrated that some microglia are derived from intraventricular macrophages, which frequently infiltrate the pallium at E12.5. To address how the infiltration of intraventricular macrophages is spatiotemporally regulated, histological analyses detecting how these cells associate with the surrounding cells at the site of infiltration into the pallial surface are essential. Using two-photon microscopy-based in vivo imaging, we demonstrated that most intraventricular macrophages adhere to the ventricular surface. This is a useful tool for imaging intraventricular macrophages maintaining their original position, but this method cannot be used for observing deeper brain regions. Meanwhile, we found that conventional cryosection-based and naked pallial slice-based observation resulted in unexpected detachment from the ventricular surface of intraventricular macrophages and their mislocation, suggesting that previous histological analyses might have failed to determine their physiological number and location in the ventricular space. To address this, we sought to establish a methodological preparation that enables us to delineate the structure and cellular interactions when intraventricular macrophages infiltrate the pallium. Here, we report that brain slices pretreated with agarose-embedding maintained adequate density and proper positioning of intraventricular macrophages on the ventricular surface. This method also enabled us to perform the immunostaining. We believe that this is helpful for conducting histological analyses to elucidate the mechanisms underlying intraventricular macrophage infiltration into the pallium and their cellular properties, leading to further understanding of the process of microglial colonization into the developing brain.

Utility of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) for prognosis of patients with recurrent high grade glioma.

2010 Background: High-Grade Gliomas (HGGs) are the most aggressive primary brain tumors in adults and molecular characterization is crucial for diagnosis and optimal disease treatment. Due to the eloquent location of many HGGs, upfront or repeat tumor sampling may be sub-optimal. Hence, there is an urgent need to develop alternative, minimally invasive means to obtain diagnostic information and determine the expected clinical behavior. Here we report that circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) can be used to identify disease defining genomic alterations and to track clonal evolution. Additionally, we demonstrate that detection of CSF ctDNA is positively correlated with leptomeningeal disease and overall survival suggesting that CSF ctDNA should be integrated into clinical decision making in the clinic. Methods: Our study includes 313 samples from 253 patients with recurrent glioma treated at Memorial Sloan Kettering Cancer Center who underwent CSF collection for routine clinical care and were sequenced using the MSK-IMPACT targeted clinical sequencing assay (468 and 505 genes). Alterations were classified as oncogenic based on OncoKB. 17% of genomic alterations detected were identified using a secondary bioinformatics analysis, following an informed approach with less stringent mutation calling criteria and Gaussian Mixture Model to call copy number events. CSF ctDNA positivity was determined by the presence of at least one oncogenic disease defining alteration or any shared alteration with the tumor. Results: Within this cohort, we found 193 CSF ctDNA positive (62%) and 120 CSF negative (38%) samples. Of note, CSF ctDNA positivity was the highest amongst histone mutant tumors with 94% CSF ctDNA positivity compared to 56% CSF ctDNA positivity for IDH-WT tumors. We noticed 44% of alterations shared between the tumor and the CSF, additionally, we noted considerable tumor evolution particularly within the growth signaling pathways (e.g. PDGFRA). The majority of the shared alterations were clonal, and we noticed the emergence of new clonal events in the CSF. Conclusions: Our cohort demonstrated that patients with positive CSF ctDNA had a significantly shorter overall survival compared to those who were CSF ctDNA negative (4.83 months vs 11.83 months, HR 2.1, p &lt; 0.001). In tandem with secondary clinical analysis, radiographic findings also correlated with CSF ctDNA positivity. Specifically, the presence of enhancing disease and contact of the tumor with the ventricular space were positively associated with detection of CSF ctDNA. Additionally, CSF ctDNA was associated with positive cytology in 21/21 cases (100%). With our improved bioinformatics pipeline, we hypothesize ctDNA from CSF may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study.

Abstract 3703: Utility of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) for prognosis of patients with recurrent high grade glioma

Abstract High-Grade Gliomas (HGGs) are the most aggressive primary brain tumors in adults and molecular characterization is crucial for diagnosis and optimal disease treatment. Due to the eloquent location of many HGGs, upfront or repeat tumor sampling may be sub-optimal. Hence, there is an urgent need to develop alternative, minimally-invasive means to obtain diagnostic information and determine the expected clinical behavior. Here we report that circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) can be used to identify disease defining genomic alterations and to track clonal evolution. Additionally, we demonstrate that detection of CSF ctDNA is positively correlated with leptomeningeal disease and overall survival suggesting that CSF ctDNA should be integrated into clinical decision making in the clinic. Our study includes 315 samples from 254 patients with recurrent glioma treated at Memorial Sloan Kettering Cancer Center who underwent CSF collection for routine clinical care and were sequenced using the MSK-IMPACT targeted clinical sequencing assay (468 and 505 genes). Alterations were classified as oncogenic based on OncoKB. 23% of genomic alterations detected were identified using a secondary bioinformatics analysis, following an informed approach with less stringent mutation calling criteria and Gaussian Mixture Model to call copy number events. CSF ctDNA positivity was determined by the presence of at least one oncogenic disease defining alteration or any shared alteration with the tumor. Within this cohort, we found 198 CSF ctDNA positive (63%) and 117 CSF negative (37%) samples. Of note, CSF ctDNA positivity was the highest amongst histone mutant tumors with 94% CSF ctDNA positivity compared to 56% CSF ctDNA positivity for IDH-WT tumors. We noticed considerable evolution of the cancer genome in patients with sequential biopsies with only 35% of alterations shared between the tumor and the CSF, in particular within the growth signaling pathways (e.g. PDGFRA). The majority of the shared alterations were clonal, and we noticed the emergence of new clonal events in the CSF. Our cohort demonstrated that patients with positive CSF ctDNA had a significantly shorter overall survival compared to those who were CSF ctDNA negative (4.83 months vs 11.83 months, HR 2.1, p &amp;lt; 0.001). In tandem with secondary clinical analysis, radiographic findings also correlated with CSF ctDNA positivity. Specifically, the presence of enhancing disease and contact of the tumor with the ventricular space were positively associated with detection of CSF ctDNA. Additionally, CSF ctDNA was associated with positive cytology in 21/21 cases (100%). With our improved bioinformatics pipeline we hypothesize ctDNA from CSF may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study. Citation Format: Bridget M. Holle, Subhiksha Nandakumar, Christoph Kreitzer, Timothy Song, Marlene Tartaro, Charli Ann J. Hertz, Johnathan Rafailov, Carl Campos, Anne S. Reiner, Robert Young, Alicia Meng, Luca Pasquini, A. Rose Brannon, Nicholas D. Socci, Maria E. Arcila, David B. Solit, Michael F. Berger, Nikolaus Schultz, Ingo K. Mellinghoff, Alexandra M. Miller. Utility of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) for prognosis of patients with recurrent high grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3703.

Effect of continuous drainage of cranial arachnoid cysts into the ventricular system by stereotactic placed catheters

Background: Surgical treatment of intracranial arachnoid cysts (iACs) is challenging. Microsurgical resection, endoscopic fenestration and cysto-peritoneal shunting are the most frequently used methods, each implying their own drawbacks. Stereotactic-guided cysto-ventricular drainage has been described as an alternative method. Here we describe our experience with this technique and how we conducted volumetric measurements to evaluate the effect of permanent drainage. Methods: Standardized stereotactic planning was performed. The planned trajectory included both the iAC and the ventricle system. The catheter was shortened to the defined length and was further fenestrated along its planned course through the iAC to allow drainage into the ventricular system. Clinical and radiological control was performed on outpatient basis after a mean follow-up of 2 (1–3) months. The overall mean follow-up was 32 months (6–59). The measurement of the cyst volume was conducted by the ABC/2-method. Results: Six patients with symptomatic arachnoid cysts (4 f, 2 m) were treated between 2010 and 2016. The overall postoperative reduction in cyst volume at the first follow-up was 36.04% (at the long-term follow-up: 38.57%). Decrease of the midline-shift was achieved in all cases and averaged 57.83% (long term: 81.88%). Clinical improvement of related symptoms could be achieved in all patients (4 patients were symptom free, two patients had alleviated symptoms). There was no case of over-drainage. The catheter had to be removed after 6 months in one case due to infection. Conclusions: We demonstrate successful symptom control and volume reduction in a small series of iACs by continuous drainage into the CSF-system through stereotactic placed catheters. This method may facilitate a self-regulated egress of entrapped cyst fluid in symptomatic patients without risk of over-drainage. A literature survey of the success rate and the complications of this approach is provided. It is concluded that this minimally- invasive method may be an alternative to established fenestration techniques especially for patients with arachnoid cysts that aren’t directly adjacent to a cisternal or ventricular CSF space.

ChOP-CT: quantitative morphometrical analysis of the Hindbrain Choroid Plexus by X-ray micro-computed tomography

The Hindbrain Choroid Plexus is a complex, cerebrospinal fluid-secreting tissue that projects into the 4th vertebrate brain ventricle. Despite its irreplaceability in the development and homeostasis of the entire central nervous system, the research of Hindbrain Choroid Plexus and other Choroid Plexuses has been neglected by neuroscientists for decades. One of the obstacles is the lack of tools that describe the complex shape of the Hindbrain Choroid Plexus in the context of brain ventricles. Here we introduce an effective tool, termed ChOP-CT, for the noninvasive, X-ray micro-computed tomography-based, three-dimensional visualization and subsequent quantitative spatial morphological analysis of developing mouse Hindbrain Choroid Plexus. ChOP-CT can reliably quantify Hindbrain Choroid Plexus volume, surface area, length, outgrowth angle, the proportion of the ventricular space occupied, asymmetries and general shape alterations in mouse embryos from embryonic day 13.5 onwards. We provide evidence that ChOP-CT is suitable for the unbiased evaluation and detection of the Hindbrain Choroid Plexus alterations within various mutant embryos. We believe, that thanks to its versatility, quantitative nature and the possibility of automation, ChOP-CT will facilitate the analysis of the Hindbrain Choroid Plexus in the mouse models. This will ultimately accelerate the screening of the candidate genes and mechanisms involved in the onset of various Hindbrain Choroid Plexus-related diseases.

Dilated cardiomyopathy in a green-winged saltator (Saltator similis)

Cardiovascular diseases are rarely reported in birds. Among pet birds, they are most documented in psittacine birds. Dilated cardiomyopathy is a myocardial disease frequently found in poultry but with few reports in both pet and wild birds. An elderly male green-winged saltator (Saltator similis) died suddenly after presenting intermittent clinical signs of dyspnea, weakness, and vocalization changes. A general increase in cardiac size with a bulging apex was observed at necropsy. The heart exhibited an enlarged left ventricular space and flaccid musculature on the cut section. The liver was diffusely enlarged with rounded edges. No other gross lesions were observed. Samples were collected in 10% formalin and routinely processed. Histologically, bundles of myocardial fibers were irregularly arranged, with markedly elongated myofibrils and irregular cell contours. Additionally, multifocal areas of disruption were observed between the myofibrils. Diffuse hepatic congestion of sinusoids and portal veins was observed, and diffuse edema in the interstitium and para bronchi was present in the lungs. The clinical signs observed were nonspecific and can be found in several diseases of the cardiovascular and respiratory systems of birds. The gross and histological findings are compatible with what has been described for dilated cardiomyopathy in birds; however, left ventricular dilatation is uncommon in avian patients. Heart diseases in pet birds are still underdiagnosed, and reports of cardiomyopathies are limited to psittacine birds. To the authors’ knowledge, this is the first report of a dilated cardiomyopathy in a passerine bird.

Racial and ethnic differences in infant survival for hydrocephaly-Texas, 1999-2017.

Congenital hydrocephaly, an abnormal accumulation of fluid within the ventricular spaces at birth, can cause disability or death if untreated. Limited information is available about survival of infants born with hydrocephaly in Texas. Therefore, the purpose of the study was to calculate survival estimates among infants born with hydrocephaly without spina bifida in Texas. A cohort of live-born infants delivered during 1999-2017 with congenital hydrocephaly without spina bifida was identified from the Texas Birth Defects Registry. Deaths within 1 year of delivery were identified using vital and medical records. One-year infant survival estimates were generated for multiple descriptive characteristics using the Kaplan-Meier method. Crude hazard ratios (HRs) for one-year survival among infants with congenital hydrocephaly by maternal and infant characteristics and adjusted HRs for maternal race and ethnicity were estimated using Cox proportional hazard models. Among 5709 infants born with congenital hydrocephaly without spina bifida, 4681 (82%) survived the first year. The following characteristics were associated with infant survival: maternal race and ethnicity, clinical classification (e.g., chromosomal or syndromic), preterm birth, birth weight, birth year, and maternal education. In the multivariable Cox proportional hazards model, differences in survival were observed by maternal race and ethnicity after adjustment for other maternal and infant characteristics. Infants of non-Hispanic Black (HR: 1.28, 95% CI: 1.04-1.58) and Hispanic (HR: 1.31, 95% CI: 1.12-1.54) women had increased risk for mortality, compared with infants of non-Hispanic White women. This study showed infant survival among a Texas cohort differed by maternal race and ethnicity, clinical classification, gestational age, birth weight, birth year, and maternal education in infants with congenital hydrocephaly without spina bifida. Findings confirm that mortality continues to be common among infants with hydrocephaly without spina bifida. Additional research is needed to identify other risk factors of mortality risk.

Hippocampal‐to‐ventricle ratio (HVR) is better related to age and cognition than Hippocampal Volume

AbstractBackgroundHippocampal volume (HCvol) is an important biomarker in the study of neurodegeneration (1‐3). Given its high variability (4) HCvol is commonly normalized using the intracranial volume (HCvol/ICV) (5). The Hippocampal‐to‐ventricle ratio (HVR) considers instead the nearby expanding ventricular space and has shown stronger negative association with age and positive association with delayed memory compared to HCvol in healthy aging (6).MethodUsing a Convolutional Neural Network (7) we extracted the volumes from the hippocampus and the surrounding temporal horn of the lateral ventricles to obtain the HCvol, HCvol/ICV and HVR on the baseline T1w MRI scans from the ADNI dataset (CN = 502, MCI = 814, AD = 323). We converted these measurements to Z‐scores using the mean and standard deviation of the CN cohort to facilitate comparisons. We used Pearson’s correlation coefficient to compare the relationships between each of the three Hippocampal measures with age, ADAS13, and the Immediate, Learning, Forgetting and Forgetting‐percentage metrics of the Rey’s Auditory Verbal Learning Test (RAVLT). Finally, we compared the correlations of HCvol/ICV and HVR with a bias‐corrected‐and‐accelerated bootstrap (BCa; 10,000 resamples) (8).ResultThe correlations of HCvol and HCvol/ICV were similar for age (‐.41 [‐.32, ‐.48] vs ‐.38 [‐.3, ‐.45]), ADAS13 (‐.28 [‐.19, ‐.45] vs ‐.26 [‐.17, ‐.45]) and RAVLT subtests (absolute values: .2 [0, .4] vs .2 [.01, .41]). HVR showed significantly stronger negative correlations with age compared to HCvol/ICV (Fig. 1; CN: BCa = .144 [.102‐.187]; MCI: BCa = .128 [.096‐.160]; AD: BCa = .068 [.012‐.122]). While the negative correlations between HVR and ADAS13 scores were higher than HCvol, the comparison was not statistically significant (Fig. 2). Figure 3 shows the relationships between HC measures and RAVLT subtests: HVR had stronger correlations than HCvol for CN and AD on the Immediate subtest, while HCvol’s relationship with Forgetting score was higher for MCI. None of these were statistically significant.ConclusionConsidering ventricular expansion and hippocampal shrinkage in the HVR better explains the variance related to age and cognition than using hippocampal volume by itself in healthy controls and patients with mild cognitive impairment and dementia.

DDEL-13. CILIA INHIBITORS SYNERGIZE WITH TEMOZOLOMIDE TO DRAMATICALLY IMPROVE SURVIVAL IN ORTHOTOPIC MURINE MODELS OF GLIOBLASTOMA

Abstract Patients with malignant brain tumors such as glioblastoma face a poor prognosis with a median survival of less than two years. Recent glymphatic studies demonstrate the interconnectivity between the fluid in the brain parenchymal and ventricular spaces. We reasoned enhancing the accumulation of a drug in the cerebral spinal fluid (CSF) of the ventricular space will also enhance the accumulation of the drug in the parenchyma where a GBM resides. To improve drug accumulation in the CSF, we modulated the motility of ependymal cell cilia. Ependymal cells coat the ventricles and display motile cilia that mechanically propel CSF through the ventricular space. Impairing ciliary motion could slow down CSF turnover without affecting the overall amount of CSF in the brain and central nervous system. To test these hypotheses, we identified FDA-approved therapeutics that are known to impair airway cilia as a “side effect.” Seven candidate drugs were administered into the ventricle of mice bearing orthotopic GBM in combination with systemic temozolomide. Five of the seven cilia-inhibiting drugs significantly improved overall survival when combined with temozolomide compared to controls. The lead candidate, lidocaine, demonstrated a synergistic relationship with temozolomide, and 100% of animals treated with the combination survived to the study endpoint tumor free. We demonstrate lidocaine can impair cilia motility in vitro and in vivo. Combining intraventricular lidocaine with temozolomide is well tolerated and results in a 2.8-fold increase in brain temozolomide concentration per dose compared to controls. Finally, we validate these data in two human PDX orthotopic xenograft GBM murine models, including an un-methylated MGMT GBM that became sensitive to temozolomide with the combination treatment. These studies offer a new concept for treating malignant brain tumors and potentially a scheme to improve the treatment of additional encephalopathies in the future.

The Narrative of an Aberrant Pericardiocentesis Catheter in the Heart: A Case Report on the Surgical Management of an Iatrogenic Left Ventricle Perforation

Pericardiocentesis catheter placement is a procedure for treating pericardial effusion and has a low complication rate. Inadvertent intraventricular perforation of a pericardiocentesis catheter is an uncommon yet a known complication of the procedure. Failure to establish adequate hemostasis during the removal of the foreign body could be catastrophic. Generically, puncture of a pericardiocentesis catheter into the ventricular space is tolerable, but the failure to achieve hemostasis in the ventricular wall amounts to injurious effects accounted to the size and caliber of the drain. Here we describe a case in which a pigtail catheter (8F) accidentally penetrated the left ventricle while attempting to drain pericardial effusion. The patient was brought to the surgical theater where the cardiac surgeon performed an off-pump left anterolateral thoracotomy and extracted the drain successfully. Pledgetted sutures (Prolene 3-0) were placed under tension and the knots were placed, thereby achieving excellent hemostasis of entry point of perforation. During the postoperative course, neither the x-ray of the chest nor an echocardiograph demonstrated hemothorax or pericardial tamponade. Five days later, the patient was discharged from our hospital.

Telovelar versus Transvermian Approach in Management of Patients with Fourth Ventricular Tumors

Background Approaching the fourth ventricle surgically is particularly challenging due to the limited working space provided by the important surrounding cerebrovascular structures. Its close relationship to the surrounding neural structures, including the brainstem and cerebellum, is the major limitation for surgical access. Various surgical routes to the fourth ventricular space will be described in the literature, including the conventional transvermian approach. Recent clinical and anatomical studies have suggested that the telovelar approach will maximize the extent of surgical exposure and working angle while minimizing operative morbidity. Objectives Our primary objective is to evaluate the efficacy and outcome of each approach in handling tumors within different parts of 4th ventricle. Our secondary objective is to analyze approach related complication and limitations of application to find best surgical option for those patients with posterior fossa lesions. Methods The following electronic databases will be searched from 2000 to 2019: PubMed, Google scholar, Cocharne database of systematic reviews, EMBASE and Science direct using Keywords ''Telovelar approach'', ''Transvermian approach'', ''fourth ventricular tumours'', ''Medullary velum''. Studies will be eligible if they contain the target Keywords in title or abstract, addressing our subject. Afterwards the full text of the article will be reviewed to exclude full texts not fulfilling the criteria or deviating from the initial impression taken from the title/abstract reviewing. References\ bibliography of the selected article will be sorted by discussion between study team (Student, Director and Codirectors). Results A total of 130 study were screened for eligibility, 6 studies were included in our systematic review for comparing the Telovelar and Transvermian approach in reaching posterior fossa lesions located within 4th ventricle regarding efficacy, clinical outcome and improvement, safety and complication. It was found that each approach has its own merits and demerits with nearly no difference between them regarding efficacy and safety, however slight superiority was linked to Telovelar approach in minimizing post-operative posterior fossa syndrome and Hydrocephalic changes. Conclusion we concluded that, Both transvermian -without sustained retraction- and telovelar approaches have no significant difference in safety, feasibility of total tumor excision, clinical outcome, postoperative complications and cerebellar mutism. The choice of either approach depends mainly on the surgeon's skills and preference, However the telovelar approach is generally preferred.