Ex Vivo Drug Screening Assay with Artificial Membranes: Characterizing Cholesterol Desorbing Competencies of Beta-Cyclodextrins.

Despite advancements in contemporary therapies, cardiovascular disease from atherosclerosis remains a leading cause of mortality worldwide. Supported lipid bilayers (SLBs) are membrane interfaces that can be constructed with varying lipid compositions. Herein, we use a solvent-assisted lipid bilayer (SALB) construction method to build SLB membranes with varying cholesterol compositions to create a lipid-sterol interface atop a piezoelectric sensor. These cholesterol-laden SLBs were utilized to investigate the mechanisms of various cholesterol-lowering drug molecules. Within a flow-cell, membranes with varying cholesterol content were exposed to cyclodextrins 2-hydroxypropyl-beta-cyclodextrin (HPßCD) and methyl-beta-cyclodextrin (MßCD). Quartz-crystal microgravimetry with dissipation monitoring (QCM-D) enabled the collection of in vitro, real-time changes in relative areal mass and dissipation. We define the cholesterol desorbing competency of a cyclodextrin species via measures of the rate of cholesterol removal, the rate of the transfer of membrane-bound cholesterol to drug-complexed cholesterol, and the binding strength of the drug to the cholesterol-ladened membrane. Desorption data revealed distinct cholesterol removal kinetics for each cyclodextrin while also supporting a model for the lipid-cholesterol-drug interface. We report that MßCD removes a quantity of cholesterol 1.61 times greater, with a speed 2.12 times greater, binding affinity to DOPC lipid interfaces 1.97 times greater, and rate of internal cholesterol transfer 3.41 times greater than HPßCD.

Developing Predictive Models to Anticipate Shunt Complications in 33,248 Pediatric Patients with Shunted Hydrocephalus Utilizing Machine Learning.

INTRODUCTION: Hydrocephalus is a common pediatric neurosurgical pathology, typically treated with a ventricular shunt, yet approximately 30% of patients experience shunt failure within the first year after surgery. As a result, the objective of the present study was to validate a predictive model of pediatric shunt complications with data retrieved from the Healthcare Cost and Utilization Project (HCUP) National Readmissions Database (NRD). METHODS: The HCUP NRD was queried from 2016 to 2017 for pediatric patients undergoing shunt placement using ICD-10 codes. Comorbidities present upon initial admission resulting in shunt placement, Johns Hopkins Adjusted Clinical Groups (JHACG) frailty-defining criteria, and Major Diagnostic Category (MDC) at admission classifications were obtained. The database was divided into training (n = 19,948), validation (n = 6,650), and testing (n = 6,650) datasets. Multivariable analysis was performed to identify significant predictors of shunt complications which were used to develop logistic regression models. Post hoc receiver operating characteristic (ROC) curves were created. RESULTS: A total of 33,248 pediatric patients aged 6.9 ± 5.7 years were included. Number of diagnoses during primary admission (OR: 1.05, 95% CI: 1.04-1.07) and initial neurological admission diagnoses (OR: 3.83, 95% CI: 3.33-4.42) positively correlated with shunt complications. Female sex (OR: 0.87, 95% CI: 0.76-0.99) and elective admissions (OR: 0.62, 95% CI: 0.53-0.72) negatively correlated with shunt complications. ROC curve for the regression model utilizing all significant predictors of readmission demonstrated area under the curve of 0.733, suggesting these factors are possible predictors of shunt complications in pediatric hydrocephalus. CONCLUSION: Efficacious and safe treatment of pediatric hydrocephalus is of paramount importance. Our machine learning algorithm delineated possible variables predictive of shunt complications with good predictive value.

siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model.

Temozolomide (TMZ) is the standard of care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug resistance mediated by a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here we report the development of an iron oxide nanoparticle (NP) system for targeted delivery of siRNAs to suppress the TMZ-resistance gene (MGMT). We show that our NP is able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially-passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ resulted in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly-prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.

Clinicopathologic characteristics of metastatic esophageal carcinoma isolated to the pineal region: A case report and review of the literature.

Metastasis to the pineal region is a rare event, and esophageal adenocarcinoma metastatic to the pineal region is exceptionally rare, with only two cases reported in the current literature. Here, we characterize a third case of metastatic esophageal adenocarcinoma to the pineal region, and compare clinicopathological characteristics among all three cases. The three patients were men, with ages at neurological presentation ranging from 48 to 65years. Time from initial esophageal adenocarcinoma diagnosis to development of neurologic symptoms ranged from 12 to 23months. Neuroimaging in all cases showed an isolated enhancing pineal region mass with sizes ranging from 1.8 to 2.2cm. All cases were believed to have local control of esophageal disease prior to metastatic sequela, with initial treatment including esophageal resection with or without chemoradiation therapy. No cases had evidence of primary site disease progression at time of metastatic presentation, nor were there signs of other sites of metastasis. All patients underwent tumor excision and were referred for subsequent radiotherapy. Overall, all three cases demonstrate similar demographics, histology, and clinical presentations. In the appropriate clinical setting it is important to keep esophageal metastasis in the differential diagnosis, particularly in the setting of isolated pineal lesions.

Shunt timing in low-weight infants in the treatment of hydrocephalus.

OBJECTIVE: The optimal timing of ventricular shunt placement in low-weight and preterm infants remains an unresolved topic in modern pediatric neurosurgery. Shunt placement for hydrocephalus is performed over a wide range of infant weights, and the standard weight threshold for shunt placement can vary substantially across institutions. The aim of this study was to investigate shunt outcome in infants of low body weight. METHODS: An IRB-approved retrospective analysis of 76 infants (29 females, 47 males) who received primary shunt placement between 2003 and 2018 was performed. Uniform criteria were used over the entire dataset to determine the safety for ventriculoperitoneal (VP) shunt placement: 1) weight near or above 1500 g, 2) feeding tolerance, and 3) lack of necrotizing enterocolitis or active systemic infection. Infants were classified into a low-weight (LW) (< 2000 g) or standard weight (SW) (2000-3000 g) group based on their body weight at the time of initial shunt placement. Shunt survival was compared between the groups. The threshold weight separating the LW and SW groups and outcomes was additionally varied and systematically reanalyzed. RESULTS: Shunts were placed in 24 LW infants and 52 SW infants over the inclusion period. Etiologies for hydrocephalus were similar across groups: predominantly intraventricular hemorrhage (54%) (p = 0.13) and open neural tube defect (29%) (p = 0.61). Both LW and SW groups had 58% 1-year shunt survival rates. Overall, 46% of shunts failed in the LW group compared with 54% in the SW group over a median follow-up of 47 months (range 0-170 months). A log-rank test comparing shunt survival rates did not show significance (p = 0.43). Groups were repartitioned using a range of threshold weights (1600-2400 g) to divide LW from SW infants. The lack of association between VP shunt placement in LW infants and time frame of revision was consistently observed over the full range of varied threshold weights. CONCLUSIONS: There was no significant difference in overall time to shunt revision between infants weighing < 2000 g and infants weighing 2000-3000 g. No correlation between weight and shunt survival was detected. Combined with other clinical features pertinent to the management of hydrocephalus in the neonatal population, this investigation provides insight toward clinical decision-making regarding infants of low birth weight and suggests that further multi-institutional study on this topic is warranted.

Minipterional craniotomy for resection of epileptogenic cavernous malformation.

Epilepsy is a common symptom of pediatric cavernous malformations. In medically refractory patients, surgery can achieve high seizure freedom rates with low morbidity. This video depicts the use of a minipterional craniotomy and transsulcal resection of a frontal opercular cavernous malformation in a 13-year-old female with medically intractable epilepsy. At 1-year follow-up, she was evaluated as Engel class I with a significant improvement in her quality of life. Principles of cavernous malformation resection for the treatment of epilepsy are also reviewed. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2441.

Quantitative noninvasive measurement of cerebrospinal fluid flow in shunted hydrocephalus.

OBJECTIVE: Standard MRI protocols lack a quantitative sequence that can be used to evaluate shunt-treated patients with a history of hydrocephalus. The objective of this study was to investigate the use of phase-contrast MRI (PC-MRI), a quantitative MR sequence, to measure CSF flow through the shunt and demonstrate PC-MRI as a useful adjunct in the clinical monitoring of shunt-treated patients. METHODS: The rapid (96 seconds) PC-MRI sequence was calibrated using a flow phantom with known flow rates ranging from 0 to 24 mL/hr. Following phantom calibration, 21 patients were scanned with the PC-MRI sequence. Multiple, successive proximal and distal measurements were gathered in 5 patients to test for measurement error in different portions of the shunt system and to determine intrapatient CSF flow variability. The study also includes the first in vivo validations of PC-MRI for CSF shunt flow by comparing phase-contrast-measured flow rate with CSF accumulation in a collection burette obtained in patients with externalized distal shunts. RESULTS: The PC-MRI sequence successfully measured CSF flow rates ranging from 6 to 54 mL/hr in 21 consecutive pediatric patients. Comparison of PC-MRI flow measurement and CSF volume collected in a bedside burette showed good agreement in a patient with an externalized distal shunt. Notably, the distal portion of the shunt demonstrated lower measurement error when compared with PC-MRI measurements acquired in the proximal catheter. CONCLUSIONS: The PC-MRI sequence provided accurate and reliable clinical measurements of CSF flow in shunt-treated patients. This work provides the necessary framework to include PC-MRI as an immediate addition to the clinical setting in the noninvasive evaluation of shunt function and in future clinical investigations of CSF physiology.

Surgical management of pediatric spinal aneurysmal bone cysts: patient series.

BACKGROUND: Aneurysmal bone cysts (ABCs) are rare, highly vascular osteolytic bone lesions that predominantly affect pediatric populations. This report evaluates the clinicopathological data of pediatric patients with spinal ABCs. The medical records for all patients at Children's Hospital Los Angeles with biopsy-proven ABCs of the spine between 1998 and 2018 were evaluated. OBSERVATIONS: Seventeen patients, 6 males and 11 females, were identified. The mean age at surgery was 10.4 years (range, 3.5-20 years). The most common presenting complaint was pain at the lesion site 16/17 (94%), followed by lower-extremity weakness 8/17 (47%). Resection and intralesional curettage were performed in all patients. Three (18%) of 17 patients underwent selective arterial embolization prior to resection. Spinal stability was compromised in 15 of 17 patients (88%), requiring instrumented fusion. Five (29%) of the 17 patients received additional therapy including radiation, calcitonin-methylprednisolone, or phenol. Four (23.5%) of 17 patients experienced a recurrence, and the mean time to recurrence was 15 months. The postoperative follow-up ranged from 6 to 108 months (median, 28 months). Reoperation occurred after an average of 35 months. At the recent follow-up, patients were free of disease. LESSONS: Gross-total resection by intralesional curettage with case-dependent instrumented spinal fusion for instability remains an effective strategy for managing pediatric spinal ABCs. Long-term follow-up is necessary to detect tumor recurrence.

Development of an ultrafast brain MR neuronavigation protocol for ventricular shunt placement.

OBJECTIVE: Advancements in MRI technology have provided improved ways to acquire imaging data and to more seamlessly incorporate MRI into modern pediatric surgical practice. One such situation is image-guided navigation for pediatric neurosurgical procedures, including intracranial catheter placement. Image-guided surgery (IGS) requires acquisition of CT or MR images, but the former carries the risk of ionizing radiation and the latter is associated with long scan times and often requires pediatric patients to be sedated. The objective of this project was to circumvent the use of CT and standard-sequence MRI in ventricular neuronavigation by investigating the use of fast MR sequences on the basis of 3 criteria: scan duration comparable to that of CT acquisition, visualization of ventricular morphology, and image registration with surface renderings comparable to standard of care. The aim of this work was to report image development, implementation, and results of registration accuracy testing in healthy subjects. METHODS: The authors formulated 11 candidate MR sequences on the basis of the standard IGS protocol, and various scan parameters were modified, such as k-space readout direction, partial k-space acquisition, sparse sampling of k-space (i.e., compressed sensing), in-plane spatial resolution, and slice thickness. To evaluate registration accuracy, the authors calculated target registration error (TRE). A candidate sequence was selected for further evaluation in 10 healthy subjects. RESULTS: The authors identified a candidate imaging protocol, termed presurgical imaging with compressed sensing for time optimization (PICO). Acquisition of the PICO protocol takes 25 seconds. The authors demonstrated noninferior TRE for PICO (3.00 ± 0.19 mm) in comparison with the default MRI neuronavigation protocol (3.35 ± 0.20 mm, p = 0.20). CONCLUSIONS: The developed and tested sequence of this work allowed accurate intraoperative image registration and provided sufficient parenchymal contrast for visualization of ventricular anatomy. Further investigations will evaluate use of the PICO protocol as a substitute for CT and conventional MRI protocols in ventricular neuronavigation.

Machine Learning Analysis of Physical Activity Data to Classify Postural Dysfunction.

BACKGROUND: Machine learning (ML) analysis of biometric data in non-controlled environments is underexplored. OBJECTIVE: To evaluate whether ML analysis of physical activity data can be employed to classify whether individuals have postural dysfunction in middle-aged and older individuals. METHODS: A 1 week period of physical activity was measured by a waist-worn uni-axial accelerometer during the 2003-2004 National Health and Nutrition Examination Survey sampling period. Features of physical activity along with basic demographic information (42 variables) were paired with ML models to predict the success or failure of a standard 30 s modified Romberg test during which participants had their eyes closed and stood upon a 3-inch compliant surface. Model performance was evaluated by area under the receiver operating characteristic curve (AUC-ROC), balanced accuracy, and F1-score. RESULTS: The cohort was comprised of 1625 participants ≥40 years (median age 61, IQR 51-71). Approximately half (47%) were diagnosed with postural dysfunction having failed the binarized (pass/fail) scoring mechanism of the modified Romberg exam. Five ML models were trained on the classification task, achieving AUC values ranging from 0.67 to 0.73. The support vector machine (SVM) and a gradient-boosted model, XGBoost, achieved the highest AUC of 0.73 (SD 0.71-0.75). Age was the most important variable for SVM classification, followed by four features that evaluated accelerometer counts at various thresholds, including those delineating total, moderate, and moderate-vigorous activity. CONCLUSIONS: ML analysis of accelerometer-derived physical activity data to classify postural dysfunction in middle-aged and older individuals is feasible in real-world environments such as the home. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3529-3533, 2023.

Supracerebellar infratentorial resection of a torcular lesion causing fulminant intracranial hypertension: illustrative case.

BACKGROUND: Venous sinus stenosis has been implicated in intracranial hypertension and can lead to papilledema and blindness. The authors report the unique case of a cerebellar transtentorial lesion resulting in venous sinus stenosis in the torcula and bilateral transverse sinuses that underwent resection. OBSERVATIONS: A 5-year-old male presented with subacute vision loss and bilateral papilledema. Imaging demonstrated a lesion causing mass effect on the torcula/transverse sinuses and findings of increased intracranial pressure (ICP). A lumbar puncture confirmed elevated pressure, and the patient underwent bilateral optic nerve sheath fenestration. Cerebral angiography and venous manometry showed elevated venous sinus pressures suggestive of venous hypertension. The patient underwent a craniotomy and supracerebellar/infratentorial approach. A stalk emanating from the cerebellum through the tentorium was identified and divided. Postoperative magnetic resonance imaging showed decreased lesion size and improved sinus patency. Papilledema resolved and other findings of elevated ICP improved. Pathology was consistent with atrophic cerebellar cortex. Serial imaging over 6 months demonstrated progressive decrease in the lesion with concurrent improvements in sinus patency. LESSONS: Although uncommon, symptoms of intracranial hypertension in patients with venous sinus lesions should prompt additional workup ranging from dedicated venous imaging to assessments of ICP and venous manometry.

Low-pass whole-genome and targeted sequencing of cell-free DNA from cerebrospinal fluid in pediatric patients with central nervous system tumors.

Background: Central nervous system tumors are the most common pediatric solid tumors and the most frequent cause of cancer-related morbidity in childhood. Significant advances in understanding the molecular features of these tumors have facilitated the development of liquid biopsy assays that may aid in diagnosis and monitoring response to therapy. In this report, we describe our comprehensive liquid biopsy platform for detection of genome-wide copy number aberrations, sequence variants, and gene fusions using cerebrospinal fluid (CSF) from pediatric patients with brain, spinal cord, and peripheral nervous system tumors. Methods: Cell-free DNA was isolated from the CSF from 55 patients, including 47 patients with tumors and 8 controls. Results: Abnormalities in cell-free DNA were detected in 24 (51%) patients including 11 with copy number alterations, 9 with sequence variants, and 7 with KIAA1549::BRAF fusions. Positive findings were obtained in patients spanning histologic subtypes, tumor grades, and anatomic locations. Conclusions: This study demonstrates the feasibility of employing this platform in routine clinical care in upfront diagnostic and monitoring settings. Future studies are required to determine the utility of this approach for assessing response to therapy and long-term surveillance.

Electrospun nanofibers for 3-D cancer models, diagnostics, and therapy.

As one of the leading causes of global mortality, cancer has prompted extensive research and development to advance efficacious drug discovery, sustained drug delivery and improved sensitivity in diagnosis. Towards these applications, nanofibers synthesized by electrospinning have exhibited great clinical potential as a biomimetic tumor microenvironment model for drug screening, a controllable platform for localized, prolonged drug release for cancer therapy, and a highly sensitive cancer diagnostic tool for capture and isolation of circulating tumor cells in the bloodstream and for detection of cancer-associated biomarkers. This review provides an overview of applied nanofiber design with focus on versatile electrospinning fabrication techniques. The influence of topographical, physical, and biochemical properties on the function of nanofiber assemblies is discussed, as well as current and foreseeable barriers to the clinical translation of applied nanofibers in the field of oncology.

Adolescent subdural empyema in setting of COVID-19 infection: illustrative case.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an ongoing viral pandemic that has affected modern medical practice and can complicate known pathology. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes symptoms that may mimic a viral pneumonia, with potential for serious sequelae, including acute respiratory distress syndrome, coagulopathy, multiorgan dysfunction, systemic vascular abnormalities, and secondary infection. OBSERVATIONS: The authors describe a case of a 15-year-old boy who presented with a right subdural empyema and sinusitis while having active COVID-19 infection. The patient initially presented with left-sided weakness, frontal sinusitis, and subdural empyema. Emergent surgery was performed for evacuation of empyema and sinus debridement. Samples of purulent material within the subdural space were tested for SARS-CoV-2 by reverse transcriptase polymerase chain reaction. The patient had a successful recovery and regained the use of his right side after combined treatment. To our knowledge, this is the first reported case of a bacterial subdural empyema associated with frontal sinusitis in a coinfected patient with COVID-19 without evidence of COVID-19 intracranial infection. LESSONS: A subdural empyema, which is a surgical emergency, was likely a superinfection caused by COVID-19. This, along with the coagulopathy caused by the virus, introduced unique challenges to the treatment of a known pathology.

Postoperative facial palsy after pediatric posterior fossa tumor resection.

OBJECTIVE: Facial palsy can be caused by masses within the posterior fossa and is a known risk of surgery for tumor resection. Although well documented in the adult literature, postoperative facial weakness after posterior fossa tumor resection in pediatric patients has not been well studied. The objective of this work was to determine the incidence of postoperative facial palsy after tumor surgery, and to investigate clinical and radiographic risk factors. METHODS: A retrospective analysis was conducted at a single large pediatric hospital. Clinical, radiographic, and histological data were examined in children who were surgically treated for posterior fossa tumors between May 1, 1994, and June 1, 2011. The incidence of postoperative facial weakness was documented. A multivariate logistic regression model was used to analyze the predictive ability of clinicoradiological variables for facial weakness. RESULTS: A total of 163 patients were included in this study. The average age at surgery was 7.4 ± 4.7 years, and tumor pathologies included astrocytoma (44%), medulloblastoma (36%), and ependymoma (20%). The lesions of 27 patients (17%) were considered high grade in nature. Thirteen patients (8%) exhibited preoperative symptoms of facial palsy. The overall incidence of postoperative facial palsy was 26% (43 patients), and the incidence of new postoperative facial palsy in patients without preoperative facial weakness was 20% (30 patients). The presence of a preoperative facial palsy had a large and significant effect in univariate analysis (OR 11.82, 95% CI 3.07-45.44, p < 0.01). Multivariate logistic regression identified recurrent operation (OR 4.45, 95% CI 1.49-13.30, p = 0.01) and other preoperative cranial nerve palsy (CNP; OR 3.01, 95% CI 1.24-7.29, p = 0.02) as significant risk factors for postoperative facial weakness. CONCLUSIONS: Facial palsy is a risk during surgical resection of posterior fossa brain tumors in the pediatric population. The study results suggest that the incidence of new postoperative facial palsy can be as high as 20%. The presence of preoperative facial palsy, an operation for recurrent tumor, and the presence of other preoperative CNPs were found to be significant risk factors for postoperative facial weakness.

Resolution of neonatal posthemorrhagic ventricular dilation coincident with patent ductus arteriosus ligation: case report.

Preterm infants commonly present with a hemodynamically significant patent ductus arteriosus (hsPDA). The authors describe the case of a preterm infant with posthemorrhagic ventricular dilation, which resolved in a temporally coincident fashion to repair of hsPDA. The presence of a PDA with left-to-right shunting was confirmed at birth on echocardiogram and was unresponsive to repeated medical intervention. Initial cranial ultrasound revealed periventricular-intraventricular hemorrhage. Follow-up serial ultrasound showed resolving intraventricular hemorrhage and progressive bilateral hydrocephalus. At 5 weeks, the ductus was ligated with the goal of improving hemodynamic stability prior to CSF diversion. However, neurosurgical intervention was not required due to improvement of ventriculomegaly occurring immediately after PDA ligation. No further ventricular dilation was observed at the 6-month follow-up.Systemic venous flow disruption and abnormal patterns of cerebral blood circulation have been previously associated with hsPDA. Systemic hemodynamic change has been reported to follow hsPDA ligation, although association with ventricular normalization has not. This case suggests that the unstable hemodynamic environment due to left-to-right shunting may also impede CSF outflow and contribute to ventriculomegaly. The authors review the literature surrounding pressure transmission between a PDA and the cerebral vessels and present a mechanism by which PDA may contribute to posthemorrhagic ventricular dilation.

Sternocleidomastoid Encephalomyosynangiosis for Treatment-Resistant Moyamoya Disease.

BACKGROUND AND IMPORTANCE: Refractory ischemic symptoms in moyamoya disease are a challenging problem, particularly in situations in which multiple direct and indirect revascularization techniques have already been employed. In addition, revascularization of the parietal lobes is difficult, as this area is a watershed between the middle cerebral artery and posterior cerebral artery distributions. CLINICAL PRESENTATION: This is the case of a 50-yr-old woman with hemibody sensorimotor deficits, who had previously undergone bilateral arterial bypass and temporalis myosynangiosis. A method for indirect surgical cerebral revascularization is described, utilizing a rotated and tunneled sternocleidomastoid flap. The perfused muscle is approximated to the cortical surface, with adjacent sulci dissected to expose the underlying vasculature. After sternocleidomastoid encephalomyosynangiosis, the patient experienced symptomatic improvement, along with the appearance of new pial collateral vasculature on diagnostic cerebral angiography. Pre- and postoperative dynamic perfusion computed tomography with acetazolamide challenge demonstrate an increase in cerebral blood flow and decrease in mean transit time, as well as improved cerebrovascular reserve. CONCLUSION: Sternocleidomastoid encephalomyosynangiosis using a tunneled muscle flap is a useful method for revascularization of the parietal and occipital lobes, particularly for refractory moyamoya in cases where a variety of other options have been exhausted.

Time-Resolved MRI Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model.

Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. High-resolution T2-weighted, T2*-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTX-mediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. SIGNIFICANCE: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.

Cerebral perfusion response to hyperoxia.

Graded levels of supplemental inspired oxygen were investigated for their viability as a noninvasive method of obtaining intravascular magnetic resonance image contrast. Administered hyperoxia has been shown to be effective as a blood oxygenation level-dependent contrast agent for magnetic resonance imaging (MRI); however, it is known that high levels of inspired fraction of oxygen result in regionally decreased perfusion in the brain potentially confounding the possibility of using hyperoxia as a means of measuring blood flow and volume. Although the effects of hypoxia on blood flow have been extensively studied, the hyperoxic regime between normoxia and 100% inspired oxygen has been only intermittently studied. Subjects were studied at four levels of hyperoxia induced during a single session while perfusion was measured using arterial spin labelling MRI. Reductions in regional perfusion of grey matter were found to occur even at moderate levels of hyperoxia; however, perfusion changes at all oxygen levels were relatively mild (less than 10%) supporting the viability of hyperoxia-induced contrast.

Dynamic forcing of end-tidal carbon dioxide and oxygen applied to functional magnetic resonance imaging.

Investigations into the blood oxygenation level-dependent (BOLD) functional MRI signal have used respiratory challenges with the aim of probing cerebrovascular physiology. Such challenges have altered the inspired partial pressures of either carbon dioxide or oxygen, typically to a fixed and constant level (fixed inspired challenge (FIC)). The resulting end-tidal gas partial pressures then depend on the subject's metabolism and ventilatory responses. In contrast, dynamic end-tidal forcing (DEF) rapidly and independently sets end-tidal oxygen and carbon dioxide to desired levels by altering the inspired gas partial pressures on a breath-by-breath basis using computer-controlled feedback. This study implements DEF in the MRI environment to map BOLD signal reactivity to CO(2). We performed BOLD (T2(*)) contrast FMRI in four healthy male volunteers, while using DEF to provide a cyclic normocapnic-hypercapnic challenge, with each cycle lasting 4 mins (PET(CO(2)) mean+/-s.d., from 40.9+/-1.8 to 46.4+/-1.6 mm Hg). This was compared with a traditional fixed-inspired (FI(CO(2))=5%) hypercapnic challenge (PET(CO(2)) mean+/-s.d., from 38.2+/-2.1 to 45.6+/-1.4 mm Hg). Dynamic end-tidal forcing achieved the desired target PET(CO(2)) for each subject while maintaining PET(O(2)) constant. As a result of CO(2)-induced increases in ventilation, the FIC showed a greater cyclic fluctuation in PET(O(2)). These were associated with spatially widespread fluctuations in BOLD signal that were eliminated largely by the control of PET(O(2)) during DEF. The DEF system can provide flexible, convenient, and physiologically well-controlled respiratory challenges in the MRI environment for mapping dynamic responses of the cerebrovasculature.