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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.

Supplementary Figure S1 provides a representative TEM image of NPCP-CTX and corresponding histogram presenting the core diameter distribution.

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.

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.

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, O(6)-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.

Despite the preponderance of iron oxide nanoparticles (NPs) designed for theranostic applications, widespread clinical translation of these NPs lags behind. A better understanding of how NP pharmacokinetics vary between small and large animal models is needed to rapidly customize NPs for optimal performance in humans. Here we use noninvasive magnetic resonance imaging (MRI) to track iron oxide NPs through a large number of organ systems in vivo to investigate NP biokinetics in both mice and nonhuman primates. We demonstrate that pharmacokinetics are similar between mice and macaques in the blood, liver, spleen, and muscle, but differ in the kidneys, brain, and bone marrow. Our study also demonstrates that full-body MRI is practical, rapid and cost-effective for tracking NPs non-invasively with high spatiotemporal resolution. Our techniques using a nonhuman primate model may provide a platform for testing a range of NP formulations.

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.

OBJECT Urgent ventriculostomy placement can be a lifesaving procedure in the setting of hydrocephalus or elevated intracranial pressure. While external ventricular drain (EVD) insertion is common, there remains a high rate of suboptimal drain placement. Here, the authors seek to demonstrate the feasibility of an ultrasound-based guidance system that can be inserted into an existing EVD catheter to provide a linear ultrasound trace that guides the user toward the ventricle. METHODS The ultrasound stylet was constructed as a thin metal tube, with dimensions equivalent to standard catheter stylets, bearing a single-element, ceramic ultrasound transducer at the tip. Ultrasound backscatter signals from the porcine ventricle were processed by custom electronics to offer real-time information about ventricular location relative to the catheter. Data collected from the prototype device were compared with reference measurements obtained using standard clinical ultrasound imaging. RESULTS A study of porcine ventricular catheterization using the experimental device yielded a high rate of successful catheter placement after a single pass (10 of 12 trials), despite the small size of pig ventricles and the lack of prior instruction on porcine ventricular architecture. A characteristic double-peak signal was identified, which originated from ultrasound reflections off of the near and far ventricular walls. Ventricular dimensions, as obtained from the width between peaks, were in agreement with standard ultrasound reference measurements (p < 0.05). Furthermore, linear ultrasound backscatter data permitted in situ measurement of the stylet distance to the ventricular wall (p < 0.05), which assisted in catheter guidance. CONCLUSIONS The authors have demonstrated the ability of the prototype ultrasound stylet to guide ventricular access in the porcine brain. The alternative design of the device makes it potentially easy to integrate into the standard workflow for bedside EVD placement. The availability of a fast, easy-to-use, inexpensive guidance system can play a role in reducing the complication rate for EVD placement.

Hepatocellular carcinoma (HCC) is an increasingly lethal malignancy for which management is critically dependent on accurate imaging. Glypican-3 (GPC3) is a cell surface receptor overexpressed in most HCCs and provides a unique target for molecular diagnostics. The use of monoclonal antibodies (mAbs) that target GPC3 (αGPC3) in PET imaging has shown promise but comes with inherent limitations associated with mAbs such as long circulation times. This study used 89Zr-conjugated F(ab′)2 fragments directed against GPC3 (89Zr-αGPC3-F(ab′)2) to evaluate the feasibility of the fragments as a diagnostic immuno-PET imaging probe. Methods: Immobilized ficin was used to digest αGPC3, creating αGPC3-F(ab′)2 fragments subsequently conjugated to 89Zr. In vivo biodistribution and PET studies were performed on GPC3-expressing HepG2 and GPC3-nonexpressing RH7777 orthotopic xenografts. Results: Reliable αGPC3-F(ab′)2 production via immobilized ficin digestion was verified by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. 89Zr-αGPC3-F(ab′)2 demonstrated F(ab′)2-dependent, antigen-specific cell binding. HepG2 tumor uptake was higher than any other tissue, peaking at 100 ± 21 percentage injected dose per gram (%ID/g) 24 h after injection, a value 33- to 38-fold higher than GPC3-nonexpressing RH7777 tumors. The blood half-life of the 89Zr-αGPC3-F(ab′)2 conjugate was approximately 11 h, compared with approximately 115 h for historic mAb controls. This shorter half-life enabled clear tumor visualization on PET 4 h after administration, with a resultant peak tumor-to-liver contrast ratio of 23.3. Blocking antigen-expressing tumors with an excess of nonradiolabeled αGPC3 resulted in decreased tumor uptake similar to native liver. The kidneys exhibited high tissue uptake, peaking at 24 h with 83 ± 12 %ID/g. HepG2 tumors ranging from 1.5 to 7 mm were clearly visible on PET, whereas larger RH7777 tumors displayed signal lower than background liver tissue. Conclusion: This study demonstrates the feasibility of using 89Zr-αGPC3-F(ab′)2 for intrahepatic tumor localization with small-animal PET. Faster blood clearance and lower background liver uptake enable excellent signal-to-noise ratios at early time points. Increased renal uptake is similar to that as has been seen with clinical radioactive peptide imaging. 89Zr-αGPC3-F(ab′)2 addresses some of the shortcomings of whole-antibody immuno-PET probes. Further optimization is warranted to maximize probe sensitivity and specificity in the process of clinical translation.

Resistance to temozolomide (TMZ) based chemotherapy in glioblastoma multiforme (GBM) has been attributed to the upregulation of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). Inhibition of MGMT using O(6)-benzylguanine (BG) has shown promise in these patients, but its clinical use is hindered by poor pharmacokinetics that leads to unacceptable toxicity. To improve BG biodistribution and efficacy, we developed superparamagnetic iron oxide nanoparticles (NP) for targeted convection-enhanced delivery (CED) of BG to GBM. The nanoparticles (NPCP-BG-CTX) consist of a magnetic core coated with a redox-responsive, cross-linked, biocompatible chitosan-PEG copolymer surface coating (NPCP). NPCP was modified through covalent attachment of BG and tumor targeting peptide chlorotoxin (CTX). Controlled, localized BG release was achieved under reductive intracellular conditions and NPCP-BG-CTX demonstrated proper trafficking of BG in human GBM cells in vitro. NPCP-BG-CTX treated cells showed a significant reduction in MGMT activity and the potentiation of TMZ toxicity. In vivo, CED of NPCP-BG-CTX produced an excellent volume of distribution (Vd) within the brain of mice bearing orthotopic human primary GBM xenografts. Significantly, concurrent treatment with NPCP-BG-CTX and TMZ showed a 3-fold increase in median overall survival in comparison to NPCP-CTX/TMZ treated and untreated animals. Furthermore, NPCP-BG-CTX mitigated the myelosuppression observed with free BG in wild-type mice when administered concurrently with TMZ. The combination of favorable physicochemical properties, tumor cell specific BG delivery, controlled BG release, and improved in vivo efficacy demonstrates the great potential of these NPs as a treatment option that could lead to improved clinical outcomes.

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 CO2. We performed BOLD (T2*) contrast FMRI in four healthy male volunteers, while using DEF to provide a cyclic normocapnichypercapnic challenge, with each cycle lasting 4 mins (PetCO2 mean±s.d., from 40.9 ± 1.8 to 46.4 ± 1.6 mm Hg). This was compared with a traditional fixed-inspired (FiCO2 = 5%) hypercapnic challenge (PetCO2 mean±s.d., from 38.2 ± 2.1 to 45.6 ± 1.4 mm Hg). Dynamic end-tidal forcing achieved the desired target PetCO2 for each subject while maintaining PetCO2 constant. As a result of CO2-induced increases in ventilation, the FIC showed a greater cyclic fluctuation in PetCO2. These were associated with spatially widespread fluctuations in BOLD signal that were eliminated largely by the control of PetCO2 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.

Combined blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL) functional MRI (fMRI) was performed for simultaneous investigation of neurovascular coupling in the primary visual cortex (PVC), primary motor cortex (PMC), and supplementary motor area (SMA). The hypercapnia-calibrated method was employed to estimate the fractional change in cerebral metabolic rate of oxygen consumption (CMR(O2)) using both a group-average and a per-subject calibration. The group-averaged calibration showed significantly different CMR(O2)-CBF coupling ratios in the three regions (PVC: 0.34 +/- 0.03; PMC: 0.24 +/- 0.03; and SMA: 0.40 +/- 0.02). Part of this difference emerges from the calculated values of the hypercapnic calibration constant M in each region (M(PVC) = 6.6 +/- 3.4, M(PMC) = 4.3 +/- 3.5, and M(SMA) = 7.2 +/- 4.1), while a relatively minor part comes from the spread and shape of the sensorimotor BOLD-CBF responses. The averages of the per-subject calibrated CMR(O2)-CBF slopes were 0.40 +/- 0.04 (PVC), 0.31 +/- 0.03 (PMC), and 0.44 +/- 0.03 (SMA). These results are 10-30% higher than group-calibrated values, and are potentially more useful for quantifying individual differences in focal functional responses. The group-average calibrated motor coupling value is increased to 0.28 +/- 0.03 when stimulus-correlated increases in end-tidal CO(2) are included. Our results support the existence of regional differences in neurovascular coupling, and argue for the importance of achieving optimal accuracy in hypercapnia calibrations to resolve method-dependent variations in published results.

This case-control study assesses the use of fetal magnetic resonance imaging and machine learning to predict the need for postnatal cerebrospinal fluid diversion in patients with fetal ventriculomegaly.

Changes in cerebral blood flow (f) and vascular volume (v) are of major interest in mapping cerebral activity and metabolism, but the relation between them currently lacks a sufficient theoretical basis. To address this we considered three models: a uniform reactive tube model (M1); an extension of M1 that includes passive arterial inflow and venous volume (M2); and a more anatomically plausible model (M3) consisting of 19 compartments representing the whole range of vascular sizes and respective CO2 reactivities, derived from literature data. We find that M2 cannot be described as the simple scaling of a tube law, but any divergence from a linear approximation is negligible within the narrow physiological range encountered experimentally. In order to represent correctly the empirically observed slope of the overall v-f relationship, the reactive bed should constitute about half of the total vascular volume, thus including a significant fraction of capillaries and/or veins. Model M3 demonstrates systematic variation of the slope of the v-f relationship between 0.16 and 1.0, depending on the vascular compartment under consideration. This is further complicated when other experimental approaches such as flow velocity are used as substitute measurements. The effect is particularly large in microvascular compartments, but when averaged with larger vessels the variations in slope are contained within 0.25 to 0.55 under conditions typical for imaging methods. We conclude that the v-f relationship is not a fixed function but that both the shape and slope depend on the composition of the reactive volume and the experimental methods used.

Purpose To develop a new method of measuring quantitative regional cerebral blood volume (CBV) using epochs of hyperoxia as an intravenous contrast agent with T2*-weighted MRI. Materials and Methods Images were acquired from six subjects (four male, two female, mean age 29 ± 3.7 years) using a sequence combining pulsed arterial spin labeling interleaved with a gradient echo echo-planar imaging (EPI) blood oxygenation level-dependent (BOLD) sequence at 3T. The hyperoxia paradigm lasted 28 minutes consisting of 4 minutes of normoxia, two 6-minute blocks of hyperoxia separated by 6 minutes of normoxia. During the hyperoxic blocks the subjects were delivered a fractional oxygen concentration of 0.5. Results The mean CBV was calculated to be 3.77 ± 1.05 mL/100 g globally, 3.93 ± 0.90 mL/100 g in gray matter (GM), and 2.52 ± 0.78 mL/100 g in white matter (WM). The mean GM/WM ratio was thus found to be 1.56. These values are comparable to those obtained in other studies. Conclusion The hyperoxia technique for measuring CBV may be particularly useful for patient groups where an injected bolus of contrast agent is contraindicated. As more functional studies are employing epochs of inspired gases for calibration purposes, this method is easily incorporated into existing paradigms to produce a noninvasive, repeatable, easily tolerated, and quantitative measurement of regional CBV. J. Magn. Reson. Imaging 2007;26:894–899. © 2007 Wiley-Liss, Inc.

The study of brain function using MRI relies on acquisition techniques that are sensitive to different aspects of the hemodynamic response contiguous to areas of neuronal activity. For this purpose different contrasts such as arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional MRI techniques have been developed to investigate cerebral blood flow (CBF) and blood oxygenation, respectively. Analysis of such data typically proceeds by separate, linear modeling of the appropriate CBF or BOLD time courses. In this work an approach is developed that provides simultaneous inference on hemodynamic changes via a nonlinear physiological model of ASL data acquired at multiple echo times. Importantly, this includes a significant contribution by changes in the static magnetization, M, to the ASL signal. Inference is carried out in a Bayesian framework. This is able to extract, from dual-echo ASL data, probabilistic estimates of percentage changes of CBF, Rmath image, and the static magnetization, M. This approach provides increased sensitivity in inferring CBF changes and reduced contamination in inferring BOLD changes when compared with general linear model approaches on single-echo ASL data. We also consider how the static magnetization, M, might be related to changes in CBV by assuming the same mechanism for water exchange as in vascular space occupancy.

Repeated bilayers of a polycation and a polyanion were assembled by adsorption from their aqueous solutions. The polycations used were PEI (poly(ethylenimine)), PAH (poly(allylamine hydrochloride)), and generation 3.0 dendrimer (poly(propylenimine)). The polyanion was PAZO (poly[1-[4-(3-carboxy-4-hydroxyphenylazo)benzenesulfonamido]-1,2-ethanediyl, sodium salt]). Second harmonic generation (SHG) and UV−vis spectroscopy were used to study the structure and formation of the superlattices. The linear increase in absorbance versus the number of bilayers suggested that a uniform and consistent amount of polymer adsorbed during each deposition cycle. The observation of a second harmonic (SH) signal from the film showed that the conjugated chromophores in the PAZO polymer were aligned with a net dipole. However, the SHG signal did not continue to increase as the number of bilayers was increased. On the basis of thorough studies of the UV and SH properties for each bilayer for 10 total bilayers, we propose that t...

The estimation of changes in CMR(O2) using functional MRI involves an essential calibration step using a vasoactive agent to induce an isometabolic change in CBF. This calibration procedure is performed most commonly using hypercapnia as the isometabolic stimulus. However, hypercapnia possesses a number of detrimental side effects. Here, a new method is presented using hyperoxia to perform the same calibration step. This procedure requires independent measurement of Pa(O2), the BOLD signal, and CBF. We demonstrate that this method yields results that are comparable to those derived using other methods. Further, the hyperoxia technique is able to provide an estimate of the calibration constant that has lower overall intersubject and intersession variability compared to the hypercapnia approach.

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.

The change in cerebral rate of oxidative metabolism (CMR(O(2))) during neural activation may be estimated from blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and arterial spin-labeling (ASL) fMRI measurements. The established method relies on an epoch of iso-metabolic blood flow increase, typically induced by CO2 breathing, to calibrate the BOLD-CBF relationship at resting-state CMR(O2). Here, we discuss the systematic bias in CMR(O2)-CBF data that can be introduced depending on the value derived for the calibration constant (M) from the CO2 breathing epoch. We demonstrate that the fidelity of BOLD-CBF data acquired during the neural activation task have low impact on the tightness of CMR(O2)-CBF coupling, as well as the coupling slope, when the derived calibration value is of a relatively moderate amplitude (M in the range of, or greater than, 10-15 at 1.5 T). Via the standard reformulation of a grid in BOLD-CBF space into the CMR(O2)-CBF plane, we demonstrate the non-linear transformation that takes place and the sources of systematic bias that result. We find that the outcome of a neurovascular coupling study may be predicted to a large extent purely from the value of the calibration constant, M, that is used. Our results suggest that the accurate determination of M is of greater importance than thought previously and indicate that BOLD-CBF data must always be supplied when considering CMR(O2)-CBF behavior in a particular brain region.

Designer nanoscaled materials have the potential to revolutionize diagnosis and treatment for glioma. This review summarizes current progress in nanoparticle-based therapies for glioma treatment including targeting, drug delivery, gene delivery, and direct tumor ablation. Preclinical and current human clinical trials are discussed. Although progress in the field has been significant over the past decade, many successful strategies demonstrated in the laboratory have yet to be implemented in human clinical trials. Looking forward, we provide examples of combined treatment strategies, which harness the potential for nanoparticles to interact with their biochemical environment, and simultaneously with externally applied photons or magnetic fields. We present our notion of the “ideal” nanoparticle for glioma, a concept that may soon be realized.