Melatonin in ventricular and subarachnoid cerebrospinal fluid: Its function in the neural glymphatic network and biological significance for neurocognitive health.

The central nervous system (CNS) is endowed with a specialized cerebrospinal fluid (CSF)/lymph network which removes toxic molecules and metabolic by-products from the neural parenchyma; collectively, this has been named the glymphatic system. It allows CSF located in the subarachnoid space which surrounds the CNS to enter the depths of the brain and spinal cord by means of Virchow-Robin perivascular and perivenous spaces. CSF in the periarterial spaces is transferred across the astrocytic end feet which line these spaces aided by AQ4 channels; in the interstitium, the fluid moves via convection through the parenchyma to be eventually discharged into the perivenous spaces. As it passes through the neural tissue, the interstitial fluid flushes metabolic by-products and extracellular toxins and debris into the CSF of the perivenous spaces. The fluid then moves to the surface of the CNS where the contaminants are absorbed into true lymphatic vessels in the dura mater from where it is shunted out of the cranial vault to the cervical lymph nodes. Pineal melatonin released directly into the CSF causes the concentration of this molecule to be much higher in the CSF of the third ventricle than in the blood. After the ventricular melatonin enters the subarachnoid and Virchow-Robin spaces it is taken into the neural tissue where it functions as a potent antioxidant and anti-inflammatory agent. Experimental evidence indicates that it removes pathogenic toxins, e.g., amyloid-ß and others, from the brain to protect against neurocognitive decline. Melatonin levels drop markedly during aging, coincident with the development of several neurodegenerative diseases and the accumulation of the associated neurotoxins.

Rapid Gastric emptying in spontaneously hypertensive rats.

OBJECTIVE: To assess the rate of gastric emptying in spontaneously hypertensive rats (SHR) and to evaluate rapid gastric emptying as a possible predisposing factor for hypertension. Rapid gastric emptying of carbohydrates, known to elevate postprandial serum glucose, has been reported to occur in many insulin-resistant states, including hypertension. SHR exhibit insulin resistance similar to human hypertensive patients. No prior studies have assessed gastric emptying of an oral glucose solution in SHR as compared with control Wistar Kyoto rats (WKY). METHODS: Using scintigraphic imaging, gastric emptying of a physiologic, orally consumed glucose solution was assessed in 12 SHR and 12 control WKY at 5 weeks of age, prior to the development of hypertension, and at 12 weeks of age after hypertension was fully established. RESULTS: At 5 weeks, the gastric half-emptying time (GHET) was 67.8 ±â€Š9.8 min for the SHR vs. 109.3 ±â€Š18 ( P  = 0.042) minutes for the WKY controls. At 12 weeks, the GHET was 37.29 ±â€Š10.3 min for the SHR vs. 138.53 ±â€Š37.6 ( P  = 0.016) min for the WKY controls. CONCLUSION: Gastric emptying was significantly more rapid in the SHR before and after the development of hypertension. Even though SHR are known to have increased sympathetic activity associated with their development of hypertension, this increased sympathetic activity does not inhibit gastric emptying. SHR are a promising animal model for investigating therapeutic agents for treating hypertension aimed at slowing the rate of gastric emptying.

Image-guided patient-specific optimization of catheter placement for convection-enhanced nanoparticle delivery in recurrent glioblastoma.

BACKGROUND: Proper catheter placement for convection-enhanced delivery (CED) is required to maximize tumor coverage and minimize exposure to healthy tissue. We developed an image-based model to patient-specifically optimize the catheter placement for rhenium-186 (186Re)-nanoliposomes (RNL) delivery to treat recurrent glioblastoma (rGBM). METHODS: The model consists of the 1) fluid fields generated via catheter infusion, 2) dynamic transport of RNL, and 3) transforming RNL concentration to the SPECT signal. Patient-specific tissue geometries were assigned from pre-delivery MRIs. Model parameters were personalized with either 1) individual-based calibration with longitudinal SPECT images, or 2) population-based assignment via leave-one-out cross-validation. The concordance correlation coefficient (CCC) was used to quantify the agreement between the predicted and measured SPECT signals. The model was then used to simulate RNL distributions from a range of catheter placements, resulting in a ratio of the cumulative RNL dose outside versus inside the tumor, the "off-target ratio" (OTR). Optimal catheter placement) was identified by minimizing OTR. RESULTS: Fifteen patients with rGBM from a Phase I/II clinical trial (NCT01906385) were recruited to the study. Our model, with either individual-calibrated or population-assigned parameters, achieved high accuracy (CCC > 0.80) for predicting RNL distributions up to 24 h after delivery. The optimal catheter placements identified using this model achieved a median (range) of 34.56 % (14.70 %-61.12 %) reduction on OTR at the 24 h post-delivery in comparison to the original placements. CONCLUSIONS: Our image-guided model achieved high accuracy for predicting patient-specific RNL distributions and indicates value for optimizing catheter placement for CED of radiolabeled liposomes.

Assessment of hepatic fatty infiltration using spectral computed tomography imaging: a pilot study.

OBJECTIVE: The objective of this study was to investigate the feasibility of using monochromatic spectral computed tomography (CT) imaging to assess fatty infiltration in liver. MATERIALS: With spectral CT imaging, phantoms with known fat concentrations were studied for scanning parameter optimization, then 52 patients enrolled into 4 groups (healthy, mild, moderate, and severe fatty infiltration) received abdominal scanning. Based on reconstructed monochromatic images, hepatic attenuation was analyzed, and dual-energy subtraction imaging (DESI) was created for quantifying fat infiltration. RESULTS: Corresponding to various hepatic fat infiltrations, 4 characteristic CT attenuation curve patterns were described. In DESI images, only fat and fatty components appeared bright. For livers without abnormal fat deposition, isolated bright pixels were visualized (% area = 0.5% ± 0.3%). With hepatic fat accumulation increasing, more bright pixels appeared in subtraction images with percentages of total liver area involved in 2.5%, 6.7%, and 13.4% of mild, moderate, and severe fat infiltration cases, respectively (P < 0.05). The corresponding CT values were as follows: 1.33, 2.53, 8.69, and 16.4 Hounsfield units (P < 0.01), which correlated with the % DESI area values (r = 0.9811). CONCLUSIONS: Spectral CT imaging is a promising method to quantitatively assess hepatic fat content and fatty infiltration with advantages compared with conventional CT imaging.

Size discrimination in rat and mouse gastric emptying.

OBJECTIVES: To investigate the relationship between particle size and gastric emptying in rodents using radiolabeled insoluble polymethyl methacrylate (PMMA) microcapsules/beads. METHODS: PMMA microcapsules (50-500 µm) and beads (0.5-3 mm) loaded with technetium-99 m diethylenetriamine pentaacetic acid ((99m) Tc-DTPA) were administered to ICR mice or Sprague Dawley (SD) rats by oral gavage. Gamma scintiscans were acquired initially following administration and then at hourly intervals to 4 hours. RESULTS: Scintiscans revealed that the smallest PMMA microcapsules (50-100 µm) or beads (0.5-1 mm) were impeded in the stomach and emptied slower than large particles in both rodent species. In mice, no significant difference in gastric emptying was found with microcapsules between 100 and 300 µm in diameter (p = 0.25) and particles more than 300 µm could not be administered. In rats, capsules containing 0.5-3 mm beads were stuck to the esophagus (up to 1 hour), this was a limitation of dosing beads of this size because they cannot be suspended in a liquid media for oral gavage purposes. Beads with diameters of 2-3 mm stayed in the stomach for up to 4 hours. CONCLUSIONS: The cut-off emptying size in ICR mice could not be determined, due to the limitation of current available dosing methods. The cut-off emptying size in SD rats was between 1.5 and 2 mm. Therefore, particles with a diameter greater than 2 mm should not be used for gastric emptying studies of intact particles in SD rats, as their emptying is retarded in the stomach.

Liposomal formulations of poorly soluble camptothecin: drug retention and biodistribution.

Camptothecin (CPT) represents a potent anticancer drug. However, its therapeutic use is impaired by both drug solubility, hydrolysis, and protein interactions in vivo. Use of liposomes as a drug-formulation approach could overcome some of these challenges. The aim of this study was to perform a mechanistic study of the incorporation and retention of the lipophilic parent CPT compound in different liposome formulations using radiolabeled CPT and thus to be able to identify promising CPT delivery systems. In this context, we also wanted to establish an appropriate mouse tumor model, in vivo scintigraphic imaging, and biodistribution methodology for testing the most promising formulation. CPT retention in various liposome formulations after incubation in buffer and serum was determined. The HT-29 mouse tumor model, (111)In-labeled liposomes, as well as (3)H-labeled CPT were used to investigate the biodistribution of liposomes and drug. The ability of different liposome formulations to retain CPT in buffer was influenced by lipid concentration and drug/lipid ratio, rather than lipid composition. The tested formulations were cleared from the blood in the following order: CPT solution > CPT liposomes > (111)In-labeled liposomes, and liposomes mainly accumulated in the liver. Lipid composition did not influence CPT retention to the same extent as earlier observed from incorporation studies. The set-up for the biodistribution study works well and is suited for future in vivo studies on CPT liposomes. The biodistribution study showed that liposomes circulated longer than free drug, but premature release of drug from liposomes occurred. Further studies to develop formulations with higher retention potential and prolonged circulation are desired.

Modulation of oxidative stability of haemoglobin inside liposome-encapsulated haemoglobin.

The major hurdle in the formulation of liposome-encapsulated haemoglobin (LEH) is the oxidation of haemoglobin (Hb) into methaemoglobin during storage and after administration. In order to reduce this oxidative degradation, we tested various reducing conditions in the presence of catalase. We found that at 37°C more than 50% of Hb oxidized to methaemoglobin within 24 h, whereas in presence of catalase, the oxidation was significantly reduced. The effect of catalase was further enhanced by a reduction mixture containing ß-NAD, d-glucose, adenine, inosine, MgCl2, KCl, KH2PO4 and Na2HPO4; only 14% methaemoglobin was generated in the presence of catalase and reduction mixture. Contrary to the expectation, glutathione, deferoxamine and homocysteine enhanced Hb oxidation. The presence of CRM inside liposomes (250 nm) significantly decreased Hb oxidation. The results suggest that catalase and a well-defined mixture of co-factors may help control Hb oxidation for improvement in the functional life of LEH.

Feasibility of eradication of breast cancer cells remaining in postlumpectomy cavity and draining lymph nodes following intracavitary injection of radioactive immunoliposomes.

Most diagnosed early stage breast cancer cases are treated by lumpectomy and adjuvant radiation therapy, which significantly decreases the locoregional recurrence but causes inevitable toxicity to normal tissue. By using a technique of preparing liposomes carrying technetium-99m ((99m)Tc), rhenium-186 ((186)Re), or rhenium-188 ((188)Re) radionuclides, as well as chemotherapeutic agents, or their combination, for cancer therapy with real time image-monitoring of pharmacokinetics and prediction of therapy effect, this study investigated the potential of a novel targeted focal radiotherapy with low systemic toxicity using radioactive immunoliposomes to treat both the surgical cavity and draining lymph nodes in a rat breast cancer xenograft positive surgical margin model. Immunoliposomes modified with either panitumumab (anti-EGFR) or bevacizumab (anti-VEGF) were remote loaded with (99m)Tc diagnostic radionuclide, and injected into the surgical cavity of female nude rats with positive margins postlumpectomy. Locoregional retention and systemic distribution of (99m)Tc-immunoliposomes were investigated by nuclear imaging, stereofluorescent microscopic imaging, and gamma counting. Histopathological examination of excised draining lymph nodes was performed. The locoregional retention of (99m)Tc-immunoliposomes in each animal was influenced by the physiological characteristics of the surgical site of individual animals. Panitumumab- and bevacizumab-liposome groups had higher intracavitary retention compared with the control liposome groups. Draining lymph node uptake was influenced by both the intracavitary radioactivity retention level and metastasis status. The panitumumab-liposome group had higher accumulation on the residual tumor surface and in the metastatic lymph nodes. Radioactive liposomes that were cleared from the cavity were metabolized quickly and accumulated at low levels in vital organs. Therapeutic radionuclide-carrying specifically targeted panitumumab- and bevacizumab-liposomes have increased potential compared to non-antibody targeted liposomes for postlumpectomy focal therapy to eradicate remaining breast cancer cells inside the cavity and draining lymph nodes with low systemic toxicity.

Nasal and Parotid Blood Pool Activity Is Significantly Correlated with Metabolic Syndrome Components and Sleep Apnea.

Background: Patients with metabolic syndrome components were frequently noted to have increased nasal and parotid activity on clinically referred scintigraphic whole-body blood pool scans. This increase in activity was not observed in patients without metabolic syndrome. Increased nasal blood pool activity in patients with elevated body mass indices (BMIs) has implications for (1) sleep apnea, (2) risk of nasal infection, and (3) possible impaired nasal lymphatic drainage of brain waste proteins. Methods: To follow-up this clinical observation, a retrospective study was performed on 200 patients having whole-body blood pool scans referred over a 3-year period. The whole-body blood pool scans were evaluated for an association between nose and parotid region of interest (ROI) to heart ROI maximum (max) pixel ratios as correlated with clinical conditions, including obesity, diabetes, hypertension, and sleep apnea. Continuous variables of BMI, hemoglobin A1c (HbA1c), blood glucose, and blood lipids were also correlated with these ratios. Results: A direct association of nose to heart max ratio (NHMR) with diabetes, sleep apnea, and hypertension was found with an increase in the ratio of +0.10 (P = 0.002), +0.13 (P = 0.0002), +0.08 (P = 0.0123), respectively. Correlation of NHMR with continuous variables had moderate correlation with BMI (r = 0.36, P < 0.0001), glucose (r = 0.27, P = 0.0001), HbA1c (r = 0.25, P = 0.0008) and less association with the number of diabetes medications (r = 0.22, P = 0.0021). Similar associations were found for parotid to heart max ratios but were weaker than the NHMR. Conclusions: Patients with metabolic syndrome components have significantly increased nasal and parotid activity on blood pool scans. These associations have implications for the treatment of sleep apnea, for nasal infections involving such agents as Covid-19, and for the risk of dementias related to decreased clearance of brain waste proteins through nasal turbinate lymphatics in patients with metabolic syndrome. If further studies support these findings, the nasal turbinates and the increased parasympathetic activity controlling their dilation could become a new therapeutic target.

Post-lumpectomy intracavitary retention and lymph node targeting of (99m)Tc-encapsulated liposomes in nude rats with breast cancer xenograft.

Liposomes are recognized drug delivery systems with tumor-targeting capability. In addition, therapeutic or diagnostic radionuclides can be efficiently loaded into liposomes. This study investigated the feasibility of utilizing radiotherapeutic liposomes as a new post-lumpectomy radiotherapy for early-stage breast cancer by determining the locoregional retention and systemic distribution of liposomes radiolabeled with technetium-99m ((99m)Tc) in an orthotopic MDA-MB-231 breast cancer xenograft nude rat model. To test this new brachytherapy approach, a positive surgical margin lumpectomy model was set up by surgically removing the xenograft and deliberately leaving a small tumor remnant in the surgical cavity. Neutral, anionic, and cationic surface-charged fluorescent liposomes of 100 and 400 nm diameter were manufactured and labeled with (99m)Tc-BMEDA. Locoregional retention and systemic distribution of (99m)Tc-liposomes injected into the post-lumpectomy cavity were determined using non-invasive nuclear imaging, ex vivo tissue gamma counting and fluorescent stereomicroscopic imaging. The results indicated that (99)Tc-liposomes were effectively retained in the surgical cavity (average retention was 55.7 ± 24.2% of injected dose for all rats at 44 h post-injection) and also accumulated in the tumor remnant (66.9 ± 100.4%/g for all rats). The majority of cleared (99m)Tc was metabolized quickly and excreted into feces and urine, exerting low radiation burden on vital organs. In certain animals (99m)Tc-liposomes significantly accumulated in the peripheral lymph nodes, especially 100 nm liposomes with anionic surface charge. The results suggest that post-lumpectomy intracavitary administration of therapeutic radionuclides delivered by 100-nm anionic liposome carrier is a potential therapy for the simultaneous treatment of the surgical cavity and the draining lymph nodes of early-stage breast cancer.

Chemoradionuclide therapy with 186Re-labeled liposomal doxorubicin in combination with radiofrequency ablation for effective treatment of head and neck cancer in a nude rat tumor xenograft model.

PURPOSE: To determine the therapeutic efficacy of rhenium 186 ((186)Re)-labeled PEGylated liposomal doxorubicin ((186)Re-liposomal doxorubicin) in combination with radiofrequency (RF) ablation of human head and neck squamous cell carcinoma (HNSCC) xenograft in nude rats. MATERIALS AND METHODS: This investigation was approved by the animal care committee. Sixty nude rats with subcutaneously implanted HNSCC xenografts (six per group) were treated with (a) RF ablation (70 °C for 5 minutes), (b) PEGylated liposomes, (c) liposomal doxorubicin, (d) (186)Re-PEGylated liposomes (1295 MBq/kg), (e) (186)Re-liposomal doxorubicin (555 MBq/kg), (f) PEGylated liposomes plus RF ablation, (g) liposomal doxorubicin plus RF ablation, (h) (186)Re-PEGylated liposomes plus RF ablation, or (i) (186)Re-liposomal doxorubicin plus RF ablation. Six rats did not receive any treatment (control group). Tumor uptake in (186)Re therapy groups was monitored with small-animal single photon emission computed tomography for 5 days. Therapeutic efficacy was monitored for 6 weeks with measurement of tumor volume, calculation of the percentage injected dose of fluorine 18 fluorodeoxyglucose (FDG) in tumor from small-animal positron emission tomography (PET) images, and determination of viable tumor volume at histopathologic examination. Significant differences between groups were determined with analysis of variance. RESULTS: The average tumor volume (± standard deviation) on the day of therapy was 1.32 cm(3) ± 0.17. At 6 weeks after therapy, control of tumor growth was better with (186)Re-liposomal doxorubicin than with liposomal doxorubicin alone (tumor volume, 2.26 cm(3) ± 0.89 vs 5.43 cm(3) ± 0.93, respectively; P < .01). The use of RF ablation with liposomal doxorubicin and (186)Re-liposomal doxorubicin further improved tumor control (tumor volume, 2.05 cm(3) ± 1.36 and 1.49 cm(3) ± 1.47, respectively). The tumor growth trend correlated with change in percentage of injected dose of FDG in tumor for all groups (R(2) = 0.85, P < .001). Viable tumor volume was significantly decreased in the group treated with (186)Re-liposomal doxorubicin plus RF ablation (0.54 cm(3) ± 0.38; P < .001 vs all groups except (186)Re-liposomal doxorubicin alone). CONCLUSION: Triple and dual therapies had an observable trend ((186)Re-liposomal doxorubicin plus RF ablation > (186)Re-liposomal doxorubicin > liposomal doxorubicin plus RF ablation > liposomal doxorubicin) of improved tumor growth control and decreased viable tumor compared with other therapies. FDG PET could be used as a noninvasive surrogate marker for tumor growth and viability in this tumor model.

Novel asparagine-derived lipid enhances distearoylphosphatidylcholine bilayer resistance to acidic conditions.

A novel asparagine-derived lipid analogue (ALA(11,17)) bearing a tetrahydropyrimidinone headgroup and two fatty chains (11 and 17 indicate the lengths of linear alkyl groups) was synthesized in high yield and purity. The thin film hydration of formulations containing 5 mol % or greater ALA(11,17) in distearoylphosphatidylcholine (DSPC) generated multilamellar vesicles (MLVs) that remained unaggregated according to optical microscopy, while those formed from DSPC only were highly clustered. The MLVs were processed into unilamellar liposomes via extrusion and were characterized by dynamic light scattering (DLS), zeta potential, turbidity, and scanning electron microscopy (SEM) analysis. Results show that the presence of ALA(11,17) in DSPC liposomes significantly alters the morphology, colloidal stability, and retention of encapsulated materials in both acidic and neutral conditions. The ability of ALA(11,17)-hybrid liposomes to encapsulate and retain inclusions under neutral and acidic conditions (pH < 2) was demonstrated by calcein dequenching experiments. DLS and SEM confirmed that ALA(11,17)/DSPC liposomes remained intact under these conditions. The bilayer integrity observed under neutral and acidic conditions and the likely biocompatibility of these fatty amino acid analogues suggest that ALA(11,17) is a promising additive for modulating phosphatidylcholine lipid bilayer properties.

Remote-loading labeling of liposomes with (99m)Tc-BMEDA and its stability evaluation: effects of lipid formulation and pH/chemical gradient.

Efficient, convenient, and stable radiolabeling plays a critical role for the monitoring of liposome behavior via either blood sampling, organ distribution, or noninvasive nuclear imaging. The direct labeling of liposome-carrying drugs without any prior modification undoubtedly is convenient and optimal for liposomal drug testing. In this article, we investigated the effect of various lipid formulations and pH/chemical gradients on the radiolabeling efficiency and entrapment stability of technetium-99m ((99m)Tc) remotely loaded into liposomes, using (99m)Tc-N,N-bis(2-mercaptoethyl)-N',N'-diethyl-ethylenediamine ((99m)Tc-BMEDA) complex. The tested liposomes either contained unsaturated lipid or possessed various surface charges. (99m)Tc could be efficiently loaded into various premanufactured liposomes containing either an ammonium sulfate pH, citrate pH, or glutathione (GSH) chemical gradient. (99m)Tc-entrapment stabilities of these liposomes in phosphate-buffered saline (PBS; pH 7.4) buffer at 25°C were mainly dependent on the pH/chemical gradient, but not lipid formulation. Stability sequence was ammonium sulfate pH-gradient>citrate pH-gradient>GSH-gradient. Stabilities of (99m)Tc-liposomes in 50% fetal bovine serum (FBS)/PBS (pH 7.4) buffer at 37°C are dependent on both lipid formulation and pH/chemical gradient. Specifically, (99m)Tc labeling of the ammonium sulfate pH-gradient liposomes were less stable in 50% FBS/PBS than in PBS, whereas noncationic liposomes with citrate pH- or GSH-gradient displayed higher stability, except that anionic citrate pH-gradient liposomes showed no stability difference in these two media. Cationic liposomes aggregated in 50% FBS/PBS, forming a new discrete fraction with larger particle sizes. These in vitro characterization results have indicated the optimism of using (99m)Tc-BMEDA for labeling pH/GSH gradient liposomes without the requirement of modifying lipid formulation for liposomal therapeutic-agent development.

Moving outside the lab: Markerless motion capture accurately quantifies sagittal plane kinematics during the vertical jump.

Markerless motion capture using deep learning approaches have potential to revolutionize the field of biomechanics by allowing researchers to collect data outside of the laboratory environment, yet there remain questions regarding the accuracy and ease of use of these approaches. The purpose of this study was to apply a markerless motion capture approach to extract lower limb angles in the sagittal plane during the vertical jump and to evaluate agreement between the custom trained model and gold standard motion capture. We performed this study using a large open source data set (N = 84) that included synchronized commercial video and gold standard motion capture. We split these data into a training set for model development (n = 69) and test set to evaluate capture performance relative to gold standard motion capture using coefficient of multiple correlations (CMC) (n = 15). We found very strong agreement between the custom trained markerless approach and marker-based motion capture within the test set across the entire movement (CMC > 0.991, RMSE < 3.22°), with at least strong CMC values across all trials for the hip (0.853 ± 0.23), knee (0.963 ± 0.471), and ankle (0.970 ± 0.055). The strong agreement between markerless and marker-based motion capture provides evidence that markerless motion capture is a viable tool to extend data collection to outside of the laboratory. As biomechanical research struggles with representative sampling practices, markerless motion capture has potential to transform biomechanical research away from traditional laboratory settings into venues convenient to populations that are under sampled without sacrificing measurement fidelity.

Fewer-Angle SPECT/CT Blood Pool Imaging for Infection and Inflammation.

A new protocol for rapid SPECT/CT blood pool imaging consisting of fewer image-angle acquisitions (fewer-angle SPECT/CT, or FASpecT/CT) was evaluated for localization of focal sites of soft-tissue inflammation, infection, and osteomyelitis. Methods: Immediately after dynamic flow and standard planar blood pool imaging with 99mTc-methylene diphosphonate, FASpecT/CT was performed with a dual-head γ-camera consisting of 6 steps over 360°, 12 total images with 30° of separation between angles, and 30 s per image, requiring a total imaging time of approximately 3 min. Images were reconstructed using iterative ordered-subset expectation maximization. Before use in a patient-care setting, various FASpecT/CT acquisition protocols were modeled using a phantom to determine the minimum number of stops and the stop duration required to produce a reliable image. Results: FASpecT/CT images provided excellent 3-dimensional localization of spine osteomyelitis, soft-tissue infection of the foot, and tendonitis of the hand and foot using a 3-min image acquisition time. The FASpecT/CT acquisition protocol required 1.3-3.5 min, including camera movement time. This was a reduction of 72%-90% from the time required for the standard 60-angle, 20-s SPECT/CT acquisition. Conclusion: The ability of FASpecT/CT blood pool images to help localize focal sites of hyperemia and inflammation can increase exam sensitivity and specificity. Additionally, using a FASpecT/CT protocol decreases imaging time by up to 90%.

Patient specific, imaging-informed modeling of rhenium-186 nanoliposome delivery via convection-enhanced delivery in glioblastoma multiforme.

Convection-enhanced delivery of rhenium-186 (186Re)-nanoliposomes is a promising approach to provide precise delivery of large localized doses of radiation for patients with recurrent glioblastoma multiforme. Current approaches for treatment planning utilizing convection-enhanced delivery are designed for small molecule drugs and not for larger particles such as186Re-nanoliposomes. To enable the treatment planning for186Re-nanoliposomes delivery, we have developed a computational fluid dynamics approach to predict the distribution of nanoliposomes for individual patients. In this work, we construct, calibrate, and validate a family of computational fluid dynamics models to predict the spatio-temporal distribution of186Re-nanoliposomes within the brain, utilizing patient-specific pre-operative magnetic resonance imaging (MRI) to assign material properties for an advection-diffusion transport model. The model family is calibrated to single photon emission computed tomography (SPECT) images acquired during and after the infusion of186Re-nanoliposomes for five patients enrolled in a Phase I/II trial (NCT Number NCT01906385), and is validated using a leave-one-out bootstrapping methodology for predicting the final distribution of the particles. After calibration, our models are capable of predicting the mid-delivery and final spatial distribution of186Re-nanoliposomes with a Dice value of 0.69 ± 0.18 and a concordance correlation coefficient of 0.88 ± 0.12 (mean ± 95% confidence interval), using only the patient-specific, pre-operative MRI data, and calibrated model parameters from prior patients. These results demonstrate a proof-of-concept for a patient-specific modeling framework, which predicts the spatial distribution of nanoparticles. Further development of this approach could enable optimizing catheter placement for future studies employing convection-enhanced delivery.

Combination radiofrequency ablation and intravenous radiolabeled liposomal Doxorubicin: imaging and quantification of increased drug delivery to tumors.

PURPOSE: To identify, with noninvasive imaging, the zone of radiopharmaceutical uptake after combination therapy with radiofrequency (RF) ablation and intravenous administration of technetium 99m ((99m)Tc) liposomal doxorubicin in a small-animal tumor model, and to quantify and correlate the uptake by using imaging and tissue counting of intratumoral doxorubicin accumulation. MATERIALS AND METHODS: This study was approved by the animal care committee. Two phases of animal experiments were performed. In the first experiment, a single human head-and-neck squamous cell carcinoma tumor was grown in each of 10 male nude rats. Seven of these animals were treated with intravenous (99m)Tc-liposomal doxorubicin followed by RF tumor ablation at a mean temperature of 70 degrees C + or - 2 for 5 minutes, and three were treated with intravenous (99m)Tc-liposomal doxorubicin only. Combination single photon emission computed tomography-computed tomography (SPECT/CT) was performed at 15 minutes, 4 hours, and 20 hours after therapy. In the second experiment, two tumors each were grown in 11 rats, but only one of the tumors was ablated after intravenous administration of (99m)Tc-liposomal doxorubicin. SPECT/CT and planar scintigraphy were performed at the same posttreatment intervals applied in the first experiment, with additional planar imaging performed at 44 hours. After imaging, tissue counting in the excised tumors was performed. Radiotracer uptake, as determined with imaging and tissue counting, was quantified and compared. In a subset of three animals, intratumoral doxorubicin accumulation was determined with fluorimetry and correlated with the imaging and tissue-counting data. RESULTS: At both SPECT/CT and planar scintigraphy, increased uptake of (99m)Tc-liposomal doxorubicin was visibly apparent in the ablated tumors. Results of quantitative analysis with both imaging and tissue counting confirmed significantly greater uptake in the RF ablation-treated tumors (P < .001). Intratumoral doxorubicin accumulation correlated closely with imaging (r = 0.9185-0.9871) and tissue-counting (r = 0.995) results. CONCLUSION: Study results show that increased delivery of intravenous liposomal doxorubicin to tumors combined with RF ablation can be depicted and quantified with noninvasive imaging.

Interventional therapy of head and neck cancer with lipid nanoparticle-carried rhenium 186 radionuclide.

PURPOSE: Minimally invasive interventional cancer therapy with drug-carrying lipid nanoparticles (ie, liposomes) via convection-enhanced delivery by an infusion pump can increase intratumoral drug concentration and retention while facilitating broad distribution throughout solid tumors. The authors investigated the utility of liposome-carrying beta-emitting radionuclides to treat head and neck cancer by direct intratumoral infusion in nude rats. MATERIALS AND METHODS: Four groups of nude rats were subcutaneously inoculated with human tongue cancer cells. After tumors reached an average size of 1.6 cm(3), the treatment group received an intratumoral infusion of liposomal rhenium-186 ((186)Re) (185 MBq [5 mCi]/cm(3) tumor). Three control groups were intratumorally infused with unlabeled liposomes, unencapsulated (186)Re-perrhenate, or unencapsulated intermediate (186)Re compound ((186)Re-N,N-bis[2-mercaptoethyl]-N',N'-diethyl-ethylenediamine [BMEDA]). In vivo distribution of (186)Re activity was measured by planar gamma-camera imaging. Tumor therapy and toxicity were assessed by tumor size, body weight, and hematology. RESULTS: Average tumor volume in the (186)Re-liposome group on posttreatment day 14 decreased to 87.7% +/- 20.1%, whereas tumor volumes increased to 395.0%-514.4% on average in the other three groups (P< .001 vs (186)Re-liposome). The (186)Re-liposomes provided much higher intratumoral retention of (186)Re activity, resulting in an average tumor radiation absorbed dose of 526.3 Gy +/- 93.3, whereas (186)Re-perrhenate and (186)Re-BMEDA groups had only 3.3 Gy +/- 1.2 and 13.4 Gy +/- 9.2 tumor doses, respectively. No systemic toxicity was observed. CONCLUSIONS: Liposomal (186)Re effectively treated head and neck cancer with minimal side effects after convection-enhanced interventional delivery. These results suggest the potential of liposomal (186)Re for clinical application in interventional therapy of cancer.

FASpecT/CT, A New SPECT/CT Acquisition With Higher Sensitivity and Efficiency in Radioiodine Thyroid Cancer Imaging.

PURPOSE: This article demonstrates the use of a new SPECT/CT acquisition protocol in patients with differentiated thyroid cancer (DTC). METHODS: SPECT/CT scans (FASpecT/CT) with fewer angle acquisitions were retrospectively reviewed in 30 DTC patients treated with radioiodine at University Hospital, San Antonio, Tex, from July 2017 to March 2019. This FASpecT/CT of 12 versus 60 to 64 sampled views for convention SPECT was made possible by iterative reconstruction. RESULTS: The FASpecT/CT protocol was judged to increase lesion detection in patients with low count rates. Furthermore, in patients with higher count rates, this technique reduced the acquisition time. FASpecT/CT patient images are shown as case examples in 4 of the 30 patients reviewed. CONCLUSIONS: This FASpecT/CT acquisition in radioiodine-treated DTC offers the potential of higher sensitivity for metastatic lymph node detection in low count rates and a significant decrease in imaging time in high count rates. These advantages make SPECT/CT imaging more acceptable for patients who have difficulty with longer imaging times, to include the pediatric population.