Objective: Radiotherapy-induced brain injury (RIBI) is a chronic side effect that affects up to 90% of brain tumor survivors treated with radiotherapy. Here, we used multiparametric magnetic resonance imaging (MRI) to identify noninvasive and clinically translatable biomarkers of RIBI.
Method: 8-week-old female, immune competent BALB/c mice were stereotactically irradiated with a single dose of 80 Gy, at a dose rate of 1.7 Gy/minute. The irradiated mice were then monitored longitudinally with MRI, behavioral tests of learning and memory, and immunohistochemistry, in comparison to nonirradiated mice.
Results: Three types of MRI biomarkers of RIBI were identified. A contrast-enhanced T 1 -weighted MRI biomarker was identified as being best suited to detect the onset of injury, by detecting changes in the blood-brain barrier (BBB) permeability. Maximum BBB permeability (18.95 ± 1.75) was detected with contrast-enhanced T 1 -weighted MRI at 1-month postirradiation in irradiated mice ( P < 0.0001, n = 3). Interestingly, maximum neuroinflammation (24.14 ± 6.72) was also detected using IBA1 and CD68 immunohistochemistry at 1-month postirradiation in irradiated mice ( P = 0.0041, n = 3). This simultaneous maximum BBB permeability and neuroinflammation detection also coincided with the detection of the onset of transient cognitive impairment, detected using the fear-conditioning behavioral test at 1-month postirradiation in irradiated mice compared to nonirradiated mice ( P = 0.0017, n = 10). A T 2 -weighted MRI hyperintensity biomarker was also identified, and determined to be best suited to detect intermediate injury. Maximum T 2 -weighted MRI hyperintensity (3.97 ± 2.07) was detected at 2-month postirradiation in the irradiated mice compared to nonirradiated mice ( P = 0.0368, n = 3). This T 2 -weighted MRI hyperintensity also correlated with maximum astrogliosis (9.92 ± 4.21), which was also detected at 2-month postirradiation using GFAP immunohistochemistry in the irradiated mice compared to nonirradiated mice ( P = 0.0215, n = 3). Finally, T 2 -weighted and T 2 *-weighted MRI hypointensity biomarkers were identified as being best suited to detect late injury, from 4-month postirradiation. These biomarkers correlated with increased iron deposition from late vascular damage, which was validated with Perls' Prussian blue histology ( P < 0.05, n = 3). These hypointense MRI biomarkers of late injury also preceded significant weight loss, severe cognitive impairment, and decreased survival in the irradiated mice compared to the nonirradiated mice.
Conclusions: Here, we identified 3 types of translational MRI biomarkers of RIBI that could enable the noninvasive longitudinal evaluation of potential RIBI prophylactic and therapeutic agents. These translational MRI biomarkers could also play a pivotal role in the management of RIBI in brain tumor survivors.
Objectives: Quantification of liver fat on computed tomography (CT) is often confounded by hepatic iron deposition and the use of iodinated contrast agents. This phantom study aimed to evaluate the feasibility and accuracy of quantifying liver fat content (LFC) in the presence of iron using spectral localizer radiographs acquired with photon-counting detector CT (PCD-CT).
Materials and methods: Sixteen liver phantoms were constructed using mixtures of liver tissue, fat, and iron to simulate 4 levels of LFC (0%, 10%, 30%, and 50%) and 4 levels of liver iron concentration (LIC: 0, 1.5, 3, and 6 mg/mL). Five additional reference phantoms (containing fat only, water only, or water-iron solutions) were included. All phantoms were scanned on a clinical PCD-CT system using 3 tube current settings (10, 50, 300 mA) to acquire spectral localizer radiography data. Material decomposition of high- and low-energy bin data yielded water and hydroxyapatite (HA) maps. HA values were analyzed as a function of LFC and LIC, and water values were correlated with corresponding HA values.
Results: Increasing LFC resulted in a linear decrease in HA values, consistent across all LIC levels (slopes=-0.0016 to -0.0023; mean=-0.0019; r=0.997 to 1.0). Conversely, increasing LIC caused a linear increase in HA values, independent of LFC (slopes=0.0147 to 0.017; mean=0.0156; r=0.978 to 1.0). When combined with water values in a 2-dimensional material space, these stable linear relationships enabled estimation of LFC irrespective of LIC. Findings were reproducible across all tube current settings.
Conclusion: Spectral localizer radiographs from PCD-CT allow quantification of liver fat content even in the presence of iron deposition. If validated in vivo, this technique may enable low-threshold opportunistic screening for hepatic steatosis and iron overload from precontrast localizer scans.
Objectives: Photon-counting CT (PC-CT) offers higher spatial resolution and enables iodine quantification compared with conventional CT. Its potential role in breast imaging is currently under evaluation.
Purpose: To assess whether prone-positioned PC-CT with iodine mapping can differentiate malignant from benign breast masses, and to evaluate the clinical utility of iodine mapping (PC-CTIodine), monoenergetic postcontrast images (PC-CTC+), and virtual noncontrast reconstructions (PC-CTVNC) for lesion conspicuity, image quality, anatomic correlation with MRI, and reader's preference.
Materials and methods: This prospective single-center study (December 2021 to August 2023) included patients with biopsy-proven breast cancer who underwent thoracoabdominal PC-CT in prone, compression-free breast positioning, breast MRI, and tomosynthesis during staging. Reconstructions included PC-CTIodine, PC-CTC+ with 65 kiloelectronvolts (keV), and PC-CTVNC. Quantitative analysis included iodine concentrations and contrast-to-noise ratio (CNR), each with additional subtype analysis; qualitative ratings included lesion conspicuity, noise, artifacts, lesion localization, and reader preferences. Statistical analysis included Kruskal-Wallis, Friedman and Wilcoxon signed-rank tests, and Cohen kappa.
Results: Among 90 potentially eligible participants, 78 participants (mean age, 55 y ± 15 SD, 77 women) with 134 breast masses (106 malignant, 28 benign) were included. Benign masses differed from malignant lesions (P < 0.001). Breast cancers showed the highest median iodine concentration [2.6 mg/mL (IQR, 2.0 to 3.3)], significantly higher than DCIS (1.7 mg/mL), fibroadenomas (0.5 mg/mL), and cysts (-0.1 mg/mL; all P < 0.05). Iodine values for papillomas and lymph nodes overlapped with cancers (P > 0.05). CNR was higher for PC-CTC+ than PC-CTIodine (P < 0.001). Readers preferred PC-CTIodine for detection and PC-CTC+ for morphologic assessment. Lesion localization matched MRI, and no relevant artifacts were observed.
Conclusion: Prone PC-CT with iodine mapping enables accurate lesion localization, quantification, and differentiation between malignant and benign breast masses. Compression-free breast positioning enhances localization accuracy. The method may serve as an accessible adjunct to MRI in staging, with complementary use of iodine and postcontrast reconstructions recommended for optimal assessment.
Background: 7T MRI received FDA/CE clearance almost 7 years ago. However, until today, it has not yet been widely adopted in clinical routine. This is mainly due to field inhomogeneities that impede whole-brain coverage. Moreover, the long scan times often associated with high-resolution imaging are an additional limiting factor.
Purpose: To combine calibration-free parallel transmit technology (pTx) using universal pulses (UP) with advanced imaging acceleration strategies to achieve homogenous multicontrast 7T MRI with whole-brain coverage and high spatial resolution in short scan time.
Materials and methods: Ten healthy volunteers were scanned both with conventional vendor-provided sequences and with custom sequences for anatomical whole-brain imaging [-weighted, -weighted, FLAIR, and susceptibility-weighted]. The scan times for the 2 anatomical protocols were matched (25 minutes). In addition, a quantitative MRI protocol [multi-parametric mapping (MPM) and chemical exchange saturation transfer (CEST)] was scanned twice using custom sequences with conventional (circular polarized) and UPs, respectively, in a scan time of 2×25 minutes. Moreover, 4 patients with different neurological diseases were scanned, namely temporal lobe epilepsy, spinocerebellar ataxia, cerebral amyloid angiopathy, and glioblastoma. For the patients, only optimized custom sequences with UPs were acquired.
Results: Compared with conventional implementations, the custom sequences provide strongly improved image homogeneity and quality with significantly higher SNR and CNR across the whole brain, including cerebellum and brain stem. Moreover, UPs improve the repeatability of derived quantitative parameters. The suggested protocol has additionally been successfully demonstrated in 4 patients with different neurological pathologies.
Conclusions: Homogeneous whole-brain 7T MRI with high spatial resolution and high image quality is possible in clinically feasible scan times. The developed protocol can be applied without any expert knowledge and is ready for clinical use. The approach could largely extend applicability of UHF MRI in neuroradiology paving the way for increased routine use of 7T MRI.
Objectives: This study aims to improve the radiopacity of absorbable bone cements through the addition of gadolinium nanoparticles (GdNP). We also aim to determine whether photon-counting CT (PCCT) provides superior contrast-to-noise ratio (CNR) between GdNP-loaded bone cement and vertebral bone when compared with energy-integrating CT (EID-CT), and to evaluate the accuracy of PCCT material decomposition for quantifying gadolinium concentration in solution and the GdNP-loaded cements.
Materials and methods: GdNPs were synthesized using a one-pot thermal decomposition method and characterized using transmission electron microscopy and dynamic light scattering. Hydroxyapatite-based bone cement was loaded with varying mass fractions of GdNPs (0% to 10% w/w), and the CNR between the GdNP-loaded cement and vertebral bone was evaluated using preclinical micro-EID-CT and micro-PCCT scanners. Gadolinium material decomposition images were used to measure the amount of gadolinium present in each of the cements. In addition, gadolinium standards (0 to 20 mg/mL) were imaged with a preclinical micro-PCCT, and the concentration of gadolinium in the vials was estimated using gadolinium material decomposition images.
Results: The synthesized GdNPs had a mean diameter of 15.42±1.82 nm. Signal intensity increased with increasing mass fractions of GdNPs for both EID-CT and PCCT. In EID-CT images, cements with ≥4% GdNP loading had higher CNRs relative to bone than the cement with no GdNP loading (P<0.05). The CNR between the 8% and 10% GdNP-loaded bone cement significantly differed from than the bone cement with no GdNP loading for all PCCT energy bins (P<0.05). The 42-51 keV energy bin yielded the largest CNRs overall when compared with the CNRs of other energy bins. Overall, the CNRs obtained from PCCT images were larger than the EID-CT CNRs. The concentration of gadolinium in the cements measured using the PCCT material decomposition images was correlated with the mass fractions of GdNP (r=0.9753). Estimated gadolinium concentrations were highly correlated with the nominal concentration of the gadolinium standards (r=0.999) and the PCCT was able to accurately quantify gadolinium concentrations with a root mean square error of 1.60 mg/mL.
Conclusions: The use of GdNPs led to a higher cement-vertebra CNR for both EID-CT and PCCT. Overall, PCCT demonstrated higher CNRs than EID-CT. Material decomposition successfully quantified the concentration of gadolinium in vials and allowed for improved visual differentiation of the GdNP-loaded bone cement from the calcium-based vertebral bodies. Thus, the incorporation of radiopaque GdNPs and imaging with PCCT improved visualization of the bone cement. These methods could be used to improve monitoring of implanted bone cements. In addition, PCCT material decomposition enabled accurate quantification of gadolinium in solution.
Objectives: Previous studies in rodents have investigated the potential effects of gadolinium-based contrast agents (GBCAs) on the peripheral nervous system; this study aimed to assess the potential effects of 2 GBCAs on the peripheral nervous system of non-human primates (NHPs) and to evaluate their toxicokinetic profile.
Materials and methods: Eighteen cynomolgus monkeys ( Macaca fascicularis ; 2 to 4 years old, Mauritian origin) of both sexes (3 animals/group/sex) were intravenously administered once with either gadobenate dimeglumine or gadoteridol at 0.3 mmol/kg, or with saline (0.6 mL/kg). This was followed by a 52-week recovery phase. Safety assessments were based on clinical observations, body weights, neurobehavioral observations, electrophysiologic nerve conduction tests, nerve assessment in skin biopsies (pre-dose and at weeks 2, 17, and 51), and clinical pathology evaluation. Blood for toxicokinetic evaluations was collected at pre-dose and at 5 minutes and at 1, 4, 7, and 24 hours post-dose.
Results: No GBCA-related changes were noted from clinical and neurobehavioral observation. All sensory and motor nerve conduction metrics remained within a normal, physiologically functional range at all time points for all animals. Hematoxylin and eosin-stained sections revealed no induced changes in epidermal and subepidermal tissues. Image analysis did not reveal histomorphometrical differences between control and GBCA-treated animals. Systemic exposure to gadolinium (Gd) was comparable between sexes and was consistent after the administration of the 2 GBCAs; mean Gd half-life values, based on data from 5 minutes to 24 hours post-dose, were about 3.5 hours for gadobenate dimeglumine and about 3 hours for gadoteridol. For both GBCAs, systemic clearance was rapid at ∼0.16 L/h/kg, with a distribution volume ranging from 0.13 to 0.17 L/kg, indicating extracellular space distribution.
Conclusion: A single intravenous administration of 0.3 mmol/kg gadobenate dimeglumine or gadoteridol in NHPs was well tolerated and did not induce effects on the peripheral nervous system.
Background: The current standard dose of extracellular, multipurpose gadolinium-based contrast agents (GBCAs) of 0.1 mmol Gd/kg body weight (bw) was first suggested in 1984, 40 years ago. Although the safety and efficacy of both higher and lower doses ("non-standard dosing") have been extensively investigated over the years, the recent introduction of high-relaxivity macrocyclic GBCAs provides, for the first time, a viable lower-dose alternative.
Objective: To systematically explore published rationales for nonstandard dosing of GBCAs and discuss the potential future impact of high-relaxivity contrast agents.
Materials and methods: A systematic literature review was conducted using Embase and MEDLINE/PubMED, covering studies published from 1991 to 2024. Publications were categorized by clinical indication, administered GBCA dose, study design, and rationale for nonstandard dosing. The dose of 0.1 mmol Gd/kg body weight was defined as the "standard" reference for comparison.
Results: Eighty-seven publications comparing different nonstandard dosing regimens with the standard dose were finally selected, which included 43 high-dose and 58 low-dose studies. The rationales for using high-dose administration were to achieve better contrast (25/43; 58%) and to improve lesion detection (15/43; 35%). These high-dose studies were performed primarily in the CNS until 2006. Twenty-nine studies (29/43; 67%) reported improved outcomes compared with standard dose, and 1 study (1/43; 2%) reported comparable outcomes. Rationales for using low-dose administration were related to (1) NSF (31/58; 53%); (2) Gd exposure (23/58; 40%); (3) cost (22/58; 38%); (4) unspecified safety (22/58; 38%); (5) Gd retention/presence (19/58; 33%); and (6) the environment (7/58; 12%). From 1991 to 2006, cost was the primary rationale for lower dose administration. From 2008, NSF was noted, from 2017 onward, Gd retention/presence emerged as an identified rationale, and most recently, to minimize environmental impact. Forty-nine of 58 (84%) investigating low-dose regimens reported comparable outcomes, 7 studies (12%) reported inferior outcomes compared with standard dose. However, 36 of the 49 low-dose studies reporting comparable outcomes modified not only the dose but additionally other parameters, or they applied a study design potentially impacting study strength. To reliably allow for a substantially lower dose across a broad range of indications, the next generation of high-relaxivity low-dose GBCAs (gadopiclenol, gadoquatrane) was developed.
Conclusions: For over 34 years, there has been a consistent demand to lower GBCA doses, with an increasing number of rationales over time. The high-relaxivity, low-dose mGBCAs show promise for reducing Gd dose while maintaining high image quality, potentially defining a new standard dose.
Background: Blooming artifacts from calcified plaques can obscure the vessel lumen, leading to overestimation of stenosis severity. Spectral coronary angiography with photon-counting detector CT (PCD-CT) provides virtual monoenergetic images (VMIs) for coronary artery disease assessment. While VMIs at high VMI energy levels reduce calcium blooming, iodine contrast is diminished, limiting diagnostic value. This study evaluated whether contrast media with an atomic number higher than iodine (high-Z) preserve vascular contrast using high VMI energy levels, thereby improving the accuracy of stenosis quantification.
Methods: A phantom with 4 and 6 mm diameter rods to mimic small diameter vessels containing eccentric calcified plaques causing 25%, 50%, and 75% diameter stenoses was scanned with a dual-source PCD-CT system. Five different contrast media, including iodine, tungsten, holmium, hafnium, and bismuth, were tested. VMIs were reconstructed from 40 to 190 keV in 1-keV steps. Vessel attenuation, contrast-to-noise ratio (CNR), and stenoses were measured. Qualitative assessment of image quality was performed.
Results: Iodine attenuation was high at lower VMI energy levels and dropped below 250 HU at >100 keV. Tungsten, holmium, hafnium, and bismuth maintained >250 HU attenuation throughout the entire energy range. Vessel CNR of iodine was high at lower and decreased at higher VMI energy levels, similar to the CNR of holmium and bismuth, though to a lesser extent. In distinction, CNRs of tungsten and hafnium were lower at lower VMI energy levels and increased to a relatively constant level at higher keV. Tungsten CNR increased with energy, approaching ~40 at high keV. Across all contrast media and stenosis degrees, stenoses were overestimated on low VMI energy levels (24% to 32.5% at 40 keV), while the degree of overestimation decreased at higher VMI energy levels (0% to 13.5% at 190 keV). At 190 keV, tungsten, hafnium, and bismuth showed ≤2.5% stenosis overestimation, compared with iodine (10% to 13.5%). Image quality varied between contrast media and energy levels: new very high-Z contrast media achieved higher scores, while iodine peaked at lower keV (55 to 70 keV) and, due to loss of contrast at higher energies, received the lowest overall scores.
Conclusions: As compared with iodine, very high-Z contrast media enable superior lumen definition and more accurate stenosis assessment, also at high VMI energy levels, which minimize calcium blooming.
Abstract: Gadopiclenol was initially developed as a high-relaxivity, nonspecific magnetic resonance imaging contrast agent to enhance image quality and thereby improve diagnostics. This design required a highly demanding Drug Target Profile, addressing not only relaxivity but also factors such as physicochemical properties of the injectable solution (viscosity, osmolality, heat sterilization compatibility), pharmacokinetics and toxicity, particularly related to the stability of the complex. These considerations led to a multiparametric molecular design based on a gadolinium complex characterized by the following features: (1) a macrocyclic, nonionic structure based on the PCTA framework with 2 water molecules in the inner sphere; (2) the introduction of steric constraints around the gadolinium to enhance stability and reduce relaxivity quenching by endogenous ions; (3) slowed rotational diffusion due to gadolinium's position at the center of the complex; and (4) the incorporation of 3 hydrophilic amino polyol pendant arms to ensure aqueous solubility, reduce binding with endogenous proteins, and enhance product safety.This rational design led to the creation of a first prototype, P03277V1. However, the occurrence of nephrogenic systemic fibrosis necessitated modifications to the Drug Target Profile, aimed at improving the complex's stability and reducing production costs. This was achieved through the discovery of an isomerization process for P03277V1, resulting in gadopiclenol, which demonstrated excellent kinetic stability.The rational design of gadopiclenol thus exemplifies the concept of Property-Based Drug Design used in medicinal chemistry. It also highlights that the complexity of designing a diagnostic agent is comparable to that of a therapeutic agent. Furthermore, the case of gadopiclenol illustrates that the medical positioning of a drug candidate can evolve during clinical development. Gadopiclenol's medical positioning shifted from being a product with high relaxivity to improve signal strength, to one intended for use at a half dose to limit gadolinium injection and minimize risks to patients, such as nephrogenic systemic fibrosis or accumulation in specific areas of the brain. Currently, gadopiclenol is approved for clinical use at a dose of 0.05 mmol/kg to minimize gadolinium exposure to patients. Whether the 0.1 mmol/kg dose can be used to enhance clinical diagnostics and improve patient management in the future remains to be seen.
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