Investigative Radiology最新文献

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.

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.

Objectives: Accurate detection and quantification of liver iron overload (LIO) in patients with thalassemia is crucial for guiding iron chelation therapy and preventing iron-related organ damage. While conventional multiecho gradient-echo (GRE) based MR at 1.5T is the clinical standard, with increasing availability of 3.0T systems, clinically reliable alternatives are needed. The ultra-short echo time (UTE) MRI sequence may offer improved assessment of LIO on 3.0T. The objective of this study was to evaluate 3.0T UTE for assessing LIO in thalassemia patients and directly compared with the standard 1.5T GRE as reference, particularly at severe overload with lower R2* values.

Materials and methods: Patients with thalassemia referred for liver iron assessment by MRI were prospectively enrolled. Each participant underwent liver iron quantification using both 1.5T GRE and 3.0T UTE sequences. For the latter, 4 different acquisition protocols were assessed: 7-echo free breathing (3.0T UTE 7E FB), 7-echo breath-hold (3.0T UTE 7E BH), 15-echo free breathing (3.0T UTE 15E FB), and 15-echo breath-hold (3.0T UTE 15E BH). The correlation between 1.5T GRE and each UTE sequence was analyzed. The agreement was further assessed using Bland-Altman analysis.

Results: Sixty-three patients were enrolled; 5 were excluded due to unmeasurably high liver iron concentration (LIC) by 1.5T MRI. The remaining 58 patients had a mean age of 34.3 ± 16.1 years; 24 (41.4%) were male, and 42 (72.4%) had thalassemia major. Regular transfusions were noted in 31 (53.4%). All 3.0T UTE sequences demonstrated excellent correlation with 1.5T GRE (R2, 0.9701-0.9827). Bland-Altman analysis indicated minimal bias and narrow limits of agreement. The 3.0T UTE 15E BH protocol yielded the strongest performance.

Conclusions: 3.0T UTE MRI sequences provide clinically feasible and accurate assessment of liver iron overload in thalassemia patients across a broad range of LIC values from 1.3 to 39.5 mg/g. These findings support the clinical utility of 3.0T UTE MRI for LIO detection and therapeutic decision-making in this population.

Objectives: Metal artifact reduction MRI can exceed specific absorption rate (SAR) limits due to high-bandwidth radiofrequency pulses, causing scan interruptions and prolonged acquisition times. The aim of the current study is to reduce SAR and potentially scan time in metal artifact reduction MRI using an optimized variable refocusing flip angle (VRFA) scheme compared with the standard constant refocusing flip angle (CRFA).

Materials and methods: Three VRFA variants (VRFA1 to VRFA3) were developed to maximize tissue signal and contrast while minimizing SAR and image blur. The optimal variant was selected through quantification of metal artifacts and image blur in phantoms and tissue signal in a volunteer. Patients with hip arthroplasty underwent CRFA and optimal VRFA imaging using high-bandwidth turbo-spin-echo (HBW-TSE) and compressed-sensing slice-encoding-for-metal-artifact-correction (CS-SEMAC) sequences. Three readers ranked paired CRFA and VRFA scans for quality. Analyses included repeated measures ANOVA, noninferiority testing, and paired t/Wilcoxon signed-rank tests.

Results: CRFA and VRFA1 to VRFA3 showed no significant differences in image blur (full-width-at-half-maximum, mean ± SD, 1.9 ± 0.2 vs 1.9 ± 0.2 vs 1.9 ± 0.3 vs 1.9 ± 0.3 pixels, P = 0.06) or metal artifacts (8.2 ± 2.8 vs 8.4 ± 2.7 vs 8.4 ± 2.6 vs 8.4 ± 2.7 pixels, P = 0.57). The optimal VRFA variant (VRFA3) preserved 81% of CRFA fat-muscle contrast at 77% SAR and 70% scan time on proton-density (PD), and 94% of fluid-muscle contrast at 80% SAR and 67% scan time on short-tau-inversion-recovery (STIR). In 23 patients [mean age, 67.3 y ± 12.2 (SD); 14 females], the optimal VRFA was noninferior to CRFA in all quality metrics (all 95% CI < noninferiority margin = 0.1) and significantly reduced SAR (mean, PD-HBW-TSE/STIR-HBW-TSE/PD-CS-SEMAC/STIR-CS-SEMAC: 1.11/1.35/1.17/1.18 vs 1.85/1.83/1.49/1.46 W/kg, all P ≤ 0.001). In HBW-TSE, reduced SAR allowed longer echo trains and 15% to 32% shorter scan times.

Conclusion: Metal artifact reduction MRI with VRFA reduces SAR without compromising image quality. It allows shorter acquisitions in HBW-TSE.

Objectives: Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging. Concerns exist regarding gadolinium deposition and its potential histopathologic tissue alterations, especially after repeated administrations of linear, less stable GBCAs. This study aimed to quantify gadolinium mass fractions in liver specimens of subjects exposed to GBCAs in correlation with histopathologic features.

Materials and methods: In this Institutional Review Board-approved study, mass fractions of gadolinium in human liver specimens ω(Gd) from 25 subjects who underwent liver tumor resection surgery and had received GBCA (1 to 9 times over 4 y), were quantitatively analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). Histomorphology was assessed based on the nonalcoholic fatty liver disease activity score (NAS). Linear regression analyses were performed with ω(Gd), time and dosage metrics, and histopathologic parameters.

Results: The median interval between last GBCA administration and surgery (T) was 14 days (range: 1 to 69 d). Gadolinium was detected in all liver samples (ω(Gd), median: 0.348 µg/g; range: 0.120 to 0.874 µg/g). No significant correlation was found between ω(Gd) and histologic scores, including inflammation and fibrosis. A strong negative correlation was found between ω(Gd) and ln(T) (P < 0.001). A positive correlation existed between ω(Gd) and the number (P = 0.010) but not the cumulative dose of previous GBCA administrations (P = 0.205).

Conclusions: Our results suggest that after intravenous administration of GBCA, a small fraction of gadolinium is retained in the liver over a time period of at least several weeks. A relationship was observed between Gadolinium retention and the number of GBCA administrations, but not with the cumulative dose and the degree of fatty liver disease.

Objectives: The objective of the study was to investigate the dose-response (signal enhancement) relationship and signal-enhancement kinetics of gadoquatrane in different anatomic regions employing different MRI pulse sequences. Gadoquatrane is a novel high-relaxivity, extracellular macrocyclic gadolinium-based contrast agent with tetrameric structure that has the potential to be used at lower Gd doses than long-established contrast agents.

Materials and methods: In this exploratory, prospective crossover study, 7 healthy pigs underwent contrast-enhanced MRI examinations with gadoquatrane (0.01, 0.03, and 0.06 mmol Gd/kg body weight) and standard doses (0.1 mmol Gd/kg) of 2 comparators, gadobutrol and gadoterate meglumine. MRI was performed on a 1.5T scanner under conditions typically used in clinical routine. Immediately after contrast-agent injection, multiphase liver MRI was done (VIBE sequence). Steady-state head-and-neck MRI followed (spin-echo and FLASH sequences alternating from 2 to 32 min after injection). Image evaluation was based on changes in signal intensity from baseline [relative signal enhancement (RSE)]. Simple linear regression analysis was used to investigate the relationship between RSE and gadoquatrane dose. The regression equations were used to estimate the comparator-equivalent doses of gadoquatrane.

Results: The RSE achieved with gadoquatrane in steady-state head-and-neck MRI and multiphase liver MRI increased with dose in all anatomic structures examined, independent of the contrast-agent distribution phase and the pulse sequence employed. Linear regression analysis showed that generally a linear model fitted the dose-response data well ( r2 ≥ 0.84). However, in spin-echo images of the cavernous sinus and VIBE images of the hepatic vein, the areas with the strongest RSE, a disproportionately low RSE was seen with the highest gadoquatrane dose ( r2 of 0.78 and 0.48, respectively).RSE equivalent to the RSE achieved with gadoterate meglumine and gadobutrol at standard dose was achieved with gadoquatrane at doses between 0.031 to 0.039 mmol Gd/kg and 0.040 to 0.049 mmol Gd/kg, respectively. Largely parallel RSE-versus-time curves suggest similar signal-enhancement kinetics for gadoquatrane and the comparators.

Conclusions: The study suggests that gadoquatrane, which demonstrated signal-enhancement kinetics similar to those of gadobutrol and gadoterate meglumine, might be utilized effectively at a dose below 0.05 mmol Gd/kg body weight, independent of the anatomic structure investigated and the pulse sequence employed. Overall, the study supports and complements the results of the clinical dose-response study of gadoquatrane.

Objectives: Diffusion weighted imaging (DWI) is a key component of multiparametric (mp) prostate MRI. DWI using echo-planar techniques is susceptible to distortion at the recto-prostatic air-tissue interface. This study was to determine whether prone patient positioning reduces adjacent rectal air and DW image distortion when compared with standard-of-care supine positioning.

Materials and methods: This prospective study included consecutive patients undergoing mpMRI for suspected PCa between 2023 and 2024. Prostate segmentation was performed on DW and contrast-enhanced images. DWI distortion was measured quantitatively. Qualitative image quality of DWI and T2-weighted imaging (T2WI) was evaluated using PI-QUAL version 2; a separate 5-point clinically based Likert scale was employed to evaluate the volume of rectal air adjacent to the prostate.

Results: Fifty-two patients were enrolled. In total, 58% of patients expressed a preference for supine imaging versus 20% for prone imaging. Qualitative DWI image quality improved significantly in the prone position [median: 4 (3 to 4)] versus supine [3 (1 to 4)]; P < 0.001. In contrast, prone T2WI quality [1 (1 to 1)] was significantly inferior than supine T2WI [3 (3-4)]; P < 0.001. Quantitative measures of rectal air were significantly lower for prone [1.13 cm 3 (0.34-2.43)] compared with supine imaging [1.96 cm 3 (0.47 to 5.81); P = 0.005]. There was no significant difference in distortion between prone [3.21 mm (2.42 to 3.82) and supine [2.95 mm (2.25 to 4.21)] positioning across all patients ( P = 0.80); however, in patients with >4 cm 3 of supine rectal air (n = 19), distortion was significantly reduced by prone imaging [3.49 mm (2.84 to 4.03)] compared with supine [4.60 mm (3.17 to 5.95)]; P = 0.02. The mean additional scanning time for the necessary prone imaging was 8 minutes 18 seconds.

Conclusions: Prone positioning significantly reduces DWI distortion artefact when rectal air is present, but consistently results in degraded T2WI quality.

Objectives: The primary objective of this study was to evaluate the visualization capability of orally administered manganese chloride tetrahydrate (ACE-MBCA [Ascelia Pharma-manganese-based contrast agent, also referred to as Orviglance or CMC-001]), a novel liver-specific contrast agent developed by Ascelia Pharma, as a liver-specific MRI contrast agent compared with that of the unenhanced MRI for focal liver lesions in a properly blinded study design. The secondary objective was to compare the performance of ACE-MBCA with gadobenate dimeglumine.

Materials and methods: Three independent readers analyzed MRI examinations from a previously completed randomized crossover clinical trial in a blinded manner in a centralized setting. The study included 20 consecutive adult patients with known or suspected liver metastases, who received both ACE-MBCA and gadobenate dimeglumine. The readers evaluated 6 types of MRI scans (unenhanced, enhanced, and combined MRI for both contrast agents) with lesion visualization [lesion border delineation (LBD) and lesion contrast (LC)] as primary outcome. To maintain the blinded nature of the study, all statistical analyses were performed by an independent statistician who was not involved in the image reading process. Differences in primary outcomes were performed using 1-sided paired t tests at a significance level of 0.025 for both parameters. For secondary outcomes (ACE-MBCA enhanced MRI visualization, lesion detection, size measurements, reader confidence, quantitative parameters, and image quality were compared with that of the other scans), descriptive statistics and 95% confidence intervals were used to evaluate differences between categories in comparative analyses, without formal hypothesis testing for most secondary endpoints.

Results: ACE-MBCA-enhanced MRI demonstrated statistically significant superior scoring over unenhanced MRI for visualizing focal liver lesions, with mean LBD scores improving from 1.8-2.3 to 2.4-2.9 and LC scores ranging from 1.8-2.3 to 2.8-3.3 across all 3 readers ( P  < 0.001). Compared with unenhanced MRI, ACE-MBCA detected significantly more lesions across all readers (mean differences 0.4-0.8 lesions, 95% CI: 0.04-1.52), particularly for small lesions (<1 cm), where detection improved from 2-6 to 3-12 lesions. Liver-to-lesion contrast and contrast-to-noise ratios were also significantly higher after ACE-MBCA enhancement. All visualization parameters of ACE-MBCA were comparable to those of gadobenate dimeglumine, with no significant differences.

Conclusions: Compared with unenhanced MRI, ACE-MBCA MRI resulted in superior visualization and a greater number of detected liver lesions. ACE-MBCA and gadobenate dimeglumine performed similarly in the visualization and detection of colorectal liver metastases.

Objective: Contrast-enhanced ultrasound (CEUS) can be used to effectively monitor hepatocellular carcinoma (HCC) treatment response to percutaneous ablation and transarterial chemoembolization. Here, we performed a supplementary analysis of a prospective study to evaluate HCC participants treated with yttrium-90 transarterial radioembolization (Y90-TARE). We evaluated the utility of quantifiable parameters obtained from CEUS up to 2 weeks posttreatment for predicting treatment response compared with the standard of care cross-sectional imaging performed 2 to 6 months posttreatment (reference standard).

Materials and methods: In this IRB-approved, prospective clinical trial, participants with HCC scheduled for Y90-TARE underwent 3 CEUS sessions. These sessions occurred 1 to 4 hours post-Y90-TARE, 1 week, and 2 weeks posttreatment. Each CEUS examination involved a 10-minute infusion of Optison (GE HealthCare) using an Acuson Sequoia 2.0 or a HELX S3000 scanner (Siemens Healthineers) with 6C1 transducer. During each CEUS examination, flash-replenishment sequences were performed at the tumor midline for CEUS replenishment imaging. Changes between baseline and 1 or 2 weeks were used for quantitative analyses. Fractional tumor vascularity (FTV in %), perfusion (in mL/s*mg), peak enhancement (au), and time to peak (TTP in seconds) were calculated offline using Matlab (MathWorks) to quantitatively evaluate TARE response. Two abdominal radiologists read the reference standard MRI or CT obtained post-Y90-TARE and characterized the tumor as nonviable (complete response) or viable (partial response/stable disease). Unpaired t tests were performed to evaluate differences in nonviable versus viable disease. ROC analysis and logistic regression were evaluated to determine diagnostic performance and disease prediction.

Results: Final analysis included 38 participants. Of these, 22 had nonviable disease (58%, 22/38) and 16 had viable disease (42%, 16/38). FTV showed a difference between nonviable and viable tumors at 2 weeks post-Y90-TARE (38% ± 24% vs 62% ± 28%, P = 0.008). In addition, there was a statistically significant difference in the change in FTV from immediately post-Y90-TARE to 2 weeks after treatment between participants with viable and nonviable disease (41% ± 31% vs 11% ± 26%, P = 0.006). No significant difference was found between viable and nonviable disease across examinations for any of the other variables (P > 0.13).

Conclusions: Quantitative CEUS appears to provide an early indicator of treatment response ∼2 weeks post-Y90-TARE.