Is a timely assessment of the hematocrit necessary for cardiovascular magnetic resonance-derived extracellular volume measurements?

BACKGROUND: Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) requires a hematocrit (Hct) to correct contrast volume distributions in blood. However, the timely assessment of Hct can be challenging and has limited the routine clinical application of ECV. The goal of the present study was to evaluate whether ECV measurements lead to significant error if a venous Hct was unavailable on the day of CMR. METHODS: 109 patients with CMR T1 mapping and two venous Hcts (Hct0: a Hct from the day of CMR, and Hct1: a Hct from a different day) were retrospectively identified. A synthetic Hct (Hctsyn) derived from native blood T1 was also assessed. The study used two different ECV methods, (1) a conventional method in which ECV was estimated from native and postcontrast T1 maps using a region-based method, and (2) an inline method in which ECV was directly measured from inline ECV mapping. ECVs measured with Hct0, Hct1, and Hctsyn were compared for each method, and the reference ECV (ECV0) was defined using the Hct0. The error between synthetic (ECVsyn) and ECV0was analyzed for the two ECV methods. RESULTS: ECV measured using Hct1 and Hctsyn were significantly correlated with ECV0 for each method. No significant differences were observed between ECV0 and ECV measured with Hct1 (ECV1; 28.4 ± 6.6% vs. 28.3 ± 6.1%, p = 0.789) and between ECV0 and ECV calculated with Hctsyn (ECVsyn; 28.4 ± 6.6% vs. 28.2 ± 6.2%, p = 0.45) using the conventional method. Similarly, ECV0 was not significantly different from ECV1 (28.5 ± 6.7% vs. 28.5 ± 6.2, p = 0.801) and ECVsyn (28.5 ± 6.7% vs. 28.4 ± 6.0, p = 0.974) using inline method. ECVsyn values revealed relatively large discrepancies in patients with lower Hcts compared with those with higher Hcts. CONCLUSIONS: Venous Hcts measured on a different day from that of the CMR examination can still be used to measure ECV. ECVsyn can provide an alternative method to quantify ECV without needing a blood sample, but significant ECV errors occur in patients with severe anemia.

In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans.

Extra-vascular molecular clearance routes from the brain and cerebrospinal fluid (CSF) remain insufficiently characterized in humans. Animal studies consistently suggest that the cribriform plate and nasal lymphatic vessels are crucial for molecular clearance from CSF. In this study, we aimed to examine human in vivo transport of a CSF tracer from CSF to nasal mucosa. We hypothesised a CSF tracer would enrich in nasal mucosa provided that nasal lymphatic drainage has a significant role in CSF molecular clearance. Consecutive magnetic resonance imaging during 48 h after intrathecal administration of a tracer (gadobutrol) was performed in 24 patients. Despite a strong enrichment of CSF tracer in CSF spaces nearby the cribriform plate, there was no significant enrichment of CSF tracer in nasal mucosa, as measured in superior, medial and inferior turbinates, or in the nasal septum. Therefore, this in vivo study questions the importance of CSF drainage to the human nasal mucosa and emphasizes the need of further human studies.

Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177Lu-DOTATOC therapy.

BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). METHODS: A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. RESULTS: The average dose values per cycle were 3.41 ± 1.28 Gy (1.91-6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14-11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47-39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1-2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p = < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation: = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. CONCLUSION: These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters.

Topical Sensor for the Assessment of Injection Quality for 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE Positron Emission Tomography.

INTRODUCTION: Calculation of the standard uptake value (SUV) and image quality in positron emission tomography (PET) hinges on accurate dose delivery. Extravasation or partial extravasation of the radiopharmaceutical dose can undermine SUV and image quality, and contribute to unnecessary imaging (time and CT dose). Topical sensor characterisation of injections has been reported, with extravasation rates ranging from 9% to 23% for 18F-FDG after manual injection. METHOD: A single site, single PET/CT scanner was used to characterise injections using an autoinjector with standardised apparatus, flush volume and infusion rate using 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE; more reflective of Australian PET facilities. 296 patients with topical application of LARA sensors were retrospectively analysed. RESULTS: Only 1.1% of studies showed evidence of partial dose extravasation. In total, 9.1% were identified to have an injection anomaly (including venous retention). No statistically significant differences were noted across the radiopharmaceuticals for demographic data. Although not demonstrating a statistically significant correlation, there was more extravasated doses associated with female patients (P = .334), right side (P = .372), and hand injections (P = .539). Extravasation was independent of dose administered (P = .495), the radiopharmaceutical (P = .887), who injected the dose (P = .343), height (P = .438), weight (P = .607) or age (P = .716). Extravasation was associated with higher glucose levels (P < .001), higher t-half (P = .019) and higher aUCR10, tc50, aUCR1 and c1 (all P < .001). CONCLUSION: Topical monitoring and characterisation of PET dose administration is possible and practical with the LARA device. Extravasation and partial extravasation of PET doses are not only readily detected but they are also preventable. The LARA device can provide the insights into variables that could eliminate extravasation as a cause of image quality or SUV accuracy issues.

The usefulness of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) sequences visual assessment in the early diagnosis of axial spondyloarthritis.

The aim of the study was to compare the diagnostic efficacy of the visual assessment of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) sequences compared to the STIR sequence in the diagnostics of active sacroiliitis in the course of axial spondyloarthritis (axSpA). The study group consisted of 49 patients who had undergone multiparametric magnetic resonance imaging of the sacroiliac joints (SIJs) due to clinical suspicion of axSpA. Two independent observers retrospectively assessed four quadrants of the SIJs for the presence of subchondral bone marrow oedema/osteitis with the use of modified SPARCC score in sequences: STIR, DWI (with ADC map) and DCE. Diagnostic efficiency parameters were calculated for DWI and DCE sequence separately, using STIR sequence as a reference. Inter-observer agreement was evaluated with the use of κ coefficient. Patients' clinical symptoms were analysed to identify the group fulfilling the imaging arm of the ASAS criteria for axSpA. Overall, 46.9% (n = 23) of patients fulfilled the imaging arm of ASAS criteria for axial spondyloarthritis. DWI with ADC map: accuracy 95.6%, sensitivity 99.4%, specificity 54.0%. DCE sequence: accuracy 96.8%, sensitivity 98.4%, specificity 79.5%. The highest level of inter-observer agreement was achieved for STIR sequence (κ = 0.888), slightly lower for DCE sequence (κ = 0.773) and the lowest for DWI with ADC (κ = 0.674). Visual assessment of the DWI and DCE sequences has high accuracy and sensitivity of bone marrow oedema/osteitis detection, but the specificity and inter-observer agreement are poor, especially for the DWI sequence with ADC maps.

Conservative gadolinium administration to patients with Duchenne muscular dystrophy: decreasing exposure, cost, and time, without change in medical management.

Cardiac MR (CMR) is increasingly used to assess for cardiac involvement in patients with Duchenne muscular dystrophy (DMD). The frequent use of gadolinium based contrast agents (GBCAs) has been called into question with reports of intracranial gadolinium deposition in patients receiving multiple administrations. We adopted a conservative GBCA administration policy, limiting the frequency of GBCA exposure in patients with previously documented late gadolinium enhancement. The aim of our study was to evaluate the clinical effects of this policy change. Data were retrospectively reviewed on 405 consecutive patients with DMD who underwent CMR evaluation. Patients were grouped into conservative GBCA administration or historical control. CMR reports were evaluated and clinical reports were reviewed to determine actionable changes. Ohio Medicaid reimbursements were used to estimate costs. A total of 187 patients comprised the conservative GBCA group and 218 patients the historical cohort. The conservative GBCA group had lower contrast administration rates (84% vs. 99%, p < 0.0001), shorter scan times (35.2 vs. 39.0 min, p < 0.0001), and lower estimated medical costs ($339 vs. $351/study). There was no change regarding the initial presence of first-time late gadolinium enhancement, and no difference in actionable change. Contrast administration substantially decreased 7 months post-policy change (65%) compared to the initial 7 months (96%, p < 0.0001). In the current era with unclear concern for intracranial gadolinium deposition, thoughtful GBCA administration is warranted in patients anticipated to undergo multiple CMRs. Our updated approach has resulted in fewer patients receiving contrast, shorter scan times, and less medical costs, without appreciable changes to patient management.

Validation of contrast enhanced cine steady-state free precession and T2-weighted CMR for assessment of ischemic myocardial area-at-risk in the presence of reperfusion injury.

The purpose of the study was to validate by histopathology, contrast enhanced cine steady-state free precession and T2-weighted CMR for the assessment of ischemic myocardial area-at-risk (AAR) in the presence of microvascular obstruction (MVO). Eleven anesthetized pigs underwent CMR 7 to 10 days post infarction. The area-at-risk was measured from T2-weighted fast spin echo (T2-STIR) and contrast-enhanced steady-state free precession magnetic resonance imaging (CE-SSFP) images using semi-automated algorithms based on a priori knowledge of perfusion territory. Also, late gadolinium enhancement (LGE) was performed to measure final infarct size (FIS). Histopathological comparison with Evans blue dye to define AAR and triphenyltetrazolium chloride to define FIS served as the reference. All infarcts demonstrated MVO on LGE images. Bland-Altman analysis showed no significant bias in AAR or myocardial salvage between T2-STIR and CE-SSFP or between CMR and histopathology. The mean differences ± 2SD from Bland-Altman analysis were: AAR: Evans Blue vs. T2-STIR [0.7%; + 13.5%; - 12.1%]; AAR: Evans Blue vs. CE-SSFP [0.1%; + 13.8%; - 13.7%]; AAR: T2-STIR vs. CE-SSFP [0.7%; + 6.2%; - 4.9%]; Salvage: Evans Blue - TTC vs. T2-STIR-LGE [0.8%; + 11.1%; - 9.6%]; Salvage: Evans Blue - TTC vs. CE-SSFP-LGE [0.1%; + 9.9%; - 9.6%]; Salvage: CE-SSFP-LGE vs. T2-STIR-LGE [0.7%; + 6.2%; - 4.9%]. Both T2-STIR and CE-SSFP sequences allow for unbiased quantification of AAR in the presence of ischemia/reperfusion injury when analysed by semi-automated algorithms. These experimental data, which was validated by histopathology, supports the use of CMR for the assessment of myocardial salvage during the subacute phase.

Comparison the cost-efficacy of furazolidone-based versus clarithromycin-based quadruple therapy in initial treatment of Helicobacter pylori infection in a variable clarithromycin drug-resistant region, a single-center, prospective, randomized, open-label study.

Helicobacter pylori (Hp) drug resistant rate to clarithromycin (CLA) has increased to 20% to 50%, which cause concerns regarding its effectiveness in eradicating Hp, we aim to evaluate the cost-effectiveness of CLA-based versus furazolidone (FZD)-based quadruple therapy, and assess factors that affect anti-Hp efficacy.One hundred eighty-five patients were enrolled in this single-center, prospective, randomized, open-label study. In FZD group, 92 patients were treated with FZD plus esomeprazole, bismuth potassium citrate, and amoxicillin for 14 days. In CLA group, 93 patients were treated with the same regimen except FZD was replaced by CLA. Patients were tested 4 weeks post-treatment to confirm eradication.Of the 185 enrolled patients, 180 completed the study. On intention-to-treat analysis, Hp eradication rates in FZD and CLA groups were 90.22% and 86.02% (P = .378); in per-protocol analysis, their eradication rates were 93.26% and 87.91%, respectively (P = .220). Overall incidence of total side effects in FZD and CLA groups was 19.57% and 13.98%, and their severe side effects were 3.26% and 2.15%, respectively (P > .05). Cost-effectiveness ratios of FZD and CLA groups were 0.75 and 1.02, and incremental cost-effectiveness ratio of FZD group over CLA group was -3.62. Eradication failures were not associated with factors including gender, age, body mass index, smoking, alcohol consumption, educational level, and urban-rural distribution in this observation (P > .05).Despite increasing drug resistance to CLA, Hp eradication rates in FZD and CLA groups have no significant difference at present; as FZD-based quadruple therapy is more cost-effective, we recommend this regimen be a first-line choice for Hp eradication.

Comparisons of Efficacy, Safety, and Cost of Chemotherapy Regimens FOLFOX4 and FOLFIRINOX in Rectal Cancer: A Randomized, Multicenter Study.

BACKGROUND The currently available chemotherapeutic regimens do not use a specifically designed drug delivery system. The objective of this study was to compare outcome measures, adverse effects, and cost of FOLFOX4 and FOLFIRINOX treatments in rectal cancer patients. MATERIAL AND METHODS We enrolled patients who, after surgery, did not undergo chemotherapy or radiotherapy (Control group); were administered 200 mg/m² folinic acid, 400 mg/m² fluorouracil, and 85 mg/m² oxaliplatin (FFO group); or were administered 400 mg/m² folinic acid, 400 mg/m² fluorouracil, 180 mg/m² irinotecan, and 85 mg/m2 oxaliplatin (FFIO group). We recorded tumor and nodal staging, carbohydrate antigen 19-9, serum carcinoembryonic antigen, total cost of treatment, disease recurrence, overall survival, and adverse effects. We used the 2-tailed paired t test following Turkey post hoc test for adverse effects, recurrence analysis, and cost of treatment at 95% of confidence level. RESULTS Surgery (p=0.00089), FOLFOX4 (p=0.000167), and FOLFIRINOX (p=0.00013) improved disease-free conditions. Only surgery failed to maintain carbohydrate antigen and carcinoembryonic antigen 19-9 levels. The cost of chemotherapeutic treatments was in the order of FFIO group > FFO group > Control group. Non-fatal treatment-emergent adverse effects were due to chemotherapeutic drugs. However, fatal chemotherapeutic treatment-emergent adverse effects were observed only in the FFIO group. Overall survival, irrespective of cancerous condition, was higher in the FFO group. CONCLUSIONS FOLFIRINOX had less total cancer recurrence than FOLFOX4. However, FOLFIRINOX had more fatal treatment-emergent adverse effects and excessive cost of treatment than FOLFOX4 regimen.

T1 Shortening in the Globus Pallidus after Multiple Administrations of Gadobutrol: Assessment with a Multidynamic Multiecho Sequence.

Purpose To determine the association between the administration of the macrocyclic contrast medium gadobutrol and T1 relaxation time in the brains of patients with normal renal function by using multidynamic multiecho (MDME) magnetic resonance (MR) imaging sequences. Materials and Methods The institutional review board approved this retrospective study, and the need to obtain written informed consent was waived. This study included 46 patients (revealed by an electronic medical record search) who had received one or more gadobutrol injections and a maximum of one MR imaging contrast medium injection other than gadobutrol before MDME sequence acquisition. One radiologist performed quantitative analyses of regions of interest on quantitative T1 maps twice to cover the normal-appearing globus pallidus (GP), frontal white matter, frontal cortex, and thalamus. The number of administrations and the cumulative dose of gadobutrol, age, intervals between administrations, sex, and treatment were investigated. Univariable and multivariable linear regression analyses of the T1 values in four brain regions and the GP-to-thalamus signal intensity (SI) ratio were performed. P values of less than the Bonferroni-corrected value of .01 were considered to indicate significant differences. Results Intraobserver reproducibility was good to excellent (intraclass correlation coefficients, 0.62-0.81). Because of high multicollinearity between the number of gadobutrol administrations and accumulated dose (r = 0.96, P < .001), the number of gadobutrol administrations was considered in the regression analyses. T1 shortening in the GP was independently associated with the number of gadobutrol administrations (P = .002). T1 in the other brain regions and the GP-to-thalamus SI ratio were not significantly associated with the number of gadobutrol administrations (P > .01). Conclusion Multiple exposures to gadobutrol are associated with T1 shortening in the GP. © RSNA, 2017 Online supplemental material is available for this article.

Non-clinical assessment of safety and gadolinium deposition after cumulative administration of gadobenate dimeglumine (MultiHance®) to neonatal and juvenile rats.

To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology. Gadolinium presence in brain, femur, kidneys, liver and skin was determined using inductively coupled plasma-mass spectrometry (ICP-MS). No effects of MultiHance on behavior, cognitive function or any other parameter were noted, even for the highest administered cumulative dose (15 mmol/kg). Gadolinium presence was variable across tissues and decreased during the 60-day treatment-free period. The highest levels were noted in the femur and the lowest levels in the brain. Gadolinium presence in juvenile rat brain following single or repeated MultiHance administrations was minimal and non-impactful.

Optimized CEST cardiovascular magnetic resonance for assessment of metabolic activity in the heart.

BACKGROUND: Previous studies have linked cardiac dysfunction to loss of metabolites in the creatine kinase system. Chemical exchange saturation transfer (CEST) is a promising metabolic cardiovascular magnetic resonance (CMR) imaging technique and has been applied in the heart for creatine mapping. However, current limitations include: (a) long scan time, (b) residual cardiac and respiratory motion, and (c) B0 field variations induced by respiratory motion. An improved CEST CMR technique was developed to address these problems. METHODS: Animals with chronic myocardial infarction (N = 15) were scanned using the proposed CEST CMR technique and a late gadolinium enhancement (LGE)  sequence as reference. The major improvements of the CEST CMR technique are: (a) Images were acquired by single-shot FLASH, significantly increasing the scan efficiency. (b) All images were registered to reduce the residual motion. (c) The acquired Z-spectrum was analyzed using 3-pool-model Lorentzian-line fitting to generate CEST signal, reducing the impact of B0 field shifting due to respiratory motion. Feasibility of the technique was tested in a porcine model with chronic myocardial infarction. CEST signal was measured in the scar, border zone and remote myocardium. Initial studies were performed in one patient. RESULTS: In all animals, healthy remote myocardial CEST signal was elevated (0.16 ± 0.02) compared to infarct CEST signal (0.09 ± 0.02, P < 0.001) and the border zone (0.12 ± 0.02, P < 0.001). For both animal and patient studies, the hypointense regions in the CEST contrast maps closely match the bright areas in the LGE images. CONCLUSIONS: The proposed CEST CMR technique was developed to address long scan times, respiratory and cardiac motion, and B0 field variations. Lower CEST signal in bright region of the LGE image is consistent with the fact that myocardial infarction has reduced metabolic activity.

T1-refBlochi: high resolution 3D post-contrast T1 myocardial mapping based on a single 3D late gadolinium enhancement volume, Bloch equations, and a reference T1.

BACKGROUND: High resolution 3D T1 mapping is important for assessment of diffuse myocardial fibrosis in left atrium or other thin-walled structures. In this work, we investigated a fast single-TI 3D high resolution T1 mapping method that directly transforms a 3D late gadolinium enhancement (LGE) volume to a 3D T1 map. METHODS: The proposed method, T1-refBlochi, is based on Bloch equation modeling of the LGE signal, a single-point calibration, and assumptions that proton density and T2* are relatively uniform in the heart. Several sources of error of this method were analyzed mathematically and with simulations. Imaging was performed in phantoms, eight swine and five patients, comparing T1-refBlochi to a standard spin-echo T1 mapping, 3D multi-TI T1 mapping, and 2D ShMOLLI, respectively. RESULTS: The method has a good accuracy and adequate precision, even considering various sources of error. In phantoms, over a range of protocols, heart-rates and T1 s, the bias ±1SD was -3 ms ± 9 ms. The porcine studies showed excellent agreement between T1-refBlochi and the multi-TI method (bias ±1SD = -6 ± 22 ms). The proton density and T2* weightings yielded ratios for scar/blood of 0.94 ± 0.01 and for myocardium/blood of 1.03 ± 0.02 in the eight swine, confirming that sufficient uniformity of proton density and T2* weightings exists among heterogeneous tissues of the heart. In the patients, the mean T1 bias ±1SD in myocardium and blood between T1-refBlochi and ShMOLLI was -9 ms ± 21 ms. CONCLUSION: T1-refBlochi provides a fast single-TI high resolution 3D T1 map of the heart with good accuracy and adequate precision.

In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy.

BACKGROUND: Absorbed doses for α-emitters are different from those for ß-emitters, as the high linear energy transfer (LET) nature of α-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE), 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu-DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Carlo model of a cylindrical 6-well plate geometry for the exposure by the radioactive incubation medium. Absorbed doses were compared to conventional irradiation of cells with 137Cs and the relative biological effect (RBE) at 10% survival was calculated. RESULTS: IC50 of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq 213Bi-DOTATATE, in majority the dose was caused by α-particle radiation. Cellular internalization determined with 111In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of 213Bi-DTPA and 213Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of 213Bi. The survival of CA20948 after exposure to 177Lu-DOTATATE and the reference 137Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with 213Bi-DOTATATE, a factor 6 lower than the 18 Gy found for 177Lu-DOTATATE and also below the 5 Gy after 137Cs external exposure. CONCLUSION: 213Bi-DTPA and 213Bi-DOTATATE lead to a factor 6 advantage in cell killing compared to 177Lu-DOTATATE. The RBE at 10% survival by 213Bi-ligand compared to 137Cs was 2.0 whereas the RBE for 177Lu-DOTATATE was 0.3 in the CA20948 in vitro model.

Cost-effectiveness of meglumine antimoniate versus miltefosine caregiver DOT for the treatment of pediatric cutaneous leishmaniasis.

BACKGROUND: Oral miltefosine has been shown to be non-inferior to first-line, injectable meglumine antimoniate (MA) for the treatment of cutaneous leishmaniasis (CL) in children. Miltefosine may be administered via in-home caregiver Directly Observed Therapy (cDOT), while patients must travel to clinics to receive MA. We performed a cost-effectiveness analysis comparing miltefosine by cDOT versus MA for pediatric CL in southwest Colombia. METHODOLOGY/PRINCIPLE FINDINGS: We developed a Monte Carlo model comparing the cost-per-cure of miltefosine by cDOT compared to MA from patient, government payer, and societal perspectives (societal = sum of patient and government payer perspective costs). Drug effectiveness and adverse events were estimated from clinical trials. Healthcare utilization and costs of travel were obtained from surveys of providers and published sources. The primary outcome was cost-per-cure reported in 2015 USD. Treatment efficacy, costs, and adherence were varied in sensitivity analysis to assess robustness of results. Treatment with miltefosine resulted in substantially lower cost-per-cure from a societal and patient perspective, and slightly higher cost-per-cure from a government payer perspective compared to MA. Mean societal cost-per-cure were $531 (SD±$239) for MA and $188 (SD±$100) for miltefosine, a mean cost-per-cure difference of +$343. Mean cost-per-cure from a patient perspective were $442 (SD ±$233) for MA and $30 (SD±$16) for miltefosine, a mean difference of +$412. Mean cost-per-cure from a government perspective were $89 (SD±$55) for MA and $158 (SD±$98) for miltefosine, with a mean difference of -$69. Results were robust across a variety of assumptions in univariate and multi-way analysis. CONCLUSIONS/SIGNIFICANCE: Treatment of pediatric cutaneous leishmaniasis with miltefosine via cDOT is cost saving from patient and societal perspectives, and moderately more costly from the government payer perspective compared to treatment with MA. Results were robust over a range of sensitivity analyses. Lower drug price for miltefosine could result in cost saving from a government perspective.

Assessment of myocardial injury after reperfused infarction by T1ρ cardiovascular magnetic resonance.

BACKGROUND: The evolution of T1ρ and of other endogenous contrast methods (T2, T1) in the first month after reperfused myocardial infarction (MI) is uncertain. We conducted a study of reperfused MI in pigs to serially monitor T1ρ, T2 and T1 relaxation, scar size and transmurality at 1 and 4 weeks post-MI. METHODS: Ten Yorkshire swine underwent 90 min of occlusion of the circumflex artery and reperfusion. T1ρ, T2 and native T1 maps and late gadolinium enhanced (LGE) cardiovascular magnetic resonance (CMR) data were collected at 1 week (n = 10) and 4 weeks (n = 5). Semi-automatic FWHM (full width half maximum) thresholding was used to assess scar size and transmurality and compared to histology. Relaxation times and contrast-to-noise ratio were compared in healthy and remote myocardium at 1 and 4 weeks. Linear regression and Bland-Altman was performed to compare infarct size and transmurality. RESULTS: Relaxation time differences between infarcted and remote myocardial tissue were ∆T1 (infarct-remote) = 421.3 ± 108.8 (1 week) and 480.0 ± 33.2 ms (4 week), ∆T1ρ = 68.1 ± 11.6 and 74.3 ± 14.2, and ∆T2 = 51.0 ± 10.1 and 59.2 ± 11.4 ms. Contrast-to-noise ratio was CNRT1 = 7.0 ± 3.5 (1 week) and 6.9 ± 2.4 (4 week), CNRT1ρ = 12.0 ± 6.2 and 12.3 ± 3.2, and CNRT2 = 8.0 ± 3.6 and 10.3 ± 5.8. Infarct size was not significantly different for T1ρ, T1 and T2 compared to LGE (p = 0.14) and significantly decreased from 1 to 4 weeks (p < 0.01). Individual infarct size changes were ∆T1ρ = -3.8%, ∆T1 = -3.5% and ∆LGE = -2.8% from 1 - 4 weeks, but there was no observed change in infarct size for T2 or histologically. CONCLUSIONS: T1ρ was highly correlated with alterations left ventricle (LV) pathology at 1 and 4 weeks post-MI and therefore it may be a useful method endogenous contrast imaging of infarction.

Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats.

OBJECTIVE: Multiple clinical and preclinical studies have reported a signal intensity increase and the presence of gadolinium (Gd) in the brain after repeated administration of Gd-based contrast agents (GBCAs). This bioanalytical study in rat brain tissue was initiated to investigate whether the residual Gd is present as intact GBCA or in other chemical forms by using tissue fractionation and chromatography. MATERIALS AND METHODS: Rats were divided randomly in 6 groups of 10 animals each. They received 10 daily injections of 2.5 mmol/kg bodyweight of 1 of 5 different GBCAs: linear GBCAs such as gadodiamide (Omniscan; GE Healthcare), gadopentetate dimeglumine (Gd-DTPA, Magnevist; Bayer), or gadobenate dimeglumine (Multihance; Bracco) and macrocyclic GBCAs such as gadobutrol (Gadovist; Bayer) and gadoterate meglumine (Gd-DOTA, Dotarem; Guerbet) or saline. On days 3 and 24 after the last injection (p.i.), 5 randomly chosen animals of each group were killed by exsanguination, and their brains were excised and divided into cerebrum, pons, and cerebellum. The brain sections were homogenized by sonication in ice-cold buffer at pH 7.4. Soluble and insoluble fractions were separated by centrifugation, and the soluble fractions were further separated by gel permeation chromatography (GPC). The Gd concentration in all tissue fractions and in the GPC eluate was measured by inductively coupled plasma-mass spectrometry. In a recovery control experiment, all GBCAs were spiked to blank brain tissue and more than 94% recovery of Gd in the tissue fractions was demonstrated. RESULTS: Only traces of the administered Gd were found in the rat brain tissue on day 3 and day 24 p.i. In the animals treated with macrocyclic GBCAs, Gd was found only in the soluble brain fraction and was present solely as low molecular weight molecules, most likely the intact GBCA. In the animals treated with linear GBCAs Gd was found to a large extent in the insoluble tissue fraction. The Gd concentration in the soluble fraction was comparable to the macrocyclic agents. According to GPC, a smaller portion of the Gd in the soluble fraction of the linear GBCAs groups was bound to macromolecules larger than 250 to 300 kDa. The nature of the Gd-containing macromolecules and the insoluble species were not determined, but they appeared to be saturable with Gd. The excretion of the soluble Gd species in the linear and macrocyclic GBCA groups was still ongoing between days 3 and 24 p.i. This was also observed for the macromolecular Gd species in the linear GBCA groups, but at a slower rate. CONCLUSIONS: The residual Gd found in the rat brain after repeated administration of all 3 linear GBCAs was present in at least 3 distinctive forms-soluble small molecules, including the intact GBCA, soluble macromolecules, and to a large extent in insoluble form. The latter 2 are most likely responsible for the prolonged signal intensity enhancement in brain structures observed in magnetic resonance imaging. No relevant differences between the 3 linear GBCAs were observed. The Gd concentrations in the brain after administration of macrocyclic GBCAs are lower, and the Gd is only present in soluble small molecules, which were slowly excreted. This underlines the crucial importance of the kinetic inertness of macrocyclic agents in the prevention of potential retention of Gd in the brain compared with the 3 linear, kinetically less restricted GBCAs.

Assessment of myocardial delayed enhancement with cardiac computed tomography in cardiomyopathies: a prospective comparison with delayed enhancement cardiac magnetic resonance imaging.

To evaluate the feasibility of cardiac CT for the evaluation of myocardial delayed enhancement (MDE) in the assessment of patients with cardiomyopathy, compared to cardiac MRI. A total of 37 patients (mean age 54.9 ± 15.7 years, 24 men) who underwent cardiac MRI to evaluate cardiomyopathy were enrolled. Dual-energy ECG-gated cardiac CT was acquired 12 min after contrast injection. Two observers evaluated cardiac MRI and cardiac CT at different kV settings (100, 120 and 140 kV) independently for MDE pattern-classification (patchy, transmural, subendocardial, epicardial and mesocardial), differentiation between ischemic and non-ischemic cardiomyopathy and MDE quantification (percentage MDE). Kappa statics and the intraclass correlation coefficient were used for statistical analysis. Among different kV settings, 100-kV CT showed excellent agreements compared to cardiac MRI for MDE detection (κ = 0.886 and 0.873, respectively), MDE pattern-classification (κ = 0.888 and 0.881, respectively) and differentiation between ischemic and non-ischemic cardiomyopathy (κ = 1.000 and 0.893, respectively) for both Observer 1 and Observer 2. The Bland-Altman plot between MRI and 100-kV CT for the percentage MDE showed a very small bias (-0.15%) with 95% limits of agreement of -7.02 and 6.72. Cardiac CT using 100 kV might be an alternative method to cardiac MRI in the assessment of cardiomyopathy, particularly in patients with contraindications to cardiac MRI.

Prognostic Benefit of Cardiac Magnetic Resonance Over Transthoracic Echocardiography for the Assessment of Ischemic and Nonischemic Dilated Cardiomyopathy Patients Referred for the Evaluation of Primary Prevention Implantable Cardioverter-Defibrillator Therapy.

BACKGROUND: The aim of this study was to determine the prognostic benefit of cardiac magnetic resonance (CMR) over transthoracic echocardiography (TTE) in ischemic cardiomyopathy and nonischemic dilated cardiomyopathy patients evaluated for primary prevention implantable cardioverter-defibrillator therapy. METHODS AND RESULTS: We enrolled 409 consecutive ischemic and dilated cardiomyopathy patients (mean age: 64±12 years; 331 men). All patients underwent TTE and CMR, and left ventricle end-diastolic volume, left ventricle end-systolic volume, and left ventricle ejection fraction (LVEF) were evaluated. In addition, late gadolinium enhancement was also assessed. All patients were followed up for major adverse cardiac events (MACE) defined as a composite end point of long runs of nonsustained ventricular tachycardia, sustained ventricular tachycardia, aborted sudden cardiac death, or sudden cardiac death. The median follow-up was 545 days. CMR showed higher left ventricle end-diastolic volume (mean difference: 43±22.5 mL), higher left ventricle end-systolic volume (mean difference: 34±20.5 mL), and lower LVEF (mean difference: -4.9±10%) as compared to TTE (P<0.01). MACE occurred in 103 (25%) patients. Patients experiencing MACE showed higher left ventricle end-diastolic volume, higher left ventricle end-systolic volume, and lower LVEF with both imaging modalities and higher late gadolinium enhancement per-patient prevalence as compared to patients without MACE. At multivariable analysis, CMR-LVEF ≤35% (hazard ratio=2.18 [1.3-3.8]) and the presence of late gadolinium enhancement (hazard ratio=2.2 [1.4-3.6]) were independently associated with MACE (P<0.01). A model based on CMR-LVEF ≤35% or CMR-LVEF ≤35% plus late gadolinium enhancement detection showed a higher performance in the prediction of MACE as compared to TTE-LVEF resulting in net reclassification improvement of 0.468 (95% confidence interval, 0.283-0.654; P<0.001) and 0.413 (95% confidence interval, 0.23-0.63; P<0.001), respectively. CONCLUSIONS: CMR provides additional prognostic stratification as compared to TTE, which may have direct impact on the indication of implantable cardioverter-defibrillator implantation.

Non-clinical safety assessment of gadoterate meglumine (Dotarem(®)) in neonatal and juvenile rats.

The purpose of this study was to assess the safety of gadoterate meglumine, a gadolinium-based contrast agent used in magnetic resonance imaging, in neonatal and juvenile rats. Rats received a single intravenous administration on postnatal day (PND) 10 or 6 administrations (from PND 10 to 30), at doses of 0, 0.6, 1.25, and 2.5 mmol/kg/administration, i.e. equivalent to approximately 1, 2 and 4-times the usual human dose. The animals were sacrificed at the end of the treatment period or after a 60-day treatment-free period. No mortality and no significant treatment-related effect on clinical signs, macroscopic and histopathological findings, development, behavior, sexual maturation and hematology parameters were observed. Minor non-adverse changes were observed in clinical biochemistry and urinary parameters. Based on AUC0-t, gadoterate meglumine was more rapidly eliminated at PND 30 vs. PND 10, reflecting maturation of kidney function. At the end of the treatment period, Gd was measurable in all organs sampled after single or repeated dosing and levels were dose-dependent as expected, the highest ones being found in kidneys. The total Gd concentrations were similar in all the organs following a single or repeated dosing. At the end of the treatment-free period, only traces of gadolinium were quantifiable, almost exclusively in kidneys, reflecting the excretory function of this organ. In conclusion, single or repeated administration of gadoterate meglumine to juvenile rats was well tolerated.