Median T2 Research Articles

Enhanced superconducting qubit performance through ammonium fluoride etch

Abstract The performance of superconducting qubits is often limited by dissipation and two-level systems (TLS) losses. The dominant sources of these losses are believed to originate from amorphous materials and defects at interfaces and surfaces, likely as a result of fabrication processes or ambient exposure. Here, we explore a novel wet chemical surface treatment at the Josephson junction-substrate and the substrate-air interfaces by replacing a buffered oxide etch (BOE) cleaning process with one that uses hydrofluoric acid followed by aqueous ammonium fluoride. We show that the ammonium fluoride etch process results in a statistically significant improvement in median T1 by ~22% (p=0.002), and a reduction in the number of strongly-coupled TLS in the tunable frequency range. Microwave resonator measurements on samples treated with the ammonium fluoride etch after niobium deposition and etching also show ~33% lower TLS-induced loss tangent compared to the BOE treated samples. As the chemical treatment primarily modifies the Josephson junction-substrate interface and substrate-air interface, we perform targeted chemical and structural characterizations to examine materials differences at these interfaces and identify multiple microscopic changes that could contribute to decreased TLS.

Circulating interleukin-8 and osteopontin are promising biomarkers of clinical outcomes in advanced melanoma patients treated with targeted therapy

BackgroundCirculating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated.MethodsCytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan–Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals.ResultsCCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality.ConclusionCirculating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.

Tobacco use increases lesion burden in familial cerebral cavernous malformation syndrome

Background: Familial cerebral cavernous malformation (CCM) syndrome is characterized by multiple, non-contiguous cavernous malformations. The lesion burden may affect morbidity. Our aim was to identify risk factors for high lesion burden in these patients. Methods: Patients with radiologically confirmed CCM were screened between 2015 and 2023. Only familial or presumed familial CCM patients were included. Demographic information and medical history at the time of diagnosis were evaluated. The first diagnostic MRI was used to determine T2 total and T2 large lesion (≥5 mm) count. Chi-square was used to determine risk factors for total T2 large lesion count ≥5. Results: Of 107 patients with familial or presumed familial CCM (55.1 % female, age 42.4 years), the median total T2 lesion count and large lesion count was 4 (range: 1–109) and 2 (range: 0–50) respectively. Current tobacco use was a risk factor for T2 large lesion count ≥5. Conclusion: Further studies combining familial cohorts and assessing length of exposure may be useful to confirm tobacco as a risk factor for T2 large lesion formation in familial CCM.

High-resolution and highly accelerated MRI T2 mapping as a tool to characterise renal tumour subtypes and grades

BackgroundClinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades.MethodsTwenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades.ResultsHigh-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037).ConclusionsBoth high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades.Trial registrationClinicalTrials.gov, NCT03741426. Registered on 13 November 2018.Relevance statementThe newly developed T2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses.Graphical

Muscle MRI as a biomarker of disease activity and progression in myotonic dystrophy type 1: a longitudinal study

IntroductionMyotonic dystrophy type 1 (DM1) is an autosomal dominant disease characterized by myotonia and progressive muscular weakness and atrophy. The aim of this study was to investigate the usefulness of longitudinal muscle MRI in detecting disease activity and progression in DM1, and to better characterize muscle edema, fat replacement and atrophy overtime.Materials and methodsThis is a prospective, observational, longitudinal study including 25 DM1 patients that performed at least two muscle MRIs. Demographic and genetic characteristics were recorded. Muscular Impairment Rating Scale (MIRS) and MRC score were performed within 3 months from MRIs at baseline (BL) and at follow-up (FU). We analysed 32 muscles of lower body (LB) and 17 muscles of upper body (UB) by T1 and STIR sequences. T1-, STIR- and atrophy scores and their variations were evaluated. Correlations between MRIs’ scores and demographic, clinical and genetic characteristics were analysed.ResultsEighty (80%) of patients showed fat replacement progression at FU. The median T1 score progression (ΔT1-score) was 1.3% per year in LB and 0.5% per year in UB. The rate of fat replacement progression was not homogenous, stratifying patients from non-progressors to fast progressors (> 3% ΔT1-score per year). Half of the STIR-positive muscles at BL showed T1-score progression at FU. Two patients with normal MRI at baseline only showed STIR-positive muscle at FU, marking the disease activity onset. STIR positivity at baseline correlated with fat replacement progression (ΔT1-score; p < 0.0001) and clinical worsening at FU (ΔMRC-score; p < 0.0001). Sixty-five (65%) of patients showed STIR- and fat replacement-independent muscle atrophy progression, more evident in UB.ConclusionsMuscle MRI represents a sensitive biomarker of disease activity, severity, and progression in DM1. STIR alterations precede fat replacement and identify patients with a higher risk of disease progression, while T1-sequences reveal atrophy and fat replacement progression before clinical worsening.

Effect of optical diagnosis training on recognition and treatment of submucosal invasive colorectal cancer in community hospitals: a prospective multicenter intervention study.

Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91). Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.

Comparison of 2D and 3D oxygen-enhanced MRI of the placenta.

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) of the human placenta is potentially a sensitive marker of in vivo oxygenation. This methodological study shows that full coverage of the placenta is possible using 3D mapping of the change in longitudinal relaxation rate (ΔR1), in a group of healthy pregnant subjects breathing elevated levels of oxygen. Twelve pregnant subjects underwent a comparison of 2D and 3D OE-MRI. ΔR1 was mapped for a single 2D slice (ss-2D), a single matched-slice from the 3D volume (ss-3D) and the full 3D volume (vol-3D). The group-average median ΔR1 values for ss-3D (0.023 s-1) and vol-3D (0.022 s-1) do not differ significantly from ss-2D (0.020 s-1), when compared using a two-tailed paired t-test (ss-3D (p = 0.58) and vol-3D (p = 0.70)). However, median baseline T1 (T1b) for ss-2D was higher (1603 ms) than T1b for ss-3D (1540 ms, p = 0.07) and significantly higher than vol-3D (1515 ms, p = 0.02), when compared using a two-tailed paired t-test. In contrast with previous studies, no correlation of median ΔR1 with gestation age at scan for the normal group (N = 10) was observed for ss-2D, likely due to the smaller gestational range. Full volume OE-MRI maps reveal sensitivity to changes in ΔR1, with some participants showing an enhanced gradient in the intermediate space between the fetal and maternal sides of the placenta in the 3D data. This study shows that it is feasible to acquire whole placental volume OE-MRI data in women with healthy pregnancy.

Reduced T2*-weighted placental MRI predicts foetal growth restriction in women with chronic rheumatic disease—a Danish explorative study

ObjectivesWomen with chronic rheumatic disease (CRD) are at greater risk of foetal growth restriction than their healthy peers. T2*-weighted magnetic resonance imaging of placenta (T2*P-MRI) is superior to conventional ultrasonography in predicting birth weight and works as a proxy metabolic mirror of the placental function. We aimed to compare T2*P-MRI in pregnant women with CRD and healthy controls. In addition, we aimed to investigate the correlation between T2*P-MRI and birth weight.MethodsUsing a General Electric (GE) 1.5 Tesla, we consecutively performed T2*-weighted placental MRI in 10 women with CRD and 18 healthy controls at gestational week (GW)24 and GW32. We prospectively collected clinical parameters during pregnancy including birth outcome and placental weight.ResultsWomen with CRD had significantly lower T2*P-MRI values at GW24 than healthy controls (median T2*(IQR) 92.1 ms (81.6; 122.4) versus 118.6 ms (105.1; 129.1), p = 0.03). T2*P-MRI values at GW24 showed a significant correlation with birth weight, as the T2*P-MRI value was reduced in all four pregnancies complicated by SGA at birth. Three out of four pregnancies complicated by SGA at birth remained undetected by routine antenatal ultrasound.ConclusionThis study demonstrates reduced T2*P-MRI values and a high proportion of SGA at birth in CRD pregnancies compared to controls, suggesting an increased risk of placental dysfunction in CRD pregnancies. T2*P-MRI may have the potential to focus clinical vigilance by identifying pregnancies at risk of SGA as early as GW24.Key Points• Placenta-related causes of foetal growth restriction in women with rheumatic disease remain to be investigated.• T2*P-MRI values at gestational week 24 predicted foetuses small for gestational age at birth.• T2*P-MRI may indicate pregnant women with chronic rheumatic disease (CRD) in need of treatment optimization.

Abstract LB181: First disclosure of XRD-0394, a novel dual ATM/DNA-PK inhibitor, that potently radiosensitizes and potentiates PARP and topoisomerase inhibitors

Abstract A majority of cancer patients receive radiation therapy (RT) as part of their treatment regimens, whether using external beam therapy or locally-delivered radioisotopes. While often effective, RT may not be efficacious for some tumors while exerting significant short-term and long-term toxicities. Thus, enhancing therapeutic effectiveness of radiation therapy remains an important goal. ATM (ataxia-telangiectasia, mutated) and DNA-PKcs (deoxyribonucleic acid [DNA]-dependent protein kinase, catalytic subunit) are related protein kinases and both are critical regulators of cellular responses to ionizing radiation. We report here the identification and initial characterization of XRD-0394, a potent, specific dual inhibitor of both ATM and DNA-PKcs, whose chemical structure will be disclosed. A dual ATM/DNA-PK inhibitor has practical and theoretical advantages over compounds which inhibit just one of these kinases: 1) blunting both DNA damage response (DDR) pathways enhances radiation-induced tumor cell kill compared to single target inhibition; and 2) simultaneous inhibition of two DDR pathways should overcome intrinsic or acquired resistance of tumor cells to either target alone. Notably, transient inhibition of both kinases by XRD-0394 has little adverse effects on cells in the absence of irradiation. XRD-0394 is orally bioavailable, with excellent pharmacological profiles, demonstrating significant in vitro and in vivo sensitizing activity in combination with ionizing radiation and in combination with immunotherapy and radiation. In addition, a CRISPR screen identified alterations in the Fanconi A/BRCA pathway as an opportunity for synthetic lethality in tumor cells exposed to XRD-0394, an insight that was validated in multiple tumor cell types. In vitro studies demonstrated synergy of XRD-0394 in combination with PARP inhibitors, particularly in BRCA-mutant cells. XRD-0394 also potentiates the effectiveness of topoisomerase inhibitors in vitro. Single doses of XRD-0394 were well-tolerated in combination with palliative RT in subjects with advanced cancer in a Phase Ia clinical trial (NCT05002140). No DLTs were observed. At a dose of 160 mg, plasma concentrations were well above the preclinical target plasma level of 530 ng/mL (1 µM) for up to 15 h and inhibition of ATM kinase activity was demonstrated by inhibition of radiation-induced pKAP1 in tumor tissue. Importantly, this concentration of drug is sufficient to induce potent radiosensitization in numerous preclinical models. The median tmax (2.3 h) and mean terminal t½ (11.1 h) at the 160 mg dose in subjects support coadministration of XRD-0394 and RT within a clinically feasible time frame. These results provide a rationale for future clinical trials with XRD-0394 in combination with RT, RT and immunotherapy, PARP inhibitors and targeted delivery of topoisomerase inhibitors. Citation Format: Tona M. Gilmer, Chun-Hsiang Lai, Kexiao Guo, Katherine Deland, Kathleen A. Ashcraft, Amy E. Stewart, Yaode Wang, Jianmin Fu, Kris C. Wood, Deborah A. Smith, Jonathan T. Yang, Christopher T. Chen, Michael F. Gensheimer, Paul B. Romesser, Steven H. Lin, David G. Kirsch, Michael B. Kastan. First disclosure of XRD-0394, a novel dual ATM/DNA-PK inhibitor, that potently radiosensitizes and potentiates PARP and topoisomerase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB181.

Volumetric Response and Survival of Patients With Bulky IDH-Mutated Grade 3 Glioma Managed With FET-FDG–Guided Integrated Boost IMRT

AimsDespite relatively favourable outcomes associated with IDH-mutant grade 3 gliomas, many patients present with diffuse non-enhancing disease involving multiple brain regions, prompting concern over both durable disease control and the morbidity associated with large volume radiation therapy. This study audits volumetric response, survival and functional outcomes in this ‘large volume’ subgroup that undergoes intensity modulated radiation therapy (IMRT). Materials and methodsFrom a prospective database of 187 patients with IDH-mutant grade 3 gliomas managed with IMRT between 2008 and 2020, recorded PTV was divided into quartiles. The top quartile, termed the ‘large volume cohort’ (LVC), was identified. IMRT involved FET-FDG guided integrated boost (59.4/54Gy in 33 fractions). Manual volumetric segmentation of baseline, four months and 13 months post-IMRT tumour were performed for T1, T2 and T1gd MRI sequences. The primary endpoint was volumetric reduction on the T1 and T2 sequences at 13 months and analysed with relapse-free survival (RFS) and overall survival (OS). Morbidity endpoints were assessed at year four post-IMRT and included performance status (ECOG PS) and employment outcomes. ResultsThe fourth quartile (LVC) identified 44 patients for whom volumetric analysis was available. The LVC had median PTV of 320cm3 compared to 186.2cm3 for the total group. Anaplastic astrocytoma and oligodendroglioma were equally distributed and tumour sites were frontal (54%), temporal (18%) and parietal lobes (16%).Median follow-up for survivors was 71.5 months. Projected 10-year RFS and OS in LVC was 40% and 62%, compared to 53% and 62% respectively in the overall cohort. The RFS (p = 0.06) and OS (p = 0.65) of the LVC was not significantly different to other PTV quartiles; however the impact of PTV volume reached significance when analysed as a continuous variable (RFS p < 0.01; OS p = 0.02).Median T1 volumes were 26.1cm3, 8.0cm3 and 5.3cm3 at months +0, +3 and +12, respectively. The corresponding T2 volumes were 120.8cm3, 29.1cm3 and 26.3cm3. The median T1 and T2 volume reductions were 77% (q1–3: 57–92%) and 78% (q1–3: 60–85%) at 13 months post-IMRT. Initial T2 volume was associated with worse RFS (p = 0.04) but not OS (p = 0.96). There was no association between median T2 volume reduction and RFS (p = 0.77).For patients assessable at year 4 post-IMRT, no late CTCAE Grade 3/4 toxicity events were recognised. 92% of patients were ECOG PS 0–1, 45% were employed at prior capacity and 28% were working with impairment. ConclusionPatients with large volume IDH-mutant Grade 3 glioma demonstrated significant tumour reduction post-IMRT, and good long-term outcomes with respect to survival and functional status. Although larger IMRT volumes were associated with poorer RFS, this was also associated with the initial volume of non-enhancing tumour.

A comprehensive analysis of APOE genotype effects on human brain structure in the UK Biobank

Alzheimer’s disease (AD) risk is increased in carriers of the apolipoprotein E (APOE) ε4 allele and decreased in ε2 allele carriers compared with the ε3ε3 genotype. The aim of this study was to determine whether: the APOE genotype affects brain grey (GM) or white matter (WM) structure; and if differences exist, the age when they become apparent and whether there are differential effects by sex. We used cross-sectional magnetic resonance imaging data from ~43,000 (28,494 after pre-processing) white British cognitively healthy participants (7,446 APOE ε4 carriers) aged 45–80 years from the UK Biobank cohort and investigated image-derived phenotypes (IDPs). We observed no statistically significant effects of APOE genotype on GM structure volumes or median T2* in subcortical structures, a measure related to iron content. The volume of white matter hyperintensities differed significantly between APOE genotype groups with higher volumes in APOE ε4ε4 (effect size 0.14 standard deviations [SD]) and ε3ε4 carriers (effect size 0.04 SD) but no differences in ε2 carriers compared with ε3ε3 carriers. WM integrity measures in the dorsal (mean diffusivity [MD]) and ventral cingulum (MD and intracellular volume fraction), posterior thalamic radiation (MD and isotropic volume fraction) and sagittal stratum (MD) indicated lower integrity in APOE ε4ε4 carriers (effect sizes around 0.2–0.3 SD) and ε3ε4 (effect sizes around 0.05 SD) carriers but no differences in ε2 carriers compared with the APOE ε3ε3 genotype. Effects did not differ between men and women. APOE ε4 homozygotes had lower WM integrity specifically at older ages with a steeper decline of WM integrity from the age of 60 that corresponds to around 5 years greater “brain age”. APOE genotype affects various white matters measures, which might be indicative of preclinical AD processes. This hypothesis can be assessed in future when clinical outcomes become available.

Echo time-dependent observed T1 and quantitative perfusion in chronic obstructive pulmonary disease using magnetic resonance imaging.

Due to hypoxic vasoconstriction, perfusion is interesting in the lungs. Magnetic Resonance Imaging (MRI) perfusion imaging based on Dynamic Contrast Enhancement (DCE) has been demonstrated in patients with Chronic Obstructive Pulmonary Diseases (COPD) using visual scores, and quantification methods were recently developed further. Inter-patient correlations of echo time-dependent observed T1 [T1(TE)] have been shown with perfusion scores, pulmonary function testing, and quantitative computed tomography. Here, we examined T1(TE) quantification and quantitative perfusion MRI together and investigated both inter-patient and local correlations between T1(TE) and quantitative perfusion. 22 patients (age 68.0 ± 6.2) with COPD were examined using morphological MRI, inversion recovery multi-echo 2D ultra-short TE (UTE) in 1-2 slices for T1(TE) mapping, and 4D Time-resolved angiography With Stochastic Trajectories (TWIST) for DCE. T1(TE) maps were calculated from 2D UTE at five TEs from 70 to 2,300 μs. Pulmonary Blood Flow (PBF) and perfusion defect (QDP) maps were produced from DCE measurements. Lungs were automatically segmented on UTE images and morphological MRI and these segmentations registered to DCE images. DCE images were separately registered to UTE in corresponding slices and divided into corresponding subdivisions. Spearman's correlation coefficients were calculated for inter-patient correlations using the entire segmented slices and for local correlations separately using registered images and subdivisions for each TE. Median T1(TE) in normal and defect areas according to QDP maps were compared. Inter-patient correlations were strongest on average at TE2 = 500 μs, reaching up to |ρ| = 0.64 for T1 with PBF and |ρ| = 0.76 with QDP. Generally, local correlations of T1 with PBF were weaker at TE2 than at TE1 or TE3 and with maximum values of |ρ| = 0.66 (from registration) and |ρ| = 0.69 (from subdivision). In 18 patients, T1 was shorter in defect areas than in normal areas, with the relative difference smallest at TE2. The inter-patient correlations of T1 with PBF and QDP found show similar strength and TE-dependence as those previously reported for visual perfusion scores and quantitative computed tomography. The local correlations and median T1 suggest that not only base T1 but also the TE-dependence of observed T1 in normal areas is closer to that found previously in healthy volunteers than in defect areas.

Longitudinal analysis of T2 relaxation time variations following radiotherapy for prostate cancer

Aim of this paper is to evaluate short and long-term changes in T2 relaxation times after radiotherapy in patients with low and intermediate risk localized prostate cancer. A total of 24 patients were selected for this retrospective study. Each participant underwent 1.5T magnetic resonance imaging on seven separate occasions: initially after the implantation of gold fiducials, the required step for Cyberknife therapy guidance, followed by MRI scans two weeks post-therapy and monthly thereafter. As part of each MRI scan, the prostate region was manually delineated, and the T2 relaxation times were calculated for quantitative analysis. The T2 relaxation times between individual follow-ups were analyzed using Repeated Measures Analysis of Variance that revealed a significant difference across all measurements (F (6, 120) = 0.611, p << 0.001). A Bonferroni post hoc test revealed significant differences in median T2 values between the baseline and subsequent measurements, particularly between pre-therapy (M0) and two weeks post-therapy (M1), as well as during the monthly interval checks (M2 - M6). Some cases showed a delayed decrease in relaxation times, indicating the prolonged effects of therapy. The changes in T2 values during the course of radiotherapy can help in monitoring radiotherapy response in unconfirmed patients, quantifying the scarring process, and recognizing the therapy failure.

Characterization of white matter lesions in multiple sclerosis using proton density and T1-relaxation measures

PurposeAlthough lesion dissemination in time is a defining characteristic of multiple sclerosis (MS), there is a limited understanding of lesion heterogeneity. Currently, conventional sequences such as fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W) data are used to assess MS lesions qualitatively. Estimating water content could provide a measure of local tissue rarefaction, or reduced tissue density, resulting from chronic inflammation. Our goal was to utilize the proton spin density (PD), derived from a rapid, multi-contrast STAGE (strategically acquired gradient echo) protocol to characterize white matter (WM) lesions seen on T2W, FLAIR and T1W data. Materials and methodsTwenty (20) subjects with relapsing-remitting MS were scanned at 3 T using T1W, T2-weighted, FLAIR and strategically acquired gradient echo (STAGE) sequences. PD and T1 maps were derived from the STAGE data. Disease severity scores, including Extended Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC), were correlated with total, high PD and high T1 lesion volumes. A probability map of high PD regions and all lesions across all subjects was generated. Five perilesional normal appearing WM (NAWM) bands surrounding the lesions were generated to compare the median PD and T1 values in each band with the lesional values and the global WM. ResultsT1W intensity was negatively correlated with PD as expected (R = −0.87, p < 0.01, R2 = 0.756) and the FLAIR signal was suppressed for high PD volumes within the lesions, roughly for PD ≥ 0.85. The threshold for high PD and T1 regions was set to 0.909 and 1953.6 ms, respectively. High PD regions showed a high probability of occurrence near the boundary of the lateral ventricles. EDSS score and nine-hole peg test (dominant and non-dominant hand) were significantly correlated with the total lesion volume and the volumes of high PD and T1 regions (p < 0.05). There was a significant difference in PD/T1 values between the high PD/T1 regions within the lesions and the remaining lesional tissue (p < 0.001). In addition, the PD values of the first NAWM perilesional band directly adjacent to the lesional boundary displayed a significant difference (p < 0.05) compared to the global WM. ConclusionLesions with high PD and T1s had the highest probability of occurrence at the boundary of the lateral ventricles and likely represent chronic lesions with significant local tissue rarefaction. Moreover, the perilesional NAWM exhibited subtly increasing PD and T1 values from the NAWM up to the lesion boundary. Unlike on the T1 maps, the perilesional band adjacent to the lesion boundary possessed a significantly higher PD value than the global WM PD values. This shows that PD maps were sensitive to the subtle changes in NAWM surrounding the lesions.

Indocyanine green fluorescent cholangiography: The new standard practice to perform laparoscopic cholecystectomy in pediatric patients. A comparative study with conventional laparoscopic technique

BackgroundThis study aimed to compare outcomes of standard laparoscopic cholecystectomy and indocyanine green fluorescent cholangiography laparoscopic cholecystectomy over a 10-year period. MethodsFrom 2013 to 2023, 173 laparoscopic cholecystectomies were performed in 2 pediatric surgery units: 83 using standard technique (G1) and 90 using indocyanine green fluorescent cholangiography (G2). Patients included 96 girls and 77 boys, with a median age of 12.3 years (range 4–17) and a median weight of 51 kg (range 19–114). The 2 groups were compared regarding the following: (1) perioperative complications rate; (2) overall length of surgery (T1); (3) length of cystic duct isolation, clipping, and sectioning (T2); (4) time of gallbladder removal (T3); (5) degree of visualization of biliary tree; (6) safety and feasibility of indocyanine green fluorescent cholangiography; (7) incidence of anatomical anomalies detected intraoperatively. ResultsAll laparoscopic cholecystectomies were accomplished without conversion to open. The perioperative complications rate was significantly higher in G1 compared with G2 (12% vs 0%; P = .0007). Median T1, T2, and T3 were significantly longer in G1 (90, 37, 35 minutes) compared with G2 (55, 17, 19 minutes) (P = .0001), respectively. The visualization rate of the complete biliary tree was significantly higher in G2 (98.8%) than in G1 (80.7%) (P = .0001). No adverse reactions to indocyanine green were recorded. The incidence of biliary anomalies detected intraoperatively was significantly higher in G2 (7.8%) than in G1 (1.2%) (P = .03). ConclusionIndocyanine green fluorescent cholangiography can be considered the new standard practice to perform laparoscopic cholecystectomy in pediatrics. Indocyanine green fluorescence provided superior visualization of biliary anatomy, increased detection of anatomic variants, faster procedure, and fewer complications compared with conventional technique. Indocyanine green fluorescent cholangiography was safe, feasible, simple, inexpensive, and a timesaving tool.

Estimating the true half-life of cardiac troponins, a novel methodological approach

Abstract Introduction Cardiac troponins (cTn) are key when diagnosing myocardial injury (MI) and are used worldwide. Still, the half-life (T½) of cTn in the bloodstream is largely unknown. Previously, T½ has been estimated to 7-20 hours following MI. However, in the clinical setting the true T½, i.e. the decay of cTn, cannot be estimated due to ongoing leakage of cTn from cardiomyocytes. Identification of the true T½ is essential to improve estimation of how long cTn leak from cardiomyocytes due to MI and to understand the pathophysiology of all diseases in the myocardium associated with raised cTn levels. Purpose To determine T½ of cTnI and cTnT in the human blood stream. Methods Patients with ST elevation myocardial infarction (STEMI) were included within 24 hours after acute reperfusion therapy and underwent plasmapheresis to "harvest" plasma with a high cTn concentration. Three to 17 weeks later patients received a re-transfusion of autologous plasma. Blood samples were drawn at 22 fixed time points over eight hours from re-transfusion. A two phased model was used to estimate T½ of cTnI and cTnT for all patients. An alpha level of &amp;lt;0.05 was considered statistically significant and differences were tested by Wilcoxon matched pairs signed rank test. Results A total of 20 participants received a re-transfusion of their own plasma. Median age was 63 years (IQR 58-70), and four participants were women (20%). Prior to re-transfusion the participants’ median concentration of cTnI was 16 ng/l (interquartile range (IQR) 12-24) and of cTnT 12 ng/l (IQR 11-18). Following re-transfusion of 180-679 ml autologous plasma, participants’ concentration of cTn was measured again. Median concentration of cTnI was 3,355 ng/l (IQR 2,135-4,690) and of cTnT 237 ng/l (IQR 160-303 ng/l). Decay of cTnI and cTnT from injection to eight hours after followed a two-phased exponential decline with a primary fast and secondary slow phase as presented in figures 1-2. Each colored curve represents a participant. Median T½ during the first phase was 11 min for cTnI (IQR 6-13 min) and 15 min for cTnT (IQR 7-18 min). The fast decline in the first phase was thought to be due to re-distribution in the extracellular space. The second phase had a median T½ of 65 min for cTnI (IQR 56-80 min) and 67 min for cTnT (IQR 51-92 min). The second phase represents the human, biological T½ of cTn. No significant difference was found between T½ of cTnI and cTnT. Conclusions This novel study design showed seven to 20-fold shorter T½ of cTnI and cTnT compared to previous estimates in the acute, clinical setting, indicating that the duration of cTn leakage from the myocardium during MI has previously been grossly underestimated. This finding challenges our understanding and interpretation of the clinical course of MI and may translate into changes in the perceived window of opportunity for myocardial salvage by interventions.Figure 1:Cardiac troponin IFigure 2:Cardiac troponin T

Quantitative T1 brain mapping in early relapsing-remitting multiple sclerosis: longitudinal changes, lesion heterogeneity and disability

ObjectivesTo quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability.MethodsSeventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving).ResultsSixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p < .001), and were associated with EDSS score at baseline (p < .05) and follow-up (supramedian: p < .01; prolonged: p < .05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p < .05).ConclusionT1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability.Clinical relevance statementMRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification.Key Points• Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis.• T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability.• Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis.Graphical abstract

Abstract 19006: Human Epididymis Protein 4 and Carcinoembryonic Antigen-125: Promising Blood Biomarkers to Identify Diffuse Myocardial Fibrosis in Patients With Severe Aortic Stenosis

Introduction: Cardiovascular magnetic resonance (CMR) T1 mapping, extracellular volume (ECV) and late gadolinium enhancement (LGE) demonstrate strong agreement with endomyocardial biopsy in evaluating myocardial fibrosis. Human epididymis protein 4(HE4) has been shown as a blood biomarker to identify fibrosis, but the relationship with other blood biomarkers is not well established yet. Hypothesis: determine the correlation between different blood biomarkers and myocardial fibrosis by CMR in patients undergoing transcatheter aortic valve implantation(TAVI). Methods: Forty-three patients were included. The cohort was divided into two groups based on the threshold values of HE4(128.5 pmol/l) and/or CA-125 (19.5 U/ml), before TAVI. Native T1 mapping and ECV were measured at 1280 ms and 26%, respectively, corresponding to the median of the population studied. LGE was qualitatively measured. Results: Patients with higher HE4 plasma levels (&gt; 128.25 pmol/l) and/or CA-125 (&gt;19.5 U/ml) prior to TAVI had more comorbidities and had higher median native T1 mapping values, 1278 ms (1239.25-1280.25) vs 1352 ms (1303.50 -1376.00), p &lt; 0.001, and LGE positive, 10 (55.6%) vs 10 (90.9%); p= 0.046, respectively. HE4 (r=0.34, p=0.03) and CA-125 (r=0.371, p=0.034) correlated with prolonged T1 mapping. No significant correlation was found with other biomarkers: troponin T (r = 0.14, p = 0.41), Nt-proBNP (r=0.28, p=0.089), IL-6 (r=0.189, p= 0.250), procalcitonin, (r =0.132, p =0.420). The addition of elevated plasma levels of HE4 and CA-125, provided significant C-statistics for myocardial fibrosis, AUC [95%CI]: 0.74 [0.58- 0.89], p= 0.008, regarding HE4 AUC [95%CI]: 0.69 [0.52- 0.85], p=0.039, and CA-125 AUC [95%CI]: 0.72 [0.57- 0.88], p= 0.014. On univariable analysis, high plasma levels of HE4 and/or Ca-125 were independently associated with diffuse fibrosis by native T1 mapping OR:9.37, [95% CI: 2.07 - 42.33], p = 0.004 and there was a trend toward focal fibrosis by LGE + OR: 8.00, [95% CI: 0.83 - 76.36], p = 0.071. Conclusion: Elevated HE4 and/or Ca-125 plasma levels correlated with prolonged native T1 mapping. The combination of HE4 values ≥ 128 pmol/l and CA-125 ≥ 19.5 U/ml may provide a useful screening biomarker to identify diffuse myocardial fibrosis in AS.

Detection of sympathetic denervation defects in Fabry disease by hybrid [11C]meta-hydroxyephedrine positron emission tomography and cardiac magnetic resonance

BackgroundMyocardial glycosphingolipid accumulation in patients with Fabry disease (FD) causes biochemical and structural changes. This study aimed to investigate sympathetic innervation in FD using hybrid cardiac positron emission tomography (PET)/magnetic resonance imaging (MRI). Methods and resultsPatients with different stages of Fabry disease were prospectively enrolled to undergo routine CMR at 1.5T, followed by 3T hybrid cardiac PET/MRI with [11C]meta-hydroxyephedrine ([11C]mHED). Fourteen patients with either no evidence of cardiac involvement (n = 5), evidence of left ventricular hypertrophy (LVH) (n = 3), or evidence of LVH and fibrosis via late gadolinium enhancement (LGE) (n = 6) were analyzed. Compared to patients without LVH, patients with LVH or LVH and LGE had lower median T1 relaxation times (ms) at 1.5 T (1007 vs. 889 vs. 941 ms, p = 0.003) and 3T (1290 vs. 1172 vs. 1184 p = .014). Myocardial denervation ([11C]mHED retention < 7%·min) was prevalent only in patients with fibrosis, where a total of 16 denervated segments was found in two patients. The respective area of denervation exceeded the area of LGE in both patients (24% vs. 36% and 4% vs. 32%). However, sympathetic innervation defects ([11C]mHED retention ≤ 9%·min) occurred in all study groups. Furthermore, a reduced sympathetic innervation correlated with an increased left ventricular mass (p = .034, rs = − 0.57) and a reduced global longitudinal strain (GLS) (p = 0.023, rs = − 0.6). ConclusionHybrid cardiac PET/MR with [11C]mHED revealed sympathetic innervation defects, accompanied by impaired GLS, in early stages of Fabry disease. However, denervation is only present in patients with advanced stages of FD showing fibrosis on CMR.

Kinetics of cardiac troponin and other biomarkers in patients with ST elevation myocardial infarction.

To examine changes in concentration, time-to-peak and the ensuing half-life of cardiac biomarkers in patients with myocardial infarction. Blood sampling was performed every third hour within 24h after percutaneous coronary intervention (PCI) on a cohort of patients with ST elevation myocardial infarction. Cardiac troponin (cTn) was measured by the Dimension Vista, Vitros, Atellica, and Alinity high-sensitivity (hs) cTnI assays, and the Elecsys hs-cTnT assay. Further, creatine kinase (CK), myoglobin, creatine kinase MB (CKMB) and other biomarkers were analyzed. A total of 36 patients completed blood sampling (median age 60years, IQR 56.4-66.5years; seven women, 19.4%). Hs-cTnI measured by the Vitros assay was the first hs-cTn to peak at 9.1h (95%-CI 6.2-10.1) after PCI and 11.7h (95%-CI 10.4-14.8) after symptoms onset. There were no notable differences between hs-cTn assays in regard to time-to-peak. Also, Vitros hs-cTnI reached the highest median ratio of concentration to upper reference level of nearly 2,000. The median half-life from peak concentration ranged from 7.6h for myoglobin (CI 6.8-8.6) to 17.8h for CK (CI 6.8-8.6). For hs-cTn assays the median T½ ranged from 12.4h for the Vista hs-cTnI assay (95%-CI 11.0-14.1h) to 17.3h for the Elecsys hs-cTnT (95%-CI 14.9-20.8h). This study updates knowledge on the kinetics of cardiac biomarkers in current clinical use. There was no notable difference in trajectories, time-to-peak or half-life between hs-cTn assays.