Voxel-based 18F-FET PET segmentation and automatic clustering of tumor voxels: A significant association with IDH1 mutation status and survival in patients with gliomas.

Aim was to develop a full automatic clustering approach of the time-activity curves (TAC) from dynamic 18F-FET PET and evaluate its association with IDH1 mutation status and survival in patients with gliomas. Thirty-seven patients (mean age: 45±13 y) with newly diagnosed gliomas and dynamic 18F-FET PET before any histopathologic investigation or treatment were retrospectively included. Each dynamic 18F-FET PET was realigned to the first image and spatially normalized in the Montreal Neurological Institute template. A tumor mask was semi-automatically generated from Z-score maps. Each brain tumor voxel was clustered in one of the 3 following centroids using dynamic time warping and k-means clustering (centroid #1: slowly increasing slope; centroid #2: rapidly increasing followed by slowly decreasing slope; and centroid #3: rapidly increasing followed by rapidly decreasing slope). The percentage of each dynamic 18F-FET TAC within tumors and other conventional 18F-FET PET parameters (maximum and mean tumor-to-brain ratios [TBRmax and TBRmean], time-to-peak [TTP] and slope) was compared between wild-type and IDH1 mutant tumors. Their prognostic value was assessed in terms of progression free-survival (PFS) and overall survival (OS) by Kaplan-Meier estimates. Twenty patients were IDH1 wild-type and 17 IDH1 mutant. Higher percentage of centroid #1 and centroid #3 within tumors were positively (P = 0.016) and negatively (P = 0.01) correlated with IDH1 mutated status. Also, TBRmax, TBRmean, TTP, and slope discriminated significantly between tumors with and without IDH1 mutation (P range 0.01 to 0.04). Progression occurred in 22 patients (59%) at a median of 13.1 months (7.6-37.6 months) and 13 patients (35%) died from tumor progression. Patients with a percentage of centroid #1 > 90% had a longer survival compared with those with a percentage of centroid #1 < 90% (P = 0.003 for PFS and P = 0.028 for OS). This remained significant after stratification on IDH1 mutation status (P = 0.029 for PFS and P = 0.034 for OS). Compared to other conventional 18F-FET PET parameters, TTP and slope were associated with PFS and OS (P range 0.009 to 0.04). Based on dynamic 18F-FET PET acquisition, we developed a full automatic clustering approach of TAC which appears to be a valuable noninvasive diagnostic and prognostic marker in patients with gliomas

Anti-thyroglobulin Antibodies as a Possible Risk Factor for Graves' Disease After Radioiodine Treatment for Toxic Nodular Goiter: Case Report.

The manifestation of Graves' disease (GD) in patients treated with radioactive iodine (RAI) for hyperfunctioning thyroid nodules (RAI-induced GD or post-RAI GD) remains a long-standing challenge in radionuclide therapy. Known risk factors for post-RAI GD include preexisting subclinical hyperthyroidism, positive thyroid peroxidase autoantibodies (TPOAb), positive TSH receptor autoantibodies (TRAb) or otherwise undiagnosed GD. However, these risk factors are not present in all patients with post-RAI GD, and therefore it cannot always be predicted in a reliable manner if a given patient has a high risk for RAI-induced GD or not. We describe the case of a 64 year-old woman known for hyperthyroidism due to toxic nodular goiter; she was treated initially with carbimazole, and then, due to recurrence, underwent RAI treatment. Three months later, symptomatic hyperthyroidism persisted. Diagnosis of new-onset GD was made based on typical ultrasound findings and newly-positive TRAb. Our patient had only positive thyroglobulin antibodies (TgAb) before RAI treatment, whereas TPOAb were negative. In the literature, TgAb have never been reported as a possible risk factor for RAI-induced GD. The present case suggests that the assessment for pre-existing autoimmunity in patients considering RAI for hyperfunctioning thyroid nodules should probably also include TgAb

Increased ¹⁸F-FDG signal recovery from small physiological structures in digital PET/CT and application to the pituitary gland.

On conventional PET/CT, and under physiological conditions, the volume of the pituitary gland (PG) is small, and its metabolic activity is commonly comparable to the surrounding background level in <sup>18</sup> F-FDG imaging. We compared the physiological <sup>18</sup> F-FDG uptake of the PG in patients imaged with digital PET (dPET) and with conventional PET (cPET). Additionally, we performed phantom experiments to characterize signal recovery and detectability of small structures. We retrospectively included 10 dPET and 10 cPET patients and measured PG SUVmax, SUVmean and SUVratio (using cerebellum as reference). We imaged a modified NEMA/IEC phantom with both dPET and cPET (background activity 5 kBq/mL, and 3× and 5× higher concentrations in ∅2-20-mm spherical inserts). Mean recovery coefficients (RCmean) and signal-difference-to-noise-ratio (SDNR) were computed to assess lesion detectability. Patients imaged with dPET presented higher PG SUVmax and SUVratio (SUVR) compared to patients imaged with cPET (4.7 ± 2.05 vs. 2.9 ± 0.64, p = 0.004; and 0.62 ± 0.25 vs 0.39 ± 0.09, p = 0.029, respectively), while there was no difference for SUVmean (2.7 ± 1.32 vs 2.1 ± 0.44, p = 0.39). Thus, with a SUV readout scale of 0-5 g/mL, normal PG appeared abnormally hot with dPET, but not with cPET. Phantom evidenced higher RCmean in dPET compared to cPET. For both 3x and 5x measurements, lesion detectability according to size was systematically superior with dPET. In conclusion, patients imaged with dPET presented higher <sup>18</sup> F-FDG physiological uptake of the PG as compared to patients imaged with cPET. These findings were supported by phantom experiments demonstrating superior signal recovery and small region detectability with dPET. Awareness of this new "higher" SUV of the normal <sup>18</sup> F-FDG uptake of the PG is important to avoid potential pitfalls in image interpretation, notably in oncologic patients treated with immunotherapy, who are at increased risk to develop hypophysitis

Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations

Imaging of ανβ3 integrin expression in rheumatoid arthritis with [68Ga]Ga-NODAGA-RGDyk PET/CT in comparison to [18F]FDG PET/CT

[Ga-68] Ga-NODAGA-RGDyk PET/CT and [F-18] FDG PET/CT were performed in a 65-year-old woman during the work-up of a squamous cell carcinoma of the tongue within a clinical study protocol. Images revealed both tracers' uptake in the primary tumor and cervical lymph nodes, but also bilaterally in the shoulders, elbows, wrists, metacarpophalangeal, interphalangeal, and hip joints. The patient had been diagnosed with rheumatoid arthritis 8 years prior to the examination. Images showed a significantly higher [F-18] FDG than [Ga-68] Ga-NODAGA-RGDyk uptake in primary tumor and cervical lymph nodes. However, the patient with moderately active rheumatoid arthritis had similar levels of [Ga-68]Ga-NODAGA-RGDyk and [F-18] FDG uptake in the involved joints, but with no [Ga-68] Ga-NODAGA-RGDyk uptake in the surrounding muscles, unlike with [F-18]FDG. Our case suggests that [Ga-68]Ga-NODAGA-RGDyk PET/CT allows imaging of integrins expression in rheumatoid arthritis, including integrins expressed in synovial angiogenesis, with potentially a better signal-to-noise ratio than on [F-18]FDG PET/CT. (C) 2021 The Author(s). Published by Elsevier Masson SAS

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL)

International audienceAbstractRare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP’s is realised

Imaging angiogenesis in atherosclerosis in large arteries with 68Ga-NODAGA-RGD PET/CT: relationship with clinical atherosclerotic cardiovascular disease.

Integrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of <sup>68</sup> Ga-NODAGA-RGD, a specific α <sub>v</sub> β <sub>3</sub> integrin ligand for PET. The data of 44 patients who underwent <sup>68</sup> Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann-Whitney U test, Pearson correlation and Spearman correlation. <sup>68</sup> Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03-2.55] vs. 1.81 [1.56-1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.33, p = 0.027), BMI (ρ = 0.38, p = 0.01), plaque burden (ρ = 0.31, p = 0.04) and hypercholesterolemia (r = 0.31, p = 0.04). <sup>68</sup> Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis

Performance of the ATLAS electromagnetic calorimeter end-cap module 0

The construction and beam test results of the ATLAS electromagnetic end-cap calorimeter pre-production module 0 are presented. The stochastic term of the energy resolution is between 10% GeV^1/2 and 12.5% GeV^1/2 over the full pseudorapidity range. Position and angular resolutions are found to be in agreement with simulation. A global constant term of 0.6% is obtained in the pseudorapidity range 2.5 eta 3.2 (inner wheel)

Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner's Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these observations we integrated information about replication rates, study-specific heterogeneity, and Winner's Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study