Academic literature on the topic '8F-FDG'

4068 Background: Variations in HER2 expression between primary tumor and metastases may contribute to drug resistance in HER2-positive mEG cancer. Whole body imaging with 89Zr-trastuzumab PET has a potential advantage over single site biopsies as it can non-invasively assess variations in HER2 expression and target engagement. 89Zr-trastuzumab PK, biodistribution and dosimetry in mEG cancer were previously published by our group (O’Donoghue, JNM 2018). We now present lesion level analysis of baseline 18F-FDG-PET and CT in comparison with baseline 89Zr-trastuzumab imaging. Methods: Patients with metastatic HER2-positive (IHC 3+, IHC 2+/FISH > 2.0) mEG cancer and RECIST 1.1 measurable disease were consented and imaged with 89Zr-trastuzumab PET, 18F-FDG-PET and CT. All visualized lesions (maximum 5 per organ) were annotated in detail using RECIST 1.1 measurements (CT) and maximum standard uptake values (SUVmax) on 89Zr-trastuzumab and 18F-FDG PET scans. Correlation of visualized disease burden between imaging modalities with clinical and pathologic characteristics was performed. Results: 33 patients with mEG adenocarcinoma were imaged with 89Zr-trastuzumab PET, 18F-FDG-PET and CT (12% esophageal, 64% GEJ, 24% gastric). HER2 status (IHC 3+ 70%; IHC2+/FISH+ 27%, NGS 3%) was assessed from biopsy of primary (66.7%) or metastasis (33.3%). Median time from diagnosis to 89Zr-trastuzumab PET was 12.6 months. At the time of 89Zr-trastuzumab PET, 39% were treatment naive, while 61% had received prior therapy including trastuzumab (58%) and afatinib (median lines 2, range 0-6). 82% of patients had the primary tumor in place and all patients had metastatic disease at the time of enrollment with metastases to lymph nodes (70%) peritoneum (24%), liver (58%), lung (33%), and/or bone (9%). Median number of RECIST 1.1 lesions measured on baseline CT was 6 (range 1-15). PET analysis is complete in 18 of 33 patients. Median number of 89Zr-trastuzumab PET positive (SUV > 3) lesions was 5.5 (range 1-11) with 5 patients having at least 1 (max 3) very intense lesion (SUV > 15). Median number of 18F-FDG-PET-positive lesions was 8 (range 1-14). Three patients had at least 1 lesion positive on 89Zr-trastuzumab-PET and negative on 8F-FDG-PET (range 0-5), and 8 patients had at least 1 lesion positive on 18F-FDG-PET and negative on 89Zr-trastuzumab-PET (range 0-7). Of the total lesions identified on 89Zr-PET but not CT, 40% were in bone. Of those identified on 89Zr but not 8F-FDG-PET, 40% were in bone, and of those on 18F-FDG- but not 89Zr-PET, 6% were in bone. Conclusions: 89Zr-trastuzumab PET effectively identifies heterogeneity of HER2 expression and allows assessment of lesions throughout the whole body. Bone lesions were better identified and appeared earlier on 89Zr-trastuzumab PET compared with CT. Additional analyses including correlation of baseline HER2 heterogeneity with overall and disease-free survival will be presented. Clinical trial information: NCT02023996.

Aim: Positron emission tomography (PET) with 18F-fluordeoxyglucose (18F-FDG) plays an essential role in the staging and tumor monitoring of head and neck squamous cell carcinoma (HNSCC). Microvessel density (MVD) is one of the clinically important histopathological features in HNSCC. The purpose of this study was to analyze possible associations between 18F-FDG-PET findings and MVD parameters in HNSCC. Materials and Methods: Overall, 22 patients with a mean age of 55.2 ± 11.0 and with different HNSCC were acquired. In all cases, whole-body 18F-FDG-PET was performed. For each tumor, the maximum and mean standardized uptake values (SUVmax; SUVmean) were determined. The MVD, including stained vessel area and total number of vessels, was estimated on CD105 stained specimens. All specimens were digitalized and analyzed by using ImageJ software 1.48v. Spearman’s correlation coefficient (r) was used to analyze associations between investigated parameters. p-values of <0.05 were taken to indicate statistical significance. Results: SUVmax correlated with vessel area (r = 0.532, p = 0.011) and vessel count (r = 0.434, p = 0.043). Receiver operating characteristic analysis identified a threshold SUVmax of 15 to predict tumors with high MVD with a sensitivity of 72.7% and specificity of 81.8%, with an area under the curve of 82.6%. Conclusion: 8F-FDG-PET parameters correlate statistically significantly with MVD in HNSCC. SUVmax may be used for discrimination of tumors with high tumor-related MVD.

Objective: By exploring and analyzing the evaluation of the short-term outcome of neuroblastoma (NB) in children by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging and ultrasonography, the detailed values of 18F-FDG PET/CT imaging and ultrasonography in diagnosing and treating NB in children were discussed. The effectiveness and superiority of the two evaluation methods were verified, providing a theoretical basis for clinical applications. Methods: Child patients with NB diagnosis were included as research objects. Except for child patients in the IVs stage, other included child patients received the same surgical therapeutic plan. The clinical materials included child patients were collected, such as 18F-FDG PET/CT results, ultrasonography results, and serum neuron specific enolase (NSE) results. The data information was input into the database and statistically analyzed by SPSS 22.0 software. The specificity as well as sensitivity of 18F-FDG PET/CT imaging, ultrasonography, and serum NSE in the clinical evaluation were comparatively analyzed. The detection rates of 8F-FDG PET/CT imaging, ultrasonography, as well as other diagnostic ways were comparatively analyzed. Results: Consequently, 10 patients had no recurrence or metastasis of NB; 2 patients had recurrence as well as metastasis of NB but survived, but the remaining 2 patients died eventually. Besides, in terms of specificity, the NSE detection was the lowest, while the specificity of 18F-FDG PET/CT and ultrasonography was the same, which was 100%. In addition, 18F-FDG PET/CT and NSE were found to be statistically significant (P < 0.05). Conclusion: The research results showed that image of the 18F-FDG PET/CT and ultrasonography were useful to diagnosis and treat NB in children, which could effectively predict the survival periods of patients. In certain aspects, these two methods were better than other traditional diagnostic methods. However, traditional diagnostic methods also had certain advantages. In the future, the clinical diagnosis and treatment of NB should value the joint application of various diagnostic methods to foster the strengths and avoid the weaknesses. The research results have provided the direction and guidance for clinical diagnosis and treatment of NB in children.

Aim. To determine the inflammation and calcification activity in aortic stenosis (AS) by assessing the accumulation of 18F-FDG and 18F-NaF in the aortic valve; to study the relationship of the AS severity, aortic calcification and the accumulation of 18F-FDG and 18F-NaF. Material and methods. The study included 62 patients with asymptomatic AS (29 patients with tricuspid (TAV) and 33 with bicuspid (BAV) aortic valve), aged 40 to 70 years. The maximum flow rate at the aortic valve (Vmax) differs from 2,4 m/s to 4,5 m/s. The mean age of patients was 59,44±7,33 years, M:W 1:1. Patients with infective endocarditis and chronic rheumatic heart disease were excluded. The AS severity was assessed according to the standard protocol of transthoracic echocardiography with the use of Vivid 7 ultrasound system (GE,USA). All patients underwent combined positron emission tomography/computed tomography (PET/CT) of the aortic valve using the Discovery 710 system. Evaluation of calcification and inflammation activity of the aortic valve was performed using 8F-NaF and 18F-FDG PET/CT. A quantitative assessment of radiopharmaceuticals accumulation was carried out using uptake ratio indices. The calcium score was calculated using SmartScore 4.0 software.Results. Patients with TAV and BAV were comparable in severity of AS, the median Vmax was 2,9 [2,6; 3,4] m/s and 2,9 [2,3; 3,3] m/s, respectively. Also, TAV and BAV patients did not differ in calcification values (Agatston score 1088 [465; 2192] and 1128 [442; 2391] HU, respectively). The association of 18F-FDG accumulation and AS severity has not been established. At the same time, the association was found between the aortic valve peak velocity and the calcium score (r=0,57, p< 0,0001), as well as the 18F-NaF accumulation values — maximum, mean and maximum to mean (r=0,37, p=0,002; r=0,46, p=0,0001 and r=0,41, p=0,0008, respectively). No association between the accumulation of 18F-FDG and 18F-NaF (r=0,098, p=0,49) was found.Conclusion. It was found that the inflammation according to 18F-FDG PET/CT does not play a significant role in AS pathogenesis. At this time, 18F-NaF PET/CT is a reliable method for the AS diagnosis and valve calcification assessment. It can be used to evaluate the prognosis and effectiveness of therapy in TAV and BAV patients.

13154 Background: To evaluate the use of 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for prediction of response and survival early during the course of treatment in patients with advanced/metastatic NSCLC. Methods: Between May 2004 and November 2005, 31 patients (gender, 23M, 8F; stage, 2IIIB/29IV, histology, 6 squamous cell ca, 22 adenoca, 3 NOS; age median 57 (30–73 y)) with histopathologically proven NSCLC stage IIIB/IV were enrolled into this study. PET-CT was performed prior to and after one cycle of treatment. Early changes of primary tumor FDG-uptake measured by standardized uptake values (SUV) were correlated with best response to therapy as assessed by CT scan according to WHO response criteria. Results: Patients underwent standard treatment with gemcitabine/vinorelbine (15), gemcitabine/cisplatin (1) gemcitabine/vinorelbine/cisplatin (1), irinotecan/cisplatin (9) or gefitinib (5). In the 25 patients evaluable for response, other 6 patients ongoing, 9 patients achieved a partial response (36%), 5 showed stable diseases and 11 were progressive. Using a cut-off value of 20% reduction of FDG-uptake as a criterion for a response in PET-CT, subsequent best response was predicted with a sensitivity of 88.9% and a specificity of 87.5%. The positive predictive value of a metabolic response was 80.0% and the negative predictive value 93.3%, respectively. There was a significant correlation between the decrease of tumor metabolic activity and subsequent best response (p< 0.001). The median time to progression for PET-CT responder was 10.1 months when compared with that of non-responders with 2.6 months (log-rank p=0.009). Conclusions: Using FDG-PET best response to standard treatment and patient outcome can be predicted very early and therefore, the use of PET-CT may allow to reduce side effects and costs of ineffective therapy in non-responding patients No significant financial relationships to disclose.

Abstract Background: Yttrium-90 ibritumomab tiuxetan (Zevalin, YZ), the first radioimmunotherapeutic agent approved for the treatment of relapsed or refractory B-cell non-Hodgkin Lymphoma (NHL), had an overall response rate of 80% vs 56% with rituximab alone based on CT assessment (IWRC criteria) without FDG PET correlation. Prior to the therapeutic administration of YZ, normal biodistribution must be confirmed by visual evaluation of whole-body In-111 Zevalin (IZ) images. Tumor uptake on IZ images has been noted to be variable and is not required to proceed with therapy. However, bulky lymphadenopathy has been reported to possibly predict poor response to radioimmunotherapy. We report our evaluation of the relation of tumor uptake on IZ images and size on CT scans to tumor response based on pre- and post-YZ therapy using FDG PET/CT scans. Methods: This retrospective review includes only patients with relapsed or refractory B-cell NHL treated with YZ who had fusion PET/CT scans pre- and post-YZ therapy and fulfilled all other standard eligibility critera for YZ. PET/CT scans were performed within 4 months prior and 8 months following IZ imaging and YZ therapy. The largest tumor mass on the pre-therapy CT was measured and categorized into subgroups of < or ≥5 cm. The IZ scans were reviewed for the presence or absence of tumor uptake over background activity. Response by CT was based on the IWRC criteria (CR/CRu, PR, Stable, and PD). Response on FDG PET was based upon comparison of the intensity of uptake in relation to adjacent background (CR, PR, Mixed and PD). Response rate comparisons by patient groups were performed with Fisher exact tests. Results: 24 patients (16M, 8F, 37–83 y.o.) fulfilled the criteria. The histologic diagnoses included: 14 follicular, 5 diffuse large B-cell, 4 mantle cell, and 1 MALT. All patients had increased FDG uptake in measurable CT lesions on the pre-therapy PET/CT scans. 14 IZ scans were positive, 10 were negative. Seven of 9 patients (78%) with lesions ≥5 cm had positive IZ versus 7 of 15 (47%) with lesions < 5 cm. The following tables display the cross-tabulation of tumor uptake on IZ, CT size, and the response to YZ. The overall response (ORR) based on FDG PET was 13/24 (54%) with a CR of 7/24 (29%) and a PR of 6/24 (25%). Excluding the patients with large cell histology, the ORR was 13/19 (68%). ORR for size ≥5 cm was 3/9 (33%) and for size <5 cm was 10/15 (66%), a suggestive but non-significant difference (p=0.2). The frequency of overall response was significantly reduced for large cell histology versus other histologies (p=0.011). The results show that those patients with tumor uptake on IZ imaging had significantly reduced overall response based on pre- and post-FDG PET/CT findings compared with patients without tumor uptake (p=0.047). Conclusions: The presence of tumor uptake on IZ imaging, tumor size (≥5 cm) and histology (large cell) may all adversely affect response to YZ. The identification of IZ tumor uptake may be related to large tumor size rather than tumor susceptibility to therapy. Responses (CR/CRu and PR) by PET # In+ In− CT≥5cm CT<5cm FL 9 4 5 1 8 DLBC 0 0 0 0 0 MCL 3 1 2 1 2 MALT 1 0 1 1 0 Nonresponses (Mixed and PD) by PET # In+ In− CT≥5cm CT<5cm FL 5 5 0 2 3 DLBC 5 3 2 3 2 MCL 1 1 0 1 0 MALT 0 0 0 0 0

: An improved computer-aided diagnosis (CAD) system is proposed for the early diagnosis of Alzheimer’s disease (AD) based on the fusion of anatomical (magnetic resonance imaging (MRI)) and functional (8F-fluorodeoxyglucose positron emission tomography (FDG-PET)) multimodal images, and which helps to address the strong ambiguity or the uncertainty produced in brain images. The merit of this fusion is that it provides anatomical information for the accurate detection of pathological areas characterized in functional imaging by physiological abnormalities. First, quantification of brain tissue volumes is proposed based on a fusion scheme in three successive steps: modeling, fusion and decision. (1) Modeling which consists of three sub-steps: the initialization of the centroids of the tissue clusters by applying the Bias corrected Fuzzy C-Means (FCM) clustering algorithm. Then, the optimization of the initial partition is performed by running genetic algorithms. Finally, the creation of white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) tissue maps by applying the Possibilistic FCM clustering algorithm. (2) Fusion using a possibilistic operator to merge the maps of the MRI and PET images highlighting redundancies and managing ambiguities. (3) Decision offering more representative anatomo-functional fusion images. Second, a support vector data description (SVDD) classifier is used that must reliably distinguish AD from normal aging and automatically detects outliers. The "divide and conquer" strategy is then used, which speeds up the SVDD process and reduces the load and cost of the calculating. The robustness of the tissue quantification process is proven against noise (20% level), partial volume effects and when inhomogeneities of spatial intensity are high. Thus, the superiority of the SVDD classifier over competing conventional systems is also demonstrated with the adoption of the 10-fold cross-validation approach for synthetic datasets (Alzheimer disease neuroimaging (ADNI) and Open Access Series of Imaging Studies (OASIS)) and real images. The percentage of classification in terms of accuracy (%), sensitivity (%), specificity (%) and area under ROC curve was 93.65%, 90.08%, 92.75% and 0.973; 91.46%, 92%, 91.78% and 0.967; 85.09%, 86.41%, 84.92% and 0.946 in the case of the ADNI, OASIS and real images respectively.

Abstract Background Pretomanid is used in combination with bedaquiline and linezolid (BPaL regimen) in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, the penetration of pretomanid in privileged sites remain unknown. Antimicrobial pharmacokinetic (PK) parameters are traditionally derived from clinical samples (blood and cerebrospinal fluid), which may not accurately represent the intralesional tissue PK, affected by drug properties, vascular supply, barrier permeability, and the microenvironment. Methods We developed 18F-pretomanid (chemically identical to pretomanid) for in vivo multi-compartment PK by positron emission tomography (PET). Dynamic 18F-pretomanid PET was used to obtain cross species pretomanid concentration-time profiles in animal models of TB (mice and rabbits) to quantify penetration into pulmonary and brain lesions. A subset of animals underwent PET/CT imaging with 18F-py-albumin and 18F-FDG to assess vascular supply and inflammation. Postmortem 18F-pretomanid autoradiography (high-resolution) and mass spectrometry were performed in infected tissues. A mouse model of TB meningitis was used to evaluate the bactericidal activity of the BPaL regimen (Figure 1). Figure 1. Experimental schematics. (A) A new synthetic approach was developed to obtain radiofluorinated pretomanid (18F-pretomanid), which is chemically identical to pretomanid and therefore undergoes identical PK and metabolism in vivo. Dynamic 18F-pretomanid PET/CT imaging was performed in validated preclinical models of tuberculosis following intravenous administration of 18F-pretomanid. (B) PET signal was quantified in multiple compartments to generate time activity curves (TACs) used to calculate area under the curve (AUC) over 0-60 minutes. A subset of animals also underwent PET/CT imaging of 18F-py-albumin to assess vascular supply to lung and brain lesions, and with 18F-FDG to confirm the presence of neuroinflammation in the mouse and rabbit models of TB meningitis. Tissue resection post-mortem was used to visualize the intralesional retention of 18F-pretomanid using high-resolution (10 µm) autoradiography. The efficacy of the BPaL regimen in TB meningitis was compared to that of standard treatment with rifampin, isoniazid, and pyrazinamide in the mouse model. Mass spectrometry was performed following oral administration of BPaL to determine brain drug levels. (C) These data provide multicompartment PK analysis, intralesional levels of pretomanid, and insights into the mechanism that govern pretomanid tissue distribution. Results 18F-Pretomanid PET provided detailed concentration-time profiles in infected tissues demonstrating excellent lung and brain tissue penetration (AUC ratio to plasma &gt; 1) in both animal species, which was spatially compartmentalized, likely due to differential vascular supply (18F-py-albumin PET) (Figure 2). Brain lesions (identified by 18F-FDG PET) demonstrated localized leakiness on 18F-py-albumin PET. Autoradiography and mass spectrometry corroborated the imaging findings. The efficacy of the BPaL regimen in TB meningitis was substantially lower than standard TB treatment (Figure 3), likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Figure 2. Spatial heterogeneity of 18F-Pretomanid penetration and vascular supply to pulmonary TB lesions. (A) A novel synthetic was devised to obtain 18F-pretomanid, which is chemically identical to pretomanid. (B) Maximum intensity projection (MIP) of 18F-Pretomanid PET/CT in M.tb.-infected mice over 3 hrs shows hepatobiliary and renal excretion, high uptake into brown fat, brain, and lungs. (C) Resection of infected lungs 30 minutes post intravenous administration of 18F-pretomanid shows heterogenous distribution of 18F-pretomanid into the lungs visible by high resolution autoradiography. Areas of pneumonia are identifiable by hematoxylin and eosin (H&E) staining of the same tissue section used for autoradiography. (D) Time-activity curves of 18F-Pretomanid in infected mouse lung (0-3 hours) and derived area under the curve (AUC) ratios to plasma (E) in infected mouse lung. Representative MIP of 18F-pretomanid (F) and 18F-py-albumin (H) PET/CT in a rabbit with cavitary TB and quantification of the AUC ratios to plasma show reduced penetration into lung lesions and cavitary wall compared to areas of unaffected lung (G and I). Data are represented as median ± interquartile range, n=3-4 group. Figure 3. Exposure levels of 18/19F-pretomanid in models of TB meningitis. (A) Experimental timeline used to assess the penetration of pretomanid into infected mouse brain before and during treatment with antimicrobials bedaquiline (B), pretomanid (Pa), and linezolid (L), and corticosteroid dexamethasone (D). (B) Representative three-dimensional MIP of 18F-pretomanid PET/CT in the CNS-TB model, 10 min post-injection, and transverse section showing high and heterogeneous brain uptake. (C) High-resolution autoradiography was performed to confirm heterogeneous penetration of 18F-pretomanid into infected brain lesions in the mouse. (D). 8F-pretomanid AUC ratios of tissue to plasma in mouse brain before (day 0) and two weeks into treatment show a reduction in penetration at week 2. (E). Pretomanid concentrations (µg/mL) in mouse plasma and brain, at day 0 and two weeks into treatment, measured by mass spectrometry and derived concentration ratios of brain to plasma (F) suggest drug accumulation due to the long half-life. (G) While 18F-py-albumin and 18F-FDG PET/CT show vascular leakage and neuroinflammation in the rabbit model of TB meningitis, the penetration of 18F-pretomanid is heterogeneous and reduced at the lesion site (indicated by white arrow). (H) Quantification of the PET signal shows variability within the same animal. Data are represented as median ± interquartile range, n=3-5 group. Figure 4. Evaluation of a pretomanid-containing regimen in TB meningitis. (A) Mice with experimentally induced TB meningitis were treated with Bedaquiline (25 mg/day), Pretomanid (100 mg/day), Linezolid (100 mg/day), and Dexamethasone (2 mg/day) or Rifampin (10 mg/day), Isoniazid (10 mg/day), Pyrazinamide (150 mg/day) and Dexamethasone (2mg/day) for 8 weeks. Treatment efficacy was determined based on the brain bacterial burden after 2, 4, 6, and 8 weeks of treatment. (B) The penetration of 76Br-bedaquiline, 18F-linezolid, and 18F-pretomanid into the brain parenchyma was measured non-invasively by PET and revealed low penetration of 76Br-bedaquiline (AUC radio to plasma 0.15) and 18F-linezolid (AUC radio to plasma 0.3). (C) Mass spectrometry analysis was performed to confirm the brain penetration of bedaquiline, linezolid, and pretomanid following oral administration. Conclusion Dynamic 18F-pretomanid PET provided holistic data on pretomanid exposures showing excellent penetration into infected lung and brain tissues. The BPaL regimen was inferior to standard TB treatment for TB meningitis. Thus, new pretomanid-containing regimens need to be developed for the treatment of MDR-TB meningitis. Disclosures Charles A. Peloquin, Pharm.D., Nothing to disclose Alvaro A. Ordonez, MD, Cubresa (Consultant)Fujirebio Diagnostics (Research Grant or Support) Sanjay K. Jain, MD, Fujirebio Diagnostics, Inc., USA (Research Grant or Support)Novobiotic LLC, USA (Research Grant or Support)T3 Pharma, Switzerland (Research Grant or Support) Sanjay K. Jain, MD, Fujirebio Diagnostics, Inc., USA (Individual(s) Involved: Self): Research Grant or Support; Novobiotic LLC, USA (Individual(s) Involved: Self): Research Grant or Support; T3 Pharma, Switzerland (Individual(s) Involved: Self): Research Grant or Support

L’objectif global de cette thèse était d’étudier, à partir de la cohorte des patients du centre de référence PXE du CHU d’Angers, différente aspects du phénotype cardiovasculaire (CV) du PXE. Ainsi, dans un premier travail, nous avons pu montrer dans l’étude GOCAPXE, que les calcifications ectopiques seraient un processus actif pouvant être détecté par une imagerie moléculaire utilisant un traceur spécifique de l’activité ostéoblastique, le 18-Fluorure de Sodium (18F-NaF); que ce processus était détectable avant même que ces calcifications ne soient visibles par les techniques d’imageries classiques; que ce processus était localisé aux zones habituellement lésées dans le PXE : les plis de flexion et le cou pour la peau et l’artère fémorale superficielle pour le vaisseau. Cette technique mériterait d’être validée dans une étude longitudinale et son rôle en tant biomarqueur diagnostique et de suivi serait ainsi envisageable. Le deuxième travail de cette thèse a été d’étudier les conséquences morphologiques et fonctionnelles d’une augmentation chronique de la pression artérielle chez les patients PXE. Cette question était pertinente car dans la littérature, la question d’une hypertension artérielle (HTA) chez les PXE reste controversée. Nous avons ainsi montré pour la première fois que dans un modèle d’HTA induite par le Deoxycorticostérone (DOCA)-Salt chez la souris Abcc6-/- cette augmentation de la pression artérielle induisait un remodelage CV avec à la fois de la fibrose et des calcifications dystrophiques. Les résultats de cette étude suggèrent la nécessité d’un contrôle optimal de la pression artérielle chez les patients PXE. Le troisième travail de cette thèse a été de caractériser une lésion de la carotide interne détectée avec une fréquence élevée dans la cohorte angevine. Nous avons pu montrer que cette anomalie était une hypoplasie de la carotide interne d’origine probablement congénitale. Chez les patients de la cohorte angevine, cette lésion était associée à des anévrismes intracrâniens mais nous n’avons pas retrouvé d’association avec la survenue d’accident vasculaire cérébral. Ainsi, les résultats de cette étude invitent les praticiens prenant en charge des patients PXE à la rechercher systématiquement dans le bilan vasculaire d’un patient PXE. Si une telle lésion est retrouvée, une imagerie vasculaire intracrânienne devrait être proposée à la recherche d’anévrismes et leur prise en charge discuté en concertation multidisciplinaire. Enfin, le dernier travail a permis de montrer qu’un traitement systémique par le Thiosulfate de Sodium (STS), utilisé dans la calciphylaxie rénale, était efficace sur la régression des calcifications artérielles et cutanées chez une jeune garçon ayant un phénotype CV gravissime résultant de la combinaison délétères de plusieurs gènes pathogènes du spectre PXE Ce traitement mériterait d’être validé dans un essai thérapeutique chez l’humain mais aussi la démonstration de ses mécanismes d’action dans le modèle murin Abcc6-/-. Nous suggérons d’utiliser ce traitement en cas de PXE sévère et rapidement progressif notamment sur le plan vasculaire. Au terme de ce travail de thèse, nous avons montré que le gène ABCC6 était impliqué dans le remodelage vasculaire à la fois au niveau développemental (Hypoplasie Carotidienne) mais aussi acquis (Fibrose, Calcification Cardiaque Dystrophique). Nous avons montré aussi que les calcifications dans le PXE étaient tissus et localisations spécifiques, que ces calcifications étaient actives. Enfin nous avons ouvert la porte à un traitement des formes graves du PXE avec le Thiosulfate de Sodium. Une approche thérapeutique multimodale ciblant plusieurs mécanismes concourant aux calcifications seraient judicieux à évaluer dans les futurs essais cliniques
Since the discovery of the ABCC6 gene in 2000, mutations are at the origin of PseudoxanthomeElastic (PXE), knowledge of genetics, pathophysiology, phenotypic characterizations have has mademajor advances, notably with the Discovery in 2013 of the fundamental role of Pyrophosphateinorganic (PPi) as a deficient anti‐calcifying factor in patients. The overall goal of this thesis was tostudy, from the cohort of patients at the center of PXE reference of the CHU d'Angers, differentaspects of cardiovascular phenotype (CV) of PXE. Thus, in a first work, we were able to show in thestudy GOCAPXE, that ectopic calcifications would be a active process that can be detected by imagingUsing a specific activity tracer Osteoblastic, 18‐sodium fluoride (18F‐NaF); that this process wasdetectable even before these calcifications are not visible by conventional imaging techniques; thatthis process was localized to areas usually injured in the PXE: flexion folds and neck for skin and thesuperficial femoral artery for the vessel. This technique should be validated in a study longitudinaland its role as a diagnostic biomarker In this way, monitoring and monitoring could be considered.The second work of this thesis was to study the morphological consequences and functional of achronic increase in blood pressure in PXE patients. This question was relevant because in theliterature, the question of a high blood pressure (hypertension) in PXE remains controversial. Wehave thus shown for the first time that in a model of HTA induced by the Deoxycorticosterone(DOCA)‐Salt in Abcc6‐/‐ this increase in blood pressure led to a CV remodeling with both fibrosis andcalcifications dystrophic. The results of this study suggest need for optimal control of blood pressurein patients. The third work of this thesis was to characterize a lesion of the internal carotid detectedwith high frequency in the Angevine cohort. We have could show that this abnormality washypoplasia of the Probably congenital internal carotid. In the patients of the angevine cohort, thislesion was associated with intracranial aneurysms but we have not found in association with theoccurrence of vascular accident brain. Thus, the results of this study invite practitioners supportingPXE patients to search for it systematically in the vascular balance of a PXE patient. If such a lesion isfound, vascular imaging Intracranial should be proposed to research Aneurysms and theirmanagement discussed in consultation multidisciplinary. Finally, the latest work has made it possibleto show that systemic treatment with Thiosulphate Sodium (STS), used in renal calciphylaxia, waseffective on the regression of arterial calcifications and skin in a young boy with a phenotype CVGravel resulting from the deleterious combination of several pathogenic genes of the PXE spectrumThis treatment would deserve be validated in a human therapeutic trial but also the demonstrationof its mechanisms of action in the Abcc6‐/‐murin model. We suggest using this treatment for severeand rapidly progressive PXE especially on the vascular plane.At the end of this thesis work, we showed that the ABCC6 gene was involved in vascular remodelingat both at the developmental level (Carotid Hypoplasia) but also acquired (Fibrosis, CardiacCalcification Dystrophic). We also showed that calcifications in PXE were tissues and locationsspecific, that these calcifications were active. Finally we have opened the door to a treatment ofsevere forms of PXE with Sodium Thiosulphate. An approach multimodal therapy targeting multiplemechanisms this would be useful to evaluate in future clinical trials