Imaging protocols for renal multiparametric MRI and MR urography: results of a consensus conference from the French Society of Genitourinary Imaging.

OBJECTIVES: To develop technical guidelines for magnetic resonance imaging aimed at characterising renal masses (multiparametric magnetic resonance imaging, mpMRI) and at imaging the bladder and upper urinary tract (magnetic resonance urography, MRU). METHODS: The French Society of Genitourinary Imaging organised a Delphi consensus conference with a two-round Delphi survey followed by a face-to-face meeting. Two separate questionnaires were issued for renal mpMRI and for MRU. Consensus was strictly defined using a priori criteria. RESULTS: Forty-two expert uroradiologists completed both survey rounds with no attrition between the rounds. Fifty-six of 84 (67%) statements of the mpMRI questionnaire and 44/71 (62%) statements of the MRU questionnaire reached final consensus. For mpMRI, there was consensus that no injection of furosemide was needed and that the imaging protocol should include T2-weighted imaging, dual chemical shift imaging, diffusion-weighted imaging (use of multiple b-values; maximal b-value, 1000 s/mm2) and fat-saturated single-bolus multiphase (unenhanced, corticomedullary, nephrographic) contrast-enhanced imaging; late imaging (more than 10 min after injection) was judged optional. For MRU, the patients should void their bladder before the examination. The protocol must include T2-weighted imaging, anatomical fast T1/T2-weighted imaging, diffusion-weighted imaging (use of multiple b-values; maximal b-value, 1000 s/mm2) and fat-saturated single-bolus multiphase (unenhanced, corticomedullary, nephrographic, excretory) contrast-enhanced imaging. An intravenous injection of furosemide is mandatory before the injection of contrast medium. Heavily T2-weighted cholangiopancreatography-like imaging was judged optional. CONCLUSION: This expert-based consensus conference provides recommendations to standardise magnetic resonance imaging of kidneys, ureter and bladder. KEY POINTS: • Multiparametric magnetic resonance imaging (mpMRI) aims at characterising renal masses; magnetic resonance urography (MRU) aims at imaging the urinary bladder and the collecting systems. • For mpMRI, no injection of furosemide is needed. • For MRU, an intravenous injection of furosemide is mandatory before the injection of contrast medium; heavily T2-weighted cholangiopancreatography-like imaging is optional.

Imaging protocols for CT urography: results of a consensus conference from the French Society of Genitourinary Imaging.

OBJECTIVES: To develop technical guidelines for computed tomography urography. METHODS: The French Society of Genitourinary Imaging organised a Delphi consensus conference with a two-round Delphi survey followed by a face-to-face meeting. Consensus was strictly defined using a priori criteria. RESULTS: Forty-two expert uro-radiologists completed both survey rounds with no attrition between the rounds. Ninety-six (70%) of the initial 138 statements of the questionnaire achieved final consensus. An intravenous injection of 20 mg of furosemide before iodinated contrast medium injection was judged mandatory. Improving the quality of excretory phase imaging through oral or intravenous hydration of the patient or through the use of an abdominal compression device was not deemed necessary. The patient should be imaged in the supine position and placed in the prone position only at the radiologist's request. The choice between single-bolus and split-bolus protocols depends on the context, but split-bolus protocols should be favoured whenever possible to decrease patient irradiation. Repeated single-slice test acquisitions should not be performed to decide of the timing of excretory phase imaging; instead, excretory phase imaging should be performed 7 min after the injection of the contrast medium. The optimal combination of unenhanced, corticomedullary phase and nephrographic phase imaging depends on the context; suggestions of protocols are provided for eight different clinical situations. CONCLUSION: This expert-based consensus conference provides recommendations to standardise the imaging protocol for computed tomography urography. KEY POINTS: • To improve excretory phase imaging, an intravenous injection of furosemide should be performed before the injection of iodinated contrast medium. • Systematic oral or intravenous hydration is not necessary to improve excretory phase imaging. • The choice between single-bolus and split-bolus protocols depends on the context, but split-bolus protocols should be favoured whenever possible to decrease patient irradiation.

Brain palpation from physiological vibrations using MRI.

We present a magnetic resonance elastography approach for tissue characterization that is inspired by seismic noise correlation and time reversal. The idea consists of extracting the elasticity from the natural shear waves in living tissues that are caused by cardiac motion, blood pulsatility, and any muscle activity. In contrast to other magnetic resonance elastography techniques, this noise-based approach is, thus, passive and broadband and does not need any synchronization with sources. The experimental demonstration is conducted in a calibrated phantom and in vivo in the brain of two healthy volunteers. Potential applications of this "brain palpation" approach for characterizing brain anomalies and diseases are foreseen.

Outcomes of extended resection for locally advanced thymic malignancies.

BACKGROUND: Thymic malignancies are rare tumors about which data are limited. Our objective here was to evaluate the outcomes and risk factors for complications and death in patients who underwent extended surgery to remove thymic malignancies. METHODS: We retrospectively included patients who underwent extended resection of locally advanced, nonmetastatic thymic malignancies at our institution. Patients were deemed eligible for resection by a multidisciplinary team. During surgery, priority was given to achieving complete resection rather than to sparing organs. RESULTS: The 108 patients had a mean age of 53 ± 15 years (range, 9-83); among them, 91 had thymoma, 12 thymic carcinoma, and 5 neuroendocrine tumor. The Masaoka stage was III or higher in 86 patients; examination of operative specimens resulted in downstaging of 22 patients. Tumor-free resection margins were achieved in 98 patients. Overall 5- and 10-year survival rates were 80% and 68%, respectively. Myasthenia gravis, present in 36 patients, was the only independent significant risk factor for major postoperative complications. Age older than 70 years, thymic carcinoma or neuroendocrine tumor, pT3 or pT4 stage, and R1 or R2 resection margins independently predicted death. The number of resected structures was not associated with survival. Thymic carcinoma or neuroendocrine tumor was independently associated with shorter disease-free survival. CONCLUSION: In an expert center, extended resection targeting complete resection rather than organ preservation provided good outcomes in patients with locally advanced thymic malignancies. The risk/benefit ratio of surgery should be assessed with special care in patients who are elderly or have myasthenia gravis.

A bilateral lung transplant and giant pulmonary artery aneurysm reconstruction with an aortic graft in a woman with pulmonary hypertension.

An aneurysm of the pulmonary artery is a rare but severe complication in patients suffering from pulmonary arterial hypertension. For these patients, a lung or heart-lung transplant is the only definitive therapy available. Our goal was to show a reconstruction strategy in a patient with a mismatch between the pulmonary artery and the donor aorta.

Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension.

The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The morphological and functional phenotyping of the right ventricle is of particular importance in the context of hemodynamic compromise in patients with ARHF. Here, we describe a method to induce ARHF in a previously described large animal model of chronic PH, and to phenotype, dynamically, right ventricular function using the gold standard method (i.e., pressure-volume PV loops) and with a non-invasive clinically available method (i.e., echocardiography). Chronic PH is first induced in pigs by left pulmonary artery ligation and right lower lobe embolism with biological glue once a week for 5 weeks. After 16 weeks, ARHF is induced by successive volume loading using saline followed by iterative pulmonary embolism until the ratio of the systolic pulmonary pressure over systemic pressure reaches 0.9 or until the systolic systemic pressure decreases below 90 mmHg. Hemodynamics are restored with dobutamine infusion (from 2.5 µg/kg/min to 7.5 µg/kg/min). PV-loops and echocardiography are performed during each condition. Each condition requires around 40 minutes for induction, hemodynamic stabilization and data acquisition. Out of 9 animals, 2 died immediately after pulmonary embolism and 7 completed the protocol, which illustrates the learning curve of the model. The model induced a 3-fold increase in mean pulmonary artery pressure. The PV-loop analysis showed that ventriculo-arterial coupling was preserved after volume loading, decreased after acute pulmonary embolism and was restored with dobutamine. Echocardiographic acquisitions allowed to quantify right ventricular parameters of morphology and function with good quality. We identified right ventricular ischemic lesions in the model. The model can be used to compare different treatments or to validate non-invasive parameters of right ventricular morphology and function in the context of ARHF.

Long-term outcomes after chest wall resection and repair with titanium bars and sternal plates.

Objectives: En-bloc complete resection remains the treatment of choice for localized chest wall (CW) tumors. Titanium bars reconstruction demonstrated encouraging results with satisfactory early outcomes. However, long-term outcomes remain under-reported. The purpose of this study is to evaluate long-term outcomes after CW resection and repair with titanium devices. Methods: From June 2012 to December 2018, we retrospectively reviewed all patients with CW tumors who underwent surgical resection and repair using titanium. Long-term outcomes were assessed. Results: We identified 87 patients who underwent CW tumor resections and titanium reconstruction. Sixty-eight patients were included in the study (excluding benign tumors, Pancoast tumors, palliative surgeries, or clavicle reconstruction). There were 29 sarcomas, 20 isolated CW metastases, eight lung cancers, four breast cancers, three thymic malignancies, two sarcomatoid mesothelioma, and one desmoid tumor. Complete resection was achieved in 64 patients (94%), while R1 resection in four patients (6%). Resection involved one rib in two patients, two ribs in thirteen, three ribs in eighteen, four ribs in nine, five ribs in two, seven ribs in one, partial sternum in fifteen, and full sternum in sixteen patients. No patient experienced flail chest. The 1-year, 3-year, and 5-year overall survival rates and disease-free survivals were 82.3%, 61.4%,57.3%, and 67.6%,57.3%,52.6%, respectively. Surgical site infection occurred in 18% (n = 12) of cases. Eleven of twelve patients had an early infection (<1 year), which required material removal in six patients. Asymptomatic connector unsealing occurred in 6% (n = 4), with only one re-intervention. Titanium allergy has never been reported. Chronic chest pain (lasting more than 3 months after surgery, with daily use of pain killer) was reported in 24% of patients. Conclusion: CW resections with titanium reconstruction are associated with long-term survivors. Titanium devices were safe, reliable, and achieved satisfactory oncological results with low morbidity and implant-related complication rates.

Pulmonary thromboendarterectomy: The Marie Lannelongue Hospital experience.

Background: Targeted medical therapy and balloon pulmonary angioplasty (BPA) entered the field of chronic thromboembolic pulmonary hypertension (CTEPH) treatment in the early 2010's. Multimodal therapy is emerging as the new gold standard for CTEPH management. Whether this change of paradigm impacted early outcomes of pulmonary endarterectomy (PEA) remains unknown. Our aim is to report our surgical experience in the era of CTEPH multimodal management. Methods: Patients who underwent PEA between 2016 and 2020 were included in the study. Early outcomes were described and compared between three groups of patients: PEA alone, PEA after targeted medical therapy induction and PEA after BPA. Results: A total of 418 patients, 225 males and 193 females, with a mean age of 59±14 years were included in the study. 336 patients underwent PEA alone, 69 after medical targeted therapy induction and 13 after unilateral BPA. Baseline preoperative pulmonary vascular resistance [4.99 (IQR, 1.71-8.48), 6.21 (IQR, 4.37-8.1), 5.03 (IQR, 4.44-7.19) wood units (WU), P=0.230, respectively] and PEA effectiveness [% decrease mean pulmonary artery pressure (mPAP), 24 (IQR, 7-42), 25 (IQR, 7-35), 23 (IQR, 3-29), P=0.580] did not differ between groups. Compared to PEA alone and PEA+BPA, the medical therapy induction group represented the most challenging group with higher baseline mPAP (45±10 vs. 42±11 and 43±11 mmHg, P=0.047), longer circulatory arrest time (30.1±15 vs. 26.6±10 and 19.6±6 min, P=0.005), higher post-PEA extracorporeal membrane oxygenation use (20.6% vs. 8.7 and 9.1%, P=0.004), higher duration on mechanical ventilation [4 (IQR, 1-12) vs. 1 (IQR, 0.5-5) and 2 (IQR, 1-3) days, P=0.005], higher complication rate (85.5% vs. 74.6% and 76.9%, P=0.052) and higher 90-day mortality (13% vs. 3.9% and 0%, P=0.002). Compared to PEA and PEA+ medical therapy induction groups, patients in the BPA induction group were older [72 (IQR, 62-76) vs. 60 (IQR, 48-69) and 62 (IQR, 52-72) years, P=0.005], and underwent shorter cardiopulmonary bypass (191.9±47.9 vs. 222±107.2 and 236.8±46.4 min, P<0.001), aortic cross clamping (54.8±21 vs. 82.7±31.4 and 80.1±32.9 min, P=0.002) and circulatory arrest time (19.6±6.2 vs. 26.6±10.8 and 30.1±15.1 min, P=0.008). Conclusions: Multimodal therapy approach to CTEPH patients did not affect effectiveness of PEA. Medical therapy and BPA could act in synergy with surgery to treat more challenging patients.

Magnetic resonance elastography of the kidneys: feasibility and reproducibility in young healthy adults.

PURPOSE: To evaluate the feasibility and reproducibility of renal magnetic resonance elastography (MRE) in young healthy volunteers. MATERIALS AND METHODS: Ten volunteers underwent renal MRE twice at a 4-5 week interval. The vibrations (45 and 76 Hz) were generated by a speaker positioned beneath the volunteers' back and centered on their left kidney. For each frequency, three sagittal slices were acquired (eight phase offsets per cycle, motion-encoding gradients successively positioned along the three directions of space). Shear velocity images were reconstructed using the curl operator combined with the local frequency estimation (LFE) algorithm. RESULTS: The mean shear velocities measured in the renal parenchyma during the two examinations were not significantly different and exhibited a mean variation of 6% at 45 Hz and 76 Hz. The mean shear velocities in renal parenchyma were 2.21 ± 0.14 m/s at 45 Hz (shear modulus of 4.9 ± 0.5 kPa) and 3.07 ± 0.17 m/s at 76 Hz (9.4 ± 0.8 kPa, P < 0.01). The mean shear velocities in the renal cortex and medulla were respectively 2.19 ± 0.13 m/s and 2.32 ± 0.16 m/s at 45 Hz (P = 0.002) and 3.06 ± 0.16 m/s and 3.10 ± 0.22 m/s at 76 Hz (P = 0.13). CONCLUSION: Renal MRE was feasible and reproducible. Two independent measurements of shear velocities in the renal parenchyma of the same subjects showed an average variability of 6%.

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure.

INTRODUCTION: Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been elucidated so far. We hypothesized that determining RV metabolic alterations could help to understand the mechanism link to the deterioration of RV function as well as help to identify new biomarkers of RV failure. METHODS: In the current study, we aimed to characterize the metabolic reprogramming associated with the RV remodeling phenotype during experimental PH induced by chronic-hypoxia-(CH) exposure or monocrotaline-(MCT) exposure in rats. Three weeks after PH initiation, we hemodynamically characterized PH (echocardiography and RV catheterization), and then we used an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry to analyze RV and LV tissues in addition to plasma samples from MCT-PH and CH-PH rat models. RESULTS: CH exposure induced adaptive RV phenotype as opposed to MCT exposure which induced maladaptive RV phenotype. We found that predominant alterations of arginine, pyrimidine, purine, and tryptophan metabolic pathways were detected on the heart (LV+RV) and plasma samples regardless of the PH model. Acetylspermidine, putrescine, guanidinoacetate RV biopsy levels, and cytosine, deoxycytidine, deoxyuridine, and plasmatic thymidine levels were correlated to RV function in the CH-PH model. It was less likely correlated in the MCT model. These pathways are well described to regulate cell proliferation, cell hypertrophy, and cardioprotection. These findings open novel research perspectives to find biomarkers for early detection of RV failure in PH.

A compact integrated microfluidic oxygenator with high gas exchange efficiency and compatibility for long-lasting endothelialization.

We have developed and tested a novel microfluidic device for blood oxygenation, which exhibits a large surface area of gas exchange and can support long-term sustainable endothelialization of blood microcapillaries, enhancing its hemocompatibility for clinical applications. The architecture of the parallel stacking of the trilayers is based on a central injection for blood and a lateral injection/output for gas which allows significant reduction in shear stress, promoting sustainable endothelialization since cells can be maintained viable for up to 2 weeks after initial seeding in the blood microchannel network. The circular design of curved blood capillaries allows covering a maximal surface area at 4 inch wafer scale, producing high oxygen uptake and carbon dioxide release in each single unit. Since the conventional bonding process based on oxygen plasma cannot be used for surface areas larger than several cm2, a new "wet bonding" process based on soft microprinting has been developed and patented. Using this new protocol, each 4 inch trilayer unit can be sealed without a collapsed membrane even at reduced 15 µm thickness and can support a high blood flow rate. The height of the blood channels has been optimized to reduce pressure drop and enhance gas exchange at a high volumetric blood flow rate up to 15 ml min-1. The simplicity of connecting different units in the stacked architecture is demonstrated for 3- or 5-unit stacked devices that exhibit remarkable performance with low primary volume, high oxygen uptake and carbon dioxide release and high flow rate of up to 80 ml min-1.

SAR228810: an antibody for protofibrillar amyloid ß peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA).

BACKGROUND: Anti-amyloid ß (Aß) immunotherapy represents a major area of drug development for Alzheimer's disease (AD). However, Aß peptide adopts multiple conformations and the pathological forms to be specifically targeted have not been identified. Aß immunotherapy-related vasogenic edema has also been severely dose limiting for antibodies with effector functions binding vascular amyloid such as bapineuzumab. These two factors might have contributed to the limited efficacy demonstrated so far in clinical studies. METHODS: To address these limitations, we have engineered SAR228810, a humanized monoclonal antibody (mAb) with limited Fc effector functions that binds specifically to soluble protofibrillar and fibrillar forms of Aß peptide and we tested it together with its murine precursor SAR255952 in vitro and in vivo. RESULTS: Unlike gantenerumab and BAN2401, SAR228810 and SAR255952 do not bind to Aß monomers, low molecular weight Aß oligomers or, in human brain sections, to Aß diffuse deposits which are not specific of AD pathology. Both antibodies prevent Aß42 oligomer neurotoxicity in primary neuronal cultures. In vivo, SAR255952, a mouse aglycosylated IgG1, dose-dependently prevented brain amyloid plaque formation and plaque-related inflammation with a minimal active dose of 3 mg/kg/week by the intraperitoneal route. No increase in plasma Aß levels was observed with SAR255952 treatment, in line with its lack of affinity for monomeric Aß. The effects of SAR255952 translated into synaptic functional improvement in ex-vivo hippocampal slices. Brain penetration and decoration of cerebral amyloid plaques was documented in live animals and postmortem. SAR255952 (up to 50 mg/kg/week intravenously) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSL mice while 3D6, the murine version of bapineuzumab, did. In immunotolerized mice, the clinical candidate SAR228810 demonstrated the same level of efficacy as the murine SAR255952. CONCLUSION: Based on the improved efficacy/safety profile in non-clinical models of SAR228810, a first-in-man single and multiple dose administration clinical study has been initiated in AD patients.

SAR110894, a potent histamine H3-receptor antagonist, displays disease-modifying activity in a transgenic mouse model of tauopathy.

INTRODUCTION: Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models. METHODS: We evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22). RESULTS: SAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1-alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout. DISCUSSION: Long-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.

Microarray analysis of nonhuman primates: validation of experimental models in neurological disorders.

Nonhuman primates (NHPs) have provided robust experimental animal models for many human-related diseases due to their similar physiologies. Nonetheless, profound differences remain in the acquisition, progression, and outcome of important diseases such as AIDS and Alzheimer's, for which the underlying basis remains obscure. We explored the utility of human high-density oligonucleotide arrays to survey the transcription profile of NHP genomes. Total RNA from prefrontal cortices of human (Homo sapiens), common chimpanzee (Pan troglodytes), cynomolgous macaque (Macaca fascicularis), and common marmoset (Callithrix jacchus) was labeled and hybridized to Affymetrix U95A GeneChip probe arrays. Corresponding data obtained previously from common chimpanzee and orangutan (Pongo pygmaeus) were added for comparison. Qualitative (present or not detected) and quantitative (expression level) analysis indicated that many genes known to be involved in human neurological disorders were present and regulated in NHPs. A gene involved in dopamine metabolism (catechol-O-methyltransferase) was absent in macaque and marmoset. Glutamate receptor 2 was up-regulated, and transcription-associated genes were down-regulated in NHPs compared with humans. We demonstrate that transcript profiling of NHPs could provide comparative genomic data to validate and better focus experimental animal models of human neurological disorders.

Heterologous expression of human {alpha}6{beta}4{beta}3{alpha}5 nicotinic acetylcholine receptors: binding properties consistent with their natural expression require quaternary subunit assembly including the {alpha}5 subunit.

Heterologous expression and lesioning studies were conducted to identify possible subunit assembly partners in nicotinic acetylcholine receptors (nAChR) containing alpha6 subunits (alpha6(*) nAChR). SH-EP1 human epithelial cells were transfected with the requisite subunits to achieve stable expression of human alpha6beta2, alpha6beta4, alpha6beta2beta3, alpha6beta4beta3, or alpha6beta4beta3alpha5 nAChR. Cells expressing subunits needed to form alpha6beta4beta3alpha5 nAChR exhibited saturable [(3)H]epibatidine binding (K(d) = 95.9 +/- 8.3 pM and B(max) = 84.5 +/- 1.6 fmol/mg of protein). The rank order of binding competition potency (K(i)) for prototypical nicotinic compounds was alpha-conotoxin MII (6 nM) > nicotine (156 nM) approximately methyllycaconitine (200 nM) > alpha-bungarotoxin (>10 microM), similar to that for nAChR in dopamine neurons displaying a distinctive pharmacology. 6-Hydroxydopamine lesioning studies indicated that beta3 and alpha5 subunits are likely partners of the alpha6 subunits in nAChR expressed in dopaminergic cell bodies. Similar to findings in rodents, quantitative real-time reverse transcription-polymerase chain reactions of human brain indicated that alpha6 subunit mRNA expression was 13-fold higher in the substantia nigra than in the cortex or the rest of the brain. Thus, heterologous expression studies suggest that the human alpha5 subunit makes a critical contribution to alpha6beta4beta3alpha5 nAChR assembly into a ligand-binding form with native alpha6(*)-nAChR-like pharmacology and of potential physiological and pathophysiological relevance.