Validation of a Novel Methodology to Evaluate Changes in the Flare Geometry of Renovisceral Bridging Stent-Grafts After Fenestrated Endovascular Aneurysm Repair

Purpose: To validate a novel method to evaluate changes in the geometry of renovisceral bridging stent-grafts (BSGs) in patients undergoing fenestrated endovascular aneurysm repair (fEVAR). Materials and Methods: Retrospective analysis was conducted of serial computed tomography angiograms (CTAs) of 10 fEVAR patients (31 BSGs) with at least 2 years of CTA follow-up. Centerline reconstructions were made through the fenestrated stent-graft (FSG) and each BSG. Flare geometry was reconstructed based on marker coordinates and a mesh of the aortic lumen. The shortest distance was calculated from the top of the flare circumference to the FSG fabric. The amount of flaring was assessed with the flare to fenestration diameter ratio and BSG compression to diameter ratio (D-ratio). All measurements were performed by 2 observers. Interobserver variability was assessed; results are presented as the intraclass correlation coefficient (ICC) and repeatability coefficient (RC). Results: Excellent interobserver agreement was achieved for BSG diameter and flare to fenestration distance calculations (ICC 0.865 and 0.944; RC 2.2% and 4.5%, respectively). Six patients had BSG-related complications during follow-up: 2 type IIIc endoleaks and 4 BSG occlusions. Five of the 6 BSGs with complications showed a considerable change in the D-ratio compared with the first postoperative CTA. Conclusion: Precise assessment of the geometry of visceral BSGs in fEVAR is feasible with the presented method. Geometrical changes that may precede later complications can be detected, which could aid in localization of the origin, but a larger series of patients is necessary to define its true clinical merit

Genome-wide association study in patients with posterior urethral valves

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC

Incremental prognostic value of hybrid [15O]H2O positron emission tomography-computed tomography: combining myocardial blood flow, coronary stenosis severity, and high-risk plaque morphology

AimsThis study sought to determine the prognostic value of combined functional testing using positron emission tomography (PET) perfusion imaging and anatomical testing using coronary computed tomography angiography (CCTA)-derived stenosis severity and plaque morphology in patients with suspected coronary artery disease (CAD).Methods and resultsIn this retrospective study, 539 patients referred for hybrid [15O]H2O PET-CT imaging because of suspected CAD were investigated. PET was used to determine myocardial blood flow (MBF), whereas CCTA images were evaluated for obstructive stenoses and high-risk plaque (HRP) morphology. Patients were followed up for the occurrence of all-cause death and non-fatal myocardial infarction (MI). During a median follow-up of 6.8 (interquartile range 4.8–7.8) years, 42 (7.8%) patients experienced events, including 23 (4.3%) deaths, and 19 (3.5%) MIs. Annualized event rates for normal vs. abnormal results of PET MBF, CCTA-derived stenosis, and HRP morphology were 0.6 vs. 2.1%, 0.4 vs. 2.1%, and 0.8 vs. 2.8%, respectively (P ConclusionPET-derived MBF, CCTA-derived stenosis severity, and HRP morphology were univariably associated with death and MI, whereas only stenosis severity and HRP morphology provided independent prognostic value.</div

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Tumor Rejection Induced by CD70-mediated Quantitative and Qualitative Effects on Effector CD8+ T Cell Formation

In vivo priming of antigen-specific CD8(+) T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8(+) T cell response are programmed. However, it is unclear to what extent CD8(+) T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8(+) T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-γ production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8(+) T cell– and IFN-γ–dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8(+) T cells

Comparison between quantitative cardiac magnetic resonance perfusion imaging and [O-15]H2O positron emission tomography

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