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Background: Mitral valve transcatheter edge-to-edge repair (M-TEER) reduces secondary mitral regurgitation (MR) in heart failure and impacts survival in selected patients as demonstrated in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial. However, long-term outcome data after M-TEER under real-world conditions are lacking., Objectives: This study sought to assess long-term efficacy and survival after M-TEER in a large real-world registry., Methods: We analyzed patients with significant secondary MR undergoing M-TEER from the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry. Long-term MR reduction, functional outcomes, survival rate, and predictors for all-cause mortality were assessed., Results: In this study, 1,628 patients undergoing M-TEER (mean age 73.8 years, mean EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 6.9%, 86.6% NYHA functional class ≥III) with available long-term data were included. Five-year survival was 35.0%. Long-term MR reduction (MR grade ≤2+: baseline 4.1%, discharge 92.2%, 5-year follow-up 85.5%; P < 0.001) and functional improvement (NYHA ≤II: baseline 13.4%, 5-year follow-up 60.1%; P < 0.001) was observed. The degree of residual MR was associated with 5-year survival (residual MR grade ≤1+: 38.6%; 2+: 30.5%; ≥3+: 22.6%; P < 0.001). Independent predictors for 5-year all-cause mortality post-M-TEER included age, renal function, residual MR, NYHA functional class, left ventricular ejection-fraction, and COAPT trial eligibility (P < 0.01 for all)., Conclusions: This extensive multicenter registry underscores the long-term efficacy of M-TEER in real-world clinical practice and identifies predictors for long-term survival. These findings contribute valuable insights for optimizing patient selection in routine clinical interventions., Competing Interests: Funding Support and Author Disclosures Dr Stocker has served as consultant for Occlutech International and received speaker honoraria from Edwards Lifesciences. Dr Stolz has received speaker honoraria from Edwards Lifesciences. Dr Weckbach has received speaker honoraria from AstraZeneca and Bayer. Dr Koell has received personal fees from Edwards Lifesciences. Dr Kalbacher has received personal fees from Abbott Medical, Edwards Lifesciences, Medtronic, and Pi-Cardia Ltd. Dr Hausleiter has received speaker honoraria from and served as a consultant for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

An amplicon-based targeted next-generation sequencing (NGS) assay for the detection of gene fusions in sarcomas was developed, validated, and implemented. This assay can detect fusions in targeted regions of 138 genes and BCOR internal tandem duplications. This study reviews our experience with testing on the first 652 patients analyzed. Gene fusions were detected in 238 (36.5%) of 652 cases, including 83 distinct fusions in the 238 fusion-positive cases, 10 of which had not been previously described. Among the 238 fusion-positive cases, the results assisted in establishing a diagnosis for 137 (58%) cases, confirmed a suspected diagnosis in 66 (28%) cases, changed a suspected diagnosis in 25 (10%) cases, and were novel fusions with unknown clinical significance in 10 (4%) cases. Twenty-six cases had gene fusions (ALK, ROS1, NTRK1, NTRK3, and COL1A1::PDGFB) for which there are targetable therapies. BCOR internal tandem duplications were identified in 6 (1.2%) of 485 patients. Among the 138 genes in the panel, 66 were involved in one or more fusions, and 72 were not involved in any fusions. There was little overlap between the genes involved as 5'-partners (31 different genes) and 3'-partners (37 different genes). This study shows the clinical utility of a next-generation sequencing gene fusion detection assay for the diagnosis and treatment of sarcomas., Competing Interests: Disclosure Statement None declared., (Copyright © 2024. Published by Elsevier Inc.)

Background: Data regarding the association of pulmonary hypertension (PH) and outcomes in patients undergoing transcatheter tricuspid valve edge-to-edge repair (T-TEER) are scarce., Objectives: To 1) investigate the impact of PH on outcomes after T-TEER and 2) to shed further light into the role of pre- and postcapillary PH in patients undergoing T-TEER for relevant tricuspid regurgitation (TR)., Methods: The study included patients from the EuroTR registry (NCT06307262) who underwent T-TEER for relevant TR from 2016 until 2023 with available invasive evaluation of sPAP using right heart catheterization. Study endpoints were procedural TR reduction, improvement in New York Heart Association (NYHA) function class and a combined endpoint of death or heart failure hospitalization (HFH) at two-years., Results: Among a total of 1230 patients (mean age 78.6 ±7.0 years; 51.4% women) increasing systolic pulmonary artery pressure (sPAP) was independently associated with increasing rates of two-year death or HFH (hazard ratio 1.027, 95% confidence interval 1.003-1.052, p=0.030; median survival follow up 343 (114-645) days). No significant survival differences were observed for patients with pre- vs. postcapillary PH. Sensitivity analysis revealed a sPAP value of 46 mmHg as optimized threshold for prediction of death or HFH. Being observed in 526 patients (42.8%), elevated sPAP > 46 mmHg was associated with more severe heart failure symptoms at baseline and follow-up. Importantly, NYHA functional class and TR severity significantly improved irrespective of PH., Conclusion: PH is an important outcome predictor in patients undergoing T-TEER for relevant TR. In contrast to previous studies, no significant differences were observed for patients with pre- and postcapillary PH in terms of survival free from HFH., (Copyright © 2024. Published by Elsevier Inc.)

Aim: The aims of this study were: i) to report the prevalence of low-risk patients with degenerative mitral regurgitation (DMR) undergoing mitral transcatheter edge-to-edge repair (M-TEER) in a real-world setting; ii) to evaluate the prognostic significance of EuroSCORE II; iii) to determine whether an optimal M-TEER provides a mortality benefit regardless of EuroSCORE-II., Methods: We analyzed data from the GIOTTO registry that enrolled patients undergoing M-TEER in Italy. We included only patients with DMR. Two groups were defined: patients with EuroSCORE<4% and with EuroSCORE≥4%. A further stratification according to variables included in the EuroSCORE-II was made. Interaction between EuroSCORE-II and optimal procedural success was evaluated. Outcome of interest was all-cause death at 2-year., Results: Among 1659 patients prospectively enrolled in the GIOTTO registry, 657 had DMR, 364 with an EuroSCORE<4% (53%) and 311 with an EuroSCORE≥4% (47%). Patients with lower EuroSCORE were older with less comorbidities. All-cause mortality was higher in patients with EuroSCORE≥ vs <4%. EuroSCORE II ≥ 4% was independently associated with an increased risk of mortality (HR 2.36, 95%CI 1.28-4.38, p = 0.007). Among variables included in the EuroSCORE-II, Left Ventricular Ejection Fraction<35% and systolic Pulmonary Artery Pressure ≥ 50mmhg were independent predictors of clinical outcome. Two-year all-cause death was higher in patients without optimal MR reduction regardless of the calculated surgical risk (p for interaction 0.3)., Conclusion: More than half of patients with DMR undergoing M-TEER had a Euroscore<4% with a median age of 81. An optimally successful M-TEER was associated with a lower mortality regardless of EuroSCORE., Competing Interests: Declaration of competing interest M.A., M.M., F.B., C.G., A.G., and C.T. received consultation and speaker fees from Abbott Vascular outside the submitted work. All other authors have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

The global diffusion of antibiotic resistance poses a severe threat to public health. Addressing antibiotic-resistant infections requires innovative approaches, such as antibacterial nanostructured surfaces (ANSs). These surfaces, featuring ordered arrays of nanostructures, exhibit the ability to kill bacteria upon contact. However, most currently developed ANSs utilize bioinert materials, lacking bioactivity crucial for promoting tissue regeneration, particularly in the context of bone infections. This study introduces ANSs composed of bioactive calcium phosphate nanocrystals. Two distinct ANSs were created through a biomineralization-inspired growth of amorphous calcium phosphate (ACP) precursors. The ANSs demonstrated efficient antibacterial properties against both Gram-negative (P. aeruginosa) and Gram-positive (S. aureus) antibiotic resistant bacteria, with up to 75 % mortality in adhered bacteria after only 4 h of contact. Notably, the ANS featuring thinner and less oriented nano-needles exhibited superior efficacy attributed to simultaneous membrane rupturing and oxidative stress induction. Moreover, the ANSs facilitate the proliferation of mammalian cells, enhancing adhesion, spreading, and reducing oxidative stress. The ANSs displayed also significant bioactivity towards human mesenchymal stem cells, promoting colonization and inducing osteogenic differentiation. Specifically, the ANS with thicker and more ordered nano-needles demonstrated heightened effects. In conclusion, ANSs introduced in this work have the potential to serve as foundation for developing bone graft materials capable of eradicate site infections while concurrently stimulating bone regeneration. STATEMENT OF SIGNIFICANCE: Nanostructured surfaces with antibacterial properties through a mechano-bactericidal mechanism have shown significant potential in fighting antibiotic resistance. However, these surfaces have not been fabricated with bioactive materials necessary for developing devices that are both antibacterial and able to stimulate tissue regeneration. This study demonstrates the feasibility of creating nanostructured surfaces of ordered calcium phosphate nano-needles through a biomineralization-inspired growth. These surfaces exhibit dual functionality, serving as effective bactericidal agents against Gram-negative and Gram-positive antibiotic-resistant bacteria while also promoting the proliferation of mammalian cells and inducing osteogenic differentiation of human mesenchymal stem cells. Consequently, this approach holds promise in the context of bone infections, introducing innovative nanostructured surfaces that could be utilized in the development of antimicrobial and osteogenic grafts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of intraprocedural results following transcatheter edge-to-edge repair (TEER) in primary mitral regurgitation (MR) is controversial., Objectives: This study sought to investigate the prognostic impact of intraprocedural residual mitral regurgitation (rMR) and mean mitral valve gradient (MPG) in patients with primary MR undergoing TEER., Methods: The PRIME-MR (Outcomes of Patients Treated With Mitral Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation) registry included consecutive patients with primary MR undergoing TEER from 2008 to 2022 at 27 international sites. Clinical outcomes were assessed according to intraprocedural rMR and mean MPG. Patients were categorized according to rMR (optimal result: ≤1+, suboptimal result: ≥2+) and MPG (low gradient: ≤5 mm Hg, high gradient: > 5 mm Hg). The prognostic impact of rMR and MPG was evaluated in a Cox regression analysis. The primary endpoint was 2-year all-cause mortality or heart failure hospitalization., Results: Intraprocedural rMR and mean MPG were available in 1,509 patients (median age = 82 years [Q1-Q3: 76.0-86.0 years], 55.1% male). Kaplan-Meier analysis according to rMR severity showed significant differences for the primary endpoint between rMR ≤1+ (29.1%), 2+ (41.7%), and ≥3+ (58.0%; P < 0.001), whereas there was no difference between patients with a low (32.4%) and high gradient (42.1%; P = 0.12). An optimal result/low gradient was achieved in most patients (n = 1,039). The worst outcomes were observed in patients with a suboptimal result/high gradient. After adjustment, rMR ≥2+ was independently linked to the primary endpoint (HR: 1.87; 95% CI: 1.32-2.65; P < 0.001), whereas MPG >5 mm Hg was not (HR: 0.78; 95% CI: 0.47-1.31; P = 0.35)., Conclusions: Intraprocedural rMR but not MPG independently predicted clinical outcomes following TEER for primary MR. When performing TEER in primary MR, optimal MR reduction seems to outweigh the impact of high transvalvular gradients., Competing Interests: Funding Support and Author Disclosures Dr Ludwig has received travel compensation from Edwards Lifesciences; has received speaker honoraria from Abbott; has received advisory fees from Bayer; and is a consultant for New Valve Technology. Dr Koell has received personal fees from Edwards Lifesciences. Dr Donal has received research facilities from GE Healthcare and Abbott. Dr Stolz has received speaker honoraria from Edwards Lifesciences. Dr Scotti has served as a consultant for Edwards Lifesciences and NeoChord Inc. Dr Melica has served as a proctor for Abbott. Dr Samim has received funding for an online course from Edwards Lifesciences. Dr Dreyfus has received consulting or speaker fees from Abbott. Dr Karam has received consultant fees from Abbott, Edwards Lifesciences, and Medtronic. Dr Kessler has received speaker honoraria for Edwards Lifesciences and Abbott. Dr Lavie Badie has served as a consultant and proctor for Abbott; and has served as a proctor for Abbott. Dr Metra has received consulting honoraria of minimal amounts from Abbott Structural, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences Roche diagnostics Novo Nordisk, in the last 3 years. Dr Iliadis has received personal fees from Abbott and Edwards Lifesciences. Dr Gerçek has received funding from the Ruhr University Bochum (Advanced Clinician Scientist); and has served as a consultant for Edwards Lifesciences. Dr Latib has served on the Advisory Board for Medtronic, Abbott Vascular, Boston Scientific, Edwards Lifesciences, Shifamed, NeoChord Inc, V-dyne, and Philips. Dr Kalbacher has received personal fees from Abbott Medical, Edwards Lifesciences, Medtronic, and Pi-Cardia Ltd. Dr Coisne has served as a consultant for Abbott, Edwards Lifesciences, and GE Healthcare; and has received speaker fees from Abbott, AstraZeneca, GE Healthcare, Merck Sharp & Dohme, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular impairment is common among patients undergoing transcatheter edge-to-edge repair for secondary mitral regurgitation (SMR). Adherence to guideline-directed medical therapy (GDMT) for heart failure is poor in these patients., Objectives: The aim of this study was to evaluate the impact of GDMT on long-term survival in this patient cohort., Methods: Within the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) international registry, we selected patients with SMR and right ventricular impairment (tricuspid annular plane systolic excursion ≤17 mm and/or echocardiographic right ventricular-to-pulmonary artery coupling <0.40 mm/mm Hg). Titrated guideline-directed medical therapy (GDMT tit ) was defined as a coprescription of 3 drug classes with at least one-half of the target dose at the latest follow-up. The primary outcome was all-cause mortality at 6 years., Results: Among 1,213 patients with SMR and right ventricular impairment, 852 had complete data on medical therapy. The 123 patients who were on GDMT tit showed a significantly higher long-term survival vs the 729 patients not on GDMT tit (61.8% vs 36.0%; P < 0.00001). Propensity score-matched analysis confirmed a significant association between GDMT tit and higher survival (61.0% vs 43.1%; P = 0.018). GDMT tit was an independent predictor of all-cause mortality (HR: 0.61; 95% CI: 0.39-0.93; P = 0.02 for patients on GDMT tit vs those not on GDMT tit ). Its association with better outcomes was confirmed among all subgroups analyzed., Conclusions: In patients with right ventricular impairment undergoing transcatheter edge-to-edge repair for SMR, titration of GDMT to at least one-half of the target dose is associated with a 40% lower risk of all-cause death up to 6 years and should be pursued independent of comorbidities., Competing Interests: Funding Support and Author Disclosures Dr Pfister is a consultant for Edwards Lifesciences; and has received speaker honoraria from Edwards Lifesciences and Abbott Vascular. Dr Iliadis is a consultant for Abbott and Edwards Lifesciences. Dr Kalbacher has received personal fees from Abbott, Edwards Lifesciences, and Pi-Cardia Ltd. Dr Metra has received consulting/speaker fees from Amgen, Livanova, Vifor Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The chapter is focused on the neoplastic peripheral nerve lesions, which primarily involve "cranial and paraspinal nerves," as outlined in the CNS volume (WHO&#95;Classification&#95;of&#95;Tumours&#95;Editorial&#95;Board, 2021). These include classic peripheral nerve sheath tumors such as schwannoma, neurofibroma, intraneural perineurioma, and malignant peripheral nerve sheath tumors, with their variants as well as new and more precisely defined entities, including hybrid nerve sheath tumors and malignant melanotic nerve sheath tumor (previously melanotic schwannoma)., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: In the first report from the MitraBridge registry, MitraClip as a bridge to heart transplantation (HTx) proved to be at 1-year an effective treatment strategy for 119 patients with advanced heart failure (HF) who were potential candidates for HTx. We aimed to determine if benefits of MitraClip procedure as a bridge-to-transplant persist up to 2-years., Methods: By the end of the enrollment period, a total of 153 advanced HF patients (median age 59 years, left ventricular ejection fraction 26.9 ± 7.7%) with significant secondary mitral regurgitation, who were potential candidates for HTx and were treated with MitraClip as a bridge-to-transplant strategy, were included in the MitraBridge registry. The primary endpoint was the 2-year composite adverse events rate of all-cause death, first hospitalization for HF, urgent HTx or LVAD implantation., Results: Procedural success was achieved in 89.5% of cases. Thirty-day mortality was 0%. At 2-year, Kaplan-Meier estimates of freedom from primary endpoint was 47%. Through 24 months, the annualized rate of HF rehospitalization per patient-year was 44%. After an overall median follow-up time of 26 (9-52) months, elective HTx was successfully performed in 30 cases (21%), 19 patients (13.5%) maintained or obtained the eligibility for transplant, and 32 patients (22.5%) no longer had an indication for HTx because of significant clinical improvement., Conclusions: After 2-years of follow-up, the use of MitraClip as a bridge-to-transplant was confirmed as an effective strategy, allowing elective HTx or eligibility for transplant in one third of patients, and no more need for transplantation in 22.5% of cases., Competing Interests: Declaration of Competing Interest A.S. has served as a consultant and received consulting fees from NeoChord Inc.; R.E.L. received speaker fees from Abbott, Boston and Edwards; M.A. received speaker fees from Abbott Vascular and Medtronic; P.G. has been a proctor for Abbot; N.M.V.M. received research grant support from Abbott Vascular, Biotronik, Medtronik, Boston Scientific, Edwards Lifesciences, Daiichi Sankyo, Abiomed en PulseCath BV; F.S. received consultancy and lecture's fees from Abbott and Edwards., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Guideline-directed medical therapy (GDMT) optimization is mandatory before transcatheter edge-to-edge mitral valve repair (M-TEER) in patients with secondary mitral regurgitation (SMR) and heart failure (HF) with reduced ejection fraction (HFrEF). However, the effect of M-TEER on GDMT is unknown., Objectives: The authors sought to evaluate frequency, prognostic implications and predictors of GDMT uptitration after M-TEER in patients with SMR and HFrEF., Methods: This is a retrospective analysis of prospectively collected data from the EuroSMR Registry. The primary events were all-cause death and the composite of all-cause death or HF hospitalization., Results: Among the 1,641 EuroSMR patients, 810 had full datasets regarding GDMT and were included in this study. GDMT uptitration occurred in 307 patients (38%) after M-TEER. Proportion of patients receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists was 78%, 89%, and 62% before M-TEER and 84%, 91%, and 66% 6 months after M-TEER (all P < 0.001). Patients with GDMT uptitration had a lower risk of all-cause death (adjusted HR: 0.62; 95% CI: 0.41-0.93; P = 0.020) and of all-cause death or HF hospitalization (adjusted HR: 0.54; 95% CI: 0.38-0.76; P < 0.001) compared with those without. Degree of MR reduction between baseline and 6-month follow-up was an independent predictor of GDMT uptitration after M-TEER (adjusted OR: 1.71; 95% CI: 1.08-2.71; P = 0.022)., Conclusions: GDMT uptitration after M-TEER occurred in a considerable proportion of patients with SMR and HFrEF and is independently associated with lower rates for mortality and HF hospitalizations. A greater decrease in MR was associated with increased likelihood for GDMT uptitration., Competing Interests: Funding Support and Author Disclosures Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Dr Baldus has received lecture fees and research support from Abbott and Edwards Lifesciences. Dr Kalbacher has received speaker honoraria from Abbott; and has received travel expenses and proctor fees from Edwards Lifesciences. Dr Lurz has received institutional research grants from Edwards Lifesciences and Abbott Vascular. Dr Petronio has been a consultant for Abbott Vascular, Boston Scientific, and Medtronic. Dr von Bardeleben has served on trial steering committees (unpaid) for Abbott, Edwards Lifesciences, Medtronic, and Neochord; and has served on advisory boards for and received speaker fees from Abbott, Edwards Lifesciences, Medtronic, Neochord, Philips, and Siemens. Dr Windecker has received institutional research, travel, or educational grants from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi, Servier, Sinomed, Terumo, Vifor, and V-Wave; has served as advisory board member and/or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis with payments to his institution; and has been an unpaid member of the steering/executive committee groups of several investigator-initiated trials that receive funding by industry. Dr Hausleiter has received speaker honoraria from Abbott Vascular. Prof Metra has received consulting honoraria for participation in steering committees or advisory boards or for speeches from Abbott Vascular, Amgen, AstraZeneca, Bayer, Edwards Lifesciences, Fresenius, Novartis, and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Secondary mitral regurgitation (SMR) is a progressive disease with characteristic pathophysiological changes that may influence prognosis. Although the staging of SMR patients suffering from heart failure with reduced ejection fraction (HFrEF) according to extramitral cardiac involvement has prognostic value in medically treated patients, such data are so far lacking for edge-to-edge mitral valve repair (M-TEER)., Objectives: This study sought to classify M-TEER patients into disease stages based on the phenotype of extramitral cardiac involvement and to assess its impact on symptomatic and survival outcomes., Methods: Based on echocardiographic and clinical assessment, patients were assigned to 1 of the following HFrEF-SMR groups: left ventricular involvement (Stage 1), left atrial involvement (Stage 2), right ventricular volume/pressure overload (Stage 3), or biventricular failure (Stage 4). A Cox regression model was implemented to investigate the impact of HFrEF-SMR stages on 2-year all-cause mortality. The symptomatic outcome was assessed with New York Heart Association functional class at follow-up., Results: Among a total of 849 eligible patients who underwent M-TEER for relevant SMR from 2008 until 2019, 9.5% (n = 81) presented with left ventricular involvement, 46% (n = 393) with left atrial involvement, 15% (n = 129) with right ventricular pressure/volume overload, and 29% (n = 246) with biventricular failure. An increase in HFrEF-SMR stage was associated with increased 2-year all-cause mortality after M-TEER (HR: 1.39; CI: 1.23-1.58; P < 0.01). Furthermore, higher HFrEF-SMR stages were associated with significantly less symptomatic improvement at follow-up., Conclusions: The classification of M-TEER patients into HFrEF-SMR stages according to extramitral cardiac involvement provides prognostic value in terms of postinterventional survival and symptomatic improvement., Competing Interests: Funding Support and Author Disclosures Dr Orban has received speaker fees from Abbott Vascular and Tomtec Imaging Systems. Dr Karam has received consultant fees from Edwards Lifesciences and Medtronic; and has received proctor fees from Abbott. Dr von Bardeleben has received institutional grants and has served as a speaker for Abbott Vascular and Edwards Lifesciences; and has performed trials unpaid for Abbott Vascular, Edwards Lifesciences, Lifetec, Medtronic, and NeoChord. Dr Iliadis has received travel support from Abbott; and has received consultant honoraria from Abbott and Edwards Lifesciences. Dr Pfister has received consultancy and speaker fee from Edwards Lifesciences; and has received speaker fee by Abbott Vascular. The Department of Cardiology of the Leiden University Medical Centre received unrestricted research grants from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, and Medtronic. Dr Higuchi has received lecture fees from Medtronic Japan, Daiichi Sankyo, and Ono Pharmaceutical Company. Dr Petronio has received consulting fees and honoraria for lectures from Abbott and Medtronic; has received consulting fees from Boston; and has received honoraria fees from Daiichi Sankyo. Dr Melica has served as a proctor for Abbott Vascular. Dr Braun has received speaker honoraria from Abbott Vascular. Dr Windecker reports research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson and Johnson, Medicure, Medtronic, Merck Sharp and Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. Dr Windecker serves as an unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis but has not received personal payments by pharmaceutical companies or device manufacturers. Dr Windecker is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Praz has received travel expenses from Abbott Vascular, Polares Medical, and Edwards Lifesiences. Dr Kalbacher has received proctor and lecture fees from Edwards Lifesciences; and has received lecture fees from Abbott Vascular. Dr Lurz has received grants from Abbott Medical and Edwards Lifesciences. Dr Bax has received speaker fees from Abbott Vascular and Edwards Lifesciences. Dr Hausleiter has received research support and speaker honoraria from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Body surface area (BSA) has been reported to be the stronger predictor for prognosis than body mass index in heart failure (HF) patients. The sex-specific association of BSA with mortality has been unclear., Methods: EuroSMR, a European multicenter registry, included patients who underwent edge-to-edge repair (TEER) for secondary mitral regurgitation (SMR). The outcome was two-year all-cause mortality., Results: The present cohort included 1594 HF patients (age, 74 ± 10 years; male, 66%). Association of calculated BSA with two-year all-cause mortality was evaluated. Patients were classified into three BSA groups: the lowest 10% (S), the highest 10% (L), and intermediate between S and L (M). Mean BSA was 1.87 ± 0.21 m 2 (male, 1.94 ± 0.18 m 2 ; female, 1.73 ± 0.18 m 2 ). The association of BSA with the endpoint in females showed a U-shaped curve, indicating worse prognosis for both S and L. The association in males followed a linear regression, demonstrating better prognosis for L. Hazard ratio (HR) of L to S in males was 0.43 (95% confidence interval [CI], 0.25-0.74; p = 0.002), whereas HR of L to M in females was 1.76 (95% CI, 1.11-2.78; p = 0.016) (p for interaction = 0.003)., Conclusions: Sex-specific association patterns demonstrate the complex influence of anthropomorphic factors in HF patients scheduled for TEER. Further investigation beyond simple evaluation of weight and height is needed for better comprehension of the obesity paradox and better prediction of the results of transcatheter therapy in HF patients., Competing Interests: Conflicts of interest Dr. Higuchi has received lecture fees from Medtronic Japan, Daiichi Sankyo, and Ono Pharmaceutical Company. Dr. Orban has received speaker fees from Abbott Vascular and Tomtec Imaging Systems. Dr. Adamo has received payment from Abbott and Medtronic. Dr. Melica has received consulting fee and honoraria for lectures from Abbott and honoraria for lectures from Edwards. Dr. Karam has received consultant fees from Abbott Vascular. Dr. Praz has received travel expenses from Abbott Vascular, Polares Medical and Edwards. LifesciencesDr. Kalbacher has received lecture fees and travel expenses by Abbott and proctor and lecture fees as well as travel expenses by Edwards Lifesciences. Dr. Schofer has received personal fees from Boston Scientific and travel compensation from Abbott Vascular and Edwards Lifesciences. Dr. Ludwig has received travel compensation from Abbott Vascular. Dr. Braun has received speaker honoraria from Abbott Vascular. Dr. Windecker has received grants from Abbott, Amgen, Astra Zeneca, BMS, Bayer, Biotronik, Boston Scientific, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi-Aventis, Sinomed, Terumo, and V-wave. Dr. Pfister has received consulting fees from Edwards Lifesciences, honoraria for lectures and financial support for attending symposia by Abbott Vascular, and honoraria for lectures from Edwards Lifesciences. Dr. von Bardeleben has received speaker fees from Abbott Vascular and Edwards Lifesciences. Dr. Lurz has received grants from Abbott Vascular, Edwards Lifesciences, and ReCor Medical. Dr. Petronio has received consulting fees and honoraria for lectures from Abbott and Medtronic, consulting fee from Boston, and honoraria fee from Daiichi Sankyo. Dr. Hausleiter has received research support and speaker honoraria from Abbott Vascular and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We developed a simple two-dimensional/two-components theoretical model that describes the structure and functionality of a VitE-TPGS system of micelles assuming a hydrophobic inner core and an outer hydrated hydrophilic shell. We then conceptually applied the developed methodology to a simple system of VitE-TPGS micelles unloaded and loaded with an active pharmaceutical ingredient, eltrombopag, to verify if the model could reliably monitor the size change of the micelle upon loading. The fit of laboratory Small Angle X-Ray Scattering data against such model allows us to extract absolute values of the micelles size under a spherical shape hypothesis as well as the distribution within the system between components and level of hydration. The intensity scale of the SAXS experimental data needs to be normalized to a reference standard (pure water) to get absolute scattered intensities. The mathematical model which has been developed under a general hypothesis of ellipsoidal micelles, is applied to our experimental data under the simplified spherical assumption, which suitably fits our experimental data., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Background: Preprocedural right ventricular-to-pulmonary artery (RV-PA) coupling is a major predictor of outcome in patients with secondary mitral regurgitation (SMR) undergoing transcatheter edge-to-edge mitral valve repair (M-TEER). However, clinical significance of changes in RV-PA coupling after M-TEER is unknown., Objectives: The aim of this study was to evaluate changes in RV-PA coupling after M-TEER, their prognostic value, and predictors of improvement., Methods: This was a retrospective observational study, including patients undergoing successful M-TEER (residual mitral regurgitation ≤2+ at discharge) for SMR at 13 European centers and with complete echocardiographic data at baseline and short-term follow-up (30-180 days). RV-PA coupling was assessed with the use of echocardiography as the ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP). All-cause death was assessed at the longest available follow-up starting from the time of the echocardiographic reassessment., Results: Among 501 patients included, 331 (66%) improved their TAPSE/PASP after M-TEER (responders) at short-term follow-up (median: 89 days; IQR: 43-159 days), whereas 170 (34%) did not (nonresponders). Lack of previous cardiac surgery, low postprocedural mitral mean gradient, low baseline TAPSE, high baseline PASP, and baseline tricuspid regurgitation were independently associated with TAPSE/PASP improvement after M-TEER. Compared with nonresponders, responders had lower New York Heart Association functional class and less heart failure hospitalizations at short-term follow-up. Improvement in TAPSE/PASP was independently associated with reduced risk of mortality at long-term follow-up (584 days; IQR: 191-1,243 days) (HR: 0.65 [95% CI: 0.42-0.92]; P = 0.017)., Conclusions: In patients with SMR, improvement in TAPSE/PASP after successful M-TEER is predicted by baseline clinical and echocardiographic variables and postprocedural mitral gradient, and is associated with a better outcome., Competing Interests: Funding Support and Author Disclosures Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Dr Estévez-Loureiro is a consultant for Abbott Vascular, Boston Scientific, and Edwards Lifesciences. Dr Pascual is a proctor for Abbott Vascular. Dr Jimenez-Quevedo has received speaker fees from Abbot Vascular. Dr Nombela-Franco is a proctor for Abbott; and has received consulting fees for Abbott and Edwards Lifesciences. Dr Petronio is a consultant for Abbott Vascular, Boston Scientific, and Medtronic. Dr Bedogni is a consultant for Medtronic; and has received speaker fees from Abbott Vascular. Dr Sinagra has received personal fees Novartis, Bayer, AstraZeneca, Boston Scientific, Vifor Pharma, Menarini, and Akcea Therapeutics. Dr Metra has received consulting honoraria for participation in steering committees or advisory boards or for speeches from Abbott Vascular, Amgen, AstraZeneca, Bayer, Edwards, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: Among patients with severe functional mitral regurgitation (FMR), atrial functional mitral regurgitation (aFMR) represents an underrecognized entity. Data regarding outcomes after mitral valve transcatheter edge-to-edge repair (M-TEER) in aFMR remain scarce., Objectives: The objective of this study was to analyze the outcome of aFMR patients undergoing M-TEER., Methods: Using patients from the international EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry undergoing M-TEER for FMR, the authors analyzed baseline characteristics and 2-year outcomes in aFMR in comparison to non-aFMR and ventricular FMR. Additionally, the impact of right ventricular dysfunction (RVD) (defined as right ventricular to pulmonary artery uncoupling) on outcome after M-TEER was assessed., Results: Among 1,608 FMR patients treated by M-TEER, 126 (7.8%) were categorized as aFMR. All 126 aFMR patients had preserved left ventricular function without regional wall motion abnormalities, left arterial dilatation and Carpentier leaflet motion type I. Procedural success (defined as mitral regurgitation ≤2+ at discharge) was 87.2% (P < 0.001) and New York Heart Association (NYHA) functional class significantly improved during follow-up (NYHA functional class III/IV: 86.5% at baseline to 36.6% at follow-up; P < 0.001). The estimated 2-year survival rate in aFMR patients was 70.4%. Two-year survival did not differ significantly between aFMR, non-aFMR, and ventricular FMR. Besides NYHA functional class IV, RVD was identified as a strong independent predictor for 2-year survival (HR: 2.82 [95% CI: 1.24-6.45]; P = 0.014)., Conclusions: aFMR is a frequent cause of FMR and can be effectively treated with M-TEER to improve symptoms at follow-up. Advanced heart failure symptoms and RVD were identified as important risk factors for survival in aFMR patients., Competing Interests: Funding Support and Author Disclosures Dr Stolz has received travel expenses from Edwards LifeSciences. Dr Orban has received speaker honoraria from Abbott Vascular and Abbot Medical; and has received speaker fees from TOMTEC Imaging Systems. Dr Karam has received speaker honoraria from Abbott Vascular; and has received consultant fees from Abbott Medical. Dr Praz has received travel expenses from Abbott Medical and Edwards LifeSciences. Dr Kalbacher has received speaker honoraria and travel expenses from Abbott Medical; and has received speaker honoraria, travel expenses, and proctor fees from Edwards LifeSciences. Dr Lubos has received speaker honoraria and research grants from Abbott Medical. Dr Braun has received speaker honoraria from Abbott Vascular. Dr Melica has received proctor fees from Abbott Medical. Dr Näbauer has received speaker honoraria from Abbott Vascular. Dr Higuchi has received lecture fees from Medtronic Japan, Daiichi Sankyo, and Ono Pharmaceutical Company. Dr Pfister has received speaker honoraria and travel expenses from Abbott Medical. Dr Iliadis has received consultant fees and travel expenses from Abbott Medical; and has received consultant fees from Edwards LifeSciences. Dr Baldus has received speaker honoraria from Abbott Medical and Edwards LifeSciences; and has received research grants from Abbott Medical. Dr Schofer has received travel expenses from Abbott Medical and Edwards LifeSciences. Dr Windecker has received research and educational grants to the institution from Abbott, Amgen, AstraZeneca, BMS, Bayer, Biotronik, Boston Scientific, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi-Aventis, Sinomed, and Terumo, V-Wave; serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V-Wave and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers; and is a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Lurz has received speaker honoraria and consultant fees from Abbott Medical. Dr Metra has received consultant fees from Abbott Medical; and has received speaker honoraria from Edwards LifeSciences. Dr Hausleiter has received speaker honoraria from and serves as consultant for Abbott Vascular and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Nucleophosmin 1 (NPM1) protein is a multifunctional nucleolar chaperone and its gene is the most frequently mutated in Acute Myeloid Leukemia (AML). AML mutations cause the unfolding of the C-terminal domain (CTD) and the protein delocalizing in the cytosol (NPM1c+). Marked aggregation endowed with an amyloid character was assessed as consequences of mutations., Scope: Herein we analyzed the effects of type C mutation on two protein regions: i) a N-terminal extended version of the CTD, named Cterm&#95;mutC and ii) a shorter polypeptide including the sequences of the second and third helices of the CTD, named H2&#95;mutC., Major Conclusions: Both demonstrated able to self-assembly with different kinetics and conformational intermediates and to provide fibers presenting large flexible regions., General Significance: The present study adds a new piece of knowledge to the effects of AML-mutations on structural biology of Nucleophosmin 1, that could be exploited in therapeutic interventions targeting selectively NPMc+., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to evaluate the results of different treatments for pelvic Osteoblastoma (OB)., Methods: We retrospectively evaluated 34 patients affected by primary pelvic OB from 3 oncologic referral centers. Patients with a minimum follow-up of 24 months were included. Local recurrence (LR) rate and complications were recorded., Results: The primary treatment was radio-frequency ablation (RFA) in 4 patients (11.8%), curettage (ILC) in 21 (61.7%) and resection (EBR) in 9 (26.5%). Mean follow-up was 8.9 years (SD ± 6.6). Local recurrence free survival (LRFS) rate after primary surgery was 79.4% at 3 and 5 years. In details, LRFS rate at 3 and 5 years was 50.0% in RFA, 81.0% in ILC and 88.9% in EBR. Post-operative complications occurred in 6/34 patients (17.7%), in particular after EBR., Conclusions: RFA is the least invasive technique to treat OB but with high LR rate. Thus, it should be reserved to very small lesions. ILC is a suitable treatment for stage II OB. For stage III OB, EBR is the treatment of choice, despite an increased risk of complications. For selected stage III OB (relatively small, periacetabular area) ILC might be considered., Competing Interests: Declaration of competing interest All the Authors have no conflict of interests to declare., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Protein aggregation is suggested as a reversible, wide-spread physiological process used by cells to regulate their growth and adapt to different stress conditions. Nucleophosmin 1(NPM1) protein is an abundant multifunctional nucleolar chaperone and its gene is the most frequently mutated in Acute Myeloid Leukemia (AML) patients. So far, the role of NPM1 mutations in leukemogenesis has remained largely elusive considering that they have the double effect of unfolding the C-terminal domain (CTD) and delocalizing the protein in the cytosol (NPM1c+). This mislocalization heavily impacts on cell cycle regulation. Our recent investigations unequivocally demonstrated an amyloid aggregation propensity introduced by AML mutations. Herein, employing complementary biophysical assays, we have characterized a N-terminal extended version of type F AML mutation of CTD and proved that it is able to form assemblies with amyloid character and fibrillar morphology. The present study represents an additional phase of knowledge to deepen the roles exerted by different types of cytoplasmatic NPM1c+ forms to develop in the future potential therapeutics for their selective targeting., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Concomitant mitral regurgitation (MR) impaired prognosis in patients undergoing transcatheter aortic valve implantation (TAVI). It has been suggested that the use of first generation self-expandable valve in patients with significant MR is associated with worse outcome as compared with balloon expandable valve. However, the impact of newer generation transcatheter devices on MR has not been investigated so far. We aim to assess the prognostic impact of MR in patients undergoing TAVI with the first-generation vs. the latest generation of self-expandable valves., Methods: We analyzed 2964 consecutive patients who underwent TAVI. Patients were classified into 4 groups according to the degree of baseline MR and the generation of self expandable valve implanted., Results: Of 1234 patients with moderate or severe MR, 817 were treated with first generation and 417 patients with second generation valves. Whereas, of 1730 patients with no or mild MR, 1130 were treated with first generation and 600 patients with second generation valves. Although, concomitant moderate-severe MR was found to be an independent predictor of mortality after TAVI, the use of newer generation self expandable valves was associated with higher survival rate at 1 year irrespective of the degree of preprocedural MR. At multivariable analysis the use of newer generation valve was associated with MR improvement throughout 1 year follow-up., Conclusion: Baseline moderate-severe MR is associated with an increase in mortality after TAVI. However, the degree of preprocedural MR doesn't impact survival when a second generation self expandable valve is used., Competing Interests: Conflict of interest statement AS. Petronio, F. Bedogni, C. Tamburino, G. Bruschi are consultants for Medtronic Inc. All other authors have no potential conflict of interest for this paper. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Intracranial germ cell tumors (GCTs) predominantly occur in the adolescent and young adult population and are most frequently located at the pineal gland. Tumor masses in the pineal region may cause ophthalmic symptoms due to compression to the midbrain, frequently presenting with Parinaud syndrome and hydrocephalus due to aqueductal compression., Methods: We conducted a single-institution cohort study of primary, pineal region GCTs to characterize the clinical presentation, as well as associated ophthalmic and hydrocephalus outcomes., Results: Fifty-six primary pineal GCTs were identified. Among the 40 isolated pineal region GCTs, 15 were germinomas while 25 were nongerminomatous GCTs. Among 43 cases of hydrocephalus, endoscopic third ventriculostomy was the primary treatment in 27 cases, which was successful in 23 but failed and required additional treatment for the rest. Pineal tumor mass was significantly larger in cases with hydrocephalus compared with those without, and the 20-mm diameter of the tumor was the crucial point for obstructive hydrocephalus. Ophthalmic symptoms were commonly observed at presentation, which included diplopia (74.3%), upward-gaze palsy (69.7%), and Argyll Robertson pupil (40%). These symptoms tended to remain, and the existence of these symptoms at presentation predicted the remaining symptoms in the follow-up., Conclusions: Intracranial GCTs presenting with ophthalmic abnormalities appear to be at increased risk of residual posttreatment symptoms, while second-look surgery presents a significant risk factor for the development of new deficits. Hydrocephalus often accompanies pineal region GCTs, and in most cases both cerebrospinal fluid diversion and tissue diagnosis can be successfully achieved via endoscopic third ventriculostomy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To discuss optimal treatment strategy for spindle cell oncocytoma (SCO) of the pituitary gland., Methods: Institutional cases were retrospectively reviewed. A systematic literature search and subsequent quantitative synthesis were performed for further analysis. The detailed features were summarized and the tumor control rate (TCR) was calculated., Results: Eighty-five patients (6 institutional and 79 literature) were included. The annual incidence was approximately 0.01-0.03/100,000. The mean age was 56 years. Vision loss was present in 60%. Seventy-three percent showed hormonal abnormalities. On magnetic resonance imaging, tumor was avidly enhancing, and the normal gland was commonly displaced anterosuperiorly. Evidence of hypervascularity was seen in 77%. Gross total resection (GTR) was achieved in only 24% because of its hypervascular, fibrous, and adhesive nature. The mean postoperative follow-up was 3.3 years for institutional cases and 2.3 years for the integrated cohort. The TCR was significantly better after GTR (5-year TCR, 75%; P = 0.012) and marginally better after non-GTR + upfront radiotherapy (5-year TCR, 76%; P = 0.103) than after non-GTR alone (5-year TCR, 24%). The TCRs for those with low Ki-67 index (≤5%) were marginally better than those with higher Ki-67 index (5-year rate, 57% vs. 23%; P = 0.110)., Conclusions: Frequent endocrine-related symptoms, hypervascular signs, and anterosuperior displacement of the gland support preoperative diagnosis of SCO. GTR seems to have better long-term tumor control, whereas the fibrous, hypervascular, and adhesive nature of SCO makes it difficult to achieve GTR. In patients with non-GTR, radiotherapy may help decrease tumor progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6-STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing-based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4-STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6-STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co-transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6-dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Childhood obesity is characterized by the loss of vascular insulin sensitivity along with altered oxidant-antioxidant state and chronic inflammation, which play a key role in the onset of endothelial dysfunction. We previously demonstrated a reduced insulin-stimulated Nitric Oxide (NO) bioavailability in Human Umbilical Vein Endothelial cells (HUVECs) cultured with plasma from obese pre-pubertal children (OB) compared to those cultured with plasma of normal-weight children (CTRL). However, mechanisms underlying endothelial dysfunction in childhood obesity remains poorly understood. Hence, the present study aimed to better investigate these mechanisms, also considering a potential involvement of mammalian Target Of Rapamycin Complex1 (mTORC1)-ribosomal protein S6 Kinase beta1 (S6K1) pathway. OB-children (N = 32, age: 9.2 ± 1.7; BMI z-score: 2.72 ± 0.31) had higher fasting insulin levels and increased HOMA-IR than CTRL-children (N = 32, age: 8.8 ± 1.2; BMI z-score: 0.33 ± 0.75). In vitro, HUVECs exposed to OB-plasma exhibited significant increase in Reactive Oxygen Species (ROS) levels, higher vascular and intercellular adhesion molecules exposure, together with increased monocytes-endothelial interaction. This was associated with unbalanced pro- and anti-atherogenic endothelial insulin stimulated signaling pathways, as measured by increased Mitogen Activated Protein Kinase (MAPK) and decreased Insulin Receptor Substrate-1 (IRS-1)/protein kinase B (Akt)/ endothelial NO Synthase (eNOS) phosphorylation levels, together with augmented S6K1 activation. Interestingly, inhibition of mTORC1-S6K1 pathway using rapamycin significantly restored the IRS-1/Akt/eNOS activation, suggesting a feedback regulation of IRS-1/Akt signal through S6K1. Overall, our in vitro data shed light on new mechanisms underlying the onset of endothelial dysfunction in childhood obesity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to evaluate whether fulfilling COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) criteria identifies patients with better outcomes after MitraClip treatment for secondary mitral regurgitation (SMR)., Background: To date, COAPT is the only trial showing a prognostic benefit of MitraClip implantation compared with conservative management., Methods: Three hundred four patients with SMR undergoing MitraClip placement in addition to optimal medical therapy at 3 European centers were analyzed. A COAPT-like profile was defined as absence of all the following criteria: severe left ventricular impairment, moderate to severe right ventricular dysfunction, severe tricuspid regurgitation, severe pulmonary hypertension, and hemodynamic instability. Freedom from all-cause death and from a composite endpoint (cardiovascular death and heart failure hospitalization) were evaluated at 2- and 5-year follow-up., Results: A COAPT-like profile was observed in 65% of the population. Compared with non-COAPT-like patients, those fulfilling COAPT criteria had greater survival free from all-cause death and from the composite endpoint at both 2 year (75% vs. 55% and 67% vs. 47%; p < 0.001 for both) and 5-year (49% vs. 25% and 40% vs. 19%; p < 0.001 for both) follow-up. Among the non-COAPT-like patients, similar outcomes were observed in those fulfilling 1 or ≥1 criterion. Left ventricular impairment had a late impact on outcomes, while right ventricular impairment, pulmonary hypertension, and hemodynamic instability had early effects. COAPT-like profile was an independent predictor of long-term outcomes, as well as administration of neurohormonal antagonists, European System for Cardiac Operative Risk Evaluation II score, and previous heart failure hospitalization., Conclusions: A COAPT-like profile, including specific echocardiographic and clinical criteria, identifies patients with SMR who have a better prognosis after MitraClip implantation., Competing Interests: Author Disclosures Dr. Metra has received consulting fees from Abbott Vascular, Amgen, AstraZeneca, Bayer, Edwards Therapeutics, Fresenius, Vifor, and Windtree Therapeutics. Dr. Petronio is a consultant for and has received research funds from Medtronic, Abbott Vascular, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients awaiting heart transplantation (HTx) often need bridging therapies to reduce worsening and progression of underlying disease. Limited data are available regarding the use of the MitraClip procedure in secondary mitral regurgitation for this clinical condition., Methods: We evaluated an international, multicenter (17 centers) registry including 119 patients (median age: 58 years) with moderate-to-severe or severe secondary mitral regurgitation and advanced heart failure (HF) (median left ventricular ejection fraction: 26%) treated with MitraClip as a bridge strategy according to 1 of the following criteria: (1) patients active on HTx list (in list group) (n = 31); (2) patients suitable for HTx but awaiting clinical decision (bridge to decision group) (n = 54); or (3) patients not yet suitable for HTx because of potentially reversible relative contraindications (bridge to candidacy group) (n = 34)., Results: Procedural success was achieved in 87.5% of cases, and 30-day survival was 100%. At 1 year, Kaplan-Meier estimates of freedom from the composite primary end-point (death, urgent HTx or left ventricular assist device implantation, first rehospitalization for HF) was 64%. At the time of last available follow-up (median: 532 days), 15% of patients underwent elective transplant, 15.5% remained or could be included in the HTx waiting list, and 23.5% had no more indication to HTx because of clinical improvement., Conclusions: MitraClip procedure as a bridge strategy to HTx in patients with advanced HF with significant mitral regurgitation was safe, and two thirds of patients remained free from adverse events at 1 year. These findings should be considered exploratory and hypothesis-generating to guide further study for percutaneous intervention in high-risk patients with advanced HF., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Available scientific evidence of transcatheter mitral valve repair with the MitraClip comes from randomized controlled trials, which showed controversial results that hardly translate into real-world practice, and from registries of relatively small sample size., Aim: To collect real-world data in a multicenter, prospective, country-level registry., Methods and Result: The Italian Society of Interventional Cardiology (GIse) Registry Of Transcatheter Treatment of Mitral Valve RegurgitaTiOn (GIOTTO) is an ongoing single-arm, multicenter, prospective registry that started enrollment in February 2016. Clinical end points were defined according to the Mitral Valve Academic Research Consortium (MVARC) criteria. From February 2016 to December 2018, 1189 patients (mean age 76 ± 9.1 years) were enrolled. The main MR etiology was functional (64.9%). MVARC technical success was 96.6%. At 30-day follow-up (n = 1131), MVARC device and procedural success were 92.5% and 87% respectively, and all-cause death was 3%. The majority of patients who died at 30-day had functional MR (69.7%). Mixed etiology (OR 0.94, 95% CI 0.02-0.61) and prolonged length of stay in ICU (OR 0.97, 95% CI 0.95-0.99) were found to be negative independent predictors of device success at 30-day. The EuroSCORE II (OR 0.96, 95% CI 0.93-0.99), LVEDV-I (OR 0.99, 95% CI 0.98-0.99) and prolonged length of stay in ICU (OR 0.98, 95% CI 0.97-0.99) were negative independent factors of MVARC procedural success at 30-day., Conclusions: The GIOTTO registry is one of the largest prospective registries available on MitraClip and shows favorable acute and 30-day safety and efficacy., Competing Interests: Declaration of competing interest Francesco Bedogni, Carmelo Grasso, Paolo Denti, Arturo Giordano, Antonio L. Bartorelli, Anna Sonia Petronio, Corrado Tamburino received fees from Abbott Vascular outside the submitted work. The other authors have no conflicts of interest to declare with the present work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: No indication are available for transcatheter aortic valve implantation (TAVI) sizing in bicuspid aortic valve (BAV). Aim of the study is to develop and validate a Multi-Slice Computed Tomography (MSCT)-based algorithm for transcatheter heart valve (THV) sizing in patients with stenotic BAV under evaluation for TAVI., Methods: A two steps method was applied: 1)evaluation of a cohort of 19 consecutive patients with type I BAV stenosis undergoing TAVI through pre and post-procedural MSCT, and development of an algorithm for THV sizing; 2)validation of the algorithm on a new cohort of 21 patients., Results: In the first cohort, a high correlation was found between the raphe-level area measured at pre-procedural MSCT and the smallest THV area measured at post-procedural MSCT (p < 0.001). Moreover, reduced THV expansion was observed among patients with higher calcium burden (p = 0.048). Then, a new algorithm for TAVI sizing in BAV was develop (CASPER: Calcium Algorithm Sizing for bicusPid Evaluation with Raphe). This algorithm is based on the reassessment of the perimeter/area derived annulus diameter, according to three main anatomical features: 1) the ratio between raphe length and annulus diameter; 2)calcium burden; 3)calcium distribution in relation to the raphe. The algorithm was then validated in a new cohort of 21 patients, achieving 100% of procedural success and excellent TAVI performance., Conclusion: MSCT assessment of raphe length, calcium burden and its distribution is of crucial relevance in the pre-procedural evaluation of patients with BAV. These anatomical features can be combined in a new and simple algorithm for TAVI sizing., Competing Interests: Declaration of competing interest Lars Søndergaard has received proctor and speaker fees, as well as institutional research grants from Boston Scientific, Natick, MA and Medtronic, Minneapolis. Francesco Bedogni, Fausto Castriota and Anna Sonia Petronio have received proctor fees from Boston Scientific, Natick, MA and Medtronic, Minneapolis., (Copyright © 2020 Society of Cardiovascular Computed Tomography. All rights reserved.)

Objectives: To evaluate long-term treatment and outcomes of patients with primary central nervous system vasculitis (PCNSV)., Methods: In this cohort of 191 consecutive patients with PCNSV seen at Mayo Clinic, Rochester, MN, over 35 years with long-term follow-up we analyzed response to and duration of therapy, frequency of relapses, long-term remission, efficacy of maintenance therapy and initial intravenous glucocorticoid (GC) pulses, survival and degree of disability. We also compared the efficacy of initial IV and oral cyclophosphamide (CYC)., Results: A favorable initial response was observed in 83% of patients treated with prednisone (PDN) alone, 81% of those treated with PDN and CYC and 95% of those initially treated with PDN and an immunosuppressant other than CYC. One or more relapses were observed in 30% of patients, 35% had discontinued therapy by last follow-up, and 21.5% maintained remission for at least 12 months after discontinuing therapy. Maintenance therapy was prescribed in 19% of all patients and 34% of patients initially treated with CYC and PDN. High disability scores (Rankin 4-6) and deaths were less frequently observed in patients receiving maintenance therapy and more frequently in patients with Aβ-related angiitis. Large vessel involvement and cerebral infarction at diagnosis were associated with a poor treatment response. Aspirin use was positively associated with long-term remission and having gadolinium-enhanced cerebral lesions or meninges was negatively associated. A high disability score at last follow-up and higher mortality rate were associated with increasing age, cerebral infarction and cognitive dysfunction at diagnosis. Lymphocytic vasculitis on biopsy was associated with a more benign course with reduced disability and mortality. Patients initially treated with mycophenolate mofetil had better outcomes compared to those treated with CYC and PDN. No therapeutic advantages were observed in the patients initially treated with intravenous GC pulses. Intravenous and oral CYC were equally effective in inducing the remission., Conclusions: The majority of patients with PCNSV responded to treatment. We found patient subsets with different outcomes. Mycophenolate mofetil may be an effective alternative to CYC., Competing Interests: Declaration of Competing Interest There were no financial support for this work or other financial interests which could create a potential conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the last few years, the possible link between obstructive sleep apnea (OSAS) and glaucoma, has attracted the interest of many scientists, especially in those forms of primary open angle glaucoma (POAG) and normal tension glaucoma (NTG), in which a progression of the disease occurs, even though intraocular pressure (IOP) is in the range of normality. The increased prevalence of POAG or NTG in patients affected by OSAS, and vice versa, has stimulated interest in the pathogenetic mechanisms that could trigger these two diseases. Hypoxia generated by apnea/hypopnea cycles has been identified as the main cause of many changes in the vascular and neurological systems, which alter the functioning not only of the optic nerve, but also of the whole organism. However, many other factors could be involved, like mechanical factors, obesity, hormonal imbalance and other sleep disorders. Furthermore, the demonstration of typical glaucomatous or glaucoma-like changes in the anatomy or function of the optic nerve and retinal nerve fiber layer by sensitive specific and diagnostic methods, such as perimetry, optical coherence tomography (OCT), optical coherence tomography angiography (OCTA) and electrophysiological exams keeps interest high for this field of study. For this reason, further investigations, hopefully a source of stronger scientific evidences, are needed., (© 2020 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the putative differences in terms of vessel density and flow area between control (CTRL), high-pressure glaucoma (HPG) and normal tension glaucoma (NTG) subjects at macular and peripapillary level. To assess the correlation between Visual Field Index (VFI), the stage of glaucoma, and optical coherence tomography angiography (OCT-A) parameters., Material and Methods: In this pilot, prospective study 46 eyes of 46 glaucomatous patients (19 NTG+27 HPG) and 25 control eyes (CTRL) of 25 subjects were recruited. All patients underwent a complete ophthalmologic examination and visual field testing. A 3×3mm volumetric macular scan (Angio Retina [3.0]) and a 4.5×4.5mm diameter peripapillary scan (Angio Disc [4.5]) were performed in the right eye using RTVue-XR Avanti (Optovue, Inc.) OCT-A., Results: Groups were homogeneous for age (P=0.784) and gender (P=0.623). Among the evaluated optic nerve head (ONH) and macular OCT-A parameters, ONH whole image (P<0.001), inside disc (P=0.021), peripapillary (P<0.001), ONH flow area (P<0.026), macula whole image (P<0.001), fovea (P<0.001), parafovea (P<0.001) showed a significant difference when CTRL group was compared to HPG group at the post hoc test. Similarly, ONH whole image (P<0.001), inside disc (P=0.005), peripapillary (P<0.001), ONH flow area (P<0.026), macula whole image (P<0.001), FOVEA (P<0.001), parafovea (P<0.001) showed a significant difference were CTRL were compared to NTG group. On the contrary, no significant difference was found when NTG and HPG groups were compared. Age was not significantly correlated with any of the OCT-A parameters. The stage of the disease showed a high, significant, correlation with ONH whole image (r=-0.81; P<0.0001), inside disc (r=-0.42; P<0.0001), peripapillary (r=-0.81; P<0.0001), RNFL (r=-0.79; P<0.0001), macula whole image (r=0.56; P<0.0001), fovea (r=-0.78; P<0.0001) and parafovea (r=0.67; P<0.0001). On the contrary, VFI showed a high, significant, correlation with ONH whole image (r=0.77; P<0.0001), inside disc (r=0.39; P=0.0018), peripapillary (r=0.713; P<0.0001), RNFL (r=0.63; P<0.0001), macula whole image (r=-0.39; P=0.0007), fovea (r=0.60; P<0.0001) and parafovea (r=-0.52; P<0.0001)., Conclusions: Our data support the usefulness of the OCT-A in the common clinical practice for diagnosis, staging, evaluating the progression of the disease as well as for better understanding of its pathogenic mechanisms., Competing Interests: Conflicts of interest None., (© 2020 Elsevier B.V. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) is the gold standard for severe valvular aortic stenosis in patients at high/prohibitive surgical risk. This procedure has also been used in patients with previous mitral valve (MV) prostheses, with contrasting outcomes reported. The aim of this study is to describe procedural and early outcomes of patients with previous MV prostheses undergoing TAVR., Methods: This is a retrospective registry of 154 patients with previous MV prostheses who underwent TAVR across high-volume medical centres at a mean of 11.7 ± 8.4 years after mitral surgery., Results: Mean mitroaortic distance at computed tomography was 9.7 ± 4.8 mm. Procedural success was achieved in 150 (97.4%) patients, with reduction of aortic gradients (42.6 ± 14.2 to 10.0 ± 7.0 mm Hg; P < 0.001). Device success was achieved in 133 (86.3%) patients. MV prosthesis interference by the TAVR device was observed in 2 patients; in both, the mitroaortic distance was <5 mm, with 1 complicated by TAVR prosthesis embolization. Periprocedural complications included 4 (2.6%) cerebrovascular accidents, 10 (6.6%) major vascular complications, 22 (14.4%) severe bleedings, 1 (0.7%) myocardial infarction, and 5 (3.2%) in-hospital deaths (all cases cardiovascular or procedure related). At a median follow-up of 13.5 (interquartile range 1.0 to 36.0) months, 26 (16.9%) deaths occurred; 15 (9.7%) were cardiac related. Late fatal mitral prosthesis thromboses occurred in 2 patients. We recorded a case of fatal hemorrhagic stroke; hospital readmission was observed in 25 (16.2%) patients due to worsening heart failure., Conclusions: TAVR in patients with previous mitral prostheses appears to be safe and feasible, with good hemodynamic results at 30-day and at longer-term follow-up., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for severe aortic stenosis (AS). AS and coronary artery disease frequently coincide, and therefore some patients may require coronary angiography (CAG) and/or intervention (PCI) post-TAVR. Due to valve stent design, most self-expanding prostheses always cover the coronary ostium, and therefore may hinder future access. The objective of this research was to evaluate the incidence, safety and feasibility of CAG/PCI in patients with prior self-expanding TAVR valves., Methods: Among 2170 patients (age 82 ± 6 years, 43% male) who underwent TAVR with Corevalve or Evolut prostheses, as part of the Italian CoreValve ClinicalService® framework (data from 13 Italian centers), the occurrence of CAG/PCI following TAVR and periprocedural characteristics were examined., Results: During median follow-up of 379 days, 41 patients (1.9%) required CAG and/or PCI (total 46; 16 CAG, 14 PCI, 16 both PCI/CAG). 56.5% of the procedures were performed under emergency/urgency settings. Left system coronary angiography was successfully performed in most cases (28/32, 87.5%), while right coronary angiography was successful only in 50.0% (16/32). PCI procedures (20 for left system, 3 for right system, 4 for graft) were successfully performed in 93.3% (28/30) of the procedures. No CAG/PCI procedure-related complications including prosthesis dislodgment or coronary ostium dissection occurred., Conclusions: CAG and PCI procedures following CoreValve TAVR is safe and mostly feasible, although the success rate of selective right coronary angiography was relatively low when compared to the left system. Further investigations are required to explore this issue., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: To assess the efficacy and safety of Rituximab (RTX) in adult primary central nervous system vasculitis (PCNSV)., Methods: We retrospectively assessed the effect of RTX in 6 patients with PCNSV. Five of the 6 were refractory to high dose glucocorticoids (GCs) and/or conventional immunosuppressants (IS). The sixth was newly diagnosed and received RTX in combination with GCs. Clinical evaluation, laboratory tests, and imaging modalities were performed at initial RTX administration and during the follow-up. Treatment response was assessed using the treating physician's global opinion regarding response and the degree of disability using the modified Rankin scale (mRS). We also performed a literature review for previous use of RTX in PCNSV using PubMed, Ovid Medline, and the Cochrane library., Results: The six patients (3 females) had a median age at diagnosis of 50.5 years (range 17-68 years). All had active disease when RTX was started. In 4 patients, RTX administration was associated with a marked reduction in the number of flares (from 18 before starting RTX to 3 after). One patient, after an initial improvement, had 2 flares when B cells were depleted and he was not able to reduce prednisone below 20 mg/day. A 6th patient had a flare when B cells recovered and retreatment with RTX re-induced and maintained remission. The median mRS score at last visit (median: 2; range 0-4) was lower than that prior to treatment (median 3; range 1-5). The median prednisone daily dose before RTX administration was significantly higher than that at last follow-up (p = .006). In the literature review, we identified 5 papers describing 7 patients treated with RTX. Six patients responded to RTX with clinical and MRI improvement with no reported flares after RTX treatment., Conclusions: Our data support a potential role for RTX treatment in selected patients with PCNSV., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Systemic Lupus Erythematosus (SLE) is a connective tissue disease that involves multiple organs. Ocular structures and visual pathways can be affected in SLE because of disease-related eye involvement or drug toxicity. All the part of the eye may be interested with an external, anterior involvement, responsible of the dry eye disease, or posterior (retina) and neuro-ophtalmic manifestations. Retinopathy in SLE is suggestive of high disease activity being a marker of poor visual outcome and prognosis for survival. The early diagnosis is thus the key to a better management and successful treatment. Antimalarial drugs are the cornerstone of SLE treatment and recently the American Academy of Ophthalmology updated the recommendations for hydroxychloroquine retinal toxicity screening which includes the standard automated visual fields and the spectral domain optical coherent tomography. More recently new imaging techniques have been investigated to assess retinal function and reveal subclinical eye involvement. In this review we focalize on the evidence of eye manifestations in SLE, the eye drug toxicity related to antimalarial agents and steroids, and the methods employed for the eye screening. Moreover, the future perspectives on new techniques, such as the optical coherence tomography angiography, are dissected giving new insights on evaluation of microvasculature of the retina and choroid in SLE., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nucleophosmin (NPM1) is the most frequently mutated gene in Acute Myeloid Leukemia (AML) patients and mutations lead to its aberrant cytoplasmatic accumulation in leukemic cells. Its C-terminal domain (CTD) is endowed with a globular structure consisting of a three-helix bundle in the wild type form that is disrupted by AML mutations. Our recent results demonstrate, unexpectedly and unequivocally, that regions of the CTD of NPM1 are prone to aggregate to amyloid states. Here we present novel studies, at solution as well as fibrillar states of a nonapeptide covering the 264-272 region of NPM1: this small fragment is the most amyloidogenic stretch of the entire protein and its conformational and aggregation properties were investigated through Circular Dichroism, Fluorescence spectroscopies, amyloid seeding assay (ASA), isothermal titration calorimetry (ITC) and electrospray ionization (ESI) mass analyses. Structural features of fibrils were investigated by means of Scanning Electron Microscopy (SEM) and Wide-Angle X-ray Scattering (WAXS). This study deepens the amyloid fibrillization process of a short stretch of the CTD likely involved in the propagative mechanism for NPMc+ cytoplasmatic accumulation in leukemogenesis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Vestibular schwannomas and meningiomas account for the great majority of lesions arising in the cerebellopontine angle. In this report, we present a case of glioneuronal heterotopia, also known as glioneuronal hamartoma, arising from cranial nerve VIII, which is an extremely uncommon lesion. Important radiologic and surgical aspects are reviewed, which may help in early recognition and intraoperative decision making when these lesions are encountered., Case Description: A healthy 29-year-old female presented with intermittent right facial numbness. Magnetic resonance imaging showed an incidental, minimally enhancing cerebellopontine angle lesion on the right cranial nerve VII-VIII complex. The patient declined serial observation and opted for operative intervention for resection. Intraoperatively, the lesion resembled neural tissue and was continuous with the VIII cranial nerve. Pathologic analysis demonstrated mature glioneuronal tissue consistent with hamartomatous brain tissue. The patient maintained normal hearing and facial nerve function after surgery. Radiologic, surgical, and pathologic characteristics are described., Conclusions: Ectopic glioneuronal tissue of cranial nerve VIII is a rare non-neoplastic lesion and should be considered in the differential diagnosis of unusual-appearing intracanalicular and cerebellopontine angle lesions. The congenital and benign nature of this entity makes observation a valid option for these cases, although they are so infrequent that they are often presumptively managed as vestibular schwannomas. Attempts to radically resect these lesions may result in higher rates of hearing loss or facial palsy due to their continuity with cranial nerves., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Giant cell ependymoma (GCE) is a rare primary central nervous system neoplasm. We report a case of GCE arising in the lateral ventricle., Case Description: A 22-year-old female presented with generalized seizures. Magnetic resonance imaging demonstrated a diffuse, nonenhancing, multicystic mass centered in the atrium of the right lateral ventricle with extension throughout the frontal and temporal horns. An initial subtotal resection yielded the signature biphasic pattern of GCE. The dominant component contained pleomorphic, bizarre-appearing giant cells with low mitotic index, and a minor component comprised monomorphic, highly cellular, mitotically active cells that formed perivascular pseudorosettes. Array-comparative genomic hybridization showed copy number abnormalities consistent with chromosomal instability without evidence of RELA- or YAP1-fusion-features most often seen in posterior fossa ependymoma group B. Given expectedly poor radiation sensitivity, a second-look surgery was undertaken to minimize residual before proton beam radiotherapy., Literature Review: Review of the literature identified 28 reported cases, with a median age of 34 and bimodal peaks at approximately 20 and 50 years of age, including 9 supratentorial, 5 infratentorial, and 15 spinal ependymomas. Two infratentorial cases involved the fourth ventricle; no cases arose from the third or lateral ventricles. Supratentorial tumors predominated in younger patients, whereas other locations were observed among older patients (21.6 vs. 46.3 years of age; P = 0.01). Cases with Ki-67 index ≥10% showed worse progression-free survival than those of <10% (P = 0.049)., Conclusion: Although rare, GCE should be considered in the differential of young patients with atypical intraventricular lesions, particularly given that extent of resection is associated with increased survival and GCE is thought to be radiation resistant., (Copyright © 2017. Published by Elsevier Inc.)

Background: Despite promising results following transcatheter aortic valve implantation (TAVI), several relevant challenges still remain. To overcome these issues, new generation devices have been developed. The purpose of the present study was to determine whether TAVI with the new self-expanding repositionable Evolut R offers potential benefits compared to the preceding CoreValve, using propensity matching., Methods: Between June 2007 and November 2015, 2148 consecutive patients undergoing TAVI either CoreValve (n=1846) or Evolut R (n=302) were prospectively included in the Italian TAVI ClinicalService® project. For the purpose of our analysis 211 patients treated with the Evolut R were matched to 211 patients treated with the CoreValve. An independent core laboratory reviewed all angiographic procedural data and an independent clinical events committee adjudicated all events., Results: Patients treated with Evolut R experienced higher 1-year overall survival (log rank test p=0.045) and a significantly lower incidence of major vascular access complications, bleeding events and acute kidney injury compared to patients treated with the CoreValve. Recapture manoeuvres to optimize valve deployment were performed 44 times, allowing a less implantation depth for the Evolut R. As a consequence, the rate of more than mild paravalvular leak and new permanent pacemaker was lower in patients receiving the Evolut R., Conclusion: In this matched comparison of high surgical risk patients undergoing TAVI, the use of Evolut R was associated with a significant survival benefit at 1year compared with the CoreValve. This was driven by lower incidence of periprocedural complications and higher rates of correct anatomic positioning., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Atypical meningioma is a World Health Organization grade II tumor with intermediate prognosis and risk of recurrence. Optimal management after gross total resection (GTR) is controversial, with observation versus adjuvant radiotherapy (RT) contentiously debated., Methods: Pathologic review was performed of all atypical meningiomas diagnosed at our institution from 1988 to 2011. Retrospective chart review documented patient demographics, extent of surgical resection, history of radiation therapy, progression-free survival (PFS), and overall survival (OS). A supplemental systematic literature review was completed in which English-language articles published since 1979 comparing observation and RT after GTR of atypical meningioma were surveyed., Results: Sixty-nine patients met inclusion criteria. Sixty-one underwent observation, and 8 received RT. Overall, 15 observation and 3 patients undergoing RT experienced tumor recurrence (5-year PFS 79% vs. 88%; P = 0.67); 19 observation and 2 patients undergoing RT died (5-year OS 89% vs. 83%; P = 0.68). Systematic review identified 9 preceding studies reporting extractable data comparing observation and RT outcomes after GTR. Recurrence was 18% and 19% after observation and RT (P = 0.9); total survival was 84% and 93% (P = 0.2). At 5 years, PFS was 81% after observation and 88% after RT (P = 0.2), whereas survival was 87% after observation and 96% after RT (P = 0.4)., Conclusions: Observation alone after GTR of atypical meningioma was not associated with increased risk of tumor recurrence or mortality. Although some preceding authors advocate for RT based on empiric experience, a systematic review also suggests that observation may provide equivalent PFS and OS to RT. Taken together, these findings indicate that observation after GTR may be a safe alternative to RT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Synchronous tumors of the cerebellopontine angle (CPA) are very rare and inconsistently described. We present 2 cases of contiguous vestibular schwannoma (VS) and meningioma and a systematic literature review of all multiple CPA tumors., Methods: Retrospective chart review and systematic literature review were performed., Results: A 64-year-old woman and a 42-year-old man presented with symptoms referable to the CPA. Magnetic resonance imaging in both patients revealed 2 separate contiguous tumors. Retrosigmoid craniotomy and tumor removal in each case confirmed VS and meningioma. Systematic literature review identified 42 previous English-language publications describing 46 patients with multiple CPA tumors. Based on Frassanito criteria, there were 4 concomitant tumors (8%), 16 contiguous tumors (33%), 3 collision tumors (6%), 13 mixed tumors (27%), and 11 tumor-to-tumor metastases (23%). Extent of resection was gross total in 16 cases and subtotal in 16 cases (50% each). Unfavorable House-Brackmann grade III-VI function was documented in 27% overall and in 33% of patients with VS and meningioma, a marked increase from the observed range in isolated VS., Conclusions: Multiple CPA tumors are rare, heterogeneous lesions with a marked predisposition toward poor facial nerve outcomes, potentially attributable to a paracrine mechanism that simultaneously drives multiple tumor growth and increases invasiveness or adhesiveness at the facial nerve-tumor interface. Preceding nomenclature has been confounding and inconsistent; we recommend classifying all multiple CPA tumors as "synchronous tumors," with "schwannoma with meningothelial hyperplasia" or "tumor-to-tumor metastases" reserved for rare, specific circumstances., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Nucleophosmin (NPM1) is a multifunctional protein involved in a variety of biological processes including the pathogenesis of several human malignancies and is the most frequently mutated gene in Acute Myeloid Leukemia (AML). To deepen the role of protein regions in its biological activities, lately we reported on the structural behavior of dissected C-terminal domain (CTD) helical fragments. Unexpectedly the H2 (residues 264-277) and H3 AML-mutated regions showed a remarkable tendency to form amyloid-like assemblies with fibrillar morphology and β-sheet structure that resulted as toxic when exposed to human neuroblastoma cells. More recently NPM1 was found to be highly expressed and toxic in neurons of mouse models of Huntington's disease (HD). Here we investigate the role of each residue in the β-strand aggregation process of H2 region of NPM1 by performing a systematic alanine scan of its sequence and structural and kinetic analyses of aggregation of derived peptides by means of Circular Dichorism (CD) and Thioflavin T (Th-T) assay. These solution state investigations pointed out the crucial role exerted by the basic amyloidogenic stretch of H2 (264-271) and to shed light on the initial and main interactions involved in fibril formation we performed studies on fibrils deriving from the related Ala peptides through the analysis of fibrils with birefringence of polarized optical microscopy and wide-angle X-ray scattering (WAXS). This analysis suggested that the presence of branched Ile 269 conferred preferential packing patterns that, instead, appeared geometrically hampered by the aromatic side-chain of Phe 268 . Present investigations could be useful to deepen the knowledge of AML molecular mechanisms and the role of cytoplasmatic aggregates of NPM1c+., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Little is known about the early and late performance of the 31mm CoreValve Revalving System (CRS, Medtronic Inc., Galway, Ireland). Our aim was to compare acute and long-term results of the 31mm CRS with other valve sizes., Methods: Consecutive patients undergoing transcatheter aortic valve implantation (TAVI) with CRS in nine Italian centers were prospectively included and dichotomized according to prosthesis size in two different groups, as follows: 31mm and other valve sizes (i.e., 23, 26, and 29mm combined). End points were defined according to Valve Academic Research Consortium definitions. Propensity score matching was performed., Results: In total, 2069 patients (n=169 [8%] in the 31mm group and n=1900 [92%] in the other valve sizes group) were included. After propensity matching, the implantation of the 31mm valve was associated with lower rates of procedural- (91.3% vs. 98.1%, p=0.030) and device-success (88.5% vs. 97.1%, p=0.016), longer procedural time (120 [80-180] min. vs. 90 [60-120] min., p<0.001), and higher rates of implantation of a second valve (10.6% vs. 2.9%, respectively, p=0.027). The rates of permanent pacemaker implantation in the 31mm group were higher but not statistically different from other valve sizes (41.7% vs. 30.9%, respectively, p=0.149). Significant improvement, without between-group differences, was observed in NYHA functional class. Cardiovascular death was lower in the 31mm valve group through 2-years (3.8% vs. 13.5%, respectively, p=0.014)., Conclusions: The acute performance of the 31mm CRS was worse than other valve sizes but no negative impact was observed in long-term outcomes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Percutaneous mitral valve repair (PMVR) is a new option for high risk patients with functional mitral regurgitation (FMR) and severely depressed left ventricular (LV) function who are not responding to optimal medical therapy. However patients with end stage heart failure have a high mortality rate despite MitraClip implantation. We sought to identify right ventricular (RV) echocardiographic predictors of outcome in a large cohort of patients with severe FMR and advanced heart failure in order to select the most appropriate candidate who could benefit from this treatment., Methods: 169 consecutive high surgical risk patients affected by severe FMR underwent PMVR with the MitraClip System. The primary end-point was cardiovascular mortality at the longest available follow-up., Results: The survival free from cardiac death was 97.6% at 30days, 86.7% at 1year, 71.5% at 2years and 61.6% at 3years. Patients who died were significantly older and had more severe comorbidities and signs of more advance heart failure. Independent predictors of cardiovascular mortality were severely impaired renal function [glomerular filtration rate (GFR)<30ml/min; OR=5.46, 95%CI=1.43-20.84, (p=0.01)] and RV systolic dysfunction [peak systolic velocity tissue Doppler imaging (PSV tdi )<9.5cm/s; OR=0.57, 95%CI=0.39-0.82, (p=0.003)]., Conclusion: Our study shows the importance of RV systolic function evaluation for the risk stratification of patients with FMR and advanced heart failure undergoing PMVR. Severe right ventricular failure identifies patients with an increased risk for cardiovascular mortality despite MitraClip treatment. RV PSV tdi is the best independent predictor of outcome in these end-stage patients for a threshold value of 9.5cm/s., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The well-described entity of Subependymal Giant Cell Astrocytoma (SEGA) in the setting of Tuberous Sclerosis Complex (TSC) is profound in current literature. It has been described in children as well as adults with or without identifiable clinical presentations of tuberous sclerosis. To our knowledge there has not been any report of a negative genetic workup of Tuberous Sclerosis Complex in an adult patient presenting with an isolated SEGA., Case Report: We present a case of a 25-year-old female with no medical history who presented to the emergency room for headaches. Further workup included gadolinium enhanced MRI of the brain which revealed a homogenously enhancing mass in the left lateral ventricle with eccentric calcification and resultant obstructive hydrocephalus. A left frontal craniotomy with an interhemispheric transcallosal approach was taken for complete removal of the mass., Discussion: Final pathological diagnosis was SEGA with suggestive cell population, positive GFAP and positive synaptophysin. Genetic testing included TSC1 (MLPA, DNA Sequencing) and TSC2 (MLPA, DNA Sequencing), which were all negative. The panel did not identify mutations associated with Tuberous Sclerosis., Conclusion: Rare cases of isolated SEGA have been reported in patients who do not have typical features of tuberous sclerosis, and may represent minimal penetrance of the disease with an attenuated phenotype. Negative genetic testing, as demonstrated, can be seen in adults with isolated SEGA. With a negative genetic workup of TSC, regular follow up may still be necessary; however this may prove to be low yield for identifying any TSC features in the future., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Adenoid cystic carcinoma (ACC) is an exocrine gland tumor accounting for approximately 10%-15% of all epithelial salivary neoplasms and occurs most often in the parotid and submandibular glands. Metastatic pituitary tumors are rare, and there is only 1 previously reported case of parotid ACC metastatic to the pituitary. Magnetic resonance elastography (MRE) is a dynamic magnetic resonance imaging (MRI)-based technique that measures the propagation of mechanically induced shear waves through a particular tissue to determine stiffness and offers a method to evaluate tissue consistency. We present the case of a 72-year-old woman with a remote history of parotid gland ACC and subsequent lung metastases presented after a fall that resulted in facial trauma. A non-contrast head computed tomography scan revealed a sellar/suprasellar mass, and follow-up MRI revealed a well-defined, enhancing 3.8-cm lesion. MRE showed the tumor to be firm. The tumor was resected through a transsphenoidal approach and was consistent with the MRE findings. Pathology returned as metastatic ACC. We report the second case of ACC metastatic to pituitary and the first firm pituitary tumor found by MRE and discuss the potential diagnostic value of MRE in pituitary lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Distant metastasis of mucinous adenocarcinoma from the gastrointestinal tract, ovaries, pancreas, lungs, breast, or urogenital system is a well-described entity. Mucinous adenocarcinomas from different primary sites are histologically identical with gland cells producing a copious amount of mucin. This report describes a very rare solitary metastasis of a mucinous adenocarcinoma of unknown origin to the facial/vestibulocochlear nerve complex in the cerebellopontine angle., Case Description: A 71-year-old woman presented with several month history of progressive neurological decline and a negative extensive workup performed elsewhere. She presented to our institution with complete left facial weakness, left-sided deafness, gait unsteadiness, headache and anorexia. A repeat magnetic resonance imaging scan of the head revealed a cystic, enhancing abnormality involving the left cerebellopontine angle and internal auditory canal. A left retrosigmoid craniotomy was performed and the lesion was completely resected. The final pathology was a mucinous adenocarcinoma of indeterminate origin. Postoperatively, the patient continued with her preoperative deficits and subsequently died of her systemic disease 6 weeks after discharge., Conclusions: The facial/vestibulocochlear nerve complex is an unusual location for metastatic disease in the central nervous system. Clinicians should consider metastatic tumor as the possible etiology of an unusual appearing mass in this location causing profound neurological deficits. The prognosis after metastatic mucinous adenocarcinoma to the cranial nerves in the cerebellopontine angle may be poor., (Copyright © 2015 Elsevier Inc. All rights reserved.)