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Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene have been associated with higher levels of somatostatin (SS) receptor subtype 5 (SSTR5) in adrenocorticotroph hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs). However, a correlation between the USP8 mutational status and favourable responses to pasireotide, the somatostatin multi-receptor ligand acting especially on SSTR5, has not been investigated yet. Here, we studied the impact of USP8 mutations on pasireotide responsiveness in human and murine corticotroph tumor cells. SSTR5 upregulation was observed in USP8 wild-type primary tumor cells transfected with S718del USP8 mutant. However, cell transfection with S718del USP8 and C40-USP8 mutants in in vitro sensitive cultures from USP8 wild-type tumors abolished their ability to respond to pasireotide and did not confer pasireotide responsiveness to the in vitro resistant culture. Pasireotide failed to reduce ACTH secretion in primary cells from one S718P USP8-mutated tumor but exerted a strong antisecretory effect in primary cells from one P720R USP8-mutated tumor. In agreement, AtT-20 cells transfection with USP8 mutants led to SSTR5 expression increase but pasireotide could reduce ACTH production and cyclin E expression in P720R USP8 overexpressing cells, only. In situ Proximity Ligation Assay and immunoflurescence experiments revealed that P720R USP8 mutant is still able to bind 14-3-3 proteins in AtT-20 cells, without affecting SSTR5 localization. In conclusion, P720R USP8 mutation might be considered as a molecular predictor of favourable response to pasireotide in corticotroph tumor cells.

Objectives: This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment., Design: Retrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma., Setting: International multicentre population-based study., Participants: A total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned)., Interventions: Patients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE)., Main Outcome Measures: The MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle., Results: A cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients' health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High - MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient's history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2-3 (p<0.05)., Conclusions: The novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning., Trial Registration Number: ISRCTN86294690; Post-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Ozaki procedure is an innovative surgical technique aiming at the reconstruction of the aortic valve with autologous pericardium to overcome the limitations of commercially available prostheses., Methods: We retrospectively analysed 71 patients who underwent Ozaki operation at our centre between October 2014 and February 2020., Results: No in-hospital death occurred. Freedom from major adverse valve-related events (MAVRE) was 97%. The aortic gradients and transvalvular velocity are significantly lower at the 3-months echocardiographic control than at the pre-discharged echocardiography (10.93 ± 5.38, p= 0,0003 vs 16.24 ± 7.67 p= 0,0004 respectively). The median follow-up period was 20.7 months (range 2 to 47 months). Four patients showed mild/moderate aortic insufficiency (5.6%) and none showed severe aortic valve insufficiency. No patients underwent reoperation., Conclusions: Mid-term outcome follow-up of Ozaki procedure showed optimal results in term of mortality, transaortic valve gradients, freedom from MAVRE and recurrence of aortic valve insufficiency., (Copyright © 2020. Published by Elsevier Inc.)

Background: Valve thrombosis - either biological or mechanical - is proved to increase patient's morbidity and mortality. No consensus exist on the best management in such cases., Case Presentation: We report the case of a 69-year-old man presenting with a late thrombosis of a transcatheter aortic valve who was medically managed until he acutely worsened, developing myocardial ischemia and cardiogenic shock., Conclusion: This unlucky case raises a word of caution about the safety of a reactive management.

Bioprosthesis are commonly used in the elderly population. Structural valve deterioration affects the long-term durability. We report an early deterioration of a Mitroflow valve caused by ring deformation and prosthetic leaflet rupture. The 69-years-old patient underwent successful redo surgery with excision of the bioprosthesis and placement of a mechanical valve.

We present the case of a 49-year-old man with an abnormal aortic valve formed by four cusps (three equal large cusps and one smaller cusp; type 1 according to Hurwits and Roberts classification) with a marked lack of coaptation that caused a severe aortic valve insufficiency. The patient underwent a repair of the defect with a tricuspidalization of the aortic valve, restoring the normal coaptation of the cusps and the normal function of the aortic valve. Postoperative course was unremarkable. The early follow-up showed a mild aortic valve insufficiency., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: It is uncertain whether mitral valve replacement is really inferior to mitral valve repair for the treatment of chronic ischemic mitral regurgitation. This multicenter study aimed at providing a contribution to this issue., Methods: Of 1006 patients with chronic ischemic mitral regurgitation and impaired left ventricular function (ejection fraction < 40%) operated on at 13 Italian institutions between 1996 and 2011, 298 (29.6%) underwent mitral valve replacement whereas 708 (70.4%) received mitral valve repair. Propensity scores were calculated by a nonparsimonious multivariable logistic regression, and 244 pairs of patients were matched successfully using calipers of width 0.2 standard deviation of the logit of the propensity scores. The postmatching median standardized difference was 0.024 (range, 0-0.037) and in none of the covariates did it exceed 10%., Results: Early deaths were 3.3% (n = 8) in mitral valve repair versus 5.3% (n = 13) in mitral valve replacement (P = .32). Eight-year survival was 81.6% ± 2.8% and 79.6% ± 4.8% (P = .42), respectively. Actual freedom from all-cause reoperation and valve-related reoperation were 64.3% ± 4.3% versus 80% ± 4.1%, and 71.3% ± 3.5% versus 85.5% ± 3.9 in mitral valve repair and mitral valve replacement, respectively (P < .001). Actual freedom from all valve-related complications was 68.3% ± 3.1% versus 69.9% ± 3.3% in mitral valve repair and mitral valve replacement, respectively (P = .78). Left ventricular function did not improved significantly, and it was comparable in the 2 groups postoperatively (36.9% vs 38.5%, P = .66). At competing regression analysis, mitral valve repair was a strong predictor of reoperation (hazard ratio, 2.84; P < .001)., Conclusions: Mitral valve replacement is a suitable option for patients with chronic ischemic mitral regurgitation and impaired left ventricular function. It provides better results in terms of freedom from reoperation with comparable valve-related complication rates., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)