Ospedale Cisanello

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

BACKGROUND: A leadless intracardiac transcatheter pacing system has been designed to avoid the need for a pacemaker pocket and transvenous lead. METHODS: In a prospective multicenter study without controls, a transcatheter pacemaker was implanted in patients who had guideline-based indications for ventricular pacing. The analysis of the primary end points began when 300 patients reached 6 months of follow-up. The primary safety end point was freedom from system-related or procedure-related major complications. The primary efficacy end point was the percentage of patients with low and stable pacing capture thresholds at 6 months (≤2.0 V at a pulse width of 0.24 msec and an increase of ≤1.5 V from the time of implantation). The safety and efficacy end points were evaluated against performance goals (based on historical data) of 83% and 80%, respectively. We also performed a post hoc analysis in which the rates of major complications were compared with those in a control cohort of 2667 patients with transvenous pacemakers from six previously published studies. RESULTS: The device was successfully implanted in 719 of 725 patients (99.2%). The Kaplan-Meier estimate of the rate of the primary safety end point was 96.0% (95% confidence interval [CI], 93.9 to 97.3; P<0.001 for the comparison with the safety performance goal of 83%); there were 28 major complications in 25 of 725 patients, and no dislodgements. The rate of the primary efficacy end point was 98.3% (95% CI, 96.1 to 99.5; P<0.001 for the comparison with the efficacy performance goal of 80%) among 292 of 297 patients with paired 6-month data. Although there were 28 major complications in 25 patients, patients with transcatheter pacemakers had significantly fewer major complications than did the control patients (hazard ratio, 0.49; 95% CI, 0.33 to 0.75; P=0.001). CONCLUSIONS: In this historical comparison study, the transcatheter pacemaker met the prespecified safety and efficacy goals; it had a safety profile similar to that of a transvenous system while providing low and stable pacing thresholds. (Funded by Medtronic; Micra Transcatheter Pacing Study ClinicalTrials.gov number, NCT02004873.).

BACKGROUND: The chief clinical characteristics of Graves' disease are hyperthyroidism and ophthalmopathy. The relation between the two and the effect of treatment for hyperthyroidism on ophthalmopathy are unclear. METHODS: We studied 443 patients with Graves' hyperthyroidism and slight or no ophthalmopathy who were randomly assigned to receive radioiodine, radioiodine followed by a 3-month course of prednisone, or methimazole for 18 months. The patients were evaluated for changes in the function and appearance of the thyroid and progression of ophthalmopathy at intervals of 1 to 2 months for 12 months. Hypothyroidism and persistent nyperthyroiaism were promptly corrected. RESULTS: Among the 150 patients treated with radioiodine, ophthalmopathy developed or worsened in 23 (15 percent) two to six months after treatment. The change was transient in 15 patients, but it persisted in 8 (5 percent), who subsequently required treatment for their eye disease. None of the 55 other patients in this group who had ophthalmopathy at base line had improvement in their eye disease. Among the 145 patients treated with radioiodine and prednisone, 50 (67 percent) of the 75 with ophthalmopathy at base line had improvement, and no patient had progression. The effects of radioiodine on thyroid function were similar in these two groups. Among the 148 patients treated with methimazole, 3 (2 percent) who had ophthalmopathy at base line improved, 4 (3 percent) had worsening of eye disease, and the remaining 141 had no change. CONCLUSIONS: Radioiodine therapy for Graves' hyperthyroidism is followed by the appearance or worsening of ophthalmopathy more often than is therapy with methimazole. Worsening of ophthalmopathy after radioiodine therapy is often transient and can be prevented by the administration of prednisone.

BACKGROUND: The prophylactic use of fluoroquinolones in patients with cancer and neutropenia is controversial and is not a recommended intervention. METHODS: We randomly assigned 760 consecutive adult patients with cancer in whom chemotherapy-induced neutropenia (<1000 neutrophils per cubic millimeter) was expected to occur for more than seven days to receive either oral levofloxacin (500 mg daily) or placebo from the start of chemotherapy until the resolution of neutropenia. Patients were stratified according to their underlying disease (acute leukemia vs. solid tumor or lymphoma). RESULTS: An intention-to-treat analysis showed that fever was present for the duration of neutropenia in 65 percent of patients who received levofloxacin prophylaxis, as compared with 85 percent of those receiving placebo (243 of 375 vs. 308 of 363; relative risk, 0.76; absolute difference in risk, -20 percent; 95 percent confidence interval, -26 to -14 percent; P=0.001). The levofloxacin group had a lower rate of microbiologically documented infections (absolute difference in risk, -17 percent; 95 percent confidence interval, -24 to -10 percent; P<0.001), bacteremias (difference in risk, -16 percent; 95 percent confidence interval, -22 to -9 percent; P<0.001), and single-agent gram-negative bacteremias (difference in risk, -7 percent; 95 percent confidence interval, -10 to -2 percent; P<0.01) than did the placebo group. Mortality and tolerability were similar in the two groups. The effects of prophylaxis were also similar between patients with acute leukemia and those with solid tumors or lymphoma. CONCLUSIONS: Prophylactic treatment with levofloxacin is an effective and well-tolerated way of preventing febrile episodes and other relevant infection-related outcomes in patients with cancer and profound and protracted neutropenia. The long-term effect of this intervention on microbial resistance in the community is not known.

Despite continuing efforts during the last decades, there is no ‘ideal prosthetic valve substitute’. Every valve prosthesis invokes new pathophysiological processes, including the risks of thromboembolism, prosthetic endocarditis, and structural valve deterioration (SVD) or non-structural valve deterioration with consequent need for reintervention (Figure 1). Bioprostheses are now increasingly used in preference to mechanical valves in the aortic position but valve dysfunction may occur over time. The literature concerning surgical prostheses has taught us that bioprosthetic valve dysfunction is a complex phenomenon whose understanding requires more than the reporting of reintervention. Further research must encompass biological, pathological and haemodynamic mechanisms, use of contemporary non-invasive imaging, evaluation of the true incidence while avoiding methodological pitfalls, and identification of clinical, technical, and prosthesis-specific predictors. Causes of bioprosthetic valve dysfunction. Since introduction in 2002 and broader clinical use in 2007, penetration of transcatheter aortic valve implantation (TAVI) has grown exponentially as a result of accruing evidence demonstrating safety and efficacy, and reduced invasiveness compared with surgery. TAVI is now the recommended therapy in elderly patients with aortic stenosis who are inoperable or at increased surgical risk1 and recent evidence has demonstrated at least its equivalence to surgery in intermediate and high-risk cohorts.2–4 However, our knowledge concerning the clinical outcomes of TAVI beyond 5 years is still limited. Although SVD is likely to be the main mechanism of bioprosthetic valve dysfunction in the longer term, definitions of SVD vary and follow-up studies are scarce. While it is possible to draw lessons from longer term experience with surgical bioprostheses, there are fundamental differences between TAVI and surgical aortic valve replacement (SAVR) (i.e. remaining valve calcification, mechanical stress, crimping of the valve tissue, valve leaflet geometry, balloon expansion or dilation, differences in haemodynamic profile, and patient-prosthesis mismatch), which may impact on the natural history of SVD (see Supplementary material online, Appendix). Critically, extended knowledge of the durability of TAVI is essential as we enter the time (>5 years after implantation) when SVD starts to occur in surgical bioprostheses. This knowledge assumes even greater importance as we consider expanding the indications for TAVI to lower risk and younger patients. As such, standardizing the definitions of valve- and patient-oriented durability outcomes is of paramount importance to enable objective evaluation of existing and novel TAVI prostheses, and their comparative efficacy vs. SAVR. In this context, the European Association of Percutaneous Cardiovascular Intervention (EAPCI) determined that improved characterization of long-term TAVI outcomes was timely. Two face-to-face meetings (September 2016, London; January 2017, Frankfurt) involving members of the EAPCI, the European Society of Cardiology (ESC), and the European Association for Cardio-Thoracic Surgery (EACTS) representing interventional cardiology, clinical cardiology, imaging and surgery, provided much of the discussion to inform the present document. Herein, we present the available evidence on TAVI SVD, addressed in terms of existing definitions, predictors, and detection. In parallel, we present a standardized definition of SVD and a new patient-oriented clinical end point named bioprosthetic valve failure (BVF) for use in future studies, which aims to capture the clinically relevant manifestations and consequences of SVD or other forms of bioprosthetic valve dysfunction. This effort precedes a registry initiated within the ESC European Observational Registries Programme (EORP) which will evaluate the incidence, presentation, mode, and timing of bioprosthetic valve dysfunction in a contemporary real-world setting. The ultimate goals of this multidisciplinary collaboration are to improve the characterization of SVD and BVF in line with similar ongoing efforts by the Valve Academic Research Consortium (VARC) 3 and optimize the future utilization of TAVI. Survival without valve reintervention or explant for SVD is an outcome still used by some published series to assess the durability of surgical bioprostheses.5 However, surgical guidelines for event reporting after cardiac valve interventions have not supported this approach since 2008, and stipulate that SVD should also be defined by clinically detectable measures other than the need for reoperation for a failing bioprosthesis (i.e. using echocardiographic criteria).6 In 2009, Zoghbi et al . 7 published a series of recommendations for the evaluation of prosthetic valves using echocardiography and Doppler ultrasound. Possible stenosis was defined as peak prosthetic aortic jet velocity 3–4 m/s, mean gradient 20–35 mmHg, and effective orifice area 0.8–1.2 cm2. Significant stenosis was defined as peak prosthetic aortic jet velocity >4 m/s, mean gradient >35 mmHg, and effective orifice area <0.8 cm2. The 2012 ESC guidelines, written in collaboration with the EACTS, recommend annual echocardiography beyond the first 5 years following bioprosthetic valve implantation (and earlier in young patients) to detect early evidence of ‘SVD, leaflet stiffening, calcification, reduced effective orifice area, and/or regurgitation’.1 Based on these guidelines, the transprosthetic gradients should be interpreted in comparison with the baseline values. This requires an early postoperative assessment to set up a reference point for future investigations and to detect important conditions such as patient-prosthesis mismatch and left ventricular dysfunction. Reoperation is recommended in symptomatic patients with a significant increase in transprosthetic gradient or severe regurgitation (Class I, Level of Evidence C) and should be considered in asymptomatic patients with significant bioprosthetic valve dysfunction, provided they remain at low-surgical risk (Class IIa, Level of Evidence C). The VARC-2 recommendations also suggest echocardiography as the principal imaging modality for assessment of bioprosthetic valve function immediately before initial hospital discharge (to establish baseline parameters) and at 6 months, 1 year, and annually thereafter.8 VARC-2 defines SVD as (i) valve-related dysfunction (mean aortic gradient ≥20 mmHg, effective orifice area ≤0.9–1.1 cm2, and/or dimensionless valve index <0.35, and/or moderate or severe prosthetic valve regurgitation) or (ii) need for a repeat procedure (TAVI or SAVR). Lancellotti et al . 9 suggested incorporating an increase in mean gradient during stress echocardiography or at follow-up (possible obstruction 10–19 mmHg; significant obstruction ≥20 mmHg). In a recent surgical series, Bourguignon et al . 10 defined SVD using strict echocardiographic criteria independent of symptomatic status, including severe aortic stenosis (mean transvalvular gradient >40 mmHg) and severe aortic regurgitation (effective regurgitant orifice area >0.30 cm2, vena contracta >0.6 cm). Of note, this definition relies on the systematic implementation, recording and reporting of echocardiographic data at pre-defined follow-up intervals, which make data interpretation problematic if these conditions are not observed.10 The clinical course of patients with bioprosthetic valves should be monitored periodically, with the interval between routine follow-up visits determined according to cardiac status, comorbidities, and other clinical factors. Various imaging techniques are available for detection of bioprosthetic valve dysfunction. These include 2D/3D echocardiography, multi-detector computed tomography (MDCT) and magnetic resonance imaging (MRI).11–13 Echocardiography is a ‘functional’ imaging modality and superior for the demonstration of valve haemodynamics (i.e. increased transvalvular gradient, valve regurgitation), whereas MDCT provides more ‘anatomical’ and structural information. MRI has the potential to combine anatomical and functional information but is not always readily available and experience in the assessment of bioprosthetic valve dysfunction is limited. These considerations have implications for the application of different imaging modalities in the assessment of bioprosthetic valve durability. Periodic echocardiographic surveillance is currently the reference standard for detection of SVD in cases unidentified at reoperation or autopsy. Stenosis or regurgitation of the bioprosthetic valve should be reported using validated quantitative or semi-quantitative methods.9 The term deterioration implies changes intrinsic to the valve (including wear, fracture, calcification, leaflet tear, and/or disruption of any component). Transoesophageal imaging can improve visualization of morphological aspects of the valve prosthesis and the additional role of 3D echocardiography in this setting is yet to be defined. Multi-detector computed tomography may be more sensitive than echocardiography in detecting valve thrombosis, particularly at early stages of the process (i.e. subclinical leaflet thrombosis without haemodynamic consequences).14 , 15 Multi-detector computed tomography criteria for TAVI thrombosis include hypo-attenuated leaflet thickening (with or without reduced leaflet motion of one or more leaflets, identifiable in two or more multiplanar curved reconstructions).11 Specific MDCT measurements include stent frame expansion and eccentricity index, number of leaflets with hypo-attenuated leaflet thickening, as well as degree of leaflet thickening, motion reduction and calcification.11 Importantly, MDCT cannot determine aortic valve gradients and is therefore of diminished utility for the diagnosis of SVD. Several large series have reported the long-term outcomes of SAVR bioprostheses with mixed results (Table 1). Importantly, the age of patients undergoing SAVR in these studies was on average lower than that of patients included in TAVI series, which makes cross-study comparisons inappropriate on the ground of long-term durability. As noted above, some of the surgical series evaluate durability in terms of survival or survival without reintervention; others expand the definition of SVD with criteria of haemodynamic progression. In a large series evaluating 2405 Carpentier-Edwards bioprostheses, survival without reintervention was 98 ± 0.2%, 96 ± 1%, and 67 ± 4% at 5, 10, and 20 years, respectively.18 Bourguignon et al . 10 evaluated 2758 Carpentier-Edwards bioprostheses using clinical and echocardiographic criteria, and reported SVD in 157 patients (123 of whom required reintervention) over a cumulative follow-up of 18 404 valve-years. All cases of SVD were late events and actuarial freedom from SVD at 15 and 20 years was 78.6 ± 2.2% and 48.5 ± 4.6%, respectively. In the Johnstone et al . 5 series assessing SVD in 12 569 patients (81 706 patient-years), actuarial of explant for SVD at 10 and 20 years were and bioprostheses have also demonstrated long-term durability in patients years or while an of SVD was with the prosthesis in of of patients with a bioprosthesis reported freedom from reoperation in and at 10 and 15 years, and freedom from reoperation for SVD in and outcomes vary with different surgical bioprostheses as demonstrated in recent surveillance of valves in and durability after surgical aortic valve replacement ± and 7 ± at 20 and years, from ± 4% at 20 years from ± 4% at 20 years and at 10 and 15 years, from and at 10 and 15 years, from reoperation for and at 10 and 15 years, ± ± ± and ± at 5, 10, and 20 years, from 98 ± 0.2%, 96 ± 1%, and 67 ± 4% at 5, 10, and 20 years, at 20 years from at 5 years ± at 20 years ± 4% at 20 years from ± and ± at 15 and 20 years, from explant to ± and ± at 15 and 20 years, of explant to and at 10 and 20 years, ± and 7 ± at 20 and years, from ± 4% at 20 years from ± 4% at 20 years and at 10 and 15 years, from and at 10 and 15 years, from reoperation for and at 10 and 15 years, ± ± ± and ± at 5, 10, and 20 years, from 98 ± 0.2%, 96 ± 1%, and 67 ± 4% at 5, 10, and 20 years, at 20 years from at 5 years ± at 20 years ± 4% at 20 years from ± and ± at 15 and 20 years, from explant to ± and ± at 15 and 20 years, of explant to and at 10 and 20 years, SVD, structural valve as any in function from any valve or as of aortic transprosthetic gradient with a effective orifice area or aortic regurgitation as severe aortic stenosis (mean transvalvular gradient >40 mmHg) or severe aortic regurgitation (effective regurgitant orifice area >0.30 cm2, vena contracta >0.6 cm). durability after surgical aortic valve replacement ± and 7 ± at 20 and years, from ± 4% at 20 years from ± 4% at 20 years and at 10 and 15 years, from and at 10 and 15 years, from reoperation for and at 10 and 15 years, ± ± ± and ± at 5, 10, and 20 years, from 98 ± 0.2%, 96 ± 1%, and 67 ± 4% at 5, 10, and 20 years, at 20 years from at 5 years ± at 20 years ± 4% at 20 years from ± and ± at 15 and 20 years, from explant to ± and ± at 15 and 20 years, of explant to and at 10 and 20 years, ± and 7 ± at 20 and years, from ± 4% at 20 years from ± 4% at 20 years and at 10 and 15 years, from and at 10 and 15 years, from reoperation for and at 10 and 15 years, ± ± ± and ± at 5, 10, and 20 years, from 98 ± 0.2%, 96 ± 1%, and 67 ± 4% at 5, 10, and 20 years, at 20 years from at 5 years ± at 20 years ± 4% at 20 years from ± and ± at 15 and 20 years, from explant to ± and ± at 15 and 20 years, of explant to and at 10 and 20 years, SVD, structural valve as any in function from any valve or as of aortic transprosthetic gradient with a effective orifice area or aortic regurgitation as severe aortic stenosis (mean transvalvular gradient >40 mmHg) or severe aortic regurgitation (effective regurgitant orifice area >0.30 cm2, vena contracta >0.6 cm). aortic valve implantation has available since and used in elderly in whom data concerning long-term durability are (Table annual echocardiography in the TAVI using a prosthesis with SAVR in high-risk demonstrated transvalvular gradient and aortic valve area up to 5 years patients at risk at follow-up data of a using a TAVI prosthesis vs. SAVR are available up to 3 years, more valve haemodynamics for TAVI without differences in In this severe patient-prosthesis mismatch was more in patients with SAVR than with and with durability after transcatheter aortic valve implantation at 5 years at 5 years to at 5 years at 5 years valve at 5 years at 5 years at 5 years to at 5 years at 5 years valve at 5 years SVD, structural valve durability after transcatheter aortic valve implantation at 5 years at 5 years to at 5 years at 5 years valve at 5 years at 5 years at 5 years to at 5 years at 5 years valve at 5 years SVD, structural valve The and Registries demonstrated valve gradients over 5 years and of SVD of and , However, it should be noted that patients were still at 5 years their age and significant at the time of valve implantation) and that definitions of SVD were not two series currently data on durability (>5 in patients before et et at Valve In the series SVD was defined as mean transvalvular gradient ≥20 an increase over time and/or aortic regurgitation that was not present following valve this 1 SVD TAVI for and 3 asymptomatic patients SVD (mean gradient and increase in comparison with patients a gradient >40 In the series freedom from SVD defined as need for reintervention was while freedom from SVD defined as severe regurgitation or need for reintervention was at patients were years after TAVI with no of SVD in two in In standardized definitions for the of future studies, the on the following should be between SVD principal and BVF clinical valve deterioration dysfunction whereas other pathological of bioprosthetic valve dysfunction (i.e. thrombosis, are and should be and However, the or process as a of BVF if it to or bioprosthetic valve dysfunction. valve dysfunction (i.e. or prosthesis patient-prosthesis late may occur early after TAVI as a result of valve dysfunction in valve-related and haemodynamic dysfunction severe new or aortic as a of Echocardiography is the principal imaging modality for the detection of SVD and the and to detect changes in valve gradients should be determined in at least two measurements to for detection and to the different of bioprosthesis TAVI and echocardiography should be before discharge or within after valve implantation (i.e. baseline at 1 after valve implantation and annually (with additional follow-up and/or of other imaging modalities as and/or determined by the (Figure at echocardiographic haemodynamic multi-detector computed SVD, structural valve valve deterioration intrinsic changes of the valve (i.e. leaflet tear, calcification, or to and/or dysfunction, which in may result in stenosis or regurgitation (Table valve deterioration can be using imaging studies or at the time of reoperation or and can in symptomatic and asymptomatic patients. valve deterioration can be as and/or valve deterioration SVD, structural valve valve deterioration SVD, structural valve The diagnosis is on haemodynamic changes in valve function by of echocardiography, even without evidence of morphological SVD haemodynamic SVD may be in patients with haemodynamic SVD by echocardiography or other imaging the two of haemodynamic SVD and detection of haemodynamic dysfunction of clinical SVD is defined as (i) mean gradient ≥20 and and/or and from baseline discharge or within of valve implantation) and/or (ii) moderate new or aortic haemodynamic SVD is defined as (i) mean gradient and/or ≥20 from baseline discharge or within of valve implantation) and/or (ii) severe new or aortic The diagnosis is on imaging of reintervention is In of the diagnosis of morphological SVD should be and or on the pathological SVD of the following leaflet (i.e. or regurgitation), leaflet (i.e. pathological thickening and/or stenosis or regurgitation), leaflet function (i.e. in stenosis and/or regurgitation), and (i.e. or The term BVF severe SVD (i.e. the with its clinical consequences avoiding of valve-related outcomes in asymptomatic patients with no clinical and is recommended by the as the main outcome of in studies assessing the long-term of TAVI and SAVR (Figure Importantly, BVF may occur in the setting of SVD but also as the of pathophysiological to SVD, such as thrombosis, or non-structural valve dysfunction. BVF any of the (i) bioprosthetic valve dysfunction at likely to the of or defined as any by bioprosthetic valve dysfunction in the of (ii) aortic valve reintervention (i.e. or and severe haemodynamic SVD. Based on the degree of BVF can be as (i.e. severe haemodynamic or (i.e. valve-related and early (i.e. up to or late (i.e. according to the timing of after valve valve failure surgical aortic valve SVD, structural valve transcatheter aortic valve valve failure surgical aortic valve SVD, structural valve transcatheter aortic valve assessment of bioprosthetic valve failure (BVF) in outcome studies of transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement SVD, structural valve the durability of prostheses important and a number of should BVF be considered a or outcome is the of BVF in an elderly is there a approach to these The following will these and on in survival for important is between valve and Valve outcomes to the intrinsic durability of the bioprosthesis (i.e. they the is the of this valve over time without In patients are more in their of a valve event during their remaining (i.e. is the of valve failing before Importantly, some valve outcomes (including haemodynamic are in which that they with time and not occur at a capture valve outcomes while it is important to consider the timing of or when assessing the or of haemodynamic SVD by of mean gradient using Doppler echocardiography, there is an important if the are while the changes data the other there is a risk of valve outcomes if the are (i.e. if echocardiography is at any time in symptomatic These are when are different with valve outcomes are more time in that they the of an event from the time of implantation to a (i.e. or a risk the risk of a valve to over time. In if the at a time when the valve is there is no to the valve have if the In other if BVF at some time during the end point is In if the with no bioprosthetic valve dysfunction, we cannot be the true durability of the prosthesis the for that valve to at a time This is more likely to occur in an and the is The term to the when the information an end point for a is a may be in a of TAVI durability (i) BVF not occur during the follow-up (ii) the before the end of the follow-up (i.e. or the is to of outcome studies is that can be or is Based on such an the survival experience of a who or is to follow-up may be by (i.e. and the outcome of as of a patients follow-up However, the of is in TAVI durability there is a between the risk of and BVF (i.e. in that (i) patients who before BVF are than who not and (ii) the of BVF is lower in patients. The relevant for a TAVI not to the intrinsic durability of the but to the of a clinical event to bioprosthetic valve dysfunction during the course of the remaining In this of actuarial may to since event an increasingly significant of the for survival from BVF as over the of (Figure may be for in the durability of a valve particularly if for is the of may for the of and a of true valve Importantly, for the reporting of should be (i) the number of patients at risk at time point the (ii) reporting and the survival when than of the initial is In to the actuarial the is the that should be used for clinical and This on a cumulative incidence provides lower than actuarial and have greater clinical utility in the of TAVI durability of the of using vs. actuarial for assessment of bioprosthetic valve failure (BVF) in studies of transcatheter aortic valve implantation (TAVI) durability. of 20 TAVI patients with follow-up 5 patients experience BVF and 15 patients with before any The and actuarial of BVF 15 patients and 5 patients experience with before any BVF (i.e. The actuarial provides a of BVF than the The of a new in the of valve using transcatheter techniques is The clinical of TAVI are increasingly well by and However, in the process of to of younger and lower risk it is important to the long-term durability of and future TAVI this we have and standardized definitions of SVD and BVF and recommendations for the timing and modalities of clinical and imaging follow-up the of these should also be extended to the evaluation of and future surgical bioprostheses, whose long-term efficacy and durability are currently addressed by a of information concerning bioprosthetic valve dysfunction and and their with bioprosthetic valve and techniques for valve implantation will data to new in and implantation and defined imaging will identification of bioprosthetic valve dysfunction to mechanical and While the process in and to that with surgical , recent evidence of valve leaflet thickening and thrombosis requires since (i) it these are of clinical and to and (ii) the for this is yet to be the aims to a large European registry of TAVI patients years by the European who TAVI at the early of this The registry will on two main aspects of data (i) of BVF at follow-up and (ii) of SVD in patients at different time important remaining in knowledge that need to be include the follow-up data beyond 10 years and our to the significant changes in and techniques over these the results of the registry will be in a understanding of results and the for TAVI in younger patients. they will a for the results of TAVI with of Supplementary material is available at European of from and from and and research from and from from and research from from and from and Lancellotti from and and from from and and research from and from and from and from and and research from and from and and research from and from and The and research from from and and research from and The to the of the following and role as of the from and research from and All the other have to

The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.

The immune response against hepatitis C virus (HCV) is rarely effective at clearing the virus, resulting in approximately 170 million chronic HCV infections worldwide. Here we report that ligation of an HCV receptor (CD81) inhibits natural killer (NK) cells. Cross-linking of CD81 by the major envelope protein of HCV (HCV-E2) or anti-CD81 antibodies blocks NK cell activation, cytokine production, cytotoxic granule release, and proliferation. This inhibitory effect was observed using both activated and resting NK cells. Conversely, on NK-like T cell clones, including those expressing NK cell inhibitory receptors, CD81 ligation delivered a costimulatory signal. Engagement of CD81 on NK cells blocks tyrosine phosphorylation through a mechanism which is distinct from the negative signaling pathways associated with NK cell inhibitory receptors for major histocompatibility complex class I. These results implicate HCV-E2-mediated inhibition of NK cells as an efficient HCV evasion strategy targeting the early antiviral activities of NK cells and allowing the virus to establish itself as a chronic infection.

The novel coronavirus disease 2019 (COVID-19) is a global pandemic spreading worldwide, and Italy represented the first European country involved. Healthcare workers (HCWs) facing COVID-19 pandemic represented an at-risk population for new psychosocial COVID-19 strain and consequent mental health symptoms. The aim of the present study was to identify the possible impact of working contextual and personal variables (age, gender, working position, years of experience, proximity to infected patients) on professional quality of life, represented by compassion satisfaction (CS), burnout, and secondary traumatization (ST), in HCWs facing COVID-19 emergency. Further, two multivariable linear regression analyses were fitted to explore the association of mental health selected outcomes, anxiety and depression, with some personal and working characteristics that are COVID-19-related. A sample of 265 HCWs of a major university hospital in central Italy was consecutively recruited at the outpatient service of the Occupational Health Department during the acute phase of COVID-19 pandemic. HCWs were assessed by Professional Quality of Life-5 (ProQOL-5), the Nine-Item Patient Health Questionnaire (PHQ-9), and the Seven-Item Generalized Anxiety Disorder scale (GAD-7) to evaluate, respectively, CS, burnout, ST, and symptoms of depression and anxiety. Females showed higher ST than males, while frontline staff and healthcare assistants reported higher CS rather than second-line staff and physicians, respectively. Burnout and ST, besides some work or personal variables, were associated to depressive or anxiety scores. The COVID-19 pandemic represents a new working challenge for HCWs and intervention strategies to prevent burnout and ST to reduce the risk of adverse mental health outcomes are needed.

Cervical ultrasound scanning (US) is considered a key examination, by all major thyroid and endocrine specialist societies for the postoperative follow-up of thyroid cancer patients to assess the risk of recurrence. Neck US imaging is readily available, non-invasive, relatively easy to perform, cost-effective, and can guide diagnostic and therapeutic procedures with low complication rates. Its main shortcoming is its operator-dependency. Because of the pivotal role of US in the care of thyroid cancer patients, the European Thyroid Association convened a panel of international experts to review technical aspects, indications, results, and limitations of cervical US in the initial staging and follow-up of thyroid cancer patients. The main aim is to establish guidelines for both a cervical US scanning protocol and US-guided diagnostic and therapeutic procedures in patients with thyroid cancer. This report presents (1) standardization of the US scanning procedure, techniques of US-guided fine-needle aspiration, and reporting of findings; (2) definition of criteria for classification of malignancy risk based on cervical US imaging characteristics of neck masses and lymph nodes; (3) indications for US-guided fine-needle aspiration and for biological in situ assessments; (4) proposal of an algorithm for the follow-up of thyroid cancer patients based on risk stratification following histopathological and cervical US findings, and (5) discussion of the potential use of US-guided localization and ablation techniques for locoregional thyroid metastases.

BACKGROUND: Complications following facial cosmetic injections have recently heightened awareness of the possibility of iatrogenic blindness. The authors conducted a systematic review of the available literature to provide the best evidence for the prevention and treatment of this serious eye injury. METHODS: The authors included in the study only the cases in which blindness was a direct consequence of a cosmetic injection procedure of the face. RESULTS: Twenty-nine articles describing 32 patients were identified. In 15 patients, blindness occurred after injections of adipose tissue; in the other 17, it followed injections of various materials, including corticosteroids, paraffin, silicone oil, bovine collagen, polymethylmethacrylate, hyaluronic acid, and calcium hydroxyapatite. CONCLUSIONS: Some precautions may minimize the risk of embolization of filler into the ophthalmic artery following facial cosmetic injections. Intravascular placement of the needle or cannula should be demonstrated by aspiration before injection and should be further prevented by application of local vasoconstrictor. Needles, syringes, and cannulas of small size should be preferred to larger ones and be replaced with blunt flexible needles and microcannulas when possible. Low-pressure injections with the release of the least amount of substance possible should be considered safer than bolus injections. The total volume of filler injected during the entire treatment session should be limited, and injections into pretraumatized tissues should be avoided. Actually, no safe, feasible, and reliable treatment exists for iatrogenic retinal embolism. Nonetheless, therapy should theoretically be directed to lowering intraocular pressure to dislodge the embolus into more peripheral vessels of the retinal circulation, increasing retinal perfusion and oxygen delivery to hypoxic tissues. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.

Background: Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods: We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results: The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions: CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections. SSTIs are a frequent clinical problem in surgical departments. In order to clarify key issues in the management of SSTIs, a task force of experts met in Bertinoro, Italy, on June 28, 2018, for a specialist multidisciplinary consensus conference under the auspices of the World Society of Emergency Surgery (WSES) and the Surgical Infection Society Europe (SIS-E). The multifaceted nature of these infections has led to a collaboration among general and emergency surgeons, intensivists, and infectious disease specialists, who have shared these clinical practice recommendations.

Hemorrhoidal disease (HD) is the most common proctological disease in the Western countries. However, its real prevalence is underestimated due to the frequent self-medication.The aim of this consensus statement is to provide evidence-based data to allow an individualized and appropriate management and treatment of HD. The strategy used to search for evidence was based on application of electronic sources such as MEDLINE, PubMed, Cochrane Review Library, CINAHL, and EMBASE.These guidelines are inclusive and not prescriptive.The recommendations were defined and graded based on the current levels of evidence and in accordance with the criteria adopted by American College of Chest Physicians. The recommendations were graded A, B, and C.

Cigarette smoke is a mixture of chemicals having direct and/or indirect toxic effects on different lung cells. We investigated the effect of cigarette smoke on human lung fibroblasts (HFL-1) oxidation and apoptosis. Cells were exposed to various concentrations (1, 5, and 10%) of cigarette smoke extract (CSE) for 3 h, and oxidative stress and apoptosis were assessed by fluorescence-activated cell sorting and confocal laser fluorescence microscopy. Both oxidative stress and apoptosis exhibited a dose-response relationship with CSE concentrations. Lung fibroblasts also showed marked DNA fragmentation at the Comet assay after exposure to 10% CSE. Coincubation of HLF-1 cells with N-acetylcysteine (1 mM) during CSE exposure significantly reduced oxidative stress, apoptosis, and DNA fragmentation, whereas preincubation (3 h) with the glutathione-depleting agent buthionine sulfoximine (125 microM) produced a significant increase of oxidative stress. Cigarette smoke is a potent source of oxidative stress, DNA damage, and apoptosis for HFL-1 cells, and we speculate that this could contribute to the development of pulmonary emphysema in the lungs of smokers.

INTRODUCTION: Pseudomonas aeruginosa nosocomial pneumonia (Pa-NP) is associated with considerable morbidity, prolonged hospitalization, increased costs, and mortality. METHODS: We conducted a retrospective cohort study of adult patients with Pa-NP to determine 1) risk factors for multidrug-resistant (MDR) strains and 2) whether MDR increases the risk for hospital death. Twelve hospitals in 5 countries (United States, n = 3; France, n = 2; Germany, n = 2; Italy, n = 2; and Spain, n = 3) participated. We compared characteristics of patients who had MDR strains to those who did not and derived regression models to identify predictors of MDR and hospital mortality. RESULTS: Of 740 patients with Pa-NP, 226 patients (30.5%) were infected with MDR strains. In multivariable analyses, independent predictors of multidrug-resistance included decreasing age (adjusted odds ratio [AOR] 0.91, 95% confidence interval [CI] 0.96-0.98), diabetes mellitus (AOR 1.90, 95% CI 1.21-3.00) and ICU admission (AOR 1.73, 95% CI 1.06-2.81). Multidrug-resistance, heart failure, increasing age, mechanical ventilation, and bacteremia were independently associated with in-hospital mortality in the Cox Proportional Hazards Model analysis. CONCLUSIONS: Among patients with Pa-NP the presence of infection with a MDR strain is associated with increased in-hospital mortality. Identification of patients at risk of MDR Pa-NP could facilitate appropriate empiric antibiotic decisions that in turn could lead to improved hospital survival.

Graves' ophthalmopathy is an debilitating disease impairing the quality of life of affected individuals.Despite recent progress in the understanding of its pathogenesis, treatment is often not satisfactory.In mild cases, local therapeutic measures (artificial tears and ointments, sunglasses, nocturnal taping of the eyes, prisms) can control symptoms and signs.In severe forms of the disease (3-5%), aggressive measures are required.If the disease is active, high-dose glucocorticoids and/or orbital radiotherapy, or orbital decompression represent the mainstay of treatment.If the disease is severe but inactive, orbital decompression is preferred.Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation.Re-habilitative (extraocular muscle or eyelid) surgery is often needed after treatment and inactivation of eye disease.Correction of both hyper-and hypothyroidism is crucial for the ophthalmopathy.Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may cause the progression of preexisting ophthalmopathy, especially in smokers.The exacerbation, however, is prevented by glucocorticoids.In addition, thyroid ablation may prove beneficial for the ophthalmopathy in view of the pathogenetic model relating eye disease to autoimmune reactions directed against antigens shared by the thyroid and the orbit.(Endocrine Reviews 21

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.