Search

We report a novel cardiomyopathy associated to Usher syndrome and related to combined mutation of MYO7A and Calreticulin genes. A 37‐year‐old man with deafness and vision impairment because of retinitis pigmentosa since childhood and a MYO7A gene mutation suggesting Usher syndrome, developed a dilated cardiomyopathy with ventricular tachyarrhythmias and recurrent syncope. At magnetic resonance cardiomyopathy was characterized by left ventricular dilatation with hypo‐contractility and mitral prolapse with valve regurgitation. At left ventricular endomyocardial biopsy, it was documented cardiomyocyte disconnection because of cytoskeletal disorganization of cell‐to‐cell contacts, including intercalated discs, and mitochondrial damage and dysfunction with significant reduction of adenosine triphosphate production in patient cultured fibroblasts. At an extensive analysis by next‐generation‐sequencing of 4183 genes potentially related to the cardiomyopathy a pathogenic mutation of calreticulin was found. The cardiomyopathy appeared to be functionally and electrically stabilized by a combination therapy including carvedilol and amiodarone at a follow‐up of 18 months.

International audience; AimsDilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non‐familial (sporadic) DCM (SDCM) across Europe.Methods and resultsPatients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01).ConclusionsWe observed that FDCM and SDCM have significant differences at baseline but similar short‐term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non‐marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence.

We report a case of myopericarditis associated to SARS-CoV-2 infection with necrotizing coronary vasculitis of intramural vessels, giving rise to biventricular apical microaneurysms and to electrical instability. Negativity of myocardial polymerase chain reaction for the most common cardiotropic viruses and for SARS-CoV-2 suggested an immune-mediated myocardial and pericardial inflammatory disease. High dose (1 mg/Kg daily) prednisone and anti-viral (Remdesivir, IDA Business, Carrigtohill, County Cork, T45 DP77, Ireland) therapy led to resolution of cardiac inflammation and ventricular arrhythmias. Morpho-molecular characterization of endomyocardial tissue may improve the outcome in subjects with SARS-CoV-2-associated myopericarditis and coronary vasculitis.

Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

Periprosthetic joint infections (PJIs) remain a challenging complication after shoulder arthroplasty. The antimicrobial peptide α-defensin has been proposed as a new synovial fluid biomarker in diagnosing PJIs. To date, only little data are available on the diagnostic accuracy of α-defensin in shoulder PJIs; thus, we aimed to evaluate its diagnostic value in a cohort of patients with a suspected shoulder PJI. Between June 2016 and June 2018, we prospectively enrolled patients with a diagnostic shoulder aspiration due to painful shoulder arthroplasty or planned revision surgery. PJI diagnostics were performed according to the Musculoskeletal Infection Society (MSIS) criteria. All patients with an antibiotic therapy within two weeks before enrollment, insufficient amount of synovial aspirate, or bloody aspiration were excluded. α-Defensin was measured in the synovial fluid using the α-defensin lateral flow (ADLF) test (Synovasure®). Out of 60 patients, we could include 29 (59% female) patients with a mean age of 70 (range, 50–92) years. A shoulder PJI was detected in five cases (Staphylococcus aureus, n = 2; Staphylococcus epidermidis, n = 2; Cutibacterium acnes, n = 1). The ADLF test was positive in seven out of 29 cases. According to the MSIS criteria, the ADLF test was false-negative in two patients and false-positive in four patients, resulting in sensitivity, specificity, and positive and negative predictive value of 60%, 83%, 43%, and 91%, respectively. The overall accuracy was 79%. The ALDF test does not appear to be useful in predicting shoulder PJIs but may be used as an additional diagnostic factor in rejecting these infections.

Background Few data about predictors and outcomes associated with prolonged SARS-CoV-2 RNA shedding (VS) are available. Methods Retrospective study including all patients admitted with COVID-19 in an Italian reference hospital for infectious diseases between March 1 and July 1, 2020. Predictors of viral clearance (VC) and prolonged VS from upper respiratory tract were assessed by Poisson regression and logistic regression analyses. The causal relation between duration of VS and probability of clinical outcomes was evaluated through inverse probability weighted Cox model. Results 536 subjects were included. Median duration of VS from symptoms onset was 18 days (IQR 12-26). The estimated 30-day probability of VC was 70.2% (95%CI:65-75). At multivariable analysis, patients with comorbidities (aIRR = 0.88, p = 0.004), lymphopenia at hospital admission (aIRR = 0.75, p = 0.032) and with moderate/severe respiratory disease (aIRR = 0.42, p 1000 ng/mL at admission (aOR = 1.76, p = 0.035) independently predicted prolonged VS. The achievement of VC doubled the chance of clinical recovery (aHR = 2.17, p

Key points Age per se does not influence outcome in CLL patients on ibrutinib, whereas CIRS score is predictive of treatment management, PFS, and EFS.ECOG-PS and neutropenia resulted as the only baseline parameters affecting overall survival., Visual Abstract, Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Prophylactic low molecular weight heparin (pLMWH) is currently recommended in COVID-19 to reduce the risk of coagulopathy. The aim of this study was to evaluate whether the antinflammatory effects of pLMWH could translate in lower rate of clinical progression in patients with COVID-19 pneumonia. Patients admitted to a COVID-hospital in Rome with SARS-CoV-2 infection and mild/moderate pneumonia were retrospectively evaluated. The primary endpoint was the time from hospital admission to orotracheal intubation/death (OTI/death). A total of 449 patients were included: 39% female, median age 63 (IQR, 50–77) years. The estimated probability of OTI/death for patients receiving pLMWH was: 9.5% (95% CI 3.2–26.4) by day 20 in those not receiving pLMWH vs. 10.4% (6.7–15.9) in those exposed to pLMWH; p-value = 0.144. This risk associated with the use of pLMWH appeared to vary by PaO2/FiO2 ratio: aHR 1.40 (95% CI 0.51–3.79) for patients with an admission PaO2/FiO2 ≤ 300 mmHg and 0.27 (0.03–2.18) for those with PaO2/FiO2 > 300 mmHg; p-value at interaction test 0.16. pLMWH does not seem to reduce the risk of OTI/death mild/moderate COVID-19 pneumonia, especially when respiratory function had already significantly deteriorated. Data from clinical trials comparing the effect of prophylactic vs. therapeutic dosage of LMWH at various stages of COVID-19 disease are needed.

Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its influence on cardiomyocyte structure, function, and hormonal receptors when associated with heart failure is still unreported. Methods: Twenty-six consecutive patients with heart failure (LVEF &lt, 40%) and normal coronaries and valves underwent left ventricular endomyocardial biopsy (EMB) for evaluation of myocardial substrate. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western blot analysis of myocardial aldosterone receptor and aquaporin-1 correlated with plasma aldosterone (AD) and renin activity (PRA). Eight patients with virus-negative inflammatory cardiomyopathy (ICM) had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy CM (6), alcohol CM (2), and diabetic CM (3) showed vacuolar degeneration and cloudy swelling of cardiomyocytes corresponding at electron microscopy to ions and water accumulation into cytosol, membrane-bound vesicles, nucleus, and other organelles, and was associated with an increased AD, PRA, and myocardial expression of aldosterone receptor (2.6 fold) and aquaporin 1 (2.7 fold). In the 8 patients recovered from ICM, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles and normalization of cytosol, nucleus, and cell organelles’ electron-density, along with down-regulation of aldosterone receptor and aquaporin-1. Conclusion: Human heart failure is associated with overexpression of myocardial aldosterone receptor and aquaporin-1. These molecular changes are paralleled by intracellular water overloading and cardiomyocyte swelling and dysfunction. Cardiac recovery is accompanied by down-regulation of hormonal receptors and normalization of cell structure and composition.

Background. The PI3Kδ inhibitor idelalisib given in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia (R/R CLL) has been associated with an objective response in 81% of cases with a median PFS of 20.3 months in a phase-3 clinical trial (Sharman et al, JCO 2019). Because the efficacy of new drugs reported in clinical trials may not translate into similar results in the day-to-day practice, we performed an observational retrospective-prospective study on the efficacy and safety of idelalisib and rituximab (IR) in R/R CLL patients treated outside of clinical trials in Italian centers belonging to the GIMEMA group. Methods. R/R CLL patients treated with IR outside of clinical trials between July 2014 and May 2017 were enrolled. Treatment was initiated at symptomatic progression; treatment response and disease progression were assessed according to the NCI criteria. The data were extracted from the medical files and entered into case record forms (CRF) by each treating physician. Computerized and manual consistency checks were performed by the GIMEMA data center on newly entered forms and queries were issued in case of inconsistencies. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), the percentage of patients on treatment at 12, 24 and 36 months, overall survival (OS) and response to the subsequent anti-leukemic treatment. Results. 149 R/R CLL patients from 35 Italian centers were included in the study. The baseline characteristics are shown in Table 1. At a median follow-up of 39.4 months, the median PFS was 22.9 months (95% CI 20.5-28.8). In univariate analysis, a shorter PFS was associated with ≥3 lines of therapy (p=0.0175) (Fig. 1a). The ORR (CR + PR) was 72.5%. Age ≤70 yrs (p=0.037) and a PS grade 3 during RI treatment were neutropenia (35% of cases), gastrointestinal disorders (17%), infections (17%) and transaminitis (6%). Conclusions. The results hereby observed show that the efficacy of IR in a cohort in a real-life RR/CLL with a long follow-up is superimposable to those reported in the pivotal clinical trial, suggesting that the patient population who received IR in the day-to-day clinical practice mirrored that enrolled in the trial. Advanced clinical stage and 3 or more previous lines of therapy were associated with shorter PFS and OS. Interestingly, PFS and objective measures of efficacy such as the proportion of patients still on treatment at 12, 24 and 36 months, as well as OS, were not influenced by the TP53 status. Furthermore, the majority of patents responded to the subsequent anti-leukemic treatment and relatively durable responses were observed in patients who discontinued IR due to toxicity. Disclosures Rigolin: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Coscia:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sunesys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Murru:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Sportoletti:Janssen: Honoraria; AbbVie: Honoraria. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Marasca:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Marchetti:Takeda: Other: Sponsored meetings; Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Mauro:Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Molica:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gozzetti:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Galieni:Celgene: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Montillo:AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Verastem: Honoraria; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria. Foà:Incyte: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Cuneo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients.

Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists’ free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised., Instituto de Estudios Inmunológicos y Fisiopatológicos

Background: Coronavirus disease 2019 (COVID-19), the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that originated in China in December 2019, was recently recognized as pandemic threat by the World Health Organization, with the potential of rapidly overloading health care systems and causing substantial mortality worldwide (www.who.int/dg/speeches/detail/who-director-general -s-opening-remarks-at-the-media-briefing-on-covid-19 —11-march -2020). Human-to-human transmission occurs mainly through respiratory droplets, but other routes are under investigation, because SARS-CoV-2 has been detected in several body fluids (1). So far, few data are available on ocular samples from patients with COVID-19, although conjunctivitis has been occasionally reported among COVID-19 symptoms, similar to infections caused by other human coronaviruses (2, 3). During the SARS epidemic, eye exposure to infectious fluids was associated with an increased risk for SARS-CoV transmission to health care workers (3, 4). Although SARS-CoV RNA was occasionally found in ocular specimens during the early phase of illness, its infectivity is unknown (2, 3). With regard to COVID-19, unprotected ocular exposure was thought to be responsible for infections that occurred in the Wuhan Fever Clinic in January 2020 (3, 4); in addition, SARS-CoV-2 RNA was detected in conjunctival secretions collected from the only patient with conjunctivitis out of 30 patients with COVID-19 from a hospital in China (5). However, further studies are needed to evaluate the infectious potential of the SARS-CoV-2 RNA detected in the ocular specimens and to determine whether transmission may occur through ocular secretions (3, 4). Objective: To present the early detection of infectious SARS-CoV-2 in ocular fluids from a patient with the first confirmed case of COVID-19 in Italy, who had been hospitalized at the National Institute for Infectious Diseases “L. Spallanzani” (INMI) in Rome. Methods and Findings: The patient, a 65-year-old woman, travelled from Wuhan, China, to Italy on 23 January 2020 and was admitted on 29 January 2020, 1 day after symptom onset. At admission to the high isolation unit at INMI, she presented with nonproductive cough, sore throat, coryza, and bilateral conjunctivitis. She had no fever until day 4, when fever (38 °C), nausea, and vomiting began. Infection with SARS-CoV-2 was confirmed by performing real-time reverse transcription polymerase chain reaction (RT-PCR) assay on sputum samples (cycle threshold value [Ct], 16.1) on the admission day, followed by viral M gene sequencing (GenBank accession number MT008022), and virus isolation on Vero E6 cell line (2019-nCoV/Italy-INMI1). The full genome sequence was obtained from either clinical sample or culture isolate (GISAID accession numbers EPI_ISL_410545 and EPI_ISL_410546). At admission, no other respiratory infections were detected (QIAstat-Dx Respiratory Panel; Qiagen).

Aim To investigate the contribution of unaffected cardiomyocytes in Fabry disease cardiomyopathy. Findings Left ventricular (LV) endomyocardial biopsies from twenty-four females (mean age 53 ± 11 ys) with Fabry disease cardiomyopathy were studied. Diagnosis of FD was based on the presence of pathogenic GLA mutation, Patients were divided in four groups according with LV maximal wall thickness (MWT): group 1 MWT ≤ 10.5 mm, group 2 MWT 10.5–15 mm, group 3 MWT 16–20 mm, group 4 MWT > 20 mm. At histology mosaic of affected and unaffected cardiomyocytes was documented. Unaffected myocytes’ size ranged from normal to severe hypertrophy. Hypertrophy of unaffected cardiomyocytes correlated with severity of MWT (p

Weight loss has been shown to improve metabolic parameters and cardiovascular risk in people with type 2 diabetes mellitus (T2DM). This phase 2 study evaluated the safety and efficacy of JNJ-64565111, a dual agonist of GLP-1 and glucagon receptors, in individuals with T2DM and class II/III obesity. In this randomized, double-blind study, participants with T2DM (HbA1c 6.5%-9.5%), body mass index of 35 to 50 kg/m2 and stable weight were randomly assigned (1:1:1:1) to placebo or JNJ-64565111 (5.0 mg, 7.4 mg or 10.0 mg). The primary endpoint was percent change from baseline in body weight at week 12. Of 195 dosed participants, 144 (73.8%) completed treatment. At week 12, placebo-subtracted body weight changes were -4.6%, -5.9% and -7.2% with JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg, respectively. All JNJ-64565111 doses were associated with no change in HbA1c and slight numerical elevation of fasting insulin. Numerical increases in fasting plasma glucose were observed with JNJ-64565111 5.0 mg and 7.4 mg. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher with JNJ-64565111 vs placebo. Overall, JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events, no HbA1c reductions, and increased fasting plasma glucose and fasting insulin.

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real‐life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression‐free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0–1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%, NOI, 3.3%, OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p &lt, 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.

ContextAtypical parathyroid adenomas (APAs) are neoplasms with uncertain malignant potential but lack unequivocal histological signs of malignancy.ObjectiveThis work aims to retrospectively evaluate the clinical and biochemical profiles of patients with APA, the outcome after parathyroidectomy (PTX), and the presence of CDC73 germline and somatic mutations.MethodsThis monocentric study was conducted on consecutive patients undergoing PTX for primary hyperparathyroidism (PHPT) between June 2000 and December 2020. Fifty-eight patients with a confirmed histopathological diagnosis of APA, and age- and sex-matched controls with parathyroid adenoma (PA) were also included.ResultsFifty-four patients had sporadic PHPT and 4 had familial isolated hyperparathyroidism (FIHP). Thirty-four patients (59%) had symptomatic disease. Serum calcium and parathyroid hormone (PTH) levels were significantly higher in symptomatic compared to asymptomatic patients (P = .048 and .008, respectively). FIHP patients were younger than their sporadic counterparts (30 ± 17 years vs 55 ± 13 years). APA patients had significantly higher serum calcium and PTH levels and lower 25-hydroxyvitamin D concentration, bone mineral density, and T score at one-third distal radius compared to those with PA. Four of 56 APA patients displayed a CDC73 germline mutation. No somatic CDC73 mutation was identified in 24 tumor specimens. The mean follow-up after surgery was 60 ± 56.4 months. All but 6 patients (90%), 5 with apparently sporadic PHPT and 1 with FIHP, were cured after surgery.ConclusionThe large majority of patients with APA, despite a moderate/severe phenotype, have a good prognosis. Germline CDC73 mutation–positive patients had a higher rate of persistent/recurrent disease. CDC73 gene alterations do not seem to have a relevant role in the tumorigenesis of sporadic APA.

Background The TIMIC trial demonstrated the short term efficacy of immunosuppression (IMS) in virus-negative inflammatory cardiomyopathy. However long term outcome of patients responsive to this treatment is still unclear. Purpose To assess the long term outcome of patients enrolled in the TIMIC trial. Methods The 85 (51 M, 34 F, 42.7±14.7 years) patients with endomyocardial biopsy proven virus-negative chronic inflammatory cardiomyopathy, enrolled in the TIMIC trial and treated either with prednisone and azathioprine (prednisone 1mg kg–1 day–1 for 4 weeks followed by 0.33 mg kg–1 day–1 for 5 months and azathioprine 2 mg kg–1 day–1 for 6 months) or placebo for 6 months, were evaluated in a long-term follow-up of up to 18 years (mean 15.2±2.0 SD, range 12–18 ys). Patients treated with placebo at the end of the 6-month enrollment because of the lack of improvement received IMS for further 6 months. Results At 6 months' follow-up 89% patients showed a significant improvement of left ventricular ejection fraction compared to baseline (LVEF rising from 27.0±5.7 to 46.2±6.4, % p This improvement was maintained in the long term follow-up (LVEF 51.1±6.4%, p Conclusion Immunosuppressive therapy of virus negative inflammatory cardiomyopathy warrants in susceptible patients a long term recovery of heart function with very low incidence of recurrences, that respond to a new TIMIC protocol dose treatment. Long term efficacy of TIMIC-IMS therapy Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): AIFA

Aims The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. ................................................................................................................................................................................................... Methods and results A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). ................................................................................................................................................................................................... Conclusion By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.

Background Guselkumab (GUS), an IL-23 antagonist, is being investigated for the treatment of IBD. GALAXI 1 is a ph2, double-blind, PBO-controlled study in pts with moderately to severely active CD with inadequate response or intolerance to conventional therapies (corticosteroid, immunosuppressant) and/or biologics (TNF antagonist, vedolizumab). Here we report early clinical outcome measures during induction with GUS vs PBO. Methods Pts with moderate to severe CD (CDAI score 220–450) were randomized 1:1:1:1:1 to GUS 200, 600 or 1200mg IV at Wks 0, 4, 8; ustekinumab (UST) ~6mg/kg IV at Wk 0 and 90mg SC at Wk8; or PBO IV. Clinical remission (CDAI score Results Two hundred fifty pts were evaluated; about 50% failed previous biologic therapy. Baseline demographics and disease characteristics were generally similar among treatment groups (mean CD duration, 8.8yr; mean CDAI, 306.2; median CRP, 5.4mg/L; median fecal calprotectin, 594.0mg/kg). At Wk4, clinical remission was achieved in 20.0% of GUS-treated pts compared with 11.8% of PBO-treated pts. A greater proportion of GUS-treated pts achieved clinical remission compared with PBO-treated pts at Wk8 (42.0% vs 15.7%) and Wk12 (54.0% vs 15.7%). Similarly, within each subgroup of pts who failed biologic therapy(BIO-failures) or conventional therapy(CON-failures), GUS-treated pts achieved a higher rate of clinical remission at Wks 4, 8 and 12 compared with PBO (Fig 1). The proportion of pts who achieved clinical response and clinical-biomarker response was also higher at Wks 4, 8 and 12 among GUS-treated pts compared with PBO-treated pts. From Wks 4 to 8 to 12, the proportion of GUS-treated pts in clinical response increased from 44.0% to 56.0% to 66.0%, respectively, and the proportion in clinical-biomarker response increased from 26.0% to 43.3% to 48.0%. In contrast, the proportion of PBO-treated pts who achieved clinical response and clinical-biomarker response remained stable or decreased from Wks 4 to 8 to 12: 25.5% to 25.5% to 23.5% and 13.7% to 9.8% to 7.8%, respectively (Fig 2). Conclusion In pts with moderately to severely active CD, induction treatment with GUS combined treatments versus PBO resulted in higher rates of overall clinical remission, clinical-biomarker response, and clinical response as early as Wk4. This continued to increase through Wk12 with treatment. The early trend for achievement of clinical remission was also evident in sub-groups of pts who failed biologic or conventional therapy.

Introduction: Chemoimmunotherapy has improved outcomes in chronic lymphocytic leukemia, yet it is not curative, with very high relapse rates, and is associated with a significant risk of toxicities. Moreover, patients with higher-risk genetic abnormalities continue to experience poorer outcomes and lower survival. Recently, novel targeted therapies have been developed to increase efficacy and reduce toxicity. Areas covered: Ibrutinib is an oral irreversible inhibitor of Bruton’s tyrosine kinase, a mediator of B-cell receptor signaling, which plays a vital role in various B-cell neoplasms. The drug has been approved for the treatment of several hematological malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, where large trials have shown outcomes never seen before even in high-risk patients. The safety profile appeared furthermore favorable, even in elderly and unfit patients. Expert opinion: Therapy with ibrutinib rarely provides MRD-negative complete remission; an indefinite maintenance is therefore needed, with the risk of developing adverse events (AE) or resistance resulting in treatment interruption or discontinuation. Novel, extremely promising, combination strategies, based on the association of ibrutinib with chemoimmunotherapy, anti-CD20 monoclonal antibody or other targeted agents, are currently being investigated, with the goal of achieving greater depth of remission, especially MRD-negativity, and removing the need for indefinite treatment.

Individuals with obesity have a heightened risk of developing serious comorbidities, and pharmacological treatments for people with obesity are limited. This phase 2 study assessed the safety and efficacy of JNJ-64565111, a dual agonist of glucagon-like peptide-1 and glucagon receptors, in individuals with class II/III obesity without type 2 diabetes. In this randomized, double-blind, placebo-controlled and open-label active-controlled, parallel-group, multicentre study, participants aged 18 to 70 years with a body mass index of 35 to 50 kg/m2 and stable weight were randomly assigned in a 1:1:2:2:2 ratio to blinded treatment with placebo; JNJ-64565111 (5.0, 7.4 or 10.0 mg, each with no dose escalation), or open-label liraglutide 3.0 mg. The primary efficacy endpoint was percent change from baseline in body weight at week 26. Four-hundred seventy four participants were randomized and 343 (72.4%) completed treatment. At week 26, placebo-subtracted body weight changes (adjusted for multiplicity) were -6.8%, -8.1% and -10.0% for the JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg groups, respectively, and -5.8% for the liraglutide group. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher in each JNJ-64565111 treatment group compared to placebo and liraglutide. JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events.

Aims Cardiomyopathies comprise a heterogeneous group of diseases, often of genetic origin. We assessed the current practice of genetic counselling and testing in the prospective European Society of Cardiology EURObservational Research Programme Cardiomyopathy Registry. Methods and results A total of 3208 adult patients from 69 centres in 18 countries were enrolled. Genetic counselling was performed in 60.8% of all patients [75.4% in hypertrophic cardiomyopathy (HCM), 39.2% in dilated cardiomyopathy (DCM), 70.8% in arrhythmogenic right ventricular cardiomyopathy (ARVC), and 49.2% in restrictive cardiomyopathy (RCM),P < 0.001]. Comparing European geographical areas, genetic counselling was performed from 42.4% to 83.3% (P < 0.001). It was provided by a cardiologist (85.3%), geneticist (15.1%), genetic counsellor (11.3%), or a nurse (7.5%) (P < 0.001). Genetic testing was performed in 37.3% of all patients (48.8% in HCM, 18.6% in DCM, 55.6% in ARVC, and 43.6% in RCM,P < 0.001). Index patients with genetic testing were younger at diagnosis and had more familial disease, family history of sudden cardiac death, or implanted cardioverter defibrillators but less co-morbidities than those not tested (P < 0.001 for each comparison). At least one disease-causing variant was found in 41.7% of index patients with genetic testing (43.3% in HCM, 33.3% in DCM, 51.4% in ARVC, and 42.9% in RCM,P = 0.13). Conclusions This is the first detailed report on the real-life practice of genetic counselling and testing in cardiomyopathies in Europe. Genetic counselling and testing were performed in a substantial proportion of patients but less often than recommended by European guidelines and much less in DCM than in HCM and ARVC, despite evidence for genetic background., This work was supported by Abbott Vascular International (2011-2021), Amgen Cardiovascular (2009-2018), AstraZeneca (2014-2021), Bayer AG (2009-2018), Boehringer Ingelheim (2009-2019), Boston Scientific (2009-2012), The Bristol Myers Squibb and Pfizer Alliance (2011-2019), Daiichi Sankyo Europe GmbH (2011-2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014-2017), Edwards (2016-2019), Gedeon Richter Plc. (2014-2016), Menarini Int. Op. (2009-2012), MSD-Merck & Co. (2011-2014), Novartis Pharma AG (2014-2020), ResMed (2014-2016), Sanofi (2009-2011), Servier (2009-2021), and Vifor (2019-2022). Funders had no role in the study design, data analyses, and manuscript drafting.

Background Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. Objectives To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. Methods Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. Results We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. Conclusions We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

Background Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis (M), which incidence, cause and responsiveness to therapy is unreported. Purpose We set out a retrospective study to report our experience in the diagnosis and management of myocarditis-associated necrotizing coronary vasculitis (M-NCV) and patients' outcome. Methods Among 5180 patients undergoing endomyocardial biopsy in our institution, 1916 received a histological diagnosis of myocarditis with associated NCV in 30 (12F, 18M, mean age 47.7 years±15). NVC endomyocardial samples were retrospectively evaluated with, immunohistochemistry for Toll like Receptor 4 (TLR4) and real-time PCR for viral genomes. Serum samples were processed for anti-heart autoantibodies and inflammatory cytokine profile (ELLA assay).Identification of an immunologic pathway (virus-, TLR4+, anti-heart abs +) was followed by immunosuppression including steroids, azathioprine, cyclophosphamide, high dose immunoglobulins and anakinra. M-NCV patients were followed for 6-months with resting ECG, Holter monitoring, 2D-echo and in 45% of cases with cardiac magnetic resonance. Increase of ≥10% in left ventricular EF was classified as response to therapy. M-NCV patients were compared to a control group of 60 consecutive patients with virus + and − lymphocithic myocarditis and a control group of 30 patients with mitral stenosis and normal LV size and function, undergoing surgical repair. Results 26 M-NCV patients presented with heart failure or cardiogenic shock; 3 with electrical instability; 1 with infarct-like symptoms. Cause of M-NCV included infectious agents (PVB19, HHV2, EBV and co-infection of Toxoplasma gondii and PVB19) in 4 patients; chest trauma in 1; drug-hypersensitivity in 2; hypereosinophilic syndrome in 1; primary autoimmune disease in 7; giant cells in 3; while it was idiopathic in the remaining cases. CMR imaging did not detect any qualitative difference between M-NVC and M patients. Anti-heart autoantibodies were positive in immune-mediated M-NCV and virus- M; in M-NCV patients in which anti-heart autoantibodies were positive, we found a cross-reaction with vessel walls. Myocardial expression of TLR4 was high in the immune-mediated forms and negative in the viral. Interleukins 1-beta was more elevated (p Conclusion NCV can be histologically detected in up to 1.5% of a large population with myocarditis. Major causes include viral, autoreactive and autoimmune processes. Intra-hospital mortality is high (24%). Presence of an immunologic pathway is associated with a beneficial response to immunosuppression. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Project ERA-CVD

While there is general agreement on the favorable impact of immunosuppression in eosinophilic, granulomatous, giant cell, drug hypersensitivity, connective tissue disorders, and cardiac rejection-associated myocarditis, its therapeutic role in inflammatory cardiomyopathy (ICM) is still debated. Previous retrospective studies reported a relevant clinical benefit in 90% of patients with virus-negative ICM and no response or cardiac impairment in 85% of patients with virus-positive ICM following immunosuppression. A randomized prospective double-blind trial using prednisone and azathioprine in addition to supportive treatment in virus-negative ICM reported a significant improvement of left ventricular ejection fraction and a significant reduction of LV dimensions in 88% of 43 treated patients compared with 42 patients receiving placebo who showed a cardiac impairment in 83% of cases (TIMIC study). These data have been confirmed by further and larger studies demonstrating a long-term control of myocardial inflammation and persistence of improved cardiac contractility.

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P = .002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P = .028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

Introduction: All the available CLL therapies differ for relevant aspects as duration of response, mode of administration, treatment duration and adverse events: the CHOICE study was designed to investigate CLL patients' Quality of Life (QoL) and preferences towards different treatment attributes through a Discrete Choice Experiment (DCE) in Italy. Due to the timeline of the study, started in Feb2020, the collected data offer an insight of patients' perception and attitude during the 1 st wave of the COVID-19 pandemic, as opposed to other DCE results available in CLL (1-2). Methods: This cross-sectional multi-center observational study enrolled patients (pts) with CLL, WATCH&WAIT (W&W) or already TREATED (around 50% each, controlled at site level), who signed the informed consent for study participation. Exclusion criteria were inability to take oral drugs, cognitive disorders that could impair questionnaire's comprehension and concomitant therapy for other malignancies. Pts were asked to fill in 3 QoL questionnaires: EQ-5D-5L, EORTC QLQ-C30, QLQ CLL-16, described elsewhere. DCE Questionnaire was composed of 9/10 blocks (for W&W/TREATED, respectively) each composed of 8 comparisons between 2 profiles with the following attributes: "Treatment and relevant duration", "PFS", "Possibility of infections", "Possible occurrence of organ damage", "Possible occurrence of diarrhea", with levels specified in Fig1. Each patient (pt) was centrally assigned to 1 block of 8 comparisons. Each pt could ask questionnaire explanations to the medical staff but self-completed it on an App specifically developed for the study. Results: 401 pts were enrolled in Italy across 16 centers (Feb-Jul 2020),199 W&W and 198 TREATED pts completed the DCE questionnaire and were included in the evaluable population. Main pts' characteristics are shown in Table 1. 73.7% of TREATED pts were ON-treatment (30.8% in 1st-line, 69.2% in further lines) and 26.3% were OFF-treatment. DCE results showed that W&W pts rated as most important the 'Possibility of infections' (relative importance, RI=36.2%), followed by 'Treatment and Relevant duration' (RI=28.0%), 'PFS' (RI=16.9%), while 'Possible occurrence of organ damage' (RI=12.5%) and 'Possible occurrence of Diarrhea' (RI=6.4%) had lower impact on the preference (Fig 1A). DCE in TREATED pts showed that they gave more importance to 'Treatment and relevant duration' (RI =33.3%) followed by 'Possibility of infections' (RI =28.8%). The RI of the other attributes was lower: 'Possible occurrence of organ damage' (RI =19.4%), 'PFS' (RI =9.8%), 'Possible occurrence of diarrhea' (RI =8.7%, Fig 1B). A sub-analysis stratifying pts from Northern regions (more impacted during the 1 st wave of the pandemic) and Center-Southern regions showed that in W&W pts from North Regions the attribute with a higher impact is 'Treatment and Relevant duration' (RI=40.3%) followed by 'Possibility of infection' (RI=27.2%), while in W&W pts from Central-Southern area, the attribute with a higher impact is 'Possibility of infection' (RI=43.4%) followed by 'Possible occurrence of Organ damage' (RI=21.6%). In TREATED pts no difference between the 2 groups has been shown and the results are consistent with the total population. Conclusions: CHOICE study was planned to understand CLL patients' preferences towards different treatment attributes, but the results have been impacted by the concurrent COVID-19 pandemic. In contrast to previously published DCEs (1-2), where PFS was the most important attribute, in the CHOICE study pts put much more emphasis on their concerns about possible infections: this could be due to the influence of the 1 st Covid-19 pandemic wave, with the relevant feeling of uncertainty, also due to the great attention that media has dedicated to the issue of infection in general, especially for vulnerable individuals such as CLL pts. The limitation in hospital access during the 1 st wave and the overall need of personal protection (masks usage) and social distancing might have influenced patients' responses too. The "infodemic" and the uncertainty had probably such a strong effect on patient's feelings, that PFS was no longer the most important attribute being substituted by the fear of hospitals access and infections. We thereby suggest that the pandemic had a great impact not only on the conduct of the study but also on patients' perception of their disease, if not properly reassured. Figure 1 Figure 1. Disclosures Molica: Astrazeneca: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Laurenti: AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; BeiGene: Honoraria. Ghia: Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Coscia: Gilead: Honoraria; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Honoraria; Janssen: Honoraria, Speakers Bureau; AstraZeneca: Honoraria; AbbVie: Honoraria, Speakers Bureau; Incyte: Honoraria. Mauro: Takeda: Consultancy, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy. Gualberti: AbbVie: Current Employment. Iannella: AbbVie: Current Employment. Finsinger: AbbVie: Current Employment. Caira: AbbVie: Current Employment. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment. We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p= 2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80% Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tedeschi:Abbvie: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Falini:Roche: Research Funding. Pulsoni:Sandoz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; roche: Consultancy, Speakers Bureau; Merk: Consultancy. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Zinzani:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features. Diagnostic and prognostic charactrization in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications. Treatment choice in Waldemstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, disease characteristics, risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation. Therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents an important step forward for a better management of the disease.

8049 Background: The treatment paradigm of Waldenström macroglobulinemia (WM) continues to evolve as new therapies expand our options for this indolent and incurable disease. While more profound responses are generally associated with longer treatment-free intervals, the impact of depth of response from fixed duration therapy in WM patients' survival needs further evaluation. In this international, multicenter cohort study, we report the prognostic impact of depth of response in WM. Methods: 319 WM patients treated with frontline fixed duration therapy [Dexamethasone/Rituximab/Cyclophosphamide (DRC), Bendamustine/Rituximab (BR), or Bortezomib/Dexamethasone/Rituximab (BDR)] were included. Response at the completion of therapy (6 months) was used in a landmark analysis for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) (defined as time from 6 months post treatment response to event or censor). Response was defined by modified IWWM-6 criteria. Associations between clinical variables and outcomes were evaluated using Cox proportional-hazard models. Results: The median age at the time of treatment initiation was 64 years (range: 29-94), 59% were men, and risk category by International Prognostic Scoring System (IPSS)-WM was low (n=67, 23%), intermediate (n=83, 29%), and high-risk (n=141, 48%). Evaluable responses at 6 months from frontline therapy [DRC (n=105; 41%), BR (n=83; 32%), BDR (n=68; 27%)] were available in 256 patients and included in the landmark analysis. Median follow-up was 63 months (95% CI: 59-70). The rate of major response (PR or better) at 6 months was 74% for the entire cohort. Five-year PFS rates from completion of therapy for patients who attained major response vs. those who did not were 71% and 43%, respectively (p

AIMS We sought to determine whether myocardial expression of Toll-like receptor 4 (TLR4) may predict the response to immunosuppression. METHODS AND RESULTS Endomyocardial biopsies from 237 patients with virus-negative inflammatory cardiomyopathy treated with immunosuppression were retrospectively examined for the expression of TLR4, differentiating those patients responding to immunosuppression (n = 193) from non-responder patients (n = 44). A semiquantitative evaluation of the immunoreactivity (grading from 0 to 4) for TLR4 and human leucocyte antigen (HLA)-DR was performed together with real-time PCR and western blot for TLR4. Cardiomyocyte apoptosis and necrosis was evaluated by in situ ligation with hairpin probes. A focal intense positive cytoplasmic immunostaining for TLR4 was observed in cardiomyocytes of all responders (P < 0.001 vs. non-responders). A grading 2 or above (2+) at baseline showed a sensitivity of 100% and 90.9% specificity with a positive predictive value of 98% as a predictor of an immunosuppression-positive response. Real-time PCR and western blot analysis for TLR4 were 4.3-fold and 4.6-fold higher, respectively, in responders vs. non-responders. Correlation between TLR4 grading and TLR4 mRNA molecular and protein expression was highly significant. HLA-DR did not discriminate between the two groups. Cardiomyocyte death by apoptosis was 3.7-fold higher in responders vs. non-responders and significantly correlated with TLR4 expression, while necrosis was comparable. Intensity of baseline TLR4 expression correlated with the variation in ejection fraction after 6 months of immunosuppression. CONCLUSION TLR4 is highly expressed in human myocarditis responding to immunosuppression. It can be considered as a new sensitive marker in patient selection predicting a good response to immunosuppressive therapy.

Objective Fulranumab is an antibody that specifically neutralizes the biological activity of human nerve growth factor. This multicenter, phase-2, randomized, double-blind (DB), placebo-controlled study evaluated the analgesic efficacy and safety of fulranumab in postherpetic neuralgia (PHN) and posttraumatic neuropathy (PTN) patients. Methods Patients (18 to 80 y) with inadequately controlled moderate-to-severe pain received study medication (subcutaneous injection) every 4 weeks. PHN patients were randomized (3:2:2:3) to receive either placebo or one of 3 doses of fulranumab: 1 mg (1 mgQ4 wk), 3 mg (3 mgQ4 wk), or 10 mg (10 mgQ4 wk). PTN patients were randomized (1:1) to receive either placebo or fulranumab 10 mgQ4 wk. Results The US Food and Drug Administration placed a clinical hold (December 23, 2010) on all trials of antinerve growth factor drugs, including fulranumab, due to identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only 49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the DB efficacy evaluation. There was no significant difference (P>0.05, fulranumab vs. placebo) for change in 7-day average of daily pain intensity scores from DB baseline to end of 12-week DB efficacy phase in PHN or PTN patients (primary endpoint). No significant difference was found with fulranumab versus placebo (P>0.05) in other efficacy measures in either PHN or PTN patients. The most common treatment-emergent adverse events (>10% incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and headache, whereas in PHN patients it was arthralgia. Discussion Fulranumab did not demonstrate efficacy in either PHN or PTN patients, but was generally well-tolerated in this small underpowered and abbreviated study.

Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenstrom's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non-IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non-IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non-IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P

Chronic Lymphocytic Leukemia (CLL) patients with +12 have been reported to have specific clinical and biologic features. We performed an analysis of the association between demographic, clinical, laboratory, biologic features and outcome in CLL patients with +12 to identify parameters predictive of disease progression, time to treatment, and survival. The study included 487 treatment-naive CLL patients with +12 from 15 academic centers, diagnosed between January 2000 and July 2016, and 816 treatment-na&iuml, ve patients with absence of Fluorescence In Situ Hybridization (FISH) abnormalities. A cohort of 250 patients with +12 CLL followed at a single US institution was used for external validation. In patients with +12, parameters associated with worse prognosis in the multivariate model were high Lactate DeHydrogenase (LDH) and &beta, 2-microglobulin and unmutated immunoglobulin heavy-chain variable region gene (IGHV). CLL patients with +12 and high LDH levels showed a shorter Progression-Free-Survival (PFS) (30 months vs. 65 months, p &lt, 0.001), Treatment-Free-Survival (TFS) (33 months vs. 69 months, 0.001), Overall Survival (OS) (131 months vs. 181 months, 0.001) and greater CLL-related mortality (29% vs. 11% at 10 years, 0.001) when compared with +12 CLL patients with normal LDH levels. The same differences were observed in the validation cohort. These data suggest that serum LDH levels can predict PFS, TFS, OS and CLL-specific survival in CLL patients with +12

Background Mutations of α‐actin gene ( ACTC 1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts. Methods and Results In an Italian family of 7 subjects, 4 aged 10 ( II ‐1), 14 ( II ‐2), 43 (I‐4) and 46 years (I‐5), presenting abnormal ECG changes, dyspnea and palpitation ( II ‐2, I‐4, and I‐5), and recurrent cerebral ischemic attack (I‐5), underwent 2‐dimensional echo, cardiac magnetic resonance, Holter monitoring, and next‐generation sequencing gene analysis. Patients II ‐2 and I‐5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age‐related prolongation of QRS duration. Two‐dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I‐4, I‐5, and II ‐2 a progressive LV hypertrophy up to 22‐mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next‐generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC . Conclusions Novel p.(Ala21Val) mutation of ACTC 1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.

The possible cardiotoxicity of tyrosine kinase inhibitors (TKIs) is a topic of extreme interest because in the clinical practice it is frequent the management of elderly patients, in which are common comorbidities and polypharmacotherapies. Several studies have been conducted to evaluate the cardiotoxicity intrinsic to TKIs, but the results are, however, often discordant between in vitro studies and clinical practice. We present a case report about a male patient with several numerous comorbidities: COPD, diabetes mellitus and coronary artery disease. After the failure of imatinib therapy, the patient has switched in second-line to nilotinib therapy, 400 mg twice a day. The therapy was discussed and arranged with the cardiologists, with strict monitoring of cardiac and metabolic parameters. The therapy with nilotinib has allowed to obtain an optimal response according to the ELN guidelines and, from the sixth month of treatment, a major molecular response was obtained. From the standpoint of cardiologists, the patient has maintained a good compensation, despite the permanence of anginal symptoms, which required repeated therapeutic adjustments. Our case shows that nilotinib may be a well tolerated and effective therapy in a patient suffering from a major heart disease, maintaining a close clinical and cardiologic monitoring.

Background— Cardiac arrhythmias are common in Fabry disease (FD) and may occur in prehypertrophic cardiomyopathy suggesting an early compromise of conduction tissue (CT). Therefore, FD X-linked and CT may be variously involved in male and female patients with FD cardiomyopathy, affecting CT function. Methods and Results— Among 74 patients with endomyocardial biopsy diagnosis of FD cardiomyopathy, 13 (6 men; 7 women; mean age, 50.1±13.5 years; maximal wall thickness, 16.7±3.7 mm) had CT included in histological specimens and 6 also at electron microscopy. CT glycolipid infiltration was defined as focal, moderate, extensive, or massive, if involved ≤30%, ≤50%, >50%, or 100% of cells; identified as loosely arranged small myocytes positive to HCN4 immunostaining, supplied by a centrally placed thick-walled arteriole. CT involvement was correlated with age, sex, and α- Gal gene mutation. CT function was evaluated by electrophysiological study and arrhythmias at Holter registration. CT infiltration was focal/moderate in 4 women with no arrhythmias and normal electrophysiological study, extensive in 3 women with atrial or ventricular arrhythmias and short HV interval, and massive in 6 men with atrial fibrillation or ventricular arrhythmias and short HV. Short PR/AH with increased refractoriness was additionally found in 3 patients with extensive/massive CT infiltration. A male patient with the shortest HV presented infra-Hissian block during decremental atrial stimulation. There was no correlation with age, maximal wall thickness, and type of gene mutation. Conclusions— CT infiltration in FD cardiomyopathy is constant in men and variable in women because of skewed X-chromosome inactivation; its extensive/massive involvement causes accelerated conduction with prolonged refractoriness and electric instability.