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Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment- related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS- CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C- reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively). Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries. It has recently been shown that the homogeneity of the chromatin landscape between CLL cells contrasts with the important observed genetic heterogeneity of the disease. To gain further insight into the consequences of disease evolution on the epigenome’s plasticity, we monitored changes in chromatin structure occurring in vivo in CLL cells from patients receiving continuous Ibrutinib treatment. Ibrutinib, an oral inhibitor of the Bruton’s tyrosine kinase (BTK) has proved to be remarkably efficient against treatment naïve (TN), heavily pre-treated and high-risk chronic lymphocytic leukaemia (CLL), with limited adverse events. We established that the chromatin landscape is significantly and globally affected in response to Ibrutinib. However, we observed that prior to treatment, CLL cells show qualitative and quantitative variations in chromatin structure correlated with both EZH2 protein level and cellular response to external stimuli. Then, under prolonged exposure to Ibrutinib, a loss of the two marks associated with lysine 27 (acetylation and trimethylation) was observed. Altogether, these data indicate that the epigenome of CLL cells from the peripheral blood change dynamically in response to stimuli and suggest that these cells might adapt to the Ibrutinib “hit” in a process leading toward a possible reduced sensitivity to treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement‐mediated intravascular hemolysis and thrombosis. The increased incidence of PNH‐driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement‐mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti‐thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in‐part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure.

Altres ajuts: The authors thank the patients who participated in this study and their supportive families, as well as the investigators, subinvestigators, and coordinators at each of the study sites. The authors thank Jerry Ping of Pharmacyclics LLC, an AbbVie Company, for his contributions to the statistical analyses and Joris Diels of Janssen and Suzy Van Sanden of Janssen-Cilag Ltd for their contributions to the crossover-adjusted overall survival analysis using the rank-preserving structural failure time method. John C. Byrd is supported by the Four Winds Foundation, D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, Sullivan CLL Research Foundation, and R35 CA197734. Editorial support was provided by Melanie Sweetlove, MSc, and was funded by Pharmacyclics LLC, an AbbVie Company. T.M. has received honoraria from Janssen, AbbVie, Gilead, Alexion, Novartis, and Roche; and has been in a consulting role for MorphoSys and Sunesis. J.R.B. has received honoraria from Janssen and Teva; has been in a consulting role for AbbVie, Acerta, Astellas, BeiGene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, Redx, Sun, Sunesis, TG Therapeutics, and Verastem; has received research funding from Gilead, Loxo, Sun, and Verastem; and has served on data safety monitoring committees for MorphoSys and Invectys. S.O. has been in a consulting role for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie, Alexion, Verastem, and Eisai; has received research funding from Kite, Regeneron, and Acerta; and has been in a consulting role and received research funding from Gilead, Pharmacyclics LLC, an AbbVie Company, TG Therapeutics, Pfizer, and Sunesis. J.C.Ba. has received honoraria from Janssen; has been in a consulting role for Genentech, Gilead, Bayer, Pharmacyclics LLC, an AbbVie Company, AbbVie, AstraZeneca, and Sandoz; and has received research funding from Pharmacyclics LLC, an AbbVie Company, Oncternal Therapeutics, and AbbVie. P.M.B. has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, and AbbVie, and has received research funding from Pharmacyclics LLC, an AbbVie Company. N.M.R. has received honoraria from and has been in a consulting role for Bristol-Myers Squibb (BMS), Genentech, AbbVie, Gilead, AstraZeneca, and Celgene; has received research funding from BMS and Merck; and has been a paid speaker for Gilead and Celgene. S.C. has received honoraria from Pharmacyclics LLC, an AbbVie Company, and Janssen; has been in a consulting role for AbbVie, Celgene, Genentech, Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Astellas, and AstraZeneca; has received research funding from AbbVie, Acerta, Celgene, Gilead, Janssen, Pharmacyclics LLC, an AbbVie Company, and Takeda; has provided expert testimony for Genentech; has received travel, accommodations and other expenses from AbbVie, BeiGene, Celgene, Genentech, Janssen, and Pharmacyclics LLC, an AbbVie Company; and has other relationships with BeiGene. C.S.T. has received honoraria from Janssen and Pharmacyclics LLC, an AbbVie Company, and research funding from Janssen. S.P.M. has received honoraria from and has been in a consulting role for Roche, AbbVie, Janssen, Gilead, and GlaxoSmithKline; has received research funding from Roche, AbbVie, and Janssen; and has been a paid speaker for Roche, AbbVie, Janssen, and Gilead. U.J. has received honoraria and research funding from Janssen, and has been in a consulting role for Janssen. T.J.K. has been in a consulting role for AbbVie, Genentech-Roche, Gilead, Pharmacyclics LLC, an AbbVie Company, and Celgene and has received research funding from AbbVie, Genentech-Roche, Pharmacyclics LLC, an AbbVie Company, and Oncternal. C.M. has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, Janssen, and AbbVie. M.M. has received honoraria from and has been in a consulting role for AbbVie, Janssen, Gilead, Roche, and AstraZeneca; has been a paid speaker for AbbVie, Janssen, and Gilead; has received research funding from Roche; and has received travel, accommodations, and expenses reimbursement from AbbVie, Janssen, and AstraZeneca. J.A.B. has received honoraria from Janssen; has been in a consulting role for Janssen; has received research funding from Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, and BeiGene; has been a paid speaker for Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen; and has received travel, accommodations, and expenses reimbursement from Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen. J.C.By. has been in consulting role for Janssen; has reported research funding from Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, and BeiGene; and has been a paid speaker for Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, and Janssen; and received travel, accommodations, and expenses reimbursement from Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, and TG Therapeutics. P.H. has received honoraria from, has been in a consulting role for and has received research funding from Janssen, Pharmacyclics LLC, an AbbVie Company, and AbbVie; and has received travel, accommodations, and expenses reimbursement from Janssen and AbbVie. S.D. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie, Celgene, Gilead, GlaxoSmithKline, and Exelixis. A.S. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie. J.P.D. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie and was formerly employed by and owned stock in CTI BioPharma. J.W. has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, and Janssen; and has received research funding from Pharmacyclics LLC, an AbbVie Company, Janssen, AbbVie, Morphosys, Karyopharm, and Loxo. Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

To evaluate the effect of different thicknesses of CAD-CAM ceramic sections on the polymerization of two different resin cements.Three CAD-CAM all-ceramic restorative materials were sectioned with four different thicknesses. A total of 240 resin cement specimens were prepared from light cured and dual cure resin cements and absorption peaks were recorded. 10 samples of each resin cement were examined before and after polymerization and served as the control group. Data were analyzed using one-way ANOVA, independent t- and Tukey HSD tests (P0.05).Control group showed the highest DOC values while samples cured under Vita Enamic section with a thickness of 2 mm presented the lowest values (P0.05). Polymerization performed under sections of 0.5 and 1 mm thicknesses provided statistically higher values. Dual cured resin cement samples showed higher DOC values compared to light cured resin cement samples. IPS Empress CAD sections with 0.5 and 1 mm thickness exhibited statistically higher values than other ceramics of the same thickness for light cured resin cement samples. A significant difference was observed between IPS Empress CAD and Vita Enamic while comparing ceramic sections of the same thickness (P0.05). There was no difference for sections of 1.5 and 2 mm (P0.05).Thickness of the restorative material for an indirect restoration is a key element to determine the type of resin cement.

Background Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Achieving minimal residual disease (MRD) negativity in CLL is an independent predictor of survival even with a variety of different treatment approaches and regardless of the line of therapy. Methods/design GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) is a seamless phase II/III, multi-centre, randomised, controlled, open, parallel-group trial for patients with CLL who have recently responded to chemotherapy. Participants will be randomised to receive either obinutuzumab (GA-101) consolidation or no treatment (as is standard). The phase II trial will assess safety and short-term efficacy in order to advise on continuation to a phase III trial. The primary objective for phase III is to assess the effect of consolidation therapy on progression-free survival (PFS). One hundred eighty-eight participants are planned to be recruited from forty research centres in the United Kingdom. Discussion There is evidence that achieving MRD eradication with alemtuzumab consolidation is associated with improvements in survival and time to progression. This trial will assess whether obinutuzumab is safe in a consolidation setting and effective at eradicating MRD and improving PFS. Trial registration ISRCTN, 64035629. Registered on 12 January 2015. EudraCT, 2014-000880-42. Registered on 12 November 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2107-0) contains supplementary material, which is available to authorized users.

Oblasti koje proučava doktorska disertacija su web programiranje i baze podataka, sa posebnim osvrtom na upravljanje, arhiviranje i pretraživanje sistema arhiviranja na internetu, koristeći različite tehnologije prenosa podataka. Osnovna suština rada je ustanoviti koji način pakovanja podataka je optimalan, uzimajući u obzir složenost koda na strani servera i klijenta, realizacijom klijent-server modela baziranog na troslojnoj arhitekturi. U disertaciji su analizirane web, web2.0, iznad web2.0 i desktop aplikacije. Radna aplikacija omogućava skladištenje podataka na strani servera, pristupajući tim podacima, koristeći različite načine formatiranja podataka, i operacija koje se primenjuju nad njima. Efekat modela je prezentiran na RIA aplikaciji. Aplikacija tipa klijent-server, bazirana na platformi Wampserver2.4-x86, realizovana u PHP/MySQL okruženju, ispunjava sve uslove troslojne veb platforme, i njen rad ne zavisi od operativnog sistema, kao ni od hardverske strukture računara. Dobijeni rezultati istraživanja se mogu podeliti u tri dela. U prvoj grupi istraživanja rezultati se odnose na različite tehnologije prenosa podataka, analizu različitih tipova aplikacija i sagledavanju zauzetosti memorije i procesora u zavisnosti od interakcije korisnika sa radnom aplikacijom. Drugu grupu čine rezultati koji predstavljaju primenu različitih tehnologija prenosa podataka. U radu je prezentirano nekoliko primera za izračunavanje različitih tehnologija prenosa podataka. U trećoj grupi su rezultati, koji opisuju primenu datog modela, na prenos podataka. Disertacija je podeljena u šest glava koje su podijeljene na poglavlja i dalje poglavlja na odeljke. U sekcijama su izneti alati, načini funkcionisanja, prednosti i mane pojedinih aplikacija.

Background Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). Methods/design FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. Discussion The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. Trial registration ISRCTN01844152. Registered on 8 August 2014, EudraCT number 2013-001944-76. Registered on 26 April 2013.