296 research outputs found

    Minor head injury in anticoagulated patients: Outcomes and analysis of clinical predictors. A prospective study

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    Background: The optimal management of patients taking oral anticoagulants who experience minor head injury (MHI) is unclear. The availability of validated protocols and reliable predictors of prognosis would be of great benefit. We investigated clinical factors as predictors of clinical outcomes and intracranial injury (ICI). Methods: We conducted a single-cohort, prospective, observational study in an ED. Our structured clinical pathway included a first head CT scan, 24 h observation and a second CT scan. The primary outcome was the occurrence of MHI-related death or re-admission to ED at day +30. The secondary outcome was the rate of delayed ICI (dICI), defined as second positive CT scan after a first negative CT scan. We assessed some clinical predictors derived from guidelines and clinical prediction rules as potential risk factors for the outcomes. Results: 450 patients with a negative first CT scan who underwent a second CT scan composed our 'study population'. The rate of the primary outcome was 4%. The rate of the secondary outcome was 4.7%. Upon univariate and multivariate analysis no statistically significant predictors for the outcomes were found. Conclusions: Previous retrospective studies showed a lot of negative predictive factors for anticoagulated patients suffering a minor head injury. In our prospective study no clinical factors emerged as predictors of poor clinical outcomes and dICI. So, even if we confirmed a low rate of adverse outcomes, the best management of these patients in ED remains not so clear and future trials are needed

    Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia

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    Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc <= 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question

    Postnatal and postweaning endocrine setting in dairy calves through hair cortisol, dehydroepiandrosterone and dehydroepiandrosterone sulphate

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    Importance of the work: The care of calves on dairy farms between birth and weaning can improve their long-term development and growth. In fact, a poor newborn health status and a high allostatic load may adversely affect development in dairy cows. To determine cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEA-S) individually is useful for an understanding of the individual state, being biomarkers of hypothalamic-pituitary-adrenal (HPA) axis activity. Objectives: As a preliminary study, to investigate the hair concentrations of cortisol, DHEA, DHEA-S and their ratios in dairy calves in two key periods of their growth characterized by considerable environmental changes. Materials & Methods: Hair sampling was conducted on clinically healthy dairy calves during the postnatal period at age 64.8±0.65 d (POP; mean±standard error; n = 73) and during the postweaning period at age 155.3±0.85 d (PWP, n = 62). The hair hormone concentrations were measured using a radioimmunoassay. Results: Hair cortisol concentrations were higher in the POP than in the PWP. Furthermore, the cortisol:DHEA and cortisol:DHEA-S ratios were higher in the first period of evaluation, showing a higher animal allostatic load at birth. Main finding: Identification was achieved non-invasively of calves with a high allostatic load through biomarkers of HPA axis activity. The evaluation of this activity is very important given its influence on many biological processes, such as energy balance, development of the reproductive system and immune response

    Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia.

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    Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≀ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question

    Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

    No full text
    Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed \u201csatellites,\u201d were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: \u2022 In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. \u2022 Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified

    Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group

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    48nononeBecause 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 < 0.01). Treatment breaks ≄14 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real-life analysis showed that IR treatment duration was longer at experienced centers, that the ECOG PS and ≄3 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial.noneRigolin G.M.; Cavazzini F.; Piciocchi A.; Arena V.; Visentin A.; Reda G.; Zamprogna G.; Cibien F.; Vitagliano O.; Coscia M.; Farina L.; Gaidano G.; Murru R.; Varettoni M.; Paolini R.; Sportoletti P.; Pietrasanta D.; Molinari A.L.; Quaglia F.M.; Laurenti L.; Marasca R.; Marchetti M.; Mauro F.R.; Crea E.; Vignetti M.; Gentile M.; Montillo M.; Foa R.; Cuneo A.; Chiarenza A.; Perbellini O.; Mannina D.; Sancetta R.; Olivieri A.; Molica S.; Pane F.; Patti C.; Iliariucci F.; Gozzetti A.; Califano C.; Galieni P.; Augello A.F.; Vallisa D.; Cura F.; Frustaci A.M.; Fazi P.; Trentin L.; Ferrara F.Rigolin, G. M.; Cavazzini, F.; Piciocchi, A.; Arena, V.; Visentin, A.; Reda, G.; Zamprogna, G.; Cibien, F.; Vitagliano, O.; Coscia, M.; Farina, L.; Gaidano, G.; Murru, R.; Varettoni, M.; Paolini, R.; Sportoletti, P.; Pietrasanta, D.; Molinari, A. L.; Quaglia, F. M.; Laurenti, L.; Marasca, R.; Marchetti, M.; Mauro, F. R.; Crea, E.; Vignetti, M.; Gentile, M.; Montillo, M.; Foa, R.; Cuneo, A.; Chiarenza, A.; Perbellini, O.; Mannina, D.; Sancetta, R.; Olivieri, A.; Molica, S.; Pane, F.; Patti, C.; Iliariucci, F.; Gozzetti, A.; Califano, C.; Galieni, P.; Augello, A. F.; Vallisa, D.; Cura, F.; Frustaci, A. M.; Fazi, P.; Trentin, L.; Ferrara, F

    EFFICACY OF IDELALISIB AND RITUXIMAB IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA TREATED OUTSIDE OF CLINICAL TRIALS. A REPORT OF THE GIMEMA WORKING GROUP

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    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 centres. Median progression-free survival (PFS) and overall survival were 22.9 and 44.5-months, respectively; performance status (PS) 652 and 653 previous lines of therapy were associated with shorter PFS and OS. 48% of patients were on treatment at 12 months; the experience of the centres ( 655 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 ORR 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<0.01). Treatment breaks 6514 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real-life analysis showed that IR treatment duration was longer at experienced centres, that the ECOG-PS and 653 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial. This article is protected by copyright. All rights reserved

    Final analysis from RESONATE : Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma

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    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)

    Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

    No full text
    Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: ‱ In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. ‱ Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified. © 2021 American Society of Hematolog
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