Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural ...abnormalities) or high-CK (CK with ≥5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter real-life retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, and TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q- /TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (P<0.0001). We herein demonstrate that CK landscape at CLL diagnosis allows the risk of RS transformation to be refined and we recapitulated clinico-biological variables into a prognostic model.
In the advanced field of Information and Communication Technology (ICT) within modern corporate frameworks, the pressing issue of non-compliance becomes increasingly crucial. Achieving the ideal ...balance—where one fosters consistent employee commitment without resorting to overly harsh penalties for possible violations—presents a complex problem. Such a nuanced relationship calls for a synchronized coordination among the company’s underlying factors, the principles of the Information Security Plan (ISP), and overarching compliance mandates. As companies step into a period where digital environments are in constant flux, the importance of securing information systems rises to a critical level. Against this backdrop, compliance stands out as a vital component, functioning as a stringent safeguard in the ongoing mission to protect precious digital assets—a mission comprehensively detailed within the ISP. This in-depth academic study sets out to rigorously explore and scrutinize the diverse opinions and beliefs of committed employees and insightful management concerning unwavering company alignment with the ISP. This is accomplished by defining a construct that centers on key dimensions: Organizational Culture, Personal Attitudes, Actors, Behavioral Intentions, and Motivational Dynamics. Eleven Hypotheses are outlined and represent the materialisation of the model. This model form a starting point from which future empirical exploration will be able to take place, propelling us towards a deeper understanding of the phenomena under scrutiny.
Received: 15 September 2023 / Accepted: 23 October 2023 / Published: 5 November 2023
Multiple myeloma (MM) is a genetically heterogeneous disease, in which the process of tumorigenesis begins and progresses through the appearance and accumulation of a tangle of genomic aberrations. ...Several are the mechanisms of DNA damage in MM, varying from single nucleotide substitutions to complex genomic events. The timing of appearance of aberrations is well studied due to the natural history of the disease, that usually progress from pre-malignant to malignant phase. Different kinds of aberrations carry different prognostic significance and have been associated with drug resistance in some studies. Certain genetic events are well known to be associated with prognosis and are incorporated in risk evaluation in MM at diagnosis in the revised International Scoring System (R-ISS). The significance of some other aberrations needs to be further explained. Since now, few phase 3 randomized trials included analysis on patient's outcomes according to genetic risk, and further studies are needed to obtain useful data to stratify the choice of initial and subsequent treatment in MM.
In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations.
We ...performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression. The genomic DNA from peripheral blood samples of 200 consecutive CLL patients was analyzed using Ion Torrent Personal Genome Machine, a NGS platform that uses semiconductor sequencing technology. Karyotype analysis was performed using efficient mitogens.
Mutations were detected in 42.0 % of cases with 42.8 % of mutated patients presenting 2 or more mutations. The presence of mutations by NGS was associated with unmutated IGHV gene (p = 0.009), CD38 positivity (p = 0.010), risk stratification by fluorescence in situ hybridization (FISH) (p < 0.001), and the complex karyotype (p = 0.003). A high risk as assessed by FISH analysis was associated with mutations affecting TP53 (p = 0.012), BIRC3 (p = 0.003), and FBXW7 (p = 0.003) while the complex karyotype was significantly associated with TP53, ATM, and MYD88 mutations (p = 0.003, 0.018, and 0.001, respectively). By multivariate analysis, the multi-hit profile (≥2 mutations by NGS) was independently associated with a shorter time to first treatment (p = 0.004) along with TP53 disruption (p = 0.040), IGHV unmutated status (p < 0.001), and advanced stage (p < 0.001). Advanced stage (p = 0.010), TP53 disruption (p < 0.001), IGHV unmutated status (p = 0.020), and the complex karyotype (p = 0.007) were independently associated with a shorter overall survival.
At diagnosis, an extensive biologic characterization including NGS and karyotype analyses using novel mitogens may offer new perspectives for a better refinement of risk stratification that could be of help in the clinical management of CLL patients.
Abstract Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome characterized by ineffective T-cell and NK response. We report the clinical course of a patient with relapsed CLL who developed ...acute symptoms soon after starting ibrutinib. Hyperpyrexia, splenomegaly, hyperferritinemia, hypertriglyceridemia, cytopenias, and a typical cytokine pattern, i.e. high interleukin (IL)−6, IL10 and IL18, were consistent with a diagnosis of HLH. Coexistent Epstein Barr virus reactivation was documented. Ibrutinib-induced impairment of NK degranulation, associated with EBV reactivation and CLL-related immunodeficiency may have contributed to the development of HLH in our patient.
n.b. The error described below was mistakenly carried forward by the production team handling this article, and thus was not the fault of the authors. The original version of this article 1 had a ...duplication of Fig. 1 in place of where Fig. 2 should have been, resulting in two displays of Fig. 1 and the absence of Fig. 2. The article has now been updated to remove the duplicate of Fig. 1 and to insert the correct Fig. 2 into its appropriate place. The two figures in question can be seen below. https://static-content.springer.com/image/art%3A10.1186%2Fs13045-016-0331-9/MediaObjects/13045_2016_331_Fig1_HTML.gif Fig. 1 Gene mutations and correlation with genomic features: circos diagrams illustrating pairwise co-occurrence of gene mutations with IGHV status, FISH results, and complex karyotype https://static-content.springer.com/image/art%3A10.1186%2Fs13045-016-0331-9/MediaObjects/13045_2016_331_Fig2_HTML.gif Fig. 2 TTFT according to number of mutations by NGS analysis (p < 0.001)
Chronic lymphocytic leukemia (CLL) displays an extremely variable clinical behaviour. Accurate prognostication and prediction of response to treatment are important in an era of effective first-line ...regimens and novel molecules for high risk patients. Because a plethora of prognostic biomarkers were identified, but few of them were validated by multivariable analysis in comprehensive prospective studies, we applied in this survey stringent criteria to select papers from the literature in order to identify the most reproducible prognostic/predictive markers. Each biomarker was analysed in terms of reproducibility across the different studies with respect to its impact on time to first treatment (TTFT), progression free survival (PFS), overall survival (OS) and response to treatment. We were able to identify the following biomarkers as the most reliable in guiding risk stratification in the daily clinical practice: 17p-/
mutations,
unmutated configuration, short telomeres and 11q-. However, the method for measuring telomere length was not validated yet and 11q- was predictive of inferior OS only in those patients who did not receive FCR-like combinations. Stage and lymphocytosis were predictive of shorter TTFT and age, high serum thymidine kinase levels and poor performance status were predictive of shorter OS. Using our criteria no parameter was found to independently predict for inferior response to treatment.
Abstract
In this article, we carry out an overview on the management options available for chronic lymphocytic leukemia (CLL) patients and discuss possible treatment decisions, taking into account ...the issue of sustainability and availability. Targeted agents have shown to be superior compared with chemoimmunotherapy (CIT) in terms of progression-free survival in high-risk CLL. In the majority of studies, however, continuous treatment was compared with fixed-duration CIT and no overall survival or progression-free survival-2 (time from randomization to second progression or death) advantage could be documented. Meanwhile, a substantial financial burden on both patients and payers has raised issues about affordability and adherence to treatment. Therefore, value-based pricing of new drugs has been used to set up price negotiation policies in several countries, and fixed-duration therapy has shown to be less costly than continuous treatment. Thus, CIT continues to have a role in the treatment of CLL patients with a favorable genetic profile, that is, with a mutated
IGHV
gene profile and a wild-type
TP53
. Targeted treatment represents the preferred choice in patients with an unmutated
IGHV
gene configuration and/or a
TP53
disruption, provided that adherence to treatment is guaranteed and bearing in mind that should costly drugs not be available for frontline treatment, new agents can be very effective as first salvage treatment.
PDF
