•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of marginal zone lymphomas.•Authorship includes a multidisciplinary group of experts from different ...institutions and countries in Europe and abroad.•A summary of recommendations is provided, including levels of evidence and grades of recommendation where applicable.•The distinct disease entities (i.e. extranodal, nodal and splenic marginal zone lymphomas) are discussed separately.•Organ-specific peculiarities are addressed in the recommendations for extranodal marginal zone lymphomas (MALT lymphomas).
The discovery of almost identical or 'stereotyped' B-cell receptor immunoglobulins (BcR IG) among unrelated patients with chronic lymphocytic leukemia (CLL) cemented the idea of antigen selection in ...disease ontogeny and evolution. The systematic analysis of the stereotypy phenomenon in CLL revealed that around one-third of CLL patients may be grouped into subsets based on shared sequence motifs within the variable heavy complementarity determining region 3. Stereotyped subsets display a strikingly similar biology of the leukemic clones, referring to many different levels, from the immunogenetic and genetic and extending to the epigenetic and functional levels. Even more importantly, the homogeneity of stereotyped subsets has clinical consequences as patients assigned to the same stereotyped subset generally exhibit an overall similar disease course and outcome. In other words, stereotypy-based patient classification of CLL has already provided a more compartmentalized view of this otherwise heterogeneous disease and can assist in refining prognostication models. While this is relevant only for the one-third of cases expressing stereotyped BcR IG; in principle, however, the findings from further analysis of the stereotyped subsets may also contribute towards improved understanding of the remaining non-stereotyped fraction of CLL patients.
The remarkable clinical heterogeneity in chronic lymphocytic leukaemia (CLL) has highlighted the need for prognostic and predictive algorithms that can be employed in clinical practice to assist ...patient management and therapy decisions. Over the last 20 years, this research field has been rewarding and many novel prognostic factors have been identified, especially at the molecular genetic level. Whilst detection of recurrent cytogenetic aberrations and determination of the immunoglobulin heavy variable gene somatic hypermutation status have an established role in outcome prediction, next‐generation sequencing has recently revealed novel mutated genes with clinical relevance (e.g. NOTCH1, SF3B1 and BIRC3). Efforts have been made to combine variables into prognostic indices; however, none has been universally adopted. Although a unifying model for all groups of patients and in all situations is appealing, this may prove difficult to attain. Alternatively, focused efforts on patient subgroups in the same clinical context and at certain clinically relevant ‘decision points’, that is at diagnosis and at initiation of first‐line or subsequent treatments, may provide a more accurate approach. In this review, we discuss the advantages and disadvantages as well as the clinical applicability of three recently proposed prognostic models, the MD Anderson nomogram, the integrated cytogenetic and mutational model and the CLL‐international prognostic index. We also consider future directions taking into account novel aspects of the disease, such as the tumour microenvironment and the dynamics of (sub)clonal evolution. These aspects are particularly relevant in view of the increasing number of new targeted therapies that have recently emerged.
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Several studies suggest that immune‐mediated pathways are important in the pathogenesis of chronic lymphocytic leukaemia (CLL). The in vivo accumulation of leukaemic lymphocytes is facilitated by ...interactions of CLL cells with other cells and soluble factors that probably occur more often within the microenvironment through classical receptor–ligand interactions. These include CD40L–CD40 and chemokine–chemokine receptor interactions as well as B cell receptor (BCR) engagement by (auto)antigens. Indeed, the categorizations of CLL patients based on immunoglobulin heavy variable (IGHV) gene mutations and structure of the clone’s BCR suggest that CLL patient outcome could be a reflection of ongoing BCR signalling in the context of other co‐signals.
The algorithm behind particle methods is extremely versatile and used in a variety of applications that range from molecular dynamics to astrophysics. For continuum mechanics applications, the ...concept of 'particle' can be generalized to include discrete portions of solid and liquid matter. This study shows that it is possible to further extend the concept of 'particle' to include artificial neurons used in Artificial Intelligence. This produces a new class of computational methods based on 'particle-neuron duals' that combines the ability of computational particles to model physical systems and the ability of artificial neurons to learn from data. The method is validated with a multiphysics model of the intestine that autonomously learns how to coordinate its contractions to propel the luminal content forward (peristalsis). Training is achieved with Deep Reinforcement Learning. The particle-neuron duality has the advantage of extending particle methods to systems where the underlying physics is only partially known, but we have observations that allow us to empirically describe the missing features in terms of reward function. During the simulation, the model evolves autonomously adapting its response to the available observations, while remaining consistent with the known physics of the system.
Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL ...and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.
The performance of colon-targeted solid dosage forms is commonly assessed using standardised pharmacopeial dissolution apparatuses like the USP II or the miniaturised replica, the mini-USP II. ...However, these fail to replicate the hydrodynamics and shear stresses in the colonic environment, which is crucial for the tablet's drug release process. In this work, computer simulations are used to create a digital twin of a dissolution apparatus and to develop a method to create a digital twin of a tablet that behaves realistically. These models are used to investigate the drug release profiles and shear rates acting on a tablet at different paddle speeds in the mini-USP II and biorelevant colon models to understand how the mini-USP II can be operated to achieve more realistic (i.e., in vivo) hydrodynamic conditions.
The behaviour of the tablet and the motility patterns used in the simulations are derived from experimental and in vivo data, respectively, to obtain profound insights into the tablet's disintegration/drug release processes. We recommend an “on-off” operating mode in the mini-USP II to generate shear rate peaks, which would better reflect the in vivo conditions of the human colon instead of constant paddle speed.
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