Key processes in the onset and evolution of chronic lymphocytic leukemia (CLL) are thought to include chronic (antigenic) activation of mature B cells through the B cell receptor (BcR), signals from ...the microenvironment, and acquisition of genetic alterations. Here we describe three families in which two or more siblings were affected by CLL. We investigated whether there are immunogenetic similarities in the leukemia-specific immunoglobulin heavy (IGH) and light (IGL/IGK) chain gene rearrangements of the siblings in each family. Furthermore, we performed array analysis to study if similarities in CLL-associated chromosomal aberrations are present within each family and screened for somatic mutations using paired tumor/normal whole-genome sequencing (WGS). In two families a consistent IGHV gene mutational status (one IGHV-unmutated, one IGHV-mutated) was observed. Intriguingly, the third family with four affected siblings was characterized by usage of the lambda IGLV3-21 gene, with the hallmark R110 mutation of the recently described clinically aggressive IGLV3-21
R110
subset. In this family, the CLL-specific rearrangements in two siblings could be assigned to either stereotyped subset #2 or the immunogenetically related subset #169, both of which belong to the broader IGLV3-21
R110
subgroup. Consistent patterns of cytogenetic aberrations were encountered in all three families. Furthermore, the CLL clones carried somatic mutations previously associated with IGHV mutational status, cytogenetic aberrations and stereotyped subsets, respectively. From these findings, we conclude that similarities in immunogenetic characteristics in familial CLL, in combination with genetic aberrations acquired, point towards shared underlying mechanisms behind CLL development within each family.
Chronic Pain Management for the Hospitalized Patient equips clinicians to provide safe and effective management of hospitalized patients with co-existing chronic pain. It provides a comprehensive ...practical guide to pain physiology, opioid and non-opioid management, pain prevention strategies, special considerations for disease states, surgical conditions, and special populations.
Inadequately treated acute pain is a global healthcare problem that causes significant patient suffering and disability, risk of chronicity, increased resource utilization, and escalating healthcare ...costs. Compounding the problem is the lack of adequate instruction in acute pain management available in medical schools worldwide. Incorporating acute pain diagnosis and management as an integral part of the medical school curriculum will allow physicians to develop a more comprehensive, compassionate approach to treating patients with acute pain syndromes and should be considered a healthcare imperative. In this article, we review the current status of pain education in educational institutions across the world, focusing on achievements, lacunae, and inadequacies. We appeal to all concerned—pain management specialists, health educators, and policymakers—to consider incorporating education on acute pain and its management at undergraduate medical levels in an integrated manner.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel ...techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed.
The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact.
Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care.
https://doi.org/10.1186/ISRCTN66987142, identifier ISRCTN66987142.
Chronic myeloid leukemia (CML) is characterized in the majority of cases by a t(9;22)(q34;q11) translocation, also called the Philadelphia chromosome, giving rise to the BCR-ABL1 fusion protein. ...Current treatment with tyrosine kinase inhibitors is directed against the constitutively active ABL1 domain of the fusion protein, and minimal residual disease (MRD) after therapy is monitored by real-time quantitative PCR (RQ-PCR) of the fusion transcript. Here, we describe a novel approach to detect and enumerate cells positive for the BCR-ABL1 fusion protein by combining the in situ proximity ligation assay with flow cytometry as readout (PLA-flow). By targeting of the BCR and ABL1 parts of the fusion protein with one antibody each, and creating strong fluorescent signals through rolling circle amplification, PLA-flow allowed sensitive detection of cells positive for the BCR-ABL1 fusion at frequencies as low as one in 10,000. Importantly, the flow cytometric results correlated strongly to those of RQ-PCR, both in diagnostic testing and for MRD measurements over time. In summary, we believe this flow cytometry-based method can serve as an attractive approach for routine measurement of cells harboring BCR-ABL1 fusions, also allowing simultaneously assessment of other cell surface markers as well as sensitive longitudinal follow-up.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Continuous peripheral nerve block (CPNB) success is largely dependent on placement of the catheter close enough to the nerve to allow effective and sustained analgesia following painful surgeries ...with a minimum volume of local anesthetic. One of the most common problems associated with CPNB involves accurate placement of the catheter tip, migration, and dislodgement of the catheter. This is of increasing importance now that catheters are left in place for prolonged periods of time to provide postoperative analgesia, and patients with peripheral nerve catheters are being discharged home with ambulatory pumps. In response to the challenges of providing safe, effective, and consistently reliable analgesia, research and development in this field is expanding rapidly. This review article presents results from recent publications addressing the subject of peripheral nerve catheter localization.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Diffuse large B-cell lymphoma (DLBCL) has been shown to be comprised of at least two prognostic entities, depending on its resemblance to normal germinal center or activated B cells, using global ...gene expression profiling. Also, the expression patterns of bcl-6, CD10 and IRF-4 (also known as MUM1) have been suggested as alternative means of identifying the germinal- and nongerminal center (activated B-cell like) groups. In the present study, we evaluated by immunohistochemistry the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 in a large material of 161 DLBCL patients. Using two different approaches, patients with germinal center phenotype displayed a significantly better survival than the nongerminal center group. Positive staining for bcl-6 or CD10 predicted for superior survival, while expression of IRF-4 alone showed no association with prognosis. Furthermore, expression of bcl-2 was associated with worse event-free survival and overall survival. In a multivariate analysis, a high international prognostic index score (3–5), non-GC phenotype and bcl-2 were independent adverse prognostic factors. Here we confirm the prognostic importance of determining the germinal- or nongerminal center phenotype in patients with DLBCL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The immunoglobulin variable heavy chain (IgVH) gene mutation status is an important prognostic factor in chronic lymphocytic leukemia (CLL), since cases with mutated VH genes show significantly ...longer survival than unmutated cases. Recently, we reported a preferential use of the VH3-21 gene in mutated CLL and showed that mutated VH3-21 cases had an inferior overall survival compared with other mutated CLL. In order to further characterize this subset, we performed VH gene analysis in 265 CLL cases and identified 31 VH3-21 cases (11.7%); 21 cases had mutated and 10 cases unmutated VH genes. Regardless of VH gene mutation status, a poor overall survival was found in the VH3-21 cases with a median survival of 83 months. These survival data confirm that VH3-21 cases do not fit into the general prognostic grouping of mutated and unmutated CLL. A large fraction of VH3-21 cases also demonstrated unique features with shorter lengths of the third complementarity determining region (CDR3) and CDR3s with highly homologous amino acid sequences. Furthermore, the VH3-21 cases showed a striking dominance of λ light chain expression, and analysis of the Igλ gene rearrangements revealed highly restricted use of the Vλ2-14/Jλ3 genes in the majority of cases. Taken together, our new findings strengthen the suggestion that VH3-21–using cases comprise a new CLL entity, irrespective of VH gene mutation status, and implicate that a common antigen epitope, perhaps of pathogenic significance, is recognized by the highly homologous VH3-21/Vλ2-14 Ig molecules expressed in individual tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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