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Abstract: The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of chronic myelomonocytic leukemia (CMML). To assess its qualitative and quantitative implications for patient care, we started with 3311 established CMML cases (according to WHO 2017 criteria) and included 2130 oligomonocytosis cases fulfilling the new CMML diagnostic criteria. Applying both 2022 classification systems, 356 and 241 of oligomonocytosis cases were newly classified as myelodysplastic (MD)-CMML (WHO and ICC 2022, respectively), most of which were diagnosed as myelodysplastic syndrome (MDS) according to the WHO 2017 classification. Importantly, 1.5 times more oligomonocytosis cases were classified as CMML according to WHO 2022 than based on ICC, because of different diagnostic criteria. Genetic analyses of the newly classified CMML cases showed a distinct mutational profile with strong enrichment of MDS-typical alterations, resulting in a transcriptional subgroup separated from established MD and myeloproliferative CMML. Despite a different cytogenetic, molecular, immunophenotypic, and transcriptional landscape, no differences in overall survival were found between newly classified and established MD-CMML cases. To the best of our knowledge, this study represents the most comprehensive analysis of routine CMML cases to date, both in terms of clinical characterization and transcriptomic analysis, placing newly classified CMML cases on a disease continuum between MDS and previously established CMML., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Systemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor-independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance., (© 2021 by The American Society of Hematology.)

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., (© 2021 by The American Society of Hematology.)

Background: With research indicating some young audiences may desire to quit using JUUL, a high-nicotine e-cigarette, we sought to explore factors that may motivate them to quit., Methods: This sequential, mixed methods study included a cross-sectional online survey of college students (n = 631) followed by in-person interviews (n = 51) with survey participants. Data were collected March-April 2019. The survey asked about intention to quit using JUUL. A latent class analysis (LCA) identified participant groups who would quit for various reasons. Participants were also asked 'Can you be too old to JUUL?' during the survey. During the interviews, participants were provided preliminary survey findings and asked about their perceptions of the data. Interview participants were also asked about their expectations for future use of JUUL., Results: Four classes emerged from the LCA, indicating costs to self (i.e., harm to lungs/brain, price; 46.8%), financial costs (36.6%), all costs (e.g., social, monetary, health; 9.3%), and harm to self (7.3%) may have influenced our sample's decision to quit using JUUL. Interviewees affirmed desires to quit using JUUL, especially after leaving college. Only 27.19% of survey participants reported an age threshold for using JUUL (M = 31.8 years, SD = 10.0); however, several interviewees explained that although someone could not be too old to JUUL, it would be 'immature' or 'childish' for adults who were not trying to quit smoking to use JUUL socially., Discussion: Comprehensive tobacco control strategies such as taxing e-cigarettes, marketing campaigns, and nicotine cessation programs are needed to help nicotine dependent young adults quit using high-nicotine e-cigarettes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The diagnosis and risk stratification of multiple myeloma (MM) is based on clinical and cytogenetic tests. Magnetic CD138 enrichment followed by interphase FISH (fluorescence in situ hybridisation) is the gold standard to identify prognostic translocations and copy number alterations (CNA). Although clinical implications of gene expression profiling (GEP) or panel based sequencing results are evident, those tests have not yet reached routine clinical application. We set up a single workflow to analyse MM of 211 patients at first diagnosis by whole genome sequencing (WGS) and RNA-Seq and validate the results by FISH analysis. We observed a 96% concordance of FISH and WGS results when assessing translocations involving the IGH locus and an overall concordance of FISH and WGS of 92% when assessing CNA. WGS analysis resulted in the identification of 17 additional MYC-translocations that were missed by FISH analysis. RNA-Seq followed by supervised clustering grouped patients in their expected genetically defined subgroup and prompted the assessment of WGS data in cases that were not congruent with FISH. This allowed the identification of additional IGH-translocations and hyperdiploid cases. We show the reliability of WGS an RNA-Seq in a clinical setting, which is a prerequisite for a novel routine diagnostic test., Competing Interests: Declaration of Competing Interest The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript, (Copyright © 2020. Published by Elsevier Inc.)

Background: Canada has insufficient cardiac rehabilitation (CR) capacity, yet unmet need is unknown. Moreover, Canada has CR guidelines, but whether delivery conforms has not been characterized by province/territory. This study aimed to establish (1) CR volumes, capacity, and density, as well as (2) the nature of programs, and (3) compare these (a) by province/territory and (b) with other high-income countries (HICs)., Methods: In this cross-sectional study, an online survey was administered to CR programs globally. National cardiac associations were engaged to facilitate program identification where available, or local champions. Density was computed using Canada's Chronic Disease Surveillance System ischemic heart disease incidence estimates. Twenty-eight HICs with CR were selected for comparison (N = 619 programs), and multilevel analyses performed., Results: CR was available in 10 of 13 (76.9%) provinces (no programs in Canada's North), with 74 of 182 programs initiating a survey (40.7% response). Program volumes (median = 250) were greatest in Ontario, but ultimately there was only 1 CR spot per 4.55 patients with ischemic heart disease nationally (similar in other HICs), and 186,187 more spots are needed annually. Most programs were funded by government/hospital sources (n = 48, 66.7%), but in 23 (31.5%), patients paid some or all of program costs out-of-pocket. Guideline-indicated conditions were accepted in more than 90% of programs. Programs had a multidisciplinary team of 6.2 ± 2.1 staff, offering 7.7 ± 1.5/10 core components (varied by province, P = 0.001; return-to-work offered less frequently than other HICs; P = 0.03), over 42.0 ± 26.0 hours (provincial and other HIC differences, P < 0.001)., Conclusions: Canadian CR capacity must be augmented, but where available, services are consistent with other HICs., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Although there are sex differences in management and outcome of acute coronary syndromes (ACS), sex is not a component of Global Registry of Acute Coronary Events (GRACE) risk score (RS) for in-hospital mortality prediction. We sought to determine the prognostic utility of GRACE RS in men and women, and whether its predictive accuracy would be augmented through sex-based modification of its components., Methods: Canadian men and women enrolled in GRACE and Canadian Registry of Acute Coronary Events were stratified as ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation ACS (NSTE-ACS). GRACE RS was calculated as per original model. Discrimination and calibration were evaluated using the c-statistic and Hosmer-Lemeshow goodness-of-fit test, respectively. Multivariable logistic regression was undertaken to assess potential interactions of sex with GRACE RS components., Results: For the overall cohort (n=14,422), unadjusted in-hospital mortality rate was higher in women than men (4.5% vs. 3.0%, p<0.001). Overall, GRACE RS c-statistic and goodness-of-fit test p-value were 0.85 (95% CI 0.83-0.87) and 0.11, respectively. While the RS had excellent discrimination for all subgroups (c-statistics >0.80), discrimination was lower for women compared to men with STEMI [0.80 (0.75-0.84) vs. 0.86 (0.82-0.89), respectively, p<0.05]. The goodness-of-fit test showed good calibration for women (p=0.86), but suboptimal for men (p=0.031). No significant interaction was evident between sex and RS components (all p>0.25)., Conclusions: The GRACE RS is a valid predictor of in-hospital mortality for both men and women with ACS. The lack of interaction between sex and RS components suggests that sex-based modification is not required., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The microenvironment provides essential growth and survival signals to chronic lymphocytic leukemia (CLL) cells and contributes to their resistance to cytotoxic agents. Pharmacologic inhibition of spleen tyrosine kinase (SYK), a key mediator of B-cell receptor (BCR) signaling, induces apoptosis in primary CLL cells and prevents stroma contact-mediated cell survival. This report demonstrates a role of SYK in molecularly defined pathways that mediate the CLL-microenvironmental crosstalk independent from the BCR. Chemokine and integrin stimulation induced SYK phosphorylation, SYK-dependent Akt phosphorylation, and F-actin formation in primary CLL cells. Inhibition of SYK by 2 pharmacologic inhibitors and siRNA-knockdown abrogated downstream SYK signaling and morphologic changes induced by these stimuli. CLL cell migration toward CXCL12, the major homing attractor, and CLL cell adhesion to VCAM-1, a major integrin ligand expressed on stromal cells, were markedly reduced by SYK inhibition. In combination with fludarabine, the SYK inhibitor R406 abrogated stroma-mediated drug resistance by preventing up-regulation of the antiapoptotic factor Mcl-1 in CLL cells. SYK blockade in CLL is a promising therapeutic principle not only for its inhibition of the BCR signaling pathway, but also by inhibiting protective stroma signals in a manner entirely independent of BCR signaling.

Kindler syndrome (KS) is a rare autosomal recessive disorder characterized by skin blistering in childhood followed by photosensitivity and progressive poikiloderma. Most cases of KS result from mutations in the KIND1 gene encoding kindlin-1, a component of focal adhesions in keratinocytes. Here, we report novel and recurrent KIND1 gene mutations in nine unrelated Italian KS individuals. A novel genomic deletion of approximately 3.9 kb was identified in four patients originating from the same Italian region. This mutation deletes exons 10 and 11 from the KIND1 mRNA leading to a truncated kindlin-1. The deletion breakpoint was embedded in AluSx repeats, specifically in identical 30-bp sequences, suggesting Alu-mediated homologous recombination as the pathogenic mechanism. KIND1 haplotype analysis demonstrated that patients with this large deletion were ancestrally related. Five additional mutations were disclosed, two of which were novel. To date, four recurrent mutations have been identified in Italian patients accounting for approximately approximately 75% of KS alleles in this population. The abundance of repetitive elements in intronic regions of KIND1, together with the identification of a large deletion, suggests that genomic rearrangements could be responsible for a significant proportion of KS cases. This finding has implications for optimal KIND1 mutational screening in KS individuals.