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The most frequent genetic aberration leading to infant ALL (iALL) is the chromosomal translocation t(4;11), generating the fusion oncogenes KMT2A:AFF1 and AFF1:KMT2A, respectively. KMT2A-r iALL displays a dismal prognosis through high relapse rates and relapse-associated mortality. Relapse occurs frequently despite ongoing chemotherapy and without the accumulation of secondary mutations. A rational explanation for the observed chemo-resistance and satisfactory treatment options remain to be elucidated. We found that elevated ICOSLG expression level at diagnosis was associated with inferior event free survival (EFS) in a cohort of 43 patients with t(4;-11) iALL and that a cohort of 18 patients with iALL at relapse displayed strongly increased ICOSLG expression. Furthermore, co-culturing t(4;11) ALL cells (ICOSLGhi) with primary T-cells resulted in the development of Tregs. This was impaired through treatment with a neutralizing ICOSLG antibody. These findings imply ICOSLG (1) as a relapse-predicting biomarker, and (2) as a therapeutic target involved in a potential immune evasion relapse-mechanism of infant t(4;11) ALL.

Introduction: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. Methods: In this study, we performed a genomic analysis of diagnosis–relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. Results: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. Conclusion: Comprehensive genomic characterization of diagnosis–relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.

In this work temperature inhomogeneities and their influence on PEMWE performance of industrial-scale stacks are investigated. Three temperature differences are examined: (i) between the inlet and outlet, (ii) in-between the cells of a stack, (iii) between the cell’s solid materials and the fluids. A validated stack model for temperature and performance is presented which is used to quantify the above-mentioned temperature fields and their influences on current density distribution and cell voltages. For a chosen scenario, with current densities of 2.0 A cm−2, fluid inlet temperatures of 60 °C and flow-rates of 0.15 kg s−1m−2, peak temperature differences amount to 8.2 K along-the-channel. This relates to inhomogeneities of current density of up to 10% inside a cell and deviations of cell voltage of 9 mV in-between cells in the center of the stack and outer cells. For higher current densities these differences increase further. More homogeneous temperatures allow operation at elevated average temperatures without exceeding temperature limitations and reduce the spread of degradation mechanisms. Hence, homogenous profiles lead to a more hole-some utilization of electrolysis stacks. Therefore, the ability to homogenize via alternative operation such as higher flow-rate, higher pressure and altered routing of fluid-flow is analyzed.

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The availability and quality of instrumental variables (IV) are frequent concerns in empirical management research when trying to overcome endogeneity problems. For endogeneity that does not arise from sample selection, management scholars have recently started to apply the Gaussian Copula (GC) approach as an alternative to IV regression. Although the GC approach has various promising features, its limitations and usefulness in a management context are still not fully understood. We discuss the GC approach as a flexible, instrument-free approach to correct for endogeneity and examine its suitability for applied management research. We use simulations to explore the limitations and practical usefulness of the GC approach relative to ordinary least squares (OLS), IV regression, and a Higher Moments (HM) estimator by simulating the impact of different degrees of violation of the key underlying assumptions of the GC approach. We show that the GC approach can recover the true parameters remarkably well if all of its assumptions are met but that its absolute and relative performance in terms of parameter recovery and estimation precision can deteriorate quickly if these assumptions are violated. This is of particular concern as some of these assumptions are not testable and violations of them are likely in many empirical management contexts. Based on our results, we provide a series of recommendations and practical guidelines for scholars who consider using the GC approach when dealing with endogeneity.

Park and Gupta’s (2012) introduction of the Gaussian Copula (GC) approach to deal with endogeneity has made a significant impact on empirical marketing research with many papers using this approach. Recent studies have however started to explore and examine the approach and its underlying assumptions more closely, resulting in a more critical picture of it. A particular challenge is the non-testable assumption that the dependency structure between the endogenous regressor and the error term should be described by a Gaussian copula. In general, there exists a limited understanding of what this assumption implies, what causes its violation, and potential remedies. Our study addresses this explicitly. We provide a detailed discussion of the dependency structure assumption and how thresholds in the data can lead to its violation and biased results. We use real and simulated data to show how threshold detection before applying the GC approach can overcome this problem and thereby provide researchers with a useful tool to increase the likelihood of the GC approach’s assumptions being met.

Item does not contain fulltext, INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.

Analysis of immunoglobulin and T-cell receptor gene rearrangements by real-time quantitative polymerase chain reaction (RQ-PCR) is the gold standard for sensitive and accurate minimal residual disease (MRD) monitoring; it has been extensively standardized and guidelines have been developed within the EuroMRD consortium (www.euromrd.org ). However, new generations of PCR-based methods are standing out as potential alternatives to RQ-PCR, such as digital PCR technology (dPCR), the third-generation implementation of conventional PCR, which has the potential to overcome some of the limitations of RQ-PCR such as allowing the absolute quantification of nucleic acid targets without the need for a calibration curve. During the last years, droplet digital PCR (ddPCR) technology has been compared to RQ-PCR in several hematologic malignancies showing its proficiency for MRD analysis. So far, no established guidelines for ddPCR MRD analysis and data interpretation have been defined and its potential is still under investigation. However, a major standardization effort is underway within the EuroMRD consortium (www.euromrd.org ) for future application of ddPCR in standard clinical practice.

Recently, we defined “CML-like” subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000–IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.

BACKGROUND: Policymakers wishing to encourage smokers unable to quit to switch to using electronic nicotine delivery systems (ENDS) also need to consider how to deter ENDS use among non-smokers. We examined whether reduced-risk messages could increase ENDS' appeal among smokers and if increased-risk messages could decrease appeal among susceptible non-smokers, occasional and former smokers. METHODOLOGY: An online discrete choice experiment tested three attributes: information message, nicotine content (0 mg or 3 mg) and flavour (tobacco, menthol or fruit). The sample comprised 352 current smokers, 118 occasional and former smokers, and 216 ENDS-susceptible never smokers. Smokers viewed reduced-risk messages that encouraged switching to ENDS, while other groups viewed increased-risk messages that discouraged ENDS use. All groups saw a typical addiction warning. We analysed the data by estimating multinomial logit regression and adjusted latent class analysis models. RESULTS: Relative to no message, reduced risk-messages increased the appeal of ENDS uptake among one class of smokers (33.5%) but decreased appeal among other smokers. However, among all smokers, reduced-risk messages increased preference more than a dissuasive addiction warning. By contrast, among occasional or former smokers, and susceptible non-smokers, all information messages discouraging ENDS use, including an addiction warning, decreased preference relative to no message. CONCLUSIONS: On-pack relative-risk messages about ENDS could make transition more attractive to smokers while increased-risk messages could deter ENDS uptake among susceptible non-smokers, occasional and former smokers. Communicating diverse messages via discrete channels could recognise heterogeneity among and between smokers and non-smokers.