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St.George Healthcare Group

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Leukemia - Mr Validity [NEW]


Several recent studies have characterized the molecular and genetic makeup of ETP-ALL/LBL.6,11,12,26 Several mutations that are common in acute myeloid leukemia such as FLT3 internal tandem duplication, FLT3 D835, and IDH1/IDH2 have been described in patients with ETP-ALL/LBL.26 This is not unexpected given that ETP cells are early hematopoietic stem cell derivatives that retain myeloid potential. These mutations are clinically actionable and thereby can provide a treatment strategy for a subset of patients with ETP-ALL/LBL. Chonghaile et al recently reported that ETP-ALL/LBL is dependent on Bcl2 and therefore Bcl2 antagonists such as ABT-199 may offer a potential therapeutic strategy.27,28 Maude et al reported aberrant activation of the Janus kinase/signal transducer and activator of transcription pathway in ETP-ALL/LBL and showed in vivo efficacy of the Jak2 inhibitor ruxolitinib.29




leukemia - Mr Validity



Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care.


Dexamethasone, a highly effective drug for the treatment of pediatric acute lymphoblastic leukemia (ALL) [1,2,3], can induce serious neurobehavioral side effects. These side effects are experienced as particularly detrimental to health-related quality of life (HRQoL) by patients and parents [4]. Recent studies emphasize that the mineralocorticoid receptor (MR) in the brain plays an important role in the regulation of mood, behavior and sleep [5, 6]. Both the glucocorticoid receptor (GR) and MR are important for the binding of endo- and exogenous glucocorticoids [5]. In animals as well as humans it has been shown that the MR plays an important role in behavior, cognition and psychiatric diseases [6,7,8,9,10,11]. Besides MR expression in the brain, cortisol affinity and MR:GR balance are thought to be associated with behavior. It has been shown, that the MR has a tenfold greater affinity for endogenous cortisol than the GR [12]. Synthetic glucocorticoids mostly have the GR as their therapeutic target: dexamethasone has a high potency to activate GRs, but does not bind MRs [13]. In patients treated with glucocorticoids the production of endogenous cortisol is suppressed. Therefore, in patients treated with high doses dexamethasone, the hypothesis is that the GR in the brain is stimulated, whereas the MR is underactivated. The disturbance of this GR:MR balance conceivably deregulates the stress-system and enhances vulnerability to stress-related problems [5].


Researchers are faced with the challenge of evaluating the MR evidence, filtering this information and deriving valid inferences. The continuously increasing amount of new scientific information coupled with the fact that two of the three MR assumptions (b and c) cannot be confirmed empirically further complicates this cumbersome task. Furthermore, the field of evaluating MR associations is rapidly evolving [6, 7]. The investigation and assessment of the potential violations of the MR assumptions, especially in the case of multiple instruments, is a key step towards a valid inference and a robust interpretation of potential causal associations. Several sensitivity analyses have been proposed that address the validity of these assumptions, and the results from MR studies that do not use them should be viewed as incomplete [8].


In this large systematic overview, we searched and mapped current literature evaluating the association of 852 distinct genetically predicted risk factors across 16 broad exposure categories in relation to 21 cancer sites and their subtypes by evaluating the results of 190 publications and over 4600 MR associations. Using a set of clear, comprehensive and easily replicable criteria to evaluate the validity of the reported associations, we found that less than 90 of the reported MR analyses presented robust evidence for causality and that the vast majority of the analyses did not perform sensitivity analyses, at least with regard to MR-Egger, WM, MRPRESSO, and MVMR. Most of the MR analyses supported by robust evidence were observed for anthropometric indices, steroid hormones, telomere length, and lipids.


We are not faced with a situation involving a harm that could not reasonably be known to have been caused by exposure to a toxic substance within the relevant ninety days. It can hardly be disputed that it has long been scientifically known that radiation exposure causes leukemia. Therefore, unlike our concurring colleague, we see no need to reach an issue that is not presented by the facts of this case.


In response to my separate opinion, my colleagues have added footnote 1 to the opinion of the Court. It makes the limited scope of that opinion clear beyond peradventure, and hence, as they quite correctly note, renders my concurrence not strictly necessary. I welcome that footnote. But having spent some time figuring out why our decision in this leukemia case does not have implications for the application of the ninety-day notice provision in situations in which the causal connection between the alleged tort and the injury is not scientifically known at the time of the exposure, I see no harm in sharing that analysis.


Relapsed pediatric B-acute lymphoblastic leukemia (B-ALL) remains as the leading cause of cancer death among children. Other than stem cell transplantation and intensified chemotherapy, no other improved treatment strategies have been approved clinically. Gene expression profiling represents a powerful approach to identify potential biomarkers and new therapeutic targets for various diseases including leukemias. However, inadequate sample size in many individual experiments has failed to provide adequate study power to yield translatable findings. With the hope of getting new insights into the biological mechanisms underpinning relapsed ALL and identifying more promising biomarkers or therapeutic targets, we conducted a meta-analysis of gene expression studies involving ALL from 3 separate studies.


We identified S100A8 as the most overexpressed gene, and the cell cycle pathway as the most promising biomarker and therapeutic target for relapsed childhood B-ALL. The validity of the results warrants further investigation. 041b061a72


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