KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone

National identity predicts public health support during a global pandemic

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics

Histopathologic assessment of hot-spot microvessel density and vascular patterns in glioblastoma: Poor observer agreement limits clinical utility as prognostic factors: a translational research project of the European Organization for Research and Treatment of Cancer Brain Tumor Group

BACKGROUND: Hot-spot microvessel density (MVD) and vascular patterns have been reported as histopathologic factors that influence prognosis in retrospective series of malignant gliomas. To investigate clinical utility, the authors systematically studied observer agreement on MVD and vascular patterns and the influence of repeatedly assessed data on patient outcomes in 2 independent glioblastoma series. METHODS: MVD and vascular patterns were assessed retrospectively by 5 observers in 1) a retrospectively compiled glioblastoma series that included 110 patients and 2) a glioblastoma series that included 233 patients who were treated within a randomized trial. MVD was determined in the field of greatest density ("hot-spot"). Predominantly classic or bizarre vascular patterns were determined by using a previously defined algorithm. RESULTS: Observer agreement on MVD was highly variable (range of kappa values, 0.464-0.901). The worst observer agreement was achieved when both the selection of hot-spots and MVD counts were performed independently. Survival analysis did not show a consistent association between repeatedly assessed MVD and patient outcome. Observer agreement on vascular patterns was poor (kappa = 0.297). Survival analysis did not show a consistent association between repeatedly assessed vascular patterns and patient outcome. CONCLUSIONS: Observer agreement on hot-spot MVD and vascular patterns in patients with glioblastoma was poor in independent assessments. MVD and vascular patterns were not associated consistently with patient outcome. Based on these findings, the authors concluded that poor observer agreement limits the clinical utility of histopathologically assessed hot-spot MVD and vascular patterns as prognostic factors in patients with glioblastoma. Improved methodologies for morphologic assessment of glioblastoma vascularization need to be identified

KRAS and CREBBP mutations: A relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone