Failure to Predict High-risk Kawasaki Disease Patients in a Population-based Study Cohort in Germany

Background: Diverse scores on high-risk Kawasaki disease (KD) patients have proven a good prognostic validity in the Japanese population. However, data on non-Japanese have been inconclusive. Do the Kobayashi, Egami and Sano scores or application of up-to-date statistical methods (Random Forest) predict response to standard intravenous immunoglobulin (IVIG) therapy and the risk of persistent coronary artery aneurysm (CAA) in patients with KD in a mainly Caucasian population in Germany? Methods: Data on 442 children (German population-based survey, 2013 and 2014) were used to assess the prognostic validity of the Kobayashi, Egami and Sano scores for being refractory to IVIG treatment and for predicting the risk of persistent CAA. Additionally, an up-to-date statistical approach (Random Forest) was applied to identify a potentially more valid score. Results: A total of 301 children were eligible for assessment of their response to IVIG treatment. Among those, 177 children were followed-up for 1 year to identify persistent CAA. Although all scores were significantly associated with being refractory to IVIG (relative risk range between 2.32 and 3.73), the prognostic properties were low (likelihood ratio positive: 1.83-4.57;sensitivity in the range of 0.28-0.53). None of the scores was a significant predictor of CAA 1 year after acute illness. Application of statistical analysis such as Random Forest did not yield a more valid score. Conclusions: None of the available scores appears to be appropriate for identifying high-risk Caucasian children with KD who might need intensified therapy

The Ursinus Weekly, May 22, 1975

Dr. Cope accepts history post at U. of Nebraska • Questionnaire summarized • UC faculty hears speaker from AAUP • U.C. Plans for Bicentennial • From the cluttered desk of the U.S.G.A. president • George Bause wins Scotland scholarship • Editorial: Last moments • Focus: Ms. Swanson • Wolsey Hall: British study • Alvarez attends seminar • Changes at library: Dr. Yost resigns post • Letters to the editor: Pets • Alumni elects • Intramural golf winners • Senior comments: Geoffery Higgins • Commencement • Earns degree • From the president • Cub and Key elects • Senior Spotlight: Dave McNamara • Reflections • Spring festival review • Study center success • New professors appointed • Ursinus bear squad • Volunteers needed at Pennhurst • Mulch queen contest • Concert review: Jesse Colin Young • Miller chosen • Dick Allen returns • Lacrosse wins 2 • Women\u27s tennis given team honors • Baseball: Season ends wrap-up • New results • Golf wins seven • Faculty-student net tournament • Intramural winnershttps://digitalcommons.ursinus.edu/weekly/1039/thumbnail.jp

The Ursinus Weekly, May 22, 1975

Dr. Cope accepts history post at U. of Nebraska • Questionnaire summarized • UC faculty hears speaker from AAUP • U.C. Plans for Bicentennial • From the cluttered desk of the U.S.G.A. president • George Bause wins Scotland scholarship • Editorial: Last moments • Focus: Ms. Swanson • Wolsey Hall: British study • Alvarez attends seminar • Changes at library: Dr. Yost resigns post • Letters to the editor: Pets • Alumni elects • Intramural golf winners • Senior comments: Geoffery Higgins • Commencement • Earns degree • From the president • Cub and Key elects • Senior Spotlight: Dave McNamara • Reflections • Spring festival review • Study center success • New professors appointed • Ursinus bear squad • Volunteers needed at Pennhurst • Mulch queen contest • Concert review: Jesse Colin Young • Miller chosen • Dick Allen returns • Lacrosse wins 2 • Women\u27s tennis given team honors • Baseball: Season ends wrap-up • New results • Golf wins seven • Faculty-student net tournament • Intramural winnershttps://digitalcommons.ursinus.edu/weekly/1039/thumbnail.jp

JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia

JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL

Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1, EBF1, PAX5, CDKN2A/B, RB1, BTG1, ETV6, and/or the PAR1 region (henceforth: B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1-deleted primary high hyperdiploid cells (~1500-fold), while thiopurine resistance was detected in IKZF1-deleted primary BCR-ABL1-like and non-BCR-ABL1-like B-other cells (~2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1plus and integrated cytogenetic and CNA classification, both predicted unfavorable outcome in the DCOG-ALL10 cohort, and associated with ex vivo drug cellular resistance to thiopurines, or L-asparaginase and thiopurines, respectively. This resistance could be attributed to overrepresentation of BCR-ABL1-like cases in these risk groups. Taken together, our data indicate that the prognostic value of CNAs in B-cell development genes is linked to subtype-related drug responses

Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease