The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma

Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population

Machine Learning Logistic Regression Model for Early Decision Making in Referral of Children with Cervical Lymphadenopathy Suspected of Lymphoma

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89–98%) and a specificity of 88% (95% CI 77–94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy.</p

Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P3.4) from 8% to 85%(P</p

Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Following Blinatumomab-Induced Remission in Pediatric Patients with Relapsed/Refractory (r/r) B-Precursor Acute Lymphoblastic Leukemia (ALL): Preliminary Results from a Phase I/II Stud

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High-Throughput Drug Library Screening in Primary KMT2A-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing

High-Throughput Drug Library Screening in Primary KMT2A-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes