Transplant and Nontransplant Salvage Therapy in Pediatric Relapsed or Refractory Hodgkin Lymphoma: The EuroNet-PHL-R1 Phase 3 Nonrandomized Clinical Trial.

Importance: The current standard-of-care salvage therapy in relapsed/refractory classic Hodgkin lymphoma (cHL) includes consolidation high-dose chemotherapy (HDCT)/autologous stem cell transplant (aSCT).

Objective: To investigate whether presalvage risk factors and fludeoxyglucose-18 (FDG) positron emission tomography (PET) response to reinduction chemotherapy can guide escalation or de-escalation between HDCT/aSCT or transplant-free consolidation with radiotherapy to minimize toxic effects while maintaining high cure rates.

Design, Setting, And Participants: EuroNet-PHL-R1 was a nonrandomized clinical trial that enrolled patients younger than 18 years with first relapsed/refractory cHL across 68 sites in 13 countries in Europe between January 2007 and January 2013.

Perfluorodecanoic acid (PFDA) increases oxidative stress through inhibition of mitochondrial β-oxidation.

PER: and polyfluoroalkyl substances (PFAS) are a large group of synthetic organic chemicals that are ubiquitous environmental pollutants. Among PFAS, perfluorodecanoic acid (PFDA) is one of the most toxic compounds, but the molecular basis behind its toxicity is not fully understood. In an interspecies comparison with placental cells (HTR-8/SVneo) and zebrafish embryos, we demonstrate that PFDA induces mitochondrial dysfunction and impairs fatty acid β-oxidation.

Off-Target Inhibition of Human Dihydroorotate Dehydrogenase (DHODH) Highlights Challenges in the Development of Fat Mass and Obesity-Associated Protein (FTO) Inhibitors.

FTO, an -methyladenosine (mA) and ,2'--dimethyladenosine (mA) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (DHODH).

Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states.

We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature.

The myth of a cancer-specific temperament: An analysis of affective temperament in cancer patients.

Objective: We investigate the prevalence of five affective temperaments (depressive, cyclothymic, hyperthymic, irritable, and anxious) in a large sample of cancer patients and associations of temperament with cancer site as well as the impact of temperament on overall survival of cancer patients.

Methods: Data for this prospective cohort study was collected in the outpatient clinic of a large cancer center. We used the Temperament Evaluation in Memphis, Pisa and San Diego - Münster Version (TEMPS-M) and recorded patient data.

Protein Engineering by Yeast Surface Display.

Protein engineering enables the improvement of existing functions of a given protein or the generation of novel functions. One of the most widely used and versatile tools in the protein engineering field is yeast surface display, where a pool of randomized proteins is expressed on the surface of yeast. The linkage of phenotype (e.

Natural killer cell-mediated cytotoxicity shapes the clonal evolution of B cell leukaemia.

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting.

BRAFV600E induces key features of LCH in iPSCs with cell type-specific phenotypes and drug responses.

Langerhans cell histiocytosis (LCH) is a clonal hematopoietic disorder defined by tumorous lesions containing CD1a+/CD207+ cells. Two severe complications of LCH are systemic hyperinflammation and progressive neurodegeneration. The scarcity of primary samples and lack of appropriate models limit our mechanistic understanding of LCH pathogenesis and affect patient care.

Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4 IL-9-expressing cells.

Background: CD4 T cells play essential roles in adaptive immunity. Distinct CD4 T-cell subsets-T1, T2, T17, T22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing T9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity.

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.

The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation.

COMPARABLE OUTCOMES AFTER BUSULFAN- OR TREOSULFAN-BASED CONDITIONING FOR ALLO-HSCT IN CHILDREN WITH ALL-RESULTS OF FORUM.

The superiority of TBI-based versus chemotherapy-conditioning for allo-HSCT in children with ALL has been established in the international, prospective phase-III FORUM study (#NCT01949129), randomizing 417 patients ≤ 18 years at diagnosis (4-21 years at HSCT) in CR, transplanted from HLA-matched sibling or unrelated donors. Due to the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the pre-specified comparison of outcomes of patients receiving busulfan-based (BU) or treosulfan-based (TREO) regimens from 2013 to 2018. 180 and 128 patients (median age 9.

HDAC1 fine-tunes Th17 polarization in vivo to restrain tissue damage in fungal infections.

Histone deacetylases (HDACs) contribute to shaping many aspects of T cell lineage functions in anti-infective surveillance; however, their role in fungus-specific immune responses remains poorly understood. Using a T cell-specific deletion of HDAC1, we uncover its critical role in limiting polarization toward Th17 by restricting expression of the cytokine receptors gp130 and transforming growth factor β receptor 2 (TGF-βRII) in a fungus-specific manner, thus limiting Stat3 and Smad2/3 signaling. Controlled release of interleukin-17A (IL-17A) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is vital to minimize apoptotic processes in renal tubular epithelial cells in vitro and in vivo.

LTβR deficiency causes lymph node aplasia and impaired B cell differentiation.

Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells.

Dedicated diagnostic approaches for mature B-cell non-Hodgkin lymphomas occurring in children, adolescents, and young adults.

Non-Hodgkin lymphoma (NHL) represents the fourth most common malignant disease among children and adolescents. Current disease classifications, including the most recent World Health Organization (WHO) classification and the International Consensus Classification (ICC), rely on a combination of clinical, epidemiological, histologic, immunophenotypic, and molecular data to define discrete clinicopathologic entities. There is growing evidence that children, adolescents, and young adults (CAYA) with B-cell NHL display unique clinical and epidemiologic characteristics.

Integrated multi-omics identifies pathways governing interspecies interaction between A. fumigatus and K. pneumoniae.

Polymicrobial co- and superinfections involving bacterial and fungal pathogens pose serious challenges for diagnosis and therapy, and are associated with elevated morbidity and mortality. However, the metabolic dynamics of bacterial-fungal interactions (BFI) and the resulting impact on disease outcome remain largely unknown. The fungus Aspergillus fumigatus and the bacterium Klebsiella pneumoniae are clinically important pathogens sharing common niches in the human body, especially in the lower respiratory tract.

The adsorption of drugs on nanoplastics has severe biological impact.

Micro- and nanoplastics can interact with various biologically active compounds forming aggregates of which the effects have yet to be understood. To this end, it is vital to characterize these aggregates of key compounds and micro- and nanoplastics. In this study, we examined the adsorption of the antibiotic tetracycline on four different nanoplastics, made of polyethylene (PE), polypropylene (PP), polystyrene (PS), and nylon 6,6 (N66) through chemical computation.

Structural insights into the DNA-binding mechanism of BCL11A: The integral role of ZnF6.

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: αγ) to adult hemoglobin (HbA: αβ) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456.

Auer rod-positive acute leukemia with predominantly lymphoid immunophenotype: Report on 11 cases and review of literature.

Background: Auer rods (AuRs) are prominent intracellular structures found almost exclusively in myeloid cell malignancies, such as acute myeloid leukemia (AML), chronic and juvenile myelomonocytic leukemia and myelodysplastic syndrome. Extremely rare AuRs have been reported in patients with acute lymphoblastic leukemia (ALL) or among ambiguous lineage leukemia patients with a dominantly lymphoblastic immunophenotype.

Procedure: We report diagnostic and follow-up data of an international cohort of 11 children suffering from leukemias with AuRs and with significant presence of T and myeloid markers, majority of whom categorized as early T-cell precursor (ETP, n = 7); or T-ALL (ETP status unknown, n = 2), ALAL (acute leukemia of ambiguous lineage, n = 1), and AML reclassified from ALAL (n = 1).

First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo.

Heat shock protein 90 (Hsp90) and topoisomerase IIα (TopoIIα) are members of the GHKL protein superfamily, both with clinically validated roles as anticancer drug targets. We report the discovery of the first class of dual inhibitors targeting the ATP-binding site of TopoIIα and the C-terminal domain of Hsp90, displaying potent cancer growth inhibition both in vitro and in vivo. Initially, a known TopoIIα inhibitor, compound 3, was shown to bind to the C-terminal domain of Hsp90, but not to its ATP-binding N-terminal domain.

Hiding in plain sight: Optimizing topoisomerase IIα inhibitors into Hsp90β selective binders.

Due to their impact on several oncogenic client proteins, the Hsp90 family of chaperones has been widely studied for the development of potential anticancer agents. Although several Hsp90 inhibitors have entered clinical trials, most were unsuccessful because they induced a heat shock response (HSR). This issue can be circumvented by using isoform-selective inhibitors, but the high similarity in the ATP-binding sites between the isoforms presents a challenge.

Helmut Gadner: A Charismatic Leader, Visionary, and Pioneer in Pediatric Oncology.

Helmut Gadner, a world-famous pediatric hematologist-oncologist, dedicated his professional life to researching pediatric cancer and advancing care for affected children, adolescents, and their families. Starting his career in the team of Hansjörg Riehm, the father of the ever-most successful BFM (abbreviation of the city names of the founding institutions, Berlin-Frankfurt-Münster) treatment concept of pediatric leukemia, the young Dr. Gadner became a passionate soldier in the fight against pediatric cancer.

Osteosarcoma as a secondary malignancy following rhabdomyosarcoma: A report of 28 affected patients from the Cooperative Osteosarcoma Study Group (COSS).

Background: Osteosarcoma may arise as a secondary malignancy following rhabdomyosarcoma (RMS). We utilized the Cooperative Osteosarcoma Study Group (COSS) database to better understand this association.

Patients And Methods: The COSS database (1980-05/2023) was searched for patients whose osteosarcoma was preceded by RMS.