Hyperferritinemia Screening to Aid Identification and Differentiation of Patients with Hyperinflammatory Disorders.

High ferritin is an important and sensitive biomarker for the various forms of hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system at UPMC Children's Hospital where serum ferritin > 1000 ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients.

Hyperferritinemia screening to aid identification and differentiation of patients with hyperinflammatory disorders.

High ferritin is an important and sensitive biomarker for hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system where serum ferritin > 1000ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients.

Biological and clinical roles of IL-18 in inflammatory diseases.

Several new discoveries have revived interest in the pathogenic potential and possible clinical roles of IL-18. IL-18 is an IL-1 family cytokine with potent ability to induce IFNγ production. However, basic investigations and now clinical observations suggest a more complex picture.

Imaging in pediatric spondyloarthritis.

Purpose Of Review: Imaging is used in the diagnosis of peripheral and axial disease in juvenile spondyloarthritis (JSpA). Imaging of the joints and entheses in children and adolescents can be challenging for those unfamiliar with the appearance of the maturing skeleton. These differences are key for rheumatologists and radiologists to be aware of.

Improvement of SLC29A3 spectrum disorder-related sensorineural hearing loss after initiation of IL-6 inhibitor.

Tocilizumab is reported to reduce systemic inflammation in individuals with SLC29A3 spectrum disorder, but its effect on hearing loss has not been described. The authors present a boy toddler with a history of prematurity, dysphagia, hypersplenism, hyperpigmentation, short height and hearing loss who was referred to the immunology clinic. He initially presented shortly after birth with abnormal hearing screens followed by positive urine test for cytomegalovirus.

Metabolic Glycan Labeling-Based Screen to Identify Bacterial Glycosylation Genes.

Bacterial cell surface glycans are quintessential drug targets due to their critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell envelope glycocalyx contains distinctive monosaccharides that are stitched together into higher order glycans to yield exclusively bacterial structures that are critical for strain fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging.

Examining treatment responses of diagnostic marrow in murine xenografts to predict relapse in children with acute lymphoblastic leukaemia.

Background: While current chemotherapy has increased cure rates for children with acute lymphoblastic leukaemia (ALL), the largest number of relapsing patients are still stratified as medium risk (MR) at diagnosis (50-60%). This highlights an opportunity to develop improved relapse-prediction models for MR patients. We hypothesised that bone marrow from MR patients who eventually relapsed would regrow faster in a patient-derived xenograft (PDX) model after induction chemotherapy than samples from patients in long-term remission.

A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921).

Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts.

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Design, Setting, And Participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma.

Background: Targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity.

Objective: To investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs).

Genome-wide association study identifies multiple risk loci for renal cell carcinoma.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls.

Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL.

Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing promising therapies for clinical assessment in high-risk patients. Patient-derived xenograft (PDX) models of ALL provide a clinically relevant platform for assessing novel drugs, with efficacy generally assessed by enumerating circulating human lymphoblasts in mouse peripheral blood (PB) as an indicator of disease burden. While allowing indirect measurement of disease burden in real time, this technique cannot assess treatment effects on internal reservoirs of disease.

A review of new agents evaluated against pediatric acute lymphoblastic leukemia by the Pediatric Preclinical Testing Program.

Acute lymphoblastic leukemia (ALL) in children exemplifies how multi-agent chemotherapy has improved the outcome for patients. Refinements in treatment protocols and improvements in supportive care for this most common pediatric malignancy have led to a cure rate that now approaches 90%. However, certain pediatric ALL subgroups remain relatively intractable to treatment and many patients who relapse face a similarly dismal outcome.

Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program.

VS-4718, a novel inhibitor of focal adhesion kinase (FAK), was tested against the Pediatric Preclinical Testing Program's (PPTP's) in vitro cell line panel and showed a median relative IC of 1.22 μM. VS-4718 was tested in vivo against the PPTP xenograft models using a dose of 50 mg/kg administered by the oral route twice daily for 21 days.

Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program.

Background: CBL0137 is a novel drug that modulates FAcilitates Chromatin Transcription (FACT), resulting in simultaneous nuclear factor-κB suppression, heat shock factor 1 suppression and p53 activation. CBL0137 has demonstrated antitumor effects in animal models of several adult cancers and neuroblastoma.

Procedures: CBL0137 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations ranging from 1.

Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia.

The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax.

TriKEs and BiKEs join CARs on the cancer immunotherapy highway.

Unprecedented clinical success has recently been achieved in cancer immunotherapy using cytotoxic T cells armed with activating tumor-specific Chimeric Antigen Receptors (CARs). Natural killer (NK) cells, potent cytotoxic effectors, also hold potential to be effectively harnessed for immunotherapy. The anti-tumor efficacy of NK cell therapies has been limited by a lack of antigen specificity and the poor persistence of NK cells in vivo.

Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant.

Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX).

Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program.

Background: MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction.

Procedures: MK-8242 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10.

Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program.

Background: NSC 750854 is a purine analog with an antitumor activity profile distinctive from that of other anticancer purines. It has shown significant activity against adult cancer preclinical models.

Procedure: NSC 750854 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.