PRMT5 Inhibition Reduces Hyperinflammation in a Murine Model of Secondary Hemophagocytic Lymphohistiocytosis (HLH).

Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially lethal hyperinflammatory syndrome characterized by pathologic immune activation and excessive production of proinflammatory cytokines leading to tissue damage and multisystem organ failure. There is an urgent need for the discovery of novel targets and development of therapeutic strategies to treat this rare but deadly syndrome. Protein Arginine Methyltransferase 5 (PRMT5) mediates T cell-based inflammatory responses, making it a potential actionable target for the treatment of HLH.

Revision wrist arthroplasty strategies.

Wrist arthrodesis performed to salvage a failed total wrist arthroplasty can be challenging owing to bone loss and poor soft tissue quality. This article focuses on the evidence base and our experience as a tertiary unit in managing this cohort of patients. A systematic and meticulous approach is required to attempt to minimize complications.

Replication and reliability of Parkinson's disease clinical subtypes.

Background: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits).

Objective: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes.

Methods: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function.

Parental rights or parental wrongs: Parents' metacognitive knowledge of the factors that influence their school choice decisions.

School choice initiatives-which empower parents to choose which schools their children attend-are built on the assumptions that parents know what features of a school are most important to their family and that they are capable of focusing on the most important features when they make their decisions. However, decades of psychological research suggest that decision makers lack metacognitive knowledge of the factors that influence their decisions. We sought to reconcile this discrepancy between the policy assumptions and the psychological research.

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2.

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally.

Long-term results and explant analysis of the ReMotion total wrist arthroplasty.

The ReMotion wrist replacement has good short- to medium-term survival with an acceptable complication profile as we previously reported in a cohort of patients with rheumatoid arthritis. We now report the long-term results of the same cohort and details of explant analysis of revisions undertaken for aseptic loosening. A total of 16 wrists were reviewed.

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031.

JCO Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC).

Children's Oncology Group's 2023 blueprint for research: Young investigators.

The Children's Oncology Group (COG) Young Investigators (YI) Committee is an administrative committee in which liaisons represent 30 COG committees, and was created to facilitate the integration of YIs into the organization, and prepare them for future COG leadership roles. The mentorship program has mentored over 400 YIs since 2005 and currently has 175 active participants. The COG YI Master Roster is a database YIs can join, which allows them to post their interests and accomplishments to COG leadership, and 321 YIs have already joined this list.

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

Background: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors.

Methods: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle.

Infectious events in pediatric patients with acute lymphoblastic leukemia/lymphoma undergoing evaluation for fever without severe neutropenia.

Background: Infections cause significant treatment-related morbidity during pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy) therapy. Fevers during periods without severe neutropenia are common, but etiologies are not well-described. This study sought to describe the bloodstream infection (BSI) and non-BSI risk in children undergoing therapy for ALL/LLy.

Progression-Free Survival and Patterns of Response in Patients With Relapsed High-Risk Neuroblastoma Treated With Irinotecan/Temozolomide/Dinutuximab/Granulocyte-Macrophage Colony-Stimulating Factor.

Purpose: Although chemoimmunotherapy is widely used for treatment of children with relapsed high-risk neuroblastoma (HRNB), little is known about timing, duration, and evolution of response after irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) therapy.

Patients And Methods: Patients eligible for this retrospective study were age < 30 years at diagnosis of HRNB and received ≥ 1 cycle of I/T/DIN/GM-CSF for relapsed or progressive disease. Patients with primary refractory disease who progressed through induction were excluded.

A bridge over troubled water-Extending induction for high-risk neuroblastoma patients with poor end-of-induction response.

A subset of high-risk neuroblastoma patients who have a poor end of Induction response may benefit from receiving chemoimmunotherapy, as bridge therapy, prior to Consolidation. Prospective studies evaluating this therapeutic approach and improved identification of biomarkers of response are warranted.

Comprehensive Genomic Profiling of High-Risk Pediatric Cancer Patients Has a Measurable Impact on Clinical Care.

Purpose: Profiling of pediatric cancers through deep sequencing of large gene panels and whole exomes is rapidly being adopted in many clinical settings. However, the most impactful approach to genomic profiling of pediatric cancers remains to be defined.

Methods: We conducted a prospective precision medicine trial, using whole-exome sequencing of tumor and germline tissue and whole-transcriptome sequencing (RNA Seq) of tumor tissue to characterize the mutational landscape of 127 tumors from 126 unique patients across the spectrum of pediatric brain tumors, hematologic malignancies, and extracranial solid tumors.

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).

Background: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors.

Methods: STARTRK-NG (NCT02650401) is a phase 1/2 trial.

Olecranon fractures: applied anatomy, clinical assessment and evidence-based management.

Olecranon fractures are common injuries, making up 10% of all fractures of the upper limb. They usually result from a fall from standing height in older people, or from a direct blow in young people. The olecranon's superficial location, with poor soft tissue and muscle protection, make it liable to fracture following direct impact.

Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity.

Monocytic-lineage inflammatory Ly6cCD103 dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6cCD103 DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth.

A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515).

Background: Prexasertib (LY2606368) is a novel, second-generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors.

Methods: Prexasertib was administered intravenously (i.

Coronavirus infection in hip fractures (CHIP) study.

Aims: Despite the COVID-19 pandemic, incidence of hip fracture has not changed. Evidence has shown increased mortality rates associated with COVID-19 infection. However, little is known about the outcomes of COVID-19 negative patients in a pandemic environment.

Limited implementation of measures to reduce nosocomial spread of COVID-19 in hip-fracture patients in the North West of England.

Hip-fracture patients are vulnerable to the outcomes of COVID-19. We performed a cross-sectional survey to determine measures employed to limit nosocomial spread of COVID-19 in 23 orthopaedic trauma departments in the North-West of England. Nineteen (87%) hospitals admitted patients to a ward prior to a negative swab, and only 9 (39%) patients were barrier nursed.

Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells.

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures.

Routine Surveillance Imaging Is Associated with Improved Postrelapse Survival in Patients with Ewing Sarcoma.

Children with Ewing sarcoma (ES) routinely undergo surveillance imaging after completion of therapy; however, the medical benefit of this imaging remains unclear. We aimed to determine whether there is a difference in survival between patients whose relapse was detected based on development of new symptoms or by routine imaging. We retrospectively reviewed all patients consecutively diagnosed with ES at Children's Healthcare of Atlanta from 2000 to 2011.