Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.

Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG.

Locoregional CAR T Cells for the Treatment of CNS Tumors in Children: Investigational Drug Service Pharmacy Activities.

Background: A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors.

Postmovement Beta Rebound in Real and Imagined Movement.

Movement disorders, such as stroke and amyotrophic lateral sclerosis, result in loss of upper limb function and, hence, severe impairments of bimanual coordination. Although motor imagery is increasingly used to enhance neurorehabilitation, cognitive and neurophysiological parameters that inform effective strategies remain elusive. The aim of the present study is to elucidate the neural dynamics that underlie learning during real and imagined movement using both unimanual and bimanual coordination patterns.

Toward Alleviating Clinician Documentation Burden: A Scoping Review of Burden Reduction Efforts.

Background:  Studies have shown that documentation burden experienced by clinicians may lead to less direct patient care, increased errors, and job dissatisfaction. Implementing effective strategies within health care systems to mitigate documentation burden can result in improved clinician satisfaction and more time spent with patients. However, there is a gap in the literature regarding evidence-based interventions to reduce documentation burden.

Feasibility of the pitch efficiency rating: A novel tool for systematic assessment of pitching mechanics in developing throwing athletes.

Background: Injuries in younger baseball athletes continue to increase despite work characterizing risk factors. Three-dimensional (3D) motion capture may identify suboptimal pitching mechanics that predispose an athlete to injury, but 3D-motion analysis is often inaccessible. Thus, there is a gap between the current biomechanics literature and its practical application in young athletes.

Epitope mapping of monoclonal antibodies: a comprehensive comparison of different technologies.

Monoclonal antibodies have become an important class of therapeutics in the last 30 years. Because the mechanism of action of therapeutic antibodies is intimately linked to their binding epitopes, identification of the epitope of an antibody to the antigen plays a central role during antibody drug development. The gold standard of epitope mapping, X-ray crystallography, requires a high degree of proficiency with no guarantee of success.

Locoregional CAR T cells for children with CNS tumors: Clinical procedure and catheter safety.

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. Based on adoptive cellular therapy's clinical success against childhood leukemia and the preclinical efficacy against pediatric CNS tumors, chimeric antigen receptor (CAR) T cells offer hope of improving outcomes for recurrent tumors and universally fatal diseases such as diffuse intrinsic pontine glioma (DIPG). However, a major obstacle for tumors of the brain and spine is ineffective T cell chemotaxis to disease sites.

A brief review of motor imagery and bimanual coordination.

Motor imagery is increasingly being used in clinical settings, such as in neurorehabilitation and brain computer interface (BCI). In stroke, patients lose upper limb function and must re-learn bimanual coordination skills necessary for the activities of daily living. Physiotherapists integrate motor imagery with physical rehabilitation to accelerate recovery.

Preclinical characterization and clinical translation of pharmacodynamic markers for MK-5890: a human CD27 activating antibody for cancer immunotherapy.

Background: Immune checkpoint inhibitors (ICI) have radically changed cancer therapy, but most patients with cancer are unresponsive or relapse after treatment. MK-5890 is a CD27 agonist antibody intended to complement ICI therapy. CD27 is a member of the tumor necrosis factor receptor superfamily that plays a critical role in promoting responses of T cells, B cells and NK cells.

Modified Manufacturing Process Modulates CD19CAR T-cell Engraftment Fitness and Leukemia-Free Survival in Pediatric and Young Adult Subjects.

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor.

Protocol-driven early tracheal extubation in patients with flaccid neuromuscular scoliosis and pre-existing lung disease.

Purpose: To review the results of a postoperative respiratory pathway for patients with muscular dystrophy (MD) and spinal muscular atrophy (SMA) undergoing spinal surgery.

Methods: With IRB approval, a retrospective review was done on all patients with SMA and MD undergoing spinal surgery on a neuromuscular protocol. Baseline demographics, perioperative results, and long-term outcomes were collected.

Evolving Surgical Management for Early-Onset Scoliosis in Spinal Muscular Atrophy Type 1 Given Improvements in Survival.

Case: We present a case of an 18-month-old child with early-onset scoliosis in the setting of spinal muscular atrophy (SMA) type 1 whose rapidly progressive scoliosis is successfully managed with magnetic growing rods, the youngest age of implantation in a patient with SMA we are currently aware of. Technical challenges, complications, and outcome are described in this case presentation.

Conclusion: Patients with SMA type 1 and early-onset scoliosis can be managed with growing-rod constructs given dramatic improvements in medical care that have expanded life expectancy.

Customised hybrid CT-MRI 3D-printed model for grade V spondylolisthesis in an adolescent.

3D-printed patient-specific models provide added value for initial clinical diagnosis, preoperative surgical and implant planning and patient and trainee education. 3D spine models are usually designed using CT data, due to the ability to rapidly image osseous structures with high spatial resolution. Combining CT and MRI to derive a composite model of bony and neurological anatomy can potentially provide even more useful information for complex cases.

Immune Function following Major Spinal Surgery and General Anesthesia.

There are reported differences in the effects that general anesthetics may have on immune function after minor surgery. To date, there are no prospective trials comparing total intravenous anesthesia (TIVA) with a volatile agent-based technique and its effects on immune function after major spinal surgery in adolescents. Twenty-six adolescents undergoing spinal fusion were randomized to receive TIVA with propofol-remifentanil or a volatile agent-based technique with desflurane-remifentanil.

Impact of Intraoperative Fluid Management on Electrolyte and Acid-Base Variables During Posterior Spinal Fusion in Adolescents.

Introduction: Various isotonic fluids may be used to maintain intravascular homeostasis during major surgical procedures. Variations in the electrolyte and buffer concentrations between these solutions may result in differential changes in electrolyte and acid-base status during fluid resuscitation. This study evaluates these changes during posterior spinal fusion in adolescents.

Defining the volume of consultations for musculoskeletal infection encountered by pediatric orthopaedic services in the United States.

Objective: Adequate resources are required to rapidly diagnose and treat pediatric musculoskeletal infection (MSKI). The workload MSKI consults contribute to pediatric orthopaedic services is unknown as prior epidemiologic studies are variable and negative work-ups are not included in national discharge databases. The hypothesis was tested that MSKI consults constitute a substantial volume of total consultations for pediatric orthopaedic services across the United States.

Etiology and Treatment of Intraoperative Hyperkalemia During Posterior Spinal Fusion in an Adolescent.

Hyperkalemia, defined as a serum or plasma potassium greater than 5.5 mEq/L, while an uncommon occurrence in children, is a serious medical problem that warrants immediate attention as it can result in serious cardiac arrhythmias and death. Although hyperkalemia may occur in the critically ill patient or in the setting of renal failure and insufficiency, there are limited reports of its occurrence during intraoperative care.

Anesthetic Care During Posterior Spinal Fusion in an Adolescent With Ebstein's Anomaly.

Ebstein's anomaly is a rare form of cyanotic congenital heart disease (CHD) that involves malformation and dysfunction of the tricuspid valve and right ventricle (RV). The severity of the defect impacts clinical presentation, survival, and treatment options. Presentation during the neonatal period with hypoxemia and cyanosis is noted in patients with severe tricuspid valve malformation, a hypoplastic RV, or RV outflow tract obstruction.

The Utility of Preoperative Neuromonitoring for Adolescent Idiopathic Scoliosis.

Background: Intraoperative neuromonitoring is well established and widely used to assist in completing corrective surgery for adolescent idiopathic scoliosis (AIS) safely. The role of preoperative measurement of somatosensory evoked potentials (SSEPs) and/or transcranial magnetic stimulation (TMS) to determine if there is transpinal pathology, however, is not clear. We sought to determine if preoperative SSEP and/or TMS measurement provided clinical benefit to patients with AIS.

Manufacture of Chimeric Antigen Receptor T Cells from Mobilized Cyropreserved Peripheral Blood Stem Cell Units Depends on Monocyte Depletion.

Cytotoxic chemotherapy and radiation can render lymphocyte repertoires qualitatively and quantitatively defective. Thus, heavily treated patients are often poor candidates for the manufacture of autologous chimeric antigen receptor (CAR)-T cell products. In the United States and Europe, children with high-risk neuroblastoma undergo apheresis early in the course of treatment to collect peripheral blood stem cells (PBSCs) for cryopreservation in preparation for high-dose chemotherapy followed by autologous stem cell rescue.

Changes in cerebral oxygenation based on intraoperative ventilation strategy.

Introduction: Cerebral oxygenation can be monitored clinically by cerebral oximetry (regional oxygen saturation, rSO) using near-infrared spectroscopy (NIRS). Changes in rSO have been shown to precede changes in pulse oximetry, providing an early detection of clinical deterioration. Cerebral oximetry values may be affected by various factors, including changes in ventilation.

Analgesic effects of methadone and magnesium following posterior spinal fusion for idiopathic scoliosis in adolescents: a randomized controlled trial.

Purpose: To provide optimal conditions for neurophysiological monitoring and rapid awakening, remifentanil is commonly used during pediatric spinal surgery. However, remifentanil may induce hyperalgesia and increase postoperative opioid requirements. We evaluated the potential of methadone or magnesium to prevent remifentanil-induced hyperalgesia.

Spinal anesthesia instead of general anesthesia for infants undergoing tendon Achilles lengthening.

Spinal anesthesia (SA) has been used relatively sparingly in the pediatric population, as it is typically reserved for patients in whom the perceived risk of general anesthesia is high due to comorbid conditions. Recently, concern has been expressed regarding the potential long-term neurocognitive effects of general anesthesia during the early stages of life. In view of this, our center has developed a program in which SA may be used as the sole agent for applicable surgical procedures.

Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells.

GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of T-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL).