Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study.

Aims: PTC518 is an orally administered, centrally and peripherally distributed huntingtin (HTT) pre-mRNA splicing modifier being developed for the treatment of Huntington's disease (HD) for which there is a high unmet medical need as there are currently no approved disease-modifying treatments. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PTC518 in healthy volunteers.

Methods: This phase 1, single-centre, randomized study in 77 healthy male and female volunteers evaluated the safety and tolerability and PK of PTC518 following single ascending doses and multiple ascending doses, PD as assessed by HTT mRNA and HTT protein levels after single and multiple doses, and food effects.

Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets.

Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG.

Localized delivery of therapeutic doxorubicin dose across the canine blood-brain barrier with hyperthermia and temperature sensitive liposomes.

Most drugs cannot penetrate the blood-brain barrier (BBB), greatly limiting the use of anti-cancer agents for brain cancer therapy. Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug in response to hyperthermia (>40 °C). Since hyperthermia also transiently opens the BBB, we hypothesized that localized hyperthermia can achieve drug delivery across the BBB when combined with TSL.

The CREST-E study of creatine for Huntington disease: A randomized controlled trial.

Objective: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease.

Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up.

Bevacizumab Therapy for Pilomyxoid Astrocytoma.

Pilomyxoid astrocytoma is a rare tumor of the central nervous system generally found in young children near the hypothalamus. Herein, we report a 19-month-old female infant with a pilomyxoid astrocytoma, who underwent surgery as well as carboplatin and vincristine chemotherapy in an attempt to delay radiation therapy to the brain. Magnetic resonance imaging revealed that the tumor had increased in tumor volume on therapy.

Immunological low-dose radiation modulates the pediatric medulloblastoma antigens and enhances antibody-dependent cellular cytotoxicity.

Background: Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy.

Subcortical DNET in a Patient With an Enzymatic Deficiency: A Rare Case and Review of the Literature.

Purpose: This case report describes a toddler with a medical history of biotinidase deficiency who presented with atypical seizures due to a brain tumor.

Methods: This is a case report.

Results: Electroencephalogram revealed a frontal lobe mass, with magnetic resonance imaging confirmation of a mass extending from the frontal lobe into the genu and anterior corpus callosum.

Delivery of a drug cache to glioma cells overexpressing platelet-derived growth factor receptor using lipid nanocarriers.

Aim: Glioblastoma multiforme is a devastating disease with no curative options due to the difficulty in achieving sufficient quantities of effective chemotherapies into the tumor past the blood-brain barrier. Micelles loaded with temozolomide (TMZ) were designed to increase the delivery of this drug into the brain.

Materials & Methods: pH-responsive micelles composed of distearoyl phosphoethanolamine-PEG-2000-amine and N-palmitoyl homocysteine were surface-functionalized with PDGF peptide and Dylight 680 fluorophore.

Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs.

Thermal Therapy Approaches for Treatment of Brain Tumors in Animals and Humans.

Primary brain tumors are often aggressive, with short survival from time of diagnosis even with standard of care therapies such as surgery, chemotherapy, and radiation therapy. Thermal therapies have been extensively investigated as both primary and adjuvant therapy. Although thermal therapies are not yet widely used clinically, there have been several promising approaches demonstrated in both animals and humans.

Neurocognitive Changes after Sustained Ketamine Administration in Children with Chronic Pain.

Introduction: Ketamine has received attention recently as an agent for chronic pain. There are concerns, however, regarding the neurocognitive changes patients might experience after ketamine exposure.

Methods: This prospective, uncontrolled study describes the neurocognitive functioning of 11 children with chronic pain before and after 2 weeks of daily oral ketamine exposure.

Diffuse intrinsic pontine gliomas: treatments and controversies.

Diffuse intrinsic pontine gliomas (DIPGs) are a fairly common pediatric brain tumor, and children with these tumors have a dismal prognosis. They generally are diagnosed within the first decade of life, and due to their location within the pons, these tumors are not surgically resectable. The median survival for children with DIPGs is less than 1 year, in spite of decades of clinical trial development of unique approaches to radiation therapy and chemotherapy.

Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature.

Objective: Chronic cancer pain is often refractory and difficult to treat. Ketamine is a medication with evidence of efficacy in the treatment of chronic pain.

Design: This article presents a synthesis of the data on ketamine for refractory cancer pain in adults and children.

Oral ketamine for children with chronic pain: a pilot phase 1 study.

Objective: To assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children.

Study Design: A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.

Incidental brain lesions in children: to treat or not to treat?

Central nervous system (CNS) lesions that are discovered incidentally when imaging children for problems that were unrelated to the detected lesion pose a dilemma to physicians. Because there are few data on the outcome of such cases, we retrospectively reviewed the clinical course of a group of children followed at our institution with brain lesions found incidentally on neuro-imaging. A database of all children with brain lesions followed at the University of Rochester medical center from 2000 to 2010 was reviewed.

Management of immune thrombocytopenic purpura in children: potential role of novel agents.

The treatment of immune thrombocytopenic purpura (ITP) in children is controversial, requiring individualized assessment of the patient and consideration of treatment options. If the platelet count is >10 000/μL and the patient is asymptomatic, a 'watch and wait' strategy is appropriate since most children with ITP will recover completely without pharmacotherapy. If therapy is indicated because of bleeding or a platelet count <10 000/μL, then treatment with glucocorticoids, intravenous immunoglobulin (IVIg), or anti-D are possible initial choices.