Clinical trial designs and endpoints.

Trials should be designed with consideration of the individual disease context and research question. Many different approaches may be justified. In this chapter, we therefore consider some of the principal components of trial design in general and within the context of the emerging field of gene and cell therapies.

Incorporating usability evaluation into iterative development of an online platform to support research participation in Parkinson's disease: a mixed methods protocol.

Introduction: Many people with Parkinson's (PwP) are not given the opportunity or do not have adequate access to participate in clinical research. To address this, we have codeveloped with users an online platform that connects PwP to clinical studies in their local area. It enables site staff to communicate with potential participants and aims to increase the participation of the Parkinson's community in research.

Multi-omic approach identifies hypoxic tumor-associated myeloid cells that drive immunobiology of high-risk pediatric ependymoma.

Ependymoma (EPN) is a devastating childhood brain tumor. Single-cell analyses have illustrated the cellular heterogeneity of EPN tumors, identifying multiple neoplastic cell states including a mesenchymal-differentiated subpopulation which characterizes the PFA1 subtype. Here, we characterize the EPN immune environment, in the context of both tumor subtypes and tumor cell subpopulations using single-cell sequencing (scRNAseq, n = 27), deconvolution of bulk tumor gene expression (n = 299), spatial proteomics (n = 54), and single-cell cytokine release assays (n = 12).

Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: A multicenter study.

Background: Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN molecular groups. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA remains largely unknown; however, the increasing use of surgery at first recurrence has now provided access to clinical samples to facilitate a better understanding of this.

Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.

Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing.

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study.

Background: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study.

Methods: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy.

Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD.

Challenges of Incorporating Digital Health Technology Outcomes in a Clinical Trial: Experiences from PD STAT.

Digital health technologies (DHTs) have great potential for use as clinical trial outcomes; however, practical issues need to be addressed in order to maximise their benefit. We describe our experience of incorporating two DHTs as secondary/exploratory outcome measures in PD STAT, a randomised clinical trial of simvastatin in people with Parkinson's disease. We found much higher rates of missing data in the DHTs than the traditional outcome measures, in particular due to technical and software difficulties.

Enhancing Trial Delivery in Parkinson's Disease: Qualitative Insights from PD STAT.

Background: Recruitment and retention of participants in clinical trials for Parkinson's disease (PD) is challenging. A qualitative study embedded in the PD STAT multi-centre randomised controlled trial of simvastatin for neuroprotection in PD explored the motivators, barriers and challenges of participants, care partners and research staff.

Objective: To outline a set of considerations informing a patient-centred approach to trial recruitment, retention, and delivery.

Integrative molecular characterization of pediatric spinal ependymoma: the UK Children's Cancer and Leukaemia Group study.

Background: Pediatric spinal ependymomas (SP-EPNs) are rare primary central nervous system tumors with heterogeneous clinical course. Considering that ependymomas in children are biologically distinct from their adult counterparts, this study aimed to define the molecular landscape of SP-EPNs in children.

Methods: In this retrospective study, we have collected tumor samples from 27 SP-EPN patients younger than 18 years and carried out the histological review, DNA methylation, and gene expression profiling.

Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas.

Molecular groups of supratentorial ependymomas comprise tumors with or -involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared as a partner gene.

A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups.

Background: Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach.

Methods And Materials: We analyzed 302 pediatric ependymoma cases.

Limit of detection of troponin discharge strategy versus usual care: randomised controlled trial.

Introduction: The clinical effectiveness of a 'rule-out' acute coronary syndrome (ACS) strategy for emergency department patients with chest pain, incorporating a single undetectable high-sensitivity cardiac troponin (hs-cTn) taken at presentation, together with a non-ischaemic ECG, remains unknown.

Methods: A randomised controlled trial, across eight hospitals in the UK, aimed to establish the clinical effectiveness of an undetectable hs-cTn and ECG (limit of detection and ECG discharge (LoDED)) discharge strategy. Eligible adult patients presented with chest pain; the treating clinician intended to perform investigations to rule out an ACS; the initial ECG was non-ischaemic; and peak symptoms occurred <6 hours previously.

Limitations of current models for testing the clinical potential of epigenetic inhibitors for treatment of pediatric ependymoma.

Background: Epigenetic modifications have been shown to play an important role in the classification and pathogenesis of the pediatric brain tumor ependymoma, suggesting they are a potential therapeutic target.

Results: Agents targeting epigenetic modifications inhibited the growth and induced the death of ependymoma cells with variable efficiency. However, this was often not at clinically achievable doses.

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered.

Effect of the Prevent Alcohol and Risk-Related Trauma in Youth (P.A.R.T.Y.) Program among senior school students.

Objective: The Prevent Alcohol and Risk-Related Trauma in Youth (P.A.R.

PI3K pathway activation provides a novel therapeutic target for pediatric ependymoma and is an independent marker of progression-free survival.

Purpose: Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis.

Lung toxicity and biodistribution of Cd/Se-ZnS quantum dots with different surface functional groups after pulmonary exposure in rats.

Background: The potential use of quantum dots (QD) in biomedical applications, as well as in other systems that take advantage of their unique physiochemical properties, has led to concern regarding their toxicity, potential systemic distribution, and biopersistence. In addition, little is known about workplace exposure to QD in research, manufacturing, or medical settings. The goal of the present study was to assess pulmonary toxicity, clearance, and biodistribution of QD with different functional groups in rats after pulmonary exposure.

Transcriptomics analysis of lungs and peripheral blood of crystalline silica-exposed rats.

Minimally invasive approaches to detect/predict target organ toxicity have significant practical applications in occupational toxicology. The potential application of peripheral blood transcriptomics as a practical approach to study the mechanisms of silica-induced pulmonary toxicity was investigated. Rats were exposed by inhalation to crystalline silica (15 mg/m(3), 6 h/day, 5 days) and pulmonary toxicity and global gene expression profiles of lungs and peripheral blood were determined at 32 weeks following termination of exposure.

Pulmonary Toxicity, Distribution, and Clearance of Intratracheally Instilled Silicon Nanowires in Rats.

Silicon nanowires (Si NWs) are being manufactured for use as sensors and transistors for circuit applications. The goal was to assess pulmonary toxicity and fate of Si NW using an experimental model. Male Sprague-Dawley rats were intratracheally instilled with 10, 25, 50, 100, or 250 g of Si NW (~20-30 nm diameter; ~2-15 m length).

Blood gene expression profiling detects silica exposure and toxicity.

Blood gene expression profiling was investigated as a minimally invasive surrogate approach to detect silica exposure and resulting pulmonary toxicity. Rats were exposed by inhalation to crystalline silica (15 mg/m³, 6 h/day, 5 days), and pulmonary damage and blood gene expression profiles were determined after latency periods (0-16 weeks). Silica exposure resulted in pulmonary toxicity as evidenced by histological and biochemical changes in the lungs.

Toxicological evaluation of lung responses after intratracheal exposure to non-dispersed titanium dioxide nanorods.

Fine- and coarse-sized titanium dioxide (TiO₂) particles are considered to be relatively inert when inhaled. The goal of this study was to assess potential lung toxicity associated with well-characterized, non-dispersed rutile TiO₂ nanorods (10 × 40 nm). In vitro bioreactivity of TiO₂ nanorods was determined by electron spin resonance (ESR) to measure free radical production.