Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion ...of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVETo perform a retrospective analysis examining the incidence and prognosis of glioma patients with leptomeningeal disease (LMD) at Memorial Sloan Kettering Cancer Center over a 15-year period ...and correlate these findings with clinicopathologic characteristics.
METHODSWe conducted a retrospective review of glioma patients with LMD at Memorial Sloan Kettering Cancer Center diagnosed from 2001 to 2016. Patients were identified through a keyword search of their electronic medical record and by ICD-9 codes.
RESULTSOne hundred three patients were identified with disseminated LMD and 85 patients with subependymal spread of disease, 4.7% of all patients with glioma. These cohorts were analyzed separately for time to development of disseminated LMD/subependymal LMD, median overall survival, and survival from LMD diagnosis. Patients were pooled for subsequent analyses (n = 188) because of comparable clinical behavior. LMD was present at glioma diagnosis in 10% of patients. In the remaining 90% of patients diagnosed at recurrence, time to LMD diagnosis, survival after LMD diagnosis, and overall survival varied by original histology. Patients with oligodendroglioma had a median survival of 10.8 (range 1.8–67.7) months, astrocytoma 6.5 (0.1–28.5) months, and glioblastoma 3.8 (0.1–32.6) months after LMD diagnosis. In addition, we found that treatment of LMD was associated with superior performance status and increased survival.
CONCLUSIONPatients with LMD diagnosed at relapse may not have decreased overall survival as compared to historical controls with parenchymal relapse and may benefit from treatment.
Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as ...lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy
, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease
. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging
, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost
. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2
, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Underrepresentation of disabled groups in clinical trials results in an inadequate evidence base for their clinical care, which drives health inequalities. This study aims to review and map the ...potential barriers and facilitators to the recruitment of disabled people in clinical trials to identify knowledge gaps and areas for further extensive research. The review addresses the question: 'What are the barriers and facilitators to recruitment of disabled people to clinical trials?'.
The Joanna Briggs Institute (JBI) Scoping review guidelines were followed to complete the current scoping review. MEDLINE and EMBASE databases were searched via Ovid. The literature search was guided by a combination of four key concepts from the research question: (1) disabled populations, (2) patient recruitment, (3) barriers and facilitators, and (4) clinical trials. Papers discussing barriers and facilitators of all types were included. Papers that did not have at least one disabled group as their population were excluded. Data on study characteristics and identified barriers and facilitators were extracted. Identified barriers and facilitators were then synthesised according to common themes.
The review included 56 eligible papers. The evidence on barriers and facilitators was largely sourced from Short Communications from Researcher Perspectives (N = 22) and Primary Quantitative Research (N = 17). Carer perspectives were rarely represented in articles. The most common disability types for the population of interest in the literature were neurological and psychiatric disabilities. A total of five emergent themes were determined across the barriers and facilitators. These were as follows: risk vs benefit assessment, design and management of recruitment protocol, balancing internal and external validity considerations, consent and ethics, and systemic factors.
Both barriers and facilitators were often highly specific to disability type and context. Assumptions should be minimised, and study design should prioritise principles of co-design and be informed by a data-driven assessment of needs for the study population. Person-centred approaches to consent that empower disabled people to exercise their right to choose should be adopted in inclusive practice. Implementing these recommendations stands to improve inclusive practices in clinical trial research, serving to produce a well-rounded and comprehensive evidence base.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Parent stress has been associated with negative outcomes for youth and may be particularly high during adolescence. Mindfulness interventions have the potential to reduce parent stress and to improve ...parenting behavior and parent-child relationship quality. The present randomized controlled study examined effects of a parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, for highly stressed parents of adolescents. Eighty-three mothers of 12- to 17-year olds reporting high stress were randomly assigned to the PM intervention or to a minimal intervention Parent Education (PE) control group. At pre- and post-intervention, mothers reported on their mindfulness, stress, parenting stress, mindful parenting, and parent-adolescent relationship quality. At pre- and post-intervention, mothers’ observed parenting behaviors and reported negative emotional responses to a laboratory parent-adolescent interaction task (PAIT) were also collected. Findings indicated that the PM intervention, compared to PE, increased mothers’ mindfulness, reduced parenting stress in two domains, increased mindful parenting related to emotional awareness in parenting, and improved parent-adolescent relationship quality. For mothers of girls (but not mothers of boys), the PM intervention also decreased negative parenting behavior and decreased negative emotional responses in PAIT. Effects sizes were medium to large. In sum, findings support parenting-focused mindfulness training as a viable intervention strategy for highly stressed parents.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•CSF is an excellent source of liquid biopsies in primary and metastatic brain tumors.•CSF has higher yield than plasma for detection of tumor-derived genomic material.•Other advantages are proximity ...to tumor and detection of brain-specific alterations.•CSF CTCs and ctDNA have many clinical applications in primary/metastatic brain tumors.
For patients with central nervous system (CNS) malignancies, liquid biopsies of the cerebrospinal fluid (CSF) may offer an unparalleled source of information about the tumor, with much less risk than traditional biopsies. Two techniques have been adapted to CSF in clinical settings: circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). CTCs have been employed mostly as a diagnostic tool for leptomeningeal metastases in epithelial tumors, although they may also have value in the prognostication and monitoring of this disease. The ctDNA technology has been studied in a variety of primary and metastatic brain and spinal cord tumors, where it can be used for diagnosis and molecular classification, with some work suggesting that it may also be useful for longitudinal tracking of tumor evolution or as a marker of residual disease. This review summarizes recent publications on the use of these two tests in CSF, focusing on their established and potential clinical applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament ...coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring. For primary CNS tumors, however, detection of ctDNA in plasma has been challenging. This is likely related at least in part to anatomic factors such as the blood-brain barrier. Due to the proximity of primary CNS tumors to the cerebrospinal fluid (CSF) space, our group and others have turned to CSF as a rich alternative source of ctDNA. Although multiple studies at this time have demonstrated the feasibility of CSF ctDNA detection across multiple types of pediatric CNS tumors, the optimal role and utility of CSF ctDNA in the clinical setting has not been established. This review discusses the work-to-date on CSF ctDNA liquid biopsy in pediatric CNS tumors and the associated technical challenges, and reviews the promising opportunities that lie ahead for integration of CSF ctDNA liquid biopsy into clinical care and clinical trial design.
When public health experts think of rural barriers to vaccines, they often initially focus on access, which makes sense with a new vaccine during a pandemic. This commentary highlights that there can ...be more complexity to vaccine uptake in rural communities. What follows are some examples of CDC’s efforts to better understand rural health and learnings to inform ongoing vaccination efforts in rural communities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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