Diffuse Intrinsic Pontine Glioma : Clinical Features, Molecular Genetics, and Novel Targeted Therapeutics

Diffuse intrinsic pontine glioma (DIPG) is a deadly paediatric brain cancer. Transient response to radiation, ineffective chemotherapeutic agents and aggressive biology result in rapid progression of symptoms and a dismal prognosis. Increased availability of tumour tissue has enabled the identification of histone gene aberrations, genetic driver mutations and methylation changes, which have resulted in molecular and phenotypic subgrouping. However, many of the underlying mechanisms of DIPG oncogenesis remain unexplained. It is hoped that more representative in vitro and preclinical models-using both xenografted material and genetically engineered mice-will enable the development of novel chemotherapeutic agents and strategies for targeted drug delivery. This review provides a clinical overview of DIPG, the barriers to progress in developing effective treatment, updates on drug development and preclinical models, and an introduction to new technologies aimed at enhancing drug delivery

Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion.

Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. The high-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma, making complete surgical resection improbable. Modeling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs). The resulting formation of hybrid organoids demonstrated an invasive tumor phenotype that was distinct from noncancerous adult neural progenitor (NP) spheroid incorporation into eCOs. These findings provide a basis for the modeling and quantification of the GBM infiltration process using a stem-cell-based organoid approach, and may be used for the identification of anti-GBM invasion strategies

Three principles for the progress of immersive technologies in healthcare training and education.

This is the final version. Available from BMJ Publishing via the DOI in this record.

Assessing national patterns and outcomes of pituitary surgery: is hospital administrative data good enough?

Purpose Patterns of surgical care, outcomes, and quality of care can be assessed using hospital administrative databases but this requires accurate and complete data. The aim of this study was to explore whether the quality of hospital administrative data was sufficient to assess pituitary surgery practice in England. Methods The study analysed Hospital Episode Statistics (HES) data from April 2013 to March 2018 on all adult patients undergoing pituitary surgery in England. A series of data quality indicators examined the attribution of cases to consultants, the coding of sellar and parasellar lesions, associated endocrine and visual disorders, and surgical procedures. Differences in data quality over time and between neurosurgical units were examined. Results A total of 5613 records describing pituitary procedures were identified. Overall, 97.3% had a diagnostic code for the tumour or lesion treated, with 29.7% (n = 1669) and 17.8% (n = 1000) describing endocrine and visual disorders, respectively. There was a significant reduction from the first to the fifth year in records that only contained a pituitary tumour code (63.7%–47.0%, p < .001). The use of procedure codes that attracted the highest tariff increased over time (66.4%–82.4%, p < .001). Patterns of coding varied widely between the 24 neurosurgical units. Conclusion The quality of HES data on pituitary surgery has improved over time but there is wide variation in the quality of data between neurosurgical units. Research studies and quality improvement programmes using these data need to check it is of sufficient quality to not invalidate their results

Polyelectrolyte Complex Templated Synthesis of Monodisperse, Sub-100 nm Porous Silica Nanoparticles for Cancer Targeted and Stimuli-Responsive Drug Delivery

Porous silica nanoparticles (PSiNPs) have long attracted interest in drug delivery research. However, conventional synthesis methods for sub-100 nm, functionalised PSiNPs typically give poor monodispersity, reproducibility, or involve complex synthetic protocols. We report a facile, reproducible, and cost-effective one-pot method for the synthesis of cancer targeting and pH responsive PSiNPs in this size range, without the need for post-synthetic modification. This was achieved by using monodisperse L-arginine (Arg)/ poly(acrylic acid) (PAA) polyelectrolyte complexes (PECs) as soft templates for silane hydrolysis and condensation. Highly uniform PSiNPs with tunable size control between 42 and 178 nm and disordered pore structure (1.1–2.7 nm) were obtained. Both PAA and Arg were retained within the PSiNPs, which enabled a high doxorubicin hydrochloride (Dox) loading capacity (22% w/w) and a 4-fold increase in drug release under weakly acidic pH compared to physiological pH. The surface presentation of Arg conferred significantly higher intracellular accumulation of Arg/PAA-PSiNPs in patient-derived glioblastoma cells compared to non-tumorigenic neural progenitor cells, which effectively translated to lower IC50 values for Dox-loaded Arg/PAA-PSiNPs than non-functionalised PSiNPs. This work brings forward new insights for the development of monodisperse PSiNPs with highly desirable built-in functionalities for biomedical applications

Symplastic scrotal leiomyoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Scrotal leiomyomas are rare tumours which are essentially benign. Recurrence and malignant transformation to leiomyosarcoma have been reported. However, a specific subgroup with increased bizarre nuclei showing increased mitosis raises the need for a closer follow-up. We report on such a case.</p> <p>Case presentation</p> <p>We report the case of a 65-year-old man who underwent a scrotal lump excision. Histology showed a well defined leiomyoma. The presence of nuclear pleomorphism and mitoses, just falling short of the criteria for malignancy, made prediction of biological behaviour difficult. The patient remains well on 4-year follow-up.</p> <p>Conclusion</p> <p>Histological evidence of increased mitosis raises the need for sustained follow-up in view of the malignant potential from the extent of mitosis. Immunohistochemistry helps in identifying those patients warranting close follow-up.</p

External validation and recalibration of an incidental meningioma prognostic model – IMPACT: protocol for an international multicentre retrospective cohort study

Introduction: Due to the increased use of CT and MRI, the prevalence of incidental findings on brain scans is increasing. Meningioma, the most common primary brain tumour, is a frequently encountered incidental finding, with an estimated prevalence of 3/1000. The management of incidental meningioma varies widely with active clinical-radiological monitoring being the most accepted method by clinicians. Duration of monitoring and time intervals for assessment, however, are not well defined. To this end, we have recently developed a statistical model of progression risk based on single-centre retrospective data. The model Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and MRI Tests (IMPACT) employs baseline clinical and imaging features to categorise the patient with an incidental meningioma into one of three risk groups: low, medium and high risk with a proposed active monitoring strategy based on the risk and temporal trajectory of progression, accounting for actuarial life expectancy. The primary aim of this study is to assess the external validity of this model. Methods and analysis: IMPACT is a retrospective multicentre study which will aim to include 1500 patients with an incidental intracranial meningioma, powered to detect a 10% progression risk. Adult patients ≥16 years diagnosed with an incidental meningioma between 1 January 2009 and 31 December 2010 will be included. Clinical and radiological data will be collected longitudinally until the patient reaches one of the study endpoints: intervention (surgery, stereotactic radiosurgery or fractionated radiotherapy), mortality or last date of follow-up. Data will be uploaded to an online Research Electronic Data Capture database with no unique identifiers. External validity of IMPACT will be tested using established statistical methods. Ethics and dissemination: Local institutional approval at each participating centre will be required. Results of the study will be reported through peer-reviewed articles and conferences and disseminated to participating centres, patients and the public using social media

Hematopoietic stem cell gene therapy for brain metastases using myeloid cell-specific gene promoters

Background: Brain metastases (BrM) develop in 20-40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain due to the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems. Methods: Green fluorescent protein (GFP)-transduced murine and non-transduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene expression analysis and subsequent validation of a series of promoter-GFP-reporter constructs in mice (n = 5). One of the promoters was used to deliver TNF-related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL versus control group). Results: HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (37.6% [SD = 7.2%] of all infiltrating cells for murine HSC progeny; 27.9% [SD = 4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3-53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (8.8%, SD = 7.8%). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (19.0 [SD = 3.4] versus 15.0 [SD = 2.0] days for TRAIL versus control group; two-sided p = 0.006), demonstrating therapeutic and translational potential of our approach. Conclusions: Our study establishes HSC gene therapy using a myeloid cell-specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions

CONSORT recommendations in abstracts of randomised, controlled trials on migraine and headache

A CONSORT statement on the content of abstracts of randomised, controlled trials (RCTs) was published in 2008. I therefore reviewed the abstracts from 2009 to 2010 published on RCTs in Cephalalgia, Headache and other (non-headache) journals. The following items were reviewed: number of patients, reporting of response either in percentages or absolute values, the use of p values, and effect size with its precision. The latter was recommended in the CONSORT statement. A total of 46 abstracts were reviewed and effect size with 95% confidence intervals was only reported in seven abstracts. The influence of the CONSORT statement on reporting in abstracts has so far only had a limited influence on the headache literature