bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurocognition and quality of life in patients with intracranial metastases – contributing factors and impact on clinical outcome
Authors: Iqbal Najmus , Daisley-Devoy Tara , Smalley Michelle , Johnson Anne , Staffurth John , Wise Richard , Powell James 
Published: October 2019

Abstract
Cognitive impairment at diagnosis is prevalent in patients with brain metastases (BM). Neurocognitive function (NCF) decline following radiotherapy is well described in this patient cohort, but the impact of baseline NCF on clinical outcome and survival is less well understood. In this study we describe NCF in patients at baseline before undergoing stereotactic radiosurgery without whole brain radiotherapy and explore its impact on overall survival and explore possible causative factors.
Baseline NCF data was collected in patients with 1–3 BM and WHO performance status 0–2. Patients underwent NCF assessments according to the RANO group and included Hopkin’s verbal learning test, controlled oral word association test, trail making test A and B and digit span. We collected quality of life (QoL) data using EORTC QLQ30/BN20 questionnaires and recorded functional assessment of cancer therapy scores.
31 patients underwent neurocognitive testing with mean age of 65 years and median overall survival was 10 months. 21 patients had a single metastasis. The most common primary site was lung (12) followed by melanoma (7). 64% of patients exhibited impaired NCF at baseline in at least 1 domain with a Z-score of >1 and this was associated with lower overall survival. Other factors associated with lower overall survival were presence of seizures, steroid use and larger tumour volume.
In this study impaired NCF at baseline was associated with lower overall survival. Intracranial disease burden and the presence of seizures were also associated with worse NCF and worse survival indicating that these may be important causative factors to consider.
Determination of meningioma brain tissue grades using Raman hyperspectral imaging
Authors: De Lelis Medeiros De Morais Camilo , Lilo Taha , Ashton Katherine , Davis Charles , Dawson Timothy , Gurusinghe Nihal , Martin Francis 
Published: October 2019

Abstract
Raman spectroscopy is a powerful tool used to analyse biological materials, where spectral biomarkers such as proteins (1500–1700 cm-1), carbohydrates (470–1200 cm-1) and phosphate groups of DNA (980, 1080–1240 cm-1) can be detected. A major advantage is that it is reagent-free and unaffected by water interference, which is ideal for biological applications. Raman hyperspectral imaging combines the chemical sensitivity of this spectrochemical technique with spatially distributed information. Herein, Raman microspectroscopy imaging (50 × 50 μm tissue area, 50× magnification, 50% laser power, 0.1 ms exposure time, 780–1858 cm-1 spectral range) was used to investigate 79 brain tissue samples (sourced from the Brain Tumour North West) in order to differentiate meningioma Grade I (n=55) versus Grade II (n=24). Meningioma is the commonest type of brain tumour with the majority of them being benign tumours (Grade I) whilst a few are aggressive or malignant (Grade II). Grade II tumours have a poor prognosis by their nature, hence new sensitive diagnostic tools are essential. Using partial least squares discriminant analysis (PLS-DA) with 20 LVs (99% explained variance), we were able to differentiate Grade I versus Grade II meningioma with a classification accuracy of 99% in an internal validation set of 23 samples (16 Grade I, seven Grade II); this was with an accuracy of 85% for an external test set of similar size. These findings highlight the potential of Raman hyperspectral imaging for differentiation of meningioma tumours.
A pilot study to establish non-invasive biomarkers for higher-grade meningioma
Authors: Baiz Daniele , Negroni Caterina , Ercolano Emanuela , L Adams Claire , Kurian Kathreena M , A Hilton David , Hanemann Oliver C 
Published: October 2019

Abstract

Introduction
Meningioma brain tumours are the most common primary tumour in adults. Despite surgery and/or radiation therapy, meningioma may recur. The 5-year recurrence rate in benign meningioma is estimated in about 10% while much greater in atypical and malignant tumours. MicroRNAs (miRNAs) represent a large class of small RNAs driving regulation of gene expression and playing a role in tumour progression and therefore proposed as diagnostic tools. Moreover, miRNAs can be released from tumour cells into the blood stream via exosomes, showing potential to be used as liquid biopsies.

Methods
Identification of novel circulating biomarkers was conducted by performing an unbiased Cancer MicroRNA qPCR Array, followed by bioinformatics analysis. In parallel, we conducted a biased in silico analysis of the miRNAs targeting Cyclin D1 and E1, recently proposed as immunohistochemical meningioma biomarkers. Validation studies performed using TaqMan® reagents.

Results
Stringent unbiased (p<0.01) miRNA profiling followed by validation in ex vivo samples revealed that the miR-9-1 is upregulated in higher-grade meningioma tissues and serum exosomes, controlled by the EGFR/AP-1 axis and correlated with lower levels of E-Cadherin, a proposed biomarker for malignant meningioma. On the contrary, biased analysis, followed by validation in vitro and ex vivo, showed that the miR-497~195 cluster is downregulated in higher-grade meningioma tissues and serum exosomes, correlating with the overexpression of GATA-4, a novel meningioma tissue biomarker.

Conclusion
Our data demonstrated that both miR-497~195 and miR-9-1 show potential to become promising non-invasive biomarkers for higher-grade meningioma, reflecting their expression status in tissues.
(DB and CN contributed equally).
Patient engagement in the design of a randomised trial of proton beam radiotherapy versus photon radiotherapy for good prognosis glioma
Authors: Powell James R , Murray Louise , Burnet Neil , Fernandez Sharon , McParland Lucy , O’Hara Daniel , Lingard Zoe , Whitfield Gillian , Short Susan C 
Published: October 2019

Abstract

Introduction
UK Neuro-Oncologists and multidisciplinary colleagues are developing one of the first randomised clinical trials of proton beam radiotherapy(PBT) to compare quality of life(QOL), cognitive function and other late effects in adults with good prognosis glioma following either PBT or photon radiotherapy. The feasibility of running randomised studies with PBT is an important consideration, particularly in respect of participants’ views of a randomised design requiring treatment at national centres. We sought patient and carer engagement on our proposals to ensure we incorporate their views.

Methods
To explore these issues, we invited patients who had previously completed radiotherapy for oligodendroglioma and their carers to attend a focus group in Manchester in November 2018. Fifteen participants attended. We sought views on our trial proposal through small group discussions centred around 5 questions, led and facilitated by neuro-oncologists, a research radiographer, neuro-psychologist and statistician.

Results
Participants strongly endorsed the trial proposal and positively highlighted the opportunity to access PBT within a clinical trial and the group recognised and supported the need for randomisation and stated this should be 1:1. Patients disliked some traditional terminology such as ‘trial’ and ‘neurocognitive tests’ and preferred ‘research study’ and ‘neurocognitive assessments’. Patient and carers expressed the need for careful consideration of issues around travel and accommodation during PBT away from home. Interestingly, participants considered that standard QOL questionnaires fail to address some important areas reflecting daily wellbeing.

Conclusion
We acknowledge and will now incorporate these important patient and carer observations to strengthen our study and add validity to the key study endpoints.
The Collagen-Prolyl Hydroxylases promote proliferation and invasion in GBM
Authors: Castellano Elena , Atkinson Aithne , O’Neill Kevin , Syed Nelofer 
Published: October 2019

Abstract
Glioblastoma Multiforme (GBM) is the most aggressive form of brain tumour, with a median survival time of just 14 months. Current standard therapy includes surgical excision, followed by chemotherapy and radiotherapy, however complete surgical excision is not usually possible due to the diffuse and infiltrative nature of the disease. To combat this, therapies inhibiting the invasion of leader migratory cells are an attractive area of research. The collagen prolyl-4 hydroxylases (C-P4Hs) are a family of proteins which catalyse the hydroxylation of proline residues on pre-pro-collagen, leading to the formation of the stable triple-helical structure of functional collagen. Collagen is a highly abundant protein, and important in several oncogenic cellular processes including proliferation, invasion and migration. We hypothesis that by inhibiting the C-P4Hs, the pro-tumorigenic effect of collagen will be inhibited in GBM. To explore this, we treated cells with ethyl 3,4-dihydroxybenzoate (EDHB) (a C-P4H inhibitor) and observed the resultant effect in GBM cells lines and primary cells through proliferation assays and 3D tumour spheroid invasion assays. Our results indicate that the addition of EDHB significantly reduces proliferation and invasion in both cell lines and primary GBM samples. Furthermore, we show that the C-P4Hs are upregulated in hypoxic conditions, which are commonly found in the clinical tumour microenvironment. Our study reveals that the C-P4H proteins may be an attractive therapeutic target to reduce invasion and proliferation and may be especially attractive as adjuvants with a cytotoxic agent such as temozolomide.
Real-world experience with Temozolomide & Sativex in patients with recurrent High Grade Gliomas
Authors: Shahabi Lillie , Le Calvez Kerlann , Dadhania Seema , Blake Catherine , Wang James , Ingle Manasi , Anichini Giulio , Peterson David , Nandi Dipankar , Camp Sophie , Saleem Waqar , Falconer Alison , O’Neill Kevin , Williams Matt 
Published: October 2019

Abstract

Background
Glioblastoma (GBM) is the most common malignant brain tumour in adults with a median survival from progression of 8 months. A recent phase 1 study of temozolomide (TMZ) and 1:1 CBD:THC (Sativex) offers evidence of efficacy in patients with recurrent GBM (NCT01812603).

Methods
All patients receiving TMZ & Sativex (75mg/m2 daily d1 – 21 q28; Sativex continuously) for relapsed GBM or grade 3 astrocytoma at our centre were identified. Patient, tumor and treatment characteristics were recorded, and response based on sequential MRI scans using modified RANO criteria assessed.

Results
13 patients were treated over 18 months. The median age was 56; 69% were male. All had received initial chemo-radiotherapy (12 patients: 60 or 59.4Gy/30–33#; 1 patient: 45Gy/15#). 6 patients underwent reresection at recurrence. 4 patients were treated at first progression, 7 at second progression, and 2 at third or later progression. The median number of cycles of TMZ and sativex was 2. The combination treatment was tolerated well by all patients treated, with no Grade 3 or 4 toxicities, the only complaints being of discomfort in mouth after spray and ‘spaced out feeling’. Patients stopped treatment due to evidence of progressive disease on sequential MRI sign or physical deterioration. Median Overall Survival (OS) from initiation was 5.9 months (177 days); Progression Free Surival (PFS) at 3 months was 50%.

Conclusion
These results highlight some discrepancies in OS in comparison to the previous trial (NCT01812603), but our patients were treated at second/ third recurrence. We agree that the combination is well tolerated.
Effectiveness of BRAF inhibitors in patients with BRAF V600 mutation positive glioma: a systematic review
Authors: Yao Ian , Dawson Sarah , Higgins Julian , McGuinness Luke , McAleenan Alexandra , Kurian Kathreena M 
Published: October 2019

Abstract

Background
BRAF inhibitor treatment with vemurafenib and dabrafenib have produced significant increases in median overall survival for BRAF V600 mutation-positive melanoma patients and are in wide clinical use. BRAF inhibitors have also been used in an ad hoc fashion in BRAF V600 mutation-positive glioma in a number of glioma subtypes with varying prognoses.

Methods
An electronic search was performed on MEDLINE and Embase on February 1, 2019 to identify studies of any design that reported the outcome of patients with BRAF V600 mutation-positive glioma treated with BRAF inhibitors. Data was collected for demographic information, tumour information (type and grading), BRAF mutation type, prior treatment regimens, type of BRAF inhibitor, dose and duration of treatment, best objective response, progression free survival (PFS), overall survival (OS), glioma specific symptomatic relief and adverse events.

Preliminary Results
Seventy-nine case reports, case series and single arm cohort studies with a total of 286 patients were included. Duration of treatment was available for 197 patients and varied from 0.1 to 54 months, with 104 patients still undergoing treatment at the time of publication. Progression occurred in 158 patients (including both low-grade and high-grade glioma) at between 0.805 and 36 months following the start of treatment. 34 people died, at between 0.329 and 40.1 months following the start of treatment.

Conclusions
Our systematic review shows varying clinical effectiveness of BRAF inhibitors in BRAF V600 mutation-positive glioma depending on low-grade or high-grade glioma. This evidence may inform future trials of BRAF inhibitors for glioma patients.
Management and outcomes of meningiomas secondary to childhood and adolescent radiation treatment
Authors: Gillespie Conor , Islim Abdurrahman , Kumar Siddhant , Rathi Nitika , Gilkes Catherine , Chavredakis Emmanuel , Lawson David , Mills Samantha , Brodbelt Andrew , Jenkinson Michael 
Published: October 2019

Abstract

Background
With the increased rate of childhood cancer survivors, a marked rise in the incidence of secondary intracranial meningiomas has been established.

Objective
Determine the outcomes of patients diagnosed with radiation-induced meningiomas (RIM).

Methods
Single-centre retrospective cohort study of patients with new or recurrent RIM (2007–2018).

Results
47 patients were identified (21 females). Mean age at radiation was 15 years (SD=14) and the most common indications were leukaemia (n=8) and childhood brain tumours (n=35; medulloblastoma and pilocytic astrocytoma (n=7 each)). 93 de-novo meningiomas were identified. The median latency period between radiation and diagnosis was 28.5 years (IQR 22–37). 61% were asymptomatic whilst the remainder manifested headache (20%), focal neurological deficit (12%) and epilepsy (5%). 32 operated de-novo RIM revealed WHO grade I (n=19; 59%), WHO grade II (n=11; 34%) and 2 intraosseous meningiomas (n=2; 6%). After a median of 5 years (IQR 3–10), 9 (28%) operated RIM recurred/progressed. At recurrence, 5 were operated (3 WHO grade I, 2 WHO grade II and 1 WHO grade III), 2 patients were palliated and 2 remain under active observation. By the end of the study period, 20 patients were harbouring multiple meningiomas and 8 patients were deceased.

Conclusion
Radiation-induced meningioma should be monitored until symptomatic. Operated RIMs have a high recurrence rate. Further radiotherapy is not effective. Further clinical and genetic analyses as part of an international multi-centre collaboration are planned.
A Bioinformatics Approach to Establishing Novel Transforming Growth Factor-Beta Target Genes in Glioblastoma.
Authors: Willison Alice , Taylor Richard , Hossain-Ibrahim Kismet , Inman Gareth 
Published: October 2019

Abstract

Introduction
TGFβ inhibition is becoming an increasingly exciting prospect for the treatment of glioblastoma (GBM) as more about its efficacy is understood. However, there is little demonstrated improvement in patient outcomes from clinical trials using small molecule inhibitors of the TGFβ receptors. Clearly, the potential of TGFβ therapy has not yet been realised. We scrutinised the TGFβ canonical genes at a cytogenetic, genetic and gene expression level for novel therapeutic targets.

Materials and Methods
10 canonical TGFβ genes were analysed. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature and graphics generated using the Cytogenetic Data Analysis System. Analysis and generation of graphics were carried out using The Cancer Genome Atlas (TCGA) Provisional Glioblastoma set of 290 whole-exome-sequenced tumours via cBioPortal. mRNA expression data were extracted from The Cancer Genome Atlas (TCGA) via cBioPortal. Kaplan-Meier graphs were generated using GraphPad Prism®, for which pairwise log rank comparisons were conducted to determine a difference in both overall survival (OS) and disease-free, progression-free (DFPF) survival.

Results
At cytogenetic and genetic levels, TGFβ genes are not markedly altered in GBM. However, mRNA expression of TGFβ2 is enhanced in GBM compared to other cancers. In addition, we correlated upregulation of both SMAD7 and SARA with improved OS and upregulation of SARA with improved DFPF survival.

Conclusions
TGFβ2 upregulation may be associated with GBM tumourigenesis and SMAD7 and SARA upregulation may be associated with improved survival. We demonstrate that three canonical genes have therapeutic potential, but their conflicting roles must be further understood before TGFβ-modulating therapies are successful.
Mass production of 2D materials by intermediate-assisted grinding exfoliation
Authors: Zhang Chi , Tan Junyang , Pan Yikun , Cai Xingke , Zou Xiaolong , Cheng Hui-Ming , Liu Bilu 
Published: October 2019

AbstractThe scalable and high-efficiency production of 2D materials is a prerequisite to their commercial use. Currently, only graphene and graphene oxide can be produced on a ton scale, and the inability to produce other 2D materials on such a large scale hinders their technological applications. Here we report a grinding exfoliation method that uses micro-particles as force intermediates to resolve applied compressive forces into a multitude of small shear forces, inducing the highly efficient exfoliation of layer materials. The method, referred to as intermediate-assisted grinding exfoliation (iMAGE), can be used for the large-scale production of many 2D materials. As an example, we have exfoliated bulk h-BN into 2D h-BN with large flake sizes, high quality and structural integrity, with a high exfoliation yield of 67%, a high production rate of 0.3 g h−1 and a low energy consumption of 3.01 × 106 J g−1. The production rate and energy consumption are one to two orders of magnitude better than previous results. Besides h-BN, this iMAGE technology has been used to exfoliate various layer materials such as graphite, black phosphorus, transition metal dichalcogenides, and metal oxides, proving its universality. Molybdenite concentrate, a natural low-cost and abundant mineral, was used as a demo for the large-scale exfoliation production of 2D MoS2 flakes. Our work indicates the huge potential of the iMAGE method to produce large amounts of various 2D materials, which paves the way for their commercial application.
Risk Factors for BI/NAP1/027 Clostridioides difficile Infections and Clinical Outcomes Compared With Non-NAP1 Strains
Authors: Mani Nandita S , Lynch John B , Fang Ferric C , Chan Jeannie D 
Published: October 2019

Abstract
We aim to describe the characteristics, risk factors, and clinical outcomes associated with NAP1 strain Clostridioides difficile infection (CDI) in this single-center, retrospective, case–control (1:1) study. We found that the NAP1 strain accounted for 19.7% of CDI, and risk factors for acquisition included residence in skilled nursing facilities, previous CDI, and proton pump inhibitor use.
Mini-Open Lateral Corpectomy for Thoracolumbar Junction Lesions
Authors: Huangxs Shengbin , Christiansen Peter A , Tan Haitao , Smith Justin S , Shaffrey Mark E , Uribe Juan S , Shaffrey Christopher I , Yen Chun-Po 
Published: October 2019

Abstract

BACKGROUND
Neoplastic, traumatic, infectious, and degenerative pathologies affecting the thoracolumbar junction pose a unique challenge to spine surgeons. Posterior or anterior approaches have traditionally been utilized to treat these lesions. Although minimally invasive surgeries through a lateral approach to the thoracic or lumbar spine have gained popularity, lateral access to the thoracolumbar junction remains technically challenging due to the overlying diaphragm positioned at the interface of the peritoneum and pleura.

OBJECTIVE
To describe a mini-open lateral retropleural retroperitoneal approach for pathologies with spinal cord/cauda equina compression at the thoracolumbar junction.

METHODS
A mini-open lateral corpectomy is described in detail in a patient with an L1 metastatic tumor.

RESULTS
Satisfactory decompression and spinal column reconstruction were achieved. The patient obtained neural function recovery following the procedure with no intra- or postoperative complications.

CONCLUSION
The morbidities associated with traditional posterior or anterior approaches to thoracolumbar junction pathologies have led to a growing interest in minimally invasive alternatives. The mini-open lateral approach allows for a safe and efficacious corpectomy and reconstruction for thoracolumbar junction pathologies. Thorough understanding of the anatomy, particularly of the diaphragm, is critical. This approach will have expanded roles in the management of patients with thoracolumbar neoplasms, fractures, infections, deformities, or degenerative diseases.
Tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex
Authors: Koo Chek Ziu , Harrison Neale , Noy Peter J. , Szyroka Justyna , Matthews Alexandra L. , Hsia Hung-En , Mueller Stephan A. , Tüshaus Johanna , Goulding Joelle , Willis Katie , Apicella Clara , Cragoe Bethany , Davis Edward , Keles Murat , Malinova Antonia , McFarlane Thomas A. , Morrison Philip R. , Sykes Michael C. , Ahmed Haroon , Di Maio Alessandro , Seipold Lisa , Saftig Paul , Cull Eleanor , Rubinstein Eric , Poulter Natalie S. , Briddon Stephen J. , Holliday Nicholas D. , Lichtenthaler Stefan F. , Tomlinson Michael G. 
Published: October 2019

AbstractA disintegrin and metalloprotease 10 (ADAM10) is essential for embryonic development and impacts on diseases such as cancer, Alzheimer’s and inflammatory diseases. ADAM10 is a ‘molecular scissor’ that proteolytically cleaves the extracellular region from over 100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors and chemokines. ADAM10 was recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function is critically dependent on a TspanC8 partner. To address this, we generated the first monoclonal antibodies to Tspan15 as a model TspanC8. These were used to show that ADAM10 is the principal Tspan15-interacting protein, that Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Together these findings suggest that ADAM10 exists as an intimate ADAM10/TspanC8 scissor complex.