Management of glioblastoma in elderly patients: A review of the literature.

High grade gliomas are the most common primary aggressive brain tumours with a very poor prognosis and a median survival of less than 2 years. The standard management protocol of newly diagnosed glioblastoma patients involves surgery followed by radiotherapy, chemotherapy in the form of temozolomide and further adjuvant temozolomide. The recent advances in molecular profiling of high-grade gliomas have further enhanced our understanding of the disease. Although the management of glioblastoma is standardised in newly diagnosed adult patients there is a lot of debate regarding the best treatment approach for the newly diagnosed elderly glioblastoma patients. In this review article we attempt to summarise the findings regarding surgery, radiotherapy, chemotherapy, and their combination in order to offer the best possible management modality for this group of patients. Elderly patients 65-70 with an excellent functional level could be considered as candidates for the standards treatment consisting of surgery, standard radiotherapy with concomitant and adjuvant temozolomide. Similarly, elderly patients above 70 with good functional status could receive the above with the exception of receiving a shorter course of radiotherapy instead of standard. In elderly GBM patients with poorer functional status and MGMT promoter methylation temozolomide chemotherapy can be considered. For elderly patients who cannot tolerate chemotherapy, hypofractionated radiotherapy is an option. In contrast to the younger adult patients, it seems that a careful individualised approach is a key element in deciding the best treatment options for this group of patients.

Thymic epithelial tumour radiotherapy in the UK: A survey of current clinical practice.

Significant variation in treatment centre setup and radiotherapy practice for thymic epithelial tumours (TET) was identified through a comprehensive survey of current UK Clinical (Radiation) Oncology practice. Multi-centre collaboration and wider TET specific multidisciplinary team meetings are needed and will be essential for developing expertise in TET radiotherapy.

Allocoprobacillus halotolerans gen. nov., sp. nov and Coprobacter tertius sp. nov., isolated from human gut microbiota.

Two novel bacterial isolates were cultured from faecal samples of patients attending the Breast Care clinic at the Norwich and Norfolk University Hospital. Strain LH1062T was isolated from a 58-year-old female diagnosed with invasive adenocarcinoma with ductal carcinoma in situ. Strain LH1063T was isolated from a healthy 51-year-old female. Isolate LH1062T was predicted to be a potential novel genus most closely related to Coprobacillus, whilst LH1063T was predicted to be a novel species belonging to Coprobacter. Both strains were characterized by polyphasic approaches including 16S rRNA gene analysis, core-genome analysis, average nucleotide identity (ANI) comparisons and phenotypic analysis. Initial screening of the 16S rRNA gene of LH1062T returned a nucleotide identity of 93.4 % to Longibaculum muris. For LH1063T, nucleotide identity was a 92.6 % to Coprobacter secundus. Further investigations showed that LH1062T had a genome size of 2.9 Mb and G+C content of 31.3 mol %. LH1063T had a genome size of 3.3Mb and G+C content of 39.2 mol %. Digital DNA-DNA hybridization (dDDH) and ANI values of LH1062T with its closest relative, Coprobacillus cateniformis JCM 10604T, were 20.9 and 79.54 %, respectively. For LH1063T, the dDDH and ANI values with its closest relative, Coprobacter secundus 177T, were 19.3 and 77.81 %, respectively. Phenotypic testing confirmed that LH1062T could not be matched to a known validly published isolate in any database; thereby indicating a novel genus for which the name Allocoprobacillus gen. nov. is now proposed with LH1062T (=DSM 114537T=NCTC 14686T) being the type strain of the proposed novel species Allocoprobacillus halotolerans sp. nov. Strain LH1063T (=DSM 114538T=NCTC 14698T) fits within the genus Coprobacter and, it being the third species within this genus, the name Coprobacter tertius sp. nov. is proposed.

Global funding for cancer research between 2016 and 2020: a content analysis of public and philanthropic investments.

BACKGROUND: Cancer is a leading cause of disease burden globally, with more than 19·3 million cases and 10 million deaths recorded in 2020. Research is crucial to understanding the determinants of cancer and the effects of interventions, and to improving outcomes. We aimed to analyse global patterns of public and philanthropic investment in cancer research. METHODS: In this content analysis, we searched the UberResearch Dimensions database and Cancer Research UK data for human cancer research funding awards from public and philanthropic funders between Jan 1, 2016, and Dec 31, 2020. Included award types were project and programme grants, fellowships, pump priming, and pilot projects. Awards focused on operational delivery of cancer care were excluded. Awards were categorised by cancer type, cross-cutting research theme, and research phase. Funding amount was compared with global burden of specific cancers, measured by disability-adjusted life-years, years lived with disability, and mortality using data from the Global Burden of Disease study. FINDINGS: We identified 66 388 awards with total investment of about US$24·5 billion in 2016-20. Investment decreased year-on-year, with the largest drop observed between 2019 and 2020. Pre-clinical research received 73·5% of the funding across the 5 years ($18 billion), phase 1-4 clinical trials received 7·4% ($1·8 billion), public health research received 9·4% ($2·3 billion), and cross-disciplinary research received 5·0% ($1·2 billion). General cancer research received the largest investment ($7·1 billion, 29·2% of the total funding). The most highly funded cancer types were breast cancer ($2·7 billion [11·2%]), haematological cancer ($2·3 billion [9·4%]), and brain cancer ($1·3 billion [5·5%]). Analysis by cross-cutting theme revealed that 41·2% of investment ($9·6 billion) went to cancer biology research, 19·6% ($4·6 billion) to drug treatment research, and 12·1% ($2·8 billion) to immuno-oncology. 1·4% of the total funding ($0·3 billion) was spent on surgery research, 2·8% ($0·7 billion) was spent on radiotherapy research, and 0·5% ($0·1 billion) was spent on global health studies. INTERPRETATION: Cancer research funding must be aligned with the global burden of cancer with more equitable funding for cancer research in low-income and middle-income countries (which account for 80% of cancer burden), both to support research relevant to these settings, and build research capacity within these countries. There is an urgent need to prioritise investment in surgery and radiotherapy research given their primacy in the treatment of many solid tumours. FUNDING: None.

Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains.

Clostridium perfringens is an anaerobic toxin-producing bacterium associated with intestinal diseases, particularly in neonatal humans and animals. Infant gut microbiome studies have recently indicated a link between C. perfringens and the preterm infant disease necrotizing enterocolitis (NEC), with specific NEC cases associated with overabundant C. perfringens termed C. perfringens-associated NEC (CPA-NEC). In the present study, we carried out whole-genome sequencing of 272 C. perfringens isolates from 70 infants across 5 hospitals in the United Kingdom. In this retrospective analysis, we performed in-depth genomic analyses (virulence profiling, strain tracking and plasmid analysis) and experimentally characterized pathogenic traits of 31 strains, including 4 from CPA-NEC patients. We found that the gene encoding toxin perfringolysin O, pfoA, was largely deficient in a human-derived hypovirulent lineage, as well as certain colonization factors, in contrast to typical pfoA-encoding virulent lineages. We determined that infant-associated pfoA+ strains caused significantly more cellular damage than pfoA- strains in vitro, and further confirmed this virulence trait in vivo using an oral-challenge C57BL/6 murine model. These findings suggest both the importance of pfoA+ C. perfringens as a gut pathogen in preterm infants and areas for further investigation, including potential intervention and therapeutic strategies.

Reciprocal Interactions Between the Gut Microbiome and Mammary Tissue Mast Cells Promote Metastatic Dissemination of HR+ Breast Tumors.

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, before breast tumor initiation, enhances early dissemination of hormone receptor-positive (HR+) mammary tumor cells. Here, we sought to determine whether cellular changes occurring in normal mammary tissues, before tumor initiation and in response to dysbiosis, enhanced dissemination of HR+ tumors. Commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in normal, non-tumor-bearing mammary tissues, a phenotypic change that persisted after tumor implantation. Pharmacological and adoptive transfer approaches demonstrated that profibrogenic mammary tissue mast cells from dysbiotic animals were sufficient to enhance dissemination of HR+ tumor cells. Using archival HR+ patient samples, we determined that enhanced collagen levels in tumor-adjacent mammary tissue positively correlated with mast cell abundance and HR+ breast cancer recurrence. Together, these data demonstrate that mast cells programmed by commensal dysbiosis activate mammary tissue fibroblasts and orchestrate early dissemination of HR+ breast tumors.

Using Immortalized Endothelial Cells to Study the Roles of Adhesion Molecules in VEGF-Induced Signaling.

The ability to study the role of specific genes in endothelial cell biology is made possible by our ability to modulate their expression through siRNA or knockout technologies. However, many in vitro protocols, particularly those of a biochemical nature, require large numbers of endothelial cells. These types of analyses are encumbered by the need to repeatedly produce and characterize primary endothelial cell cultures and can be greatly facilitated by the use of immortalized microvascular endothelial cells. However, we have found that the manipulation of gene expression in these cells is not always straight forward. Here we describe how we alter gene expression in polyoma middle T antigen immortalized microvascular endothelial cells isolated from wild-type and genetically modified mice to study the role of cell adhesion molecules in downstream assays.

Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis.

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known coreceptors for VEGFRs, core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathologic angiogenesis. Here we demonstrate, using NRP1 ECKO , NRP2 ECKO , and NRP1/NRP2 ECKO mouse models, that maximum inhibition of primary tumor development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2 ECKO animals. Mechanistic studies revealed that codepleting NRP1 and NRP2 in mouse-microvascular endothelial cells stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumor angiogenesis. Significance: The findings presented in this study demonstrate that tumor angiogenesis and growth can be arrested completely by cotargeting endothelial NRP1 and NRP2. We provide new insight into the mechanisms of action regulating NRP-dependent tumor angiogenesis and signpost a novel approach to halt tumor progression.

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth.

The gut microbiota's function in regulating health has seen it linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer (BrCa). This study found that antibiotic-induced perturbation of the gut microbiota significantly increases tumor progression in multiple BrCa mouse models. Metagenomics highlights the common loss of several bacterial species following antibiotic administration. One such bacteria, Faecalibaculum rodentium, rescued this increased tumor growth. Single-cell transcriptomics identified an increased number of cells with a stromal signature in tumors, and subsequent histology revealed an increased abundance of mast cells in the tumor stromal regions. We show that administration of a mast cell stabilizer, cromolyn, rescues increased tumor growth in antibiotic treated animals but has no influence on tumors from control cohorts. These findings highlight that BrCa-microbiota interactions are different from other cancers studied to date and suggest new research avenues for therapy development.

Endothelial neuropilin-2 influences angiogenesis by regulating actin pattern development and α5-integrin-p-FAK complex recruitment to assembling adhesion sites.

The ability to form a variety of cell-matrix connections is crucial for angiogenesis to take place. Without stable anchorage to the extracellular matrix (ECM), endothelial cells (ECs) are unable to sense, integrate and disseminate growth factor stimulated responses that drive growth of a vascular bed. Neuropilin-2 (NRP2) is a widely expressed membrane-bound multifunctional non-tyrosine kinase receptor, which has previously been implicated in influencing cell adhesion and migration by interacting with α5-integrin and regulating adhesion turnover. α5-integrin, and its ECM ligand fibronectin (FN) are both known to be upregulated during the formation of neo-vasculature. Despite being descriptively annotated as a candidate biomarker for aggressive cancer phenotypes, the EC-specific roles for NRP2 during developmental and pathological angiogenesis remain unexplored. The data reported here support a model whereby NRP2 actively promotes EC adhesion and migration by regulating dynamic cytoskeletal remodeling and by stimulating Rab11-dependent recycling of α5-integrin-p-FAK complexes to newly assembling adhesion sites. Furthermore, temporal depletion of EC-NRP2 in vivo impairs primary tumor growth by disrupting vessel formation. We also demonstrate that EC-NRP2 is required for normal postnatal retinal vascular development, specifically by regulating cell-matrix adhesion. Upon loss of endothelial NRP2, vascular outgrowth from the optic nerve during superficial plexus formation is disrupted, likely due to reduced FAK phosphorylation within sprouting tip cells.

Exploring the impact of gut microbiota and diet on breast cancer risk and progression.

There is emerging evidence that resident microbiota communities, that is, the microbiota, play a key role in cancer outcomes and anticancer responses. Although this has been relatively well studied in colorectal cancer and melanoma, other cancers, such as breast cancer (BrCa), have been largely overlooked to date. Importantly, many of the environmental factors associated with BrCa incidence and progression are also known to impact the microbiota, for example, diet and antibiotics. Here, we explore BrCa risk factors from large epidemiology studies and microbiota associations, and more recent studies that have directly profiled BrCa patients' gut microbiotas. We also discuss how in vivo studies have begun to unravel the immune mechanisms whereby the microbiota may influence BrCa responses, and finally we examine how diet and specific nutrients are also linked to BrCa outcomes. We also consider future research avenues and important considerations with respect to study design and implementation, and we highlight some of the important unresolved questions, which currently limit our overall understanding of the mechanisms underpinning microbiota-BrCa responses.

NRP2 as an Emerging Angiogenic Player; Promoting Endothelial Cell Adhesion and Migration by Regulating Recycling of α5 Integrin.

Angiogenesis relies on the ability of endothelial cells (ECs) to migrate over the extracellular matrix via integrin receptors to respond to an angiogenic stimulus. Of the two neuropilin (NRP) orthologs to be identified, both have been reported to be expressed on normal blood and lymphatic ECs, and to play roles in the formation of blood and lymphatic vascular networks during angiogenesis. Whilst the role of NRP1 and its interactions with integrins during angiogenesis has been widely studied, the role of NRP2 in ECs is poorly understood. Here we demonstrate that NRP2 promotes Rac-1 mediated EC adhesion and migration over fibronectin (FN) matrices in a mechanistically distinct fashion to NRP1, showing no dependence on ß3 integrin (ITGB3) expression, or VEGF stimulation. Furthermore, we highlight evidence of a regulatory crosstalk between NRP2 and α5 integrin (ITGA5) in ECs, with NRP2 depletion eliciting an upregulation of ITGA5 expression and disruptions in ITGA5 cellular organization. Finally, we propose a mechanism whereby NRP2 promotes ITGA5 recycling in ECs; NRP2 depleted ECs were found to exhibit reduced levels of total ITGA5 subunit recycling compared to wild-type (WT) ECs. Our findings expose NRP2 as a novel angiogenic player by promoting ITGA5-mediated EC adhesion and migration on FN.

Cancer Burden Is Controlled by Mural Cell-ß3-Integrin Regulated Crosstalk with Tumor Cells.

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-ß3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-ß3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell ß3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by ß3-integrin, providing a previously unrecognized mechanism of cancer growth control.

ADAMTS-1 and syndecan-4 intersect in the regulation of cell migration and angiogenesis.

ADAMTS-1 is an extracellular protease with critical roles in organogenesis and angiogenesis. Here we demonstrate a functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration and angiogenesis. Knockdown of ADAMTS-1 in endothelial cells resulted in a parallel reduction in cell surface syndecan-4, attributable to increased matrix metalloproteinase-9 (MMP9) activity. Knockdown of either ADAMTS-1 or syndecan-4 increased cellular responses to vascular endothelial growth factor A isoform VEGFA164, and increased ex vivo aortic ring microvessel sprouting. On fibronectin, knockdown of either protein enhanced migration and promoted formation of long α5 integrin-containing fibrillar adhesions. However, integrin α5 null cells still showed increased migration in response to ADAMTS-1 and syndecan-4 siRNA treatment. Plating of naïve endothelial cells on cell-conditioned matrix from ADAMTS-1 and syndecan-4 knockdown cells demonstrated that the altered adhesive behaviour was matrix dependent, and this correlated with a lack of expression of fibulin-1: an extracellular matrix co-factor for ADAMTS-1 that is known to inhibit migration. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via collaboration with MMP9 and fibulin-1.This article has an associated First Person interview with the first author of the paper.

Radical accelerated radiotherapy for non-small cell lung cancer (NSCLC): A 5-year retrospective review of two dose fractionation schedules.

BACKGROUND AND PURPOSE: Numerous fractionation regimes are used for inoperable NSCLC patients not suitable for stereotactic ablative radiotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART, 54 Gy, 36 fractions over 12 days) and hypofractionated accelerated radiotherapy (55 Gy, 20 fractions over 4 weeks) are recommended UK schedules. In this single-centre retrospective analysis, we compare both fractionation schemes for patients treated at our institution from 2010 to 15. MATERIALS AND METHODS: Clinical demographic, tumour and survival data were collected alongside radiotherapy dosimetric data from the Varian Eclipse Scripting application programming interface. Differences were assessed using independent samples t-tests. Multivariate survival analysis was performed using Cox regression. RESULTS: We identified 563 eligible patients; 43% received CHART and 57% hypofractionated radiotherapy. Median age was 71 years, 56% were male, 95% PET staged with 53% WHO performance status 0-1. 30%, 14%, 50% and 6% were stage I, II, III and IV, respectively. 38% of patients underwent induction chemotherapy. 99% completed their prescribed radiotherapy treatment. Overall response rate was 50% with a 6.5% 90-day mortality rate. Median disease-free survival was 19 months, 50% recurred locally. Median overall survival was 22.5 months with 48% alive at 2 years. Multivariate analysis identified histology, stage, performance status, chemotherapy and radiotherapy response as independent predictors of survival; no significant differences between radiotherapy regimes were observed. CONCLUSION: In our centre, CHART and hypofractionated accelerated radiotherapy produce similar outcomes. Dose escalation studies are in progress to develop these schedules to match outcomes reported in concurrent chemo-radiation studies.

Correction: The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth.

[This corrects the article DOI: 10.18632/oncotarget.23378.].

Spatial Comparison of CT-Based Surrogates of Lung Ventilation With Hyperpolarized Helium-3 and Xenon-129 Gas MRI in Patients Undergoing Radiation Therapy.

PURPOSE: To develop and apply an image acquisition and analysis strategy for spatial comparison of computed tomography (CT)-ventilation images with hyperpolarized gas magnetic resonance imaging (MRI). METHODS AND MATERIALS: Eleven lung cancer patients underwent xenon-129 (129Xe) and helium-3 (3He) ventilation MRI and coregistered proton (1H) anatomic MRI. Expiratory and inspiratory breath-hold CTs were used for deformable image registration and calculation of 3 CT-ventilation metrics: Hounsfield unit (CTHU), Jacobian (CTJac), and specific gas volume change (CTSGV). Inspiration CT and hyperpolarized gas ventilation MRI were registered via same-breath anatomic 1H-MRI. Voxel-wise Spearman correlation coefficients were calculated between each CT-ventilation image and its corresponding 3He-/129Xe-MRI, and for the mean values in regions of interest (ROIs) ranging from fine to coarse in-plane dimensions of 5 × 5, 10 × 10, 15 × 15, and 20 × 20, located within the lungs as defined by the same-breath 1H-MRI lung mask. Correlation of 3He and 129Xe-MRI was also assessed. RESULTS: Spatial correlation of CT-ventilation against 3He/129Xe-MRI increased with ROI size. For example, for CTHU, mean ± SD Spearman coefficients were 0.37 ± 0.19/0.33 ± 0.17 at the voxel-level and 0.52 ± 0.20/0.51 ± 0.18 for 20 × 20 ROIs, respectively. Correlations were stronger for CTHU than for CTJac or CTSGV. Correlation of 3He with 129Xe-MRI was consistently higher than either gas against CT-ventilation maps over all ROIs (P < .05). No significant differences were observed between CT-ventilation versus 3He-MRI and CT-ventilation versus 129Xe-MRI. CONCLUSION: Comparison of ventilation-related measures from CT and registered hyperpolarized gas MRI is feasible at a voxel level using a dedicated acquisition and analysis protocol. Moderate correlation between CT-ventilation and MRI exists at a regional level. Correlation between MRI and CT is significantly less than that between 3He and 129Xe-MRI, suggesting that CT-ventilation surrogate measures may not be measuring lung ventilation alone.

The ß3-integrin endothelial adhesome regulates microtubule-dependent cell migration.

Integrin ß3 is seen as a key anti-angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro- or anti-angiogenic depends on the context in which it is expressed. To understand precisely ß3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the ß3-dependent adhesome. We show that depletion of ß3-integrin in this cell type leads to changes in microtubule behaviour that control cell migration. ß3-integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2-driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when ß3-integrin levels are reduced.