Long-term exposure to ambient air pollution and incidence of brain tumours: The Danish Nurse Cohort.

PubMed

Jørgensen, Jeanette Therming; Johansen, Martin Søes; Ravnskjær, Line; Andersen, Klaus Kaae; Bräuner, Elvira Vaclavik; Loft, Steffen; Ketzel, Matthias; Becker, Thomas; Brandt, Jørgen; Hertel, Ole; Andersen, Zorana Jovanovic

2016-07-01

Air pollution has been considered a potent environmental risk factor for neuropathology through neuroinflammation and oxidative stress, which might also cause brain tumour formation. However, epidemiological evidence on the association between air pollution and brain tumours in humans is sparse, with no data on exposure to particles. In this study we aim to examine associations between long-term exposure to ambient air pollution and risk for development of brain tumours. We used the Danish Nurse Cohort with 28,731 female nurses (age≥44years) recruited in 1993 or 1999 when self-reported information on lifestyle was collected. We obtained data on the incidence of brain tumours until 2013 from the Danish Cancer Register, and estimated annual mean concentrations of particulate matter with diameter<2.5μm (PM2.5), particulate matter with diameter<10μm (PM10), nitrogen oxides (NOx) and nitrogen dioxide (NO2) at the residence since 1990 using an atmospheric integrated chemistry-transport models system, and examined the association between the 3-year running mean of pollutants and brain tumour incidence using time-varying Cox regression, separately for total brain tumours, and for tumour subtypes by location (brain or meninges), and by malignancy (malignant or benign), and estimated hazard ratios and 95% confidence intervals per increase in interquartile range of exposure. Of 25,143 tumour-free nurses at recruitment, 121 developed brain cancer during 15.7 years of follow-up. We found a weak positive association between total brain tumours and PM2.5 (1.06; 0.80-1.40 per 3.37μg/m(3)), NO2 (1.09; 0.91-1.29) per 7.5μg/m(3), and NOx (1.02; 0.93-1.12 per 10.22μg/m(3)), and none with PM10 (0.93; 0.70-1.23 per 3.31μg/m(3)). Associations with PM2.5 and NO2 were stronger for tumours located in meninges than in brain, and for benign than for malignant tumours. Finally, association of total brain tumours with PM2.5 was modified by BMI, and was statistically significantly enhanced in obese women (2.03; 1.35-3.05). We found weak evidence for association between risk of brain tumours and long-term exposure to air pollution in women older than 44 years. However, we present novel results that obese women may be susceptible, as well as a positive tendency towards elevated risk for meninges and benign tumours, which require further investigation. Copyright © 2016 Elsevier B.V. All rights reserved.

Tumour cell dispersion by the ultrasonic aspirator during brain tumour resection.

PubMed

Preston, J K; Masciopinto, J; Salamat, M S; Badie, B

1999-10-01

Ultrasonic aspirators are commonly used to resect brain tumours because they allow safe, rapid and accurate removal of diseased tissue. Since ultrasonic aspirators generate a spray of aerosolized irrigating fluid around the instrument tip, we questioned whether this spray might contain viable tumours cells that could contribute to intraoperative spread of tumour fragments. To test this hypothesis, we collected the spray produced during the resection of nine brain tumours with an ultrasonic aspirator and semi-quantitatively analysed it for tumour presence. The aerosolized irrigation fluid was found to contain intact tumour cells or clumps of tumour cells in all nine instances, and there was a trend of increasing tumour cell dispersion with increasing ultrasonic aspiration times. Further examination is required to determine if this intraoperative dispersion of apparently viable tumour fragments contributes to local neoplasm recurrence.

Brain tumour classification and abnormality detection using neuro-fuzzy technique and Otsu thresholding.

PubMed

Renjith, Arokia; Manjula, P; Mohan Kumar, P

2015-01-01

Brain tumour is one of the main causes for an increase in transience among children and adults. This paper proposes an improved method based on Magnetic Resonance Imaging (MRI) brain image classification and image segmentation approach. Automated classification is encouraged by the need of high accuracy when dealing with a human life. The detection of the brain tumour is a challenging problem, due to high diversity in tumour appearance and ambiguous tumour boundaries. MRI images are chosen for detection of brain tumours, as they are used in soft tissue determinations. First of all, image pre-processing is used to enhance the image quality. Second, dual-tree complex wavelet transform multi-scale decomposition is used to analyse texture of an image. Feature extraction extracts features from an image using gray-level co-occurrence matrix (GLCM). Then, the Neuro-Fuzzy technique is used to classify the stages of brain tumour as benign, malignant or normal based on texture features. Finally, tumour location is detected using Otsu thresholding. The classifier performance is evaluated based on classification accuracies. The simulated results show that the proposed classifier provides better accuracy than previous method.

Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells

PubMed Central

Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi

2015-01-01

Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. PMID:25910782

Intracavitary moderator balloon combined with (252)Cf brachytherapy and boron neutron capture therapy, improving dosimetry in brain tumour and infiltrations.

PubMed

Brandão, S F; Campos, T P R

2015-07-01

This article proposes a combination of californium-252 ((252)Cf) brachytherapy, boron neutron capture therapy (BNCT) and an intracavitary moderator balloon catheter applied to brain tumour and infiltrations. Dosimetric evaluations were performed on three protocol set-ups: (252)Cf brachytherapy combined with BNCT (Cf-BNCT); Cf-BNCT with a balloon catheter filled with light water (LWB) and the same set-up with heavy water (HWB). Cf-BNCT-HWB has presented dosimetric advantages to Cf-BNCT-LWB and Cf-BNCT in infiltrations at 2.0-5.0 cm from the balloon surface. However, Cf-BNCT-LWB has shown superior dosimetry up to 2.0 cm from the balloon surface. Cf-BNCT-HWB and Cf-BNCT-LWB protocols provide a selective dose distribution for brain tumour and infiltrations, mainly further from the (252)Cf source, sparing the normal brain tissue. Malignant brain tumours grow rapidly and often spread to adjacent brain tissues, leading to death. Improvements in brain radiation protocols have been continuously achieved; however, brain tumour recurrence is observed in most cases. Cf-BNCT-LWB and Cf-BNCT-HWB represent new modalities for selectively combating brain tumour infiltrations and metastasis.

Supervised learning based multimodal MRI brain tumour segmentation using texture features from supervoxels.

PubMed

Soltaninejad, Mohammadreza; Yang, Guang; Lambrou, Tryphon; Allinson, Nigel; Jones, Timothy L; Barrick, Thomas R; Howe, Franklyn A; Ye, Xujiong

2018-04-01

Accurate segmentation of brain tumour in magnetic resonance images (MRI) is a difficult task due to various tumour types. Using information and features from multimodal MRI including structural MRI and isotropic (p) and anisotropic (q) components derived from the diffusion tensor imaging (DTI) may result in a more accurate analysis of brain images. We propose a novel 3D supervoxel based learning method for segmentation of tumour in multimodal MRI brain images (conventional MRI and DTI). Supervoxels are generated using the information across the multimodal MRI dataset. For each supervoxel, a variety of features including histograms of texton descriptor, calculated using a set of Gabor filters with different sizes and orientations, and first order intensity statistical features are extracted. Those features are fed into a random forests (RF) classifier to classify each supervoxel into tumour core, oedema or healthy brain tissue. The method is evaluated on two datasets: 1) Our clinical dataset: 11 multimodal images of patients and 2) BRATS 2013 clinical dataset: 30 multimodal images. For our clinical dataset, the average detection sensitivity of tumour (including tumour core and oedema) using multimodal MRI is 86% with balanced error rate (BER) 7%; while the Dice score for automatic tumour segmentation against ground truth is 0.84. The corresponding results of the BRATS 2013 dataset are 96%, 2% and 0.89, respectively. The method demonstrates promising results in the segmentation of brain tumour. Adding features from multimodal MRI images can largely increase the segmentation accuracy. The method provides a close match to expert delineation across all tumour grades, leading to a faster and more reproducible method of brain tumour detection and delineation to aid patient management. Copyright © 2018 Elsevier B.V. All rights reserved.

Screening for invasion of the individual human brain tumour in an autologous confrontation system in vitro.

PubMed

de Ridder, L

1999-01-01

Invasiveness is the major cause of death in patients bearing a brain tumour. The invasiveness or infiltrative capacity of a primary brain tumour has a prognostic value for the evaluation of the process in vivo. So a model to imitate invasion might give information on the in vivo behaviour and outcome of the disease for the individual patient. The developed in vitro model represents an assay in which the patients' brain tumour-derived cells are confronted with connective tissue from the patient himself, i.e. an autologous system to evaluate the individual behaviour of the tumour, in contrast to other invasion models. The test can be applied with tumour-derived material collected by a stereotactic biopsy.

A qualitative assessment of the supportive care and resource needs of patients undergoing craniotomy for benign brain tumours.

PubMed

Wong, Janice; Mendelsohn, Daniel; Nyhof-Young, Joyce; Bernstein, Mark

2011-11-01

As past literature has focused on support needs of patients with malignant brain tumours, the support needs of patients with benign brain tumours have largely been overlooked. The purpose of this study was to evaluate the supportive care and resource needs of patients undergoing craniotomy for benign brain tumours. Individual, semi-structured interviews were conducted with patients who had undergone craniotomy for a benign brain tumour within the past 2 years. Interviews were audio-recorded, transcribed, anonymized and subjected to descriptive thematic analysis by multiple investigators in the grounded theory tradition. Twenty-nine patients (20 women, 20-88 years of age) with World Health Organization grade I brain tumours (25 meningioma) were interviewed. Five overarching themes emerged: (1) need for formal support from diagnosis onwards; (2) complexity of supportive needs during postoperative recovery; (3) importance of regular long-term monitoring by physicians; (4) influence of psychosocial factors on supportive needs; and (5) existence of barriers to equal access to available supports. Patients' supportive care needs are temporally dependent on disease course and treatment, and modifiable by demographic and psychosocial factors. Findings of this study show that patients with benign tumours lacked but needed many supportive care resources currently available to cancer patients. Many of the potential solutions to this current gap in supportive care involve extending support resources already available for cancer patients to patients with benign brain tumours. We thus suggest recommendations to improve service gaps and reduce disparities in supportive care for patients with benign brain tumours.

Hierarchical probabilistic Gabor and MRF segmentation of brain tumours in MRI volumes.

PubMed

Subbanna, Nagesh K; Precup, Doina; Collins, D Louis; Arbel, Tal

2013-01-01

In this paper, we present a fully automated hierarchical probabilistic framework for segmenting brain tumours from multispectral human brain magnetic resonance images (MRIs) using multiwindow Gabor filters and an adapted Markov Random Field (MRF) framework. In the first stage, a customised Gabor decomposition is developed, based on the combined-space characteristics of the two classes (tumour and non-tumour) in multispectral brain MRIs in order to optimally separate tumour (including edema) from healthy brain tissues. A Bayesian framework then provides a coarse probabilistic texture-based segmentation of tumours (including edema) whose boundaries are then refined at the voxel level through a modified MRF framework that carefully separates the edema from the main tumour. This customised MRF is not only built on the voxel intensities and class labels as in traditional MRFs, but also models the intensity differences between neighbouring voxels in the likelihood model, along with employing a prior based on local tissue class transition probabilities. The second inference stage is shown to resolve local inhomogeneities and impose a smoothing constraint, while also maintaining the appropriate boundaries as supported by the local intensity difference observations. The method was trained and tested on the publicly available MICCAI 2012 Brain Tumour Segmentation Challenge (BRATS) Database [1] on both synthetic and clinical volumes (low grade and high grade tumours). Our method performs well compared to state-of-the-art techniques, outperforming the results of the top methods in cases of clinical high grade and low grade tumour core segmentation by 40% and 45% respectively.

Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse.

PubMed

Shelton, Laura M; Huysentruyt, Leanne C; Mukherjee, Purna; Seyfried, Thomas N

2010-07-23

GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer. We recently developed a novel brain cancer model in the inbred VM mouse strain that shares several characteristics with human GBM. Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion. CR targets glycolysis and rapid tumour cell growth in part by lowering circulating glucose levels. The VM-M3 tumour cells were implanted intracerebrally in the syngeneic VM mouse host. Approx. 12-15 days post-implantation, brains were removed and both ipsilateral and contralateral hemispheres were imaged to measure bioluminescence of invading tumour cells. CR significantly reduced the invasion of tumour cells from the implanted ipsilateral hemisphere into the contralateral hemisphere. The total percentage of Ki-67-stained cells within the primary tumour and the total number of blood vessels was also significantly lower in the CR-treated mice than in the mice fed ad libitum, suggesting that CR is anti-proliferative and anti-angiogenic. Our findings indicate that the VM-M3 GBM model is a valuable tool for studying brain tumour cell invasion and for evaluating potential therapeutic approaches for managing invasive brain cancer. In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

Intracavitary moderator balloon combined with 252Cf brachytherapy and boron neutron capture therapy, improving dosimetry in brain tumour and infiltrations

PubMed Central

Brandão, S F

2015-01-01

Objective: This article proposes a combination of californium-252 (252Cf) brachytherapy, boron neutron capture therapy (BNCT) and an intracavitary moderator balloon catheter applied to brain tumour and infiltrations. Methods: Dosimetric evaluations were performed on three protocol set-ups: 252Cf brachytherapy combined with BNCT (Cf-BNCT); Cf-BNCT with a balloon catheter filled with light water (LWB) and the same set-up with heavy water (HWB). Results: Cf-BNCT-HWB has presented dosimetric advantages to Cf-BNCT-LWB and Cf-BNCT in infiltrations at 2.0–5.0 cm from the balloon surface. However, Cf-BNCT-LWB has shown superior dosimetry up to 2.0 cm from the balloon surface. Conclusion: Cf-BNCT-HWB and Cf-BNCT-LWB protocols provide a selective dose distribution for brain tumour and infiltrations, mainly further from the 252Cf source, sparing the normal brain tissue. Advances in knowledge: Malignant brain tumours grow rapidly and often spread to adjacent brain tissues, leading to death. Improvements in brain radiation protocols have been continuously achieved; however, brain tumour recurrence is observed in most cases. Cf-BNCT-LWB and Cf-BNCT-HWB represent new modalities for selectively combating brain tumour infiltrations and metastasis. PMID:25927876

Rebound nystagmus: EOG analysis of a case with a floccular tumour.

PubMed Central

Yamazaki, A; Zee, D S

1979-01-01

Eye movements were recorded and quantitatively analysed in a patient with a tumour initially involving the cerebellar flocculus. Ocular motor abnormalities included (1) impaired smooth pursuit, (2) impaired cancellation of the vestibulo-ocular reflex when fixating an object rotating with the head, and (3) gaze paretic and rebound nystagmus. Comparable findings have been reported in monkeys with experimental floccular lesions. The rebound nystagmus (but not the other ocular motor abnormalities) disappeared when the tumour appeared to invade the brain stem in the region near the vestibular nuclei. This finding suggests that the floccular lesion unmasked a bias which created rebound nystagmus and that the bias probably arose in the vestibular nuclei. PMID:508695

Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours.

PubMed

Wilson, Martin; Cummins, Carole L; Macpherson, Lesley; Sun, Yu; Natarajan, Kal; Grundy, Richard G; Arvanitis, Theodoros N; Kauppinen, Risto A; Peet, Andrew C

2013-01-01

Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. (1)H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients. Short echo time (30ms) single voxel (1)H MRS was performed on children attending Birmingham Children's Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power. Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p<0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p<5e-5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules. MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Prognostic factors and survival according to tumour subtype in women presenting with breast cancer brain metastases at initial diagnosis.

PubMed

Leone, José Pablo; Leone, Julieta; Zwenger, Ariel Osvaldo; Iturbe, Julián; Leone, Bernardo Amadeo; Vallejo, Carlos Teodoro

2017-03-01

The presence of brain metastases at the time of initial breast cancer diagnosis (BMIBCD) is uncommon. Hence, the prognostic assessment and management of these patients is very challenging. The aim of this study was to analyse the influence of tumour subtype compared with other prognostic factors in the survival of patients with BMIBCD. We evaluated women with BMIBCD, reported to Surveillance, Epidemiology and End Results program from 2010 to 2013. Patients with other primary malignancy were excluded. Univariate and multivariate analyses were performed to determine the effects of each variable on overall survival (OS). We included 740 patients. Median OS for the whole population was 10 months, and 20.7% of patients were alive at 36 months. Tumour subtype distribution was: 46.6% hormone receptor (HR)+/HER2-, 17% HR+/HER2+, 14.1% HR-/HER2+ and 22.3% triple-negative. Univariate analysis showed that the presence of liver metastases, lung metastases and triple-negative patients (median OS 6 months) had worse prognosis. The HR+/HER2+ subtype had the longest OS with a median of 22 months. In multivariate analysis, older age (hazard ratio 1.8), lobular histology (hazard ratio 2.08), triple-negative subtype (hazard ratio 2.25), liver metastases (hazard ratio 1.6) and unmarried patients (hazard ratio 1.39) had significantly shorter OS. Although the prognosis of patients with BMIBCD is generally poor, 20.7% were still alive 3 years after the diagnosis. There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS are age at diagnosis, marital status, histology and liver metastases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence

NASA Astrophysics Data System (ADS)

Xue, Jingwei; Zhao, Zekai; Zhang, Lei; Xue, Lingjing; Shen, Shiyang; Wen, Yajing; Wei, Zhuoyuan; Wang, Lu; Kong, Lingyi; Sun, Hongbin; Ping, Qineng; Mo, Ran; Zhang, Can

2017-07-01

Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.

Childhood brain tumours and use of mobile phones: comparison of a case-control study with incidence data.

PubMed

Aydin, Denis; Feychting, Maria; Schüz, Joachim; Röösli, Martin

2012-05-20

The first case-control study on mobile phone use and brain tumour risk among children and adolescents (CEFALO study) has recently been published. In a commentary published in Environmental Health, Söderqvist and colleagues argued that CEFALO suggests an increased brain tumour risk in relation to wireless phone use. In this article, we respond and show why consistency checks of case-control study results with observed time trends of incidence rates are essential, given the well described limitations of case-control studies and the steep increase of mobile phone use among children and adolescents during the last decade. There is no plausible explanation of how a notably increased risk from use of wireless phones would correspond to the relatively stable incidence time trends for brain tumours among children and adolescents observed in the Nordic countries. Nevertheless, an increased risk restricted to heavy mobile phone use, to very early life exposure, or to rare subtypes of brain tumours may be compatible with stable incidence trends at this time and thus further monitoring of childhood brain tumour incidence rate time trends is warranted.

Depression in adult patients with primary brain tumours: a review of independent risk factors.

PubMed

Pidani, Anum Sadruddin; Rao, Aaida Mumtaz; Shamim, Muhammad Shahzad

2018-04-01

Depression is considered an under-diagnosed problem, especially in patients with malignancies. Patients with brain tumours in particular, have a relatively higher risk of developing depression, which is multifactorial. Herein, the authors review the recent literature on the prevalence of depression in patients with brain tumours, and explore the various risk factors involved. .

Residential Radon and Brain Tumour Incidence in a Danish Cohort

PubMed Central

Bräuner, Elvira V.; Andersen, Zorana J.; Andersen, Claus E.; Pedersen, Camilla; Gravesen, Peter; Ulbak, Kaare; Hertel, Ole; Loft, Steffen; Raaschou-Nielsen, Ole

2013-01-01

Background Increased brain tumour incidence over recent decades may reflect improved diagnostic methods and clinical practice, but remain unexplained. Although estimated doses are low a relationship between radon and brain tumours may exist. Objective To investigate the long-term effect of exposure to residential radon on the risk of primary brain tumour in a prospective Danish cohort. Methods During 1993–1997 we recruited 57,053 persons. We followed each cohort member for cancer occurrence from enrolment until 31 December 2009, identifying 121 primary brain tumour cases. We traced residential addresses from 1 January 1971 until 31 December 2009 and calculated radon concentrations at each address using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate-ratios (IRR) and 95% confidence intervals (CI) for the risk of primary brain tumours associated with residential radon exposure with adjustment for age, sex, occupation, fruit and vegetable consumption and traffic-related air pollution. Effect modification by air pollution was assessed. Results Median estimated radon was 40.5 Bq/m3. The adjusted IRR for primary brain tumour associated with each 100 Bq/m3 increment in average residential radon levels was 1.96 (95% CI: 1.07; 3.58) and this was exposure-dependently higher over the four radon exposure quartiles. This association was not modified by air pollution. Conclusions We found significant associations and exposure-response patterns between long-term residential radon exposure radon in a general population and risk of primary brain tumours, adding new knowledge to this field. This finding could be chance and needs to be challenged in future studies. PMID:24066143

In-vivo imaging of the morphology and blood perfusion of brain tumours in rats with UHR-OCT (Conference Presentation)

NASA Astrophysics Data System (ADS)

Bizheva, Kostadinka; Tan, Bingyao; Fisher, Carl J.; Mason, Erik; Lilge, Lothar D.

2017-02-01

Brain tumors are characterized with morphological changes at cellular level such as enlarged, non-spherical nuclei, microcalcifications, cysts, etc., and are highly vascularized. In this study, two research-grade optical coherence tomography (OCT) systems operating at 800 nm and 1060 nm with axial resolution of 0.95 µm and 3.5 µm in biological tissue respectively, were used to image in vivo and ex vivo the structure of brain tumours in rats. Female Fischer 344 rats were used for this study, which has received ethics clearance by the Animal Research Ethics Committees of the University of Waterloo and the University Health Network, Toronto. Brain tumours were induced by injection of rat brain cancer cell line (RG2 glioma) through a small craniotomy. Presence of brain tumours was verified by MRI imaging on day 7 post tumour cells injection. The in vivo OCT imaging session was conducted on day 14 of the study with the 1060 nm OCT system and both morphological OCT, Doppler OCT and OMAG images were acquired from the brain tumour and the surrounding healthy brain tissue. After completion of the imaging procedure, the brains were harvested, fixed in formalin and reimaged after 2 weeks with the 800 nm OCT system. The in vivo and ex vivo OCT morphological images were correlated with H and E histology. Results from this study demonstrate that UHR-OCT can distinguish between healthy and cancerous brain tissue based on differences in structural and vascular pattern.

Medulloblastoma genotype dictates blood brain barrier phenotype

PubMed Central

Phoenix, Timothy N.; Patmore, Deanna M.; Boop, Scott; Boulos, Nidal; Jacus, Megan O.; Patel, Yogesh T.; Roussel, Martine F; Finkelstein, David; Goumnerova, Lilian; Perreault, Sebastien; Wadhwa, Elizabeth; Cho, Yoon-Jae; Stewart, Clinton F.; Gilbertson, Richard J.

2016-01-01

SUMMARY The childhood brain tumour medulloblastoma includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant Beta-Catenin in WNT-medulloblastoma – an essentially curable form of the disease – induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoural chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma – a less curable disease subtype – contains an intact blood brain barrier, rendering this tumour impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumour vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumours. PMID:27050100

Childhood brain tumours and use of mobile phones: comparison of a case–control study with incidence data

PubMed Central

2012-01-01

The first case–control study on mobile phone use and brain tumour risk among children and adolescents (CEFALO study) has recently been published. In a commentary published in Environmental Health, Söderqvist and colleagues argued that CEFALO suggests an increased brain tumour risk in relation to wireless phone use. In this article, we respond and show why consistency checks of case–control study results with observed time trends of incidence rates are essential, given the well described limitations of case–control studies and the steep increase of mobile phone use among children and adolescents during the last decade. There is no plausible explanation of how a notably increased risk from use of wireless phones would correspond to the relatively stable incidence time trends for brain tumours among children and adolescents observed in the Nordic countries. Nevertheless, an increased risk restricted to heavy mobile phone use, to very early life exposure, or to rare subtypes of brain tumours may be compatible with stable incidence trends at this time and thus further monitoring of childhood brain tumour incidence rate time trends is warranted. PMID:22607537

Role of surgery in brain metastases.

PubMed

Laghari, Altaf Ali; Ahmed, Syed Ijlal; Shamim, Muhammad Shahzad

2017-08-01

Brain metastases remain the commonest type of brain tumour, being four times more common than primary brain tumours. Although surgical intervention may be recommended for one of various reasons in the management of these tumours, including but not limited to conformation of diagnosis, relief of mass effect, improvement of neurological status and prolongation of survival, the guidelines for management of brain metastases remain largely subjective and therefore controversial. Herein the authors have attempted to review some of the existing evidence on role of surgery in the management of brain metastases and have presented their selected guidelines for the readers.

Characterization of brain tumours with spin-spin relaxation: pilot case study reveals unique T 2 distribution profiles of glioblastoma, oligodendroglioma and meningioma.

PubMed

Laule, Cornelia; Bjarnason, Thorarin A; Vavasour, Irene M; Traboulsee, Anthony L; Wayne Moore, G R; Li, David K B; MacKay, Alex L

2017-11-01

Prolonged spin-spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T 2 relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T 2 decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T 2 components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T 2 decay. T 2 relaxation times were increased in tumour tissue and each tumour showed a distinct T 2 distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T 2 relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T 2 distribution profile, and has the potential to be a non-invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted.

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma.

PubMed

Bougnaud, Sébastien; Golebiewska, Anna; Oudin, Anaïs; Keunen, Olivier; Harter, Patrick N; Mäder, Lisa; Azuaje, Francisco; Fritah, Sabrina; Stieber, Daniel; Kaoma, Tony; Vallar, Laurent; Brons, Nicolaas H C; Daubon, Thomas; Miletic, Hrvoje; Sundstrøm, Terje; Herold-Mende, Christel; Mittelbronn, Michel; Bjerkvig, Rolf; Niclou, Simone P

2016-05-31

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

PubMed Central

Bougnaud, Sébastien; Golebiewska, Anna; Oudin, Anaïs; Keunen, Olivier; Harter, Patrick N.; Mäder, Lisa; Azuaje, Francisco; Fritah, Sabrina; Stieber, Daniel; Kaoma, Tony; Vallar, Laurent; Brons, Nicolaas H.C.; Daubon, Thomas; Miletic, Hrvoje; Sundstrøm, Terje; Herold-Mende, Christel; Mittelbronn, Michel; Bjerkvig, Rolf; Niclou, Simone P.

2016-01-01

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma. PMID:27049916

Imaging biomarkers of angiogenesis and the microvascular environment in cerebral tumours

PubMed Central

Thompson, G; Mills, S J; Coope, D J; O’connor, J P B; Jackson, A

2011-01-01

Conventional contrast-enhanced CT and MRI are now in routine clinical use for the diagnosis, treatment and monitoring of diseases in the brain. The presence of contrast enhancement is a proxy for the pathological changes that occur in the normally highly regulated brain vasculature and blood-brain barrier. With recognition of the limitations of these techniques, and a greater appreciation for the nuanced mechanisms of microvascular change in a variety of pathological processes, novel techniques are under investigation for their utility in further interrogating the microvasculature of the brain. This is particularly important in tumours, where the reliance on angiogenesis (new vessel formation) is crucial for tumour growth, and the resulting microvascular configuration and derangement has profound implications for diagnosis, treatment and monitoring. In addition, novel therapeutic approaches that seek to directly modify the microvasculature require more sensitive and specific biological markers of baseline tumour behaviour and response. The currently used imaging biomarkers of angiogenesis and brain tumour microvascular environment are reviewed. PMID:22433824

Automated glioblastoma segmentation based on a multiparametric structured unsupervised classification.

PubMed

Juan-Albarracín, Javier; Fuster-Garcia, Elies; Manjón, José V; Robles, Montserrat; Aparici, F; Martí-Bonmatí, L; García-Gómez, Juan M

2015-01-01

Automatic brain tumour segmentation has become a key component for the future of brain tumour treatment. Currently, most of brain tumour segmentation approaches arise from the supervised learning standpoint, which requires a labelled training dataset from which to infer the models of the classes. The performance of these models is directly determined by the size and quality of the training corpus, whose retrieval becomes a tedious and time-consuming task. On the other hand, unsupervised approaches avoid these limitations but often do not reach comparable results than the supervised methods. In this sense, we propose an automated unsupervised method for brain tumour segmentation based on anatomical Magnetic Resonance (MR) images. Four unsupervised classification algorithms, grouped by their structured or non-structured condition, were evaluated within our pipeline. Considering the non-structured algorithms, we evaluated K-means, Fuzzy K-means and Gaussian Mixture Model (GMM), whereas as structured classification algorithms we evaluated Gaussian Hidden Markov Random Field (GHMRF). An automated postprocess based on a statistical approach supported by tissue probability maps is proposed to automatically identify the tumour classes after the segmentations. We evaluated our brain tumour segmentation method with the public BRAin Tumor Segmentation (BRATS) 2013 Test and Leaderboard datasets. Our approach based on the GMM model improves the results obtained by most of the supervised methods evaluated with the Leaderboard set and reaches the second position in the ranking. Our variant based on the GHMRF achieves the first position in the Test ranking of the unsupervised approaches and the seventh position in the general Test ranking, which confirms the method as a viable alternative for brain tumour segmentation.

Case-control study on the use of cellular and cordless phones and the risk for malignant brain tumours.

PubMed

Hardell, L; Mild, K H; Carlberg, M

2002-10-01

To investigate the use of cellular and cordless phones and the risk for malignant brain tumours. A case-control study was performed on 649 patients aged 20-80 years of both sexes with malignant brain tumour diagnosed from 1 January 1997 to 30 June 2000. All patients were alive during the time of the study and had histopathology verified brain tumours. One matched control to each case was selected from the Swedish Population Register. The study area was the Uppsala-Orebro, Stockholm, Linköping and Göteborg medical regions of Sweden. Exposure was assessed by a questionnaire answered by 588 (91%) cases and 581 (90%) controls. Phone usage was defined as 'ever use' and usage starting within 1 year before diagnosis was disregarded. Overall, no significantly increased risks were found: analogue cellular phones yielded an odds ratio (OR)=1.13, 95% confidence interval (CI)=0.82-1.57, digital cellular phones OR=1.13, CI=0.86-1.48, and cordless phones OR=1.13, CI=0.85-1.50. For ipsilateral (same side) radiofrequency exposure, analogue mobile phones gave OR=1.85, CI=1.16-2.96, for all malignant brain tumours. For astrocytoma, this risk was OR=1.95, CI=1.12-3.39. For all malignant brain tumours, digital mobile phones yielded OR=1.59, CI=1.05-2.41, and cordless phones yielded OR=1.46, CI=0.96-2.23, in the analysis of ipsilateral exposure. The ipsilateral use of an analogue cellular phone yielded a significantly increased risk for malignant brain tumours.

P15.04DEVELOPMENT OF A NEW QUESTIONNAIRE TO MEASURE INSTRUMENTAL ACTIVITIES OF DAILY LIVING (I-ADL) IN PATIENTS WITH PRIMARY BRAIN TUMOURS: RESULTS OF PHASE 1

PubMed Central

Dirven, L.; Meijer, W.; Sikkes, S.A.M.; Reijneveld, J.C.; Aaronson, N.K.; Uitdehaag, B.M.J.; Taphoorn, M. J. B.

2014-01-01

BACKGROUND: Next to health-related quality of life, information on daily life functioning in brain tumour patients is essential. Instrumental Activities of Daily Living (I-ADL) are complex daily activities, such as food preparation and shopping. I-ADL may be negatively influenced by a cognitive decline, characteristic of brain tumor patients. OBJECTIVE: In the first phase of this project, we generated a provisional list of items measuring I-ADL that are relevant for primary brain tumour patients. METHODS: Questions from the Amsterdam IADL Questionnaire®, a 70-item questionnaire developed and validated to measure I-ADL in patients with dementia, were evaluated for relevance to brain tumour patients. In addition, new activities were generated. In the first step, 6 professional experts in neuro-oncology and 10 primary brain tumour patient-proxy dyads were asked to evaluate items in the Amsterdam IADL Questionnaire®. Experts had to indicate if these activities (1) could be considered as I-ADL, (2) were affected in brain tumour patients and (3) were clearly formulated. Patients and their proxies only needed to answer the latter two questions. In the second step, the same 6 experts, and in addition 6 other patient-proxy dyads were asked to generate new activities. To do so, in-depth interviews were conducted. Decision rules were determined to aid in deciding which items to retain (step 1) or to add (step 2). Activities that were indicated as IADL, affected and clearly formulated were retained. Activities that were considered as IADL and affected, but not clearly formulated, were rephrased. New activities that were frequently generated were added to the existing list of items. RESULTS: In step 1, experts indicated that 37% of the activities described in the Amsterdam IADL questionnaire® fulfilled all three criteria: conform the definition of IADL, clearly formulated and affected in brain tumour patients. Twenty-three per cent of the activities were affected and conform the provided definition, but not clearly formulated. According to patients and their proxies, 19% and 17% of the activities were clearly formulated and affected in brain tumour patients, respectively. Moreover, 1-3% of the activities were indicated to be affected, but not clearly formulated. Several new activities (concerning social interaction and work) were generated in step 2. With the decision rules as guide, it was decided in consensus that a total of 30 questions of the Amsterdam IADL questionnaire® could also be used to measure I-ADL in primary brain tumour patients. In addition, 16 new questions covering other relevant activities for brain tumour patients were added. CONCLUSION: This first phase resulted in a provisional questionnaire of 46 items intending to measure I-ADL in primary brain tumour patients. The next step is to validate this provisional questionnaire in a larger sample of patients.

Emotional and personality changes following brain tumour resection.

PubMed

Jenkins, Lisanne M; Drummond, Katharine J; Andrewes, David G

2016-07-01

Psychological distress has a high prevalence in brain tumour patients, and understanding the emotional and personality changes that may follow neurosurgery is important for clinical management of these patients. We aimed to characterise these emotional and personality changes using subjective, observer-rated and clinical measures. We examined subjective changes in emotional experience and observer-rated changes to personality disturbances following neurosurgery for brain tumours (n=44), compared to a control group that had undergone spinal surgery (n=26). Participants completed the Hospital Anxiety and Depression Scale and a Subjective Emotional Change Questionnaire. Observers who knew the patients well also completed the Iowa Rating Scale of Personality Change. Compared to controls, patients with tumours reported significantly more changes to their subjective experience of emotions following neurosurgery, particularly anger, disgust and sadness. For the observer-ratings, tumour patients were described as having significant changes in the personality disturbances of irritability, impulsivity, moodiness, inflexibility, and being easily overwhelmed. Anxiety and depression were not significantly different between groups. Neurosurgical resection of a brain tumour is a major life event that changes patients' subjective experiences of different emotions, and leads to observer-rated changes in personality. In this study, these changes were not accompanied by increases in anxiety or depression. We conclude with a discussion of biological and psychosocial mechanisms that can impact emotional functioning and personality in patients with brain tumours. Copyright © 2015 Elsevier Ltd. All rights reserved.

Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres

NASA Astrophysics Data System (ADS)

Jain, Anjana; Betancur, Martha; Patel, Gaurangkumar D.; Valmikinathan, Chandra M.; Mukhatyar, Vivek J.; Vakharia, Ajit; Pai, S. Balakrishna; Brahma, Barunashish; MacDonald, Tobey J.; Bellamkonda, Ravi V.

2014-03-01

Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.

Automated Glioblastoma Segmentation Based on a Multiparametric Structured Unsupervised Classification

PubMed Central

Juan-Albarracín, Javier; Fuster-Garcia, Elies; Manjón, José V.; Robles, Montserrat; Aparici, F.; Martí-Bonmatí, L.; García-Gómez, Juan M.

2015-01-01

Automatic brain tumour segmentation has become a key component for the future of brain tumour treatment. Currently, most of brain tumour segmentation approaches arise from the supervised learning standpoint, which requires a labelled training dataset from which to infer the models of the classes. The performance of these models is directly determined by the size and quality of the training corpus, whose retrieval becomes a tedious and time-consuming task. On the other hand, unsupervised approaches avoid these limitations but often do not reach comparable results than the supervised methods. In this sense, we propose an automated unsupervised method for brain tumour segmentation based on anatomical Magnetic Resonance (MR) images. Four unsupervised classification algorithms, grouped by their structured or non-structured condition, were evaluated within our pipeline. Considering the non-structured algorithms, we evaluated K-means, Fuzzy K-means and Gaussian Mixture Model (GMM), whereas as structured classification algorithms we evaluated Gaussian Hidden Markov Random Field (GHMRF). An automated postprocess based on a statistical approach supported by tissue probability maps is proposed to automatically identify the tumour classes after the segmentations. We evaluated our brain tumour segmentation method with the public BRAin Tumor Segmentation (BRATS) 2013 Test and Leaderboard datasets. Our approach based on the GMM model improves the results obtained by most of the supervised methods evaluated with the Leaderboard set and reaches the second position in the ranking. Our variant based on the GHMRF achieves the first position in the Test ranking of the unsupervised approaches and the seventh position in the general Test ranking, which confirms the method as a viable alternative for brain tumour segmentation. PMID:25978453

Brain tumours and exposure to pesticides: a case–control study in southwestern France

PubMed Central

Provost, Dorothée; Cantagrel, Anne; Lebailly, Pierre; Jaffré, Anne; Loyant, Véronique; Loiseau, Hugues; Vital, Anne; Brochard, Patrick; Baldi, Isabelle

2007-01-01

Background Brain tumours are often disabling and rapidly lethal; their aetiology is largely unknown. Among potential risk factors, pesticides are suspected. Objective To examine the relationship between exposure to pesticides and brain tumours in adults in a population‐based case–control study in southwestern France. Methods Between May 1999 and April 2001, 221 incident cases of brain tumours and 442 individually matched controls selected from the general population were enrolled. Histories of occupational and environmental exposures, medical and lifestyle information were collected. A cumulative index of occupational exposure to pesticides was created, based on expert review of lifelong jobs and tasks. Separate analyses were performed for gliomas and meningiomas. Results A non‐statistically significant increase in risk was found for brain tumours when all types of occupational exposure to pesticides were considered (OR = 1.29, 95% CI 0.87 to 1.91) and slightly higher but still non‐statistically significant when gliomas were considered separately (OR = 1.47, 95% CI 0.81 to 2.66). In the highest quartile of the cumulative index, a significant association was found for brain tumours (OR = 2.16, 95% CI 1.10 to 4.23) and for gliomas (OR = 3.21, 95% CI 1.13 to 9.11), but not for meningiomas. A significant increase in risk was also seen for the treatment of home plants (OR = 2.24, 95% CI 1.16 to 4.30) owing to environmental exposure to pesticides. Conclusions These data suggest that a high level of occupational exposure to pesticides might be associated with an excess risk of brain tumours, and especially of gliomas. PMID:17537748

Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

PubMed

Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika; Wang, Zhaoming; Henriksson, Roger; Hallmans, Göran; Bondy, Melissa L; Johansen, Christoffer; Feychting, Maria; Ahlbom, Anders; Kitahara, Cari M; Wang, Sophia S; Ruder, Avima M; Carreón, Tania; Butler, Mary Ann; Inskip, Peter D; Purdue, Mark; Hsing, Ann W; Mechanic, Leah; Gillanders, Elizabeth; Yeager, Meredith; Linet, Martha; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

2013-05-15

Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours. Copyright © 2012 UICC.

Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma

NASA Astrophysics Data System (ADS)

Setua, Sonali; Ouberai, Myriam; Piccirillo, Sara G.; Watts, Colin; Welland, Mark

2014-08-01

Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies.Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies. Electronic supplementary information (ESI) available: Additional figures. See DOI: 10.1039/c4nr03693j

Medical exposure to ionising radiation and the risk of brain tumours: Interphone study group, Germany.

PubMed

Blettner, Maria; Schlehofer, Brigitte; Samkange-Zeeb, Florence; Berg, Gabriele; Schlaefer, Klaus; Schüz, Joachim

2007-09-01

The role of exposure to low doses of ionising radiation in the aetiology of brain tumours has yet to be clarified. The objective of this study was to investigate the association between medically or occupationally related exposure to ionising radiation and brain tumours. We used self-reported medical and occupational data collected during the German part of a multinational case-control study on mobile phone use and the risk of brain tumours (Interphone study) for the analyses. For any exposure to medical ionising radiation we found odds ratios (ORs) of 0.63 (95% confidence interval (CI)=0.48-0.83), 1.08 (95% CI=0.80-1.45) and 0.97 (95% CI=0.54-1.75) for glioma, meningioma and acoustic neuroma, respectively. Elevated ORs were found for meningioma (OR 2.32, 95% CI: 0.90-5.96) and acoustic neuroma (OR 6.45, 95% CI: 0.62-67.16) for radiotherapy to the head and neck regions. We did not find any significant increased risk of brain tumours for exposure to medical ionising radiation.

A region-based segmentation of tumour from brain CT images using nonlinear support vector machine classifier.

PubMed

Nanthagopal, A Padma; Rajamony, R Sukanesh

2012-07-01

The proposed system provides new textural information for segmenting tumours, efficiently and accurately and with less computational time, from benign and malignant tumour images, especially in smaller dimensions of tumour regions of computed tomography (CT) images. Region-based segmentation of tumour from brain CT image data is an important but time-consuming task performed manually by medical experts. The objective of this work is to segment brain tumour from CT images using combined grey and texture features with new edge features and nonlinear support vector machine (SVM) classifier. The selected optimal features are used to model and train the nonlinear SVM classifier to segment the tumour from computed tomography images and the segmentation accuracies are evaluated for each slice of the tumour image. The method is applied on real data of 80 benign, malignant tumour images. The results are compared with the radiologist labelled ground truth. Quantitative analysis between ground truth and the segmented tumour is presented in terms of segmentation accuracy and the overlap similarity measure dice metric. From the analysis and performance measures such as segmentation accuracy and dice metric, it is inferred that better segmentation accuracy and higher dice metric are achieved with the normalized cut segmentation method than with the fuzzy c-means clustering method.

L-Phenylalanine preloading reduces the (10)B(n, α)(7)Li dose to the normal brain by inhibiting the uptake of boronophenylalanine in boron neutron capture therapy for brain tumours.

PubMed

Watanabe, Tsubasa; Tanaka, Hiroki; Fukutani, Satoshi; Suzuki, Minoru; Hiraoka, Masahiro; Ono, Koji

2016-01-01

Boron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. Previously, high doses of one of the boron compounds used for BNCT, L-BPA, were found to reduce the boron-derived irradiation dose to the central nervous system. However, injection with a high dose of L-BPA is not feasible in clinical settings. We aimed to find an alternative method to improve the therapeutic efficacy of this therapy. We examined the effects of oral preloading with various analogues of L-BPA in a xenograft tumour model and found that high-dose L-phenylalanine reduced the accumulation of L-BPA in the normal brain relative to tumour tissue. As a result, the maximum irradiation dose in the normal brain was 19.2% lower in the L-phenylalanine group relative to the control group. This study provides a simple strategy to improve the therapeutic efficacy of conventional boron compounds for BNCT for brain tumours and the possibility to widen the indication of BNCT to various kinds of other tumours. Copyright © 2015. Published by Elsevier Ireland Ltd.

Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma.

PubMed

Head, R J; Fay, M F; Cosgrove, L; Y C Fung, K; Rundle-Thiele, D; Martin, J H

2017-12-02

Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O 6 -methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.

Tumour-associated glial host cells display a stem-like phenotype with a distinct gene expression profile and promote growth of GBM xenografts.

PubMed

Leiss, Lina; Mutlu, Ercan; Øyan, Anne; Yan, Tao; Tsinkalovsky, Oleg; Sleire, Linda; Petersen, Kjell; Rahman, Mohummad Aminur; Johannessen, Mireille; Mitra, Sidhartha S; Jacobsen, Hege K; Talasila, Krishna M; Miletic, Hrvoje; Jonassen, Inge; Li, Xingang; Brons, Nicolaas H; Kalland, Karl-Henning; Wang, Jian; Enger, Per Øyvind

2017-02-07

Little is known about the role of glial host cells in brain tumours. However, supporting stromal cells have been shown to foster tumour growth in other cancers. We isolated stromal cells from patient-derived glioblastoma (GBM) xenografts established in GFP-NOD/scid mice. With simultaneous removal of CD11b + immune and CD31 + endothelial cells by fluorescence activated cell sorting (FACS), we obtained a population of tumour-associated glial cells, TAGs, expressing markers of terminally differentiaed glial cell types or glial progenitors. This cell population was subsequently characterised using gene expression analyses and immunocytochemistry. Furthermore, sphere formation was assessed in vitro and their glioma growth-promoting ability was examined in vivo. Finally, the expression of TAG related markers was validated in human GBMs. TAGs were highly enriched for the expression of glial cell proteins including GFAP and myelin basic protein (MBP), and immature markers such as Nestin and O4. A fraction of TAGs displayed sphere formation in stem cell medium. Moreover, TAGs promoted brain tumour growth in vivo when co-implanted with glioma cells, compared to implanting only glioma cells, or glioma cells and unconditioned glial cells from mice without tumours. Genome-wide microarray analysis of TAGs showed an expression profile distinct from glial cells from healthy mice brains. Notably, TAGs upregulated genes associated with immature cell types and self-renewal, including Pou3f2 and Sox2. In addition, TAGs from highly angiogenic tumours showed upregulation of angiogenic factors, including Vegf and Angiopoietin 2. Immunohistochemistry of three GBMs, two patient biopsies and one GBM xenograft, confirmed that the expression of these genes was mainly confined to TAGs in the tumour bed. Furthermore, their expression profiles displayed a significant overlap with gene clusters defining prognostic subclasses of human GBMs. Our data demonstrate that glial host cells in brain tumours are functionally distinct from glial cells of healthy mice brains. Furthermore, TAGs display a gene expression profile with enrichment for genes related to stem cells, immature cell types and developmental processes. Future studies are needed to delineate the biological mechanisms regulating the brain tumour-host interplay.

Mutation and deletion analysis of GFRα-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours

PubMed Central

Gimm, O; Gössling, A; Marsh, D J; Dahia, P L M; Mulligan, L M; Deimling, A von; Eng, C

1999-01-01

Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRα-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRα-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRα-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRα-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRα-1 and/or nearby genes may contribute to the pathogenesis of these tumours. © 1999 Cancer Research Campaign PMID:10408842

Functional MRI and intraoperative brain mapping to evaluate brain plasticity in patients with brain tumours and hemiparesis

PubMed Central

Roux, F; Boulanouar, K; Ibarrola, D; Tremoulet, M; Chollet, F; Berry, I

2000-01-01

OBJECTIVE—To support the hypothesis about the potential compensatory role of ipsilateral corticofugal pathways when the contralateral pathways are impaired by brain tumours.
METHODS—Retrospective analysis was carried out on the results of functional MRI (fMRI) of a selected group of five paretic patients with Rolandic brain tumours who exhibited an abnormally high ipsilateral/contralateral ratio of activation—that is, movements of the paretic hand activated predominately the ipsilateral cortex. Brain activation was achieved with a flexion extension of the fingers. Statistical parametric activation was obtained using a t test and a threshold of p<0.001. These patients, candidates for tumour resection, also underwent cortical intraoperative stimulation that was correlated to the fMRI spatial data using three dimensional reconstructions of the brain. Three patients also had postoperative control fMRI.
RESULTS—The absence of fMRI activation of the primary sensorimotor cortex normally innervating the paretic hand for the threshold chosen, was correlated with completely negative cortical responses of the cortical hand area during the operation. The preoperative fMRI activation of these patients predominantly found in the ipsilateral frontal and primary sensorimotor cortices could be related to the residual ipsilateral hand function. Postoperatively, the fMRI activation returned to more classic patterns of activation, reflecting the consequences of therapy.
CONCLUSION—In paretic patients with brain tumours, ipsilateral control could be implicated in the residual hand function, when the normal primary pathways are impaired. The possibility that functional tissue still remains in the peritumorous sensorimotor cortex even when the preoperative fMRI and the cortical intraoperative stimulations are negative, should be taken into account when planning the tumour resection and during the operation.

 PMID:10990503

The developmental origin of brain tumours: a cellular and molecular framework.

PubMed

Azzarelli, Roberta; Simons, Benjamin D; Philpott, Anna

2018-05-14

The development of the nervous system relies on the coordinated regulation of stem cell self-renewal and differentiation. The discovery that brain tumours contain a subpopulation of cells with stem/progenitor characteristics that are capable of sustaining tumour growth has emphasized the importance of understanding the cellular dynamics and the molecular pathways regulating neural stem cell behaviour. By focusing on recent work on glioma and medulloblastoma, we review how lineage tracing contributed to dissecting the embryonic origin of brain tumours and how lineage-specific mechanisms that regulate stem cell behaviour in the embryo may be subverted in cancer to achieve uncontrolled proliferation and suppression of differentiation. © 2018. Published by The Company of Biologists Ltd.

A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data.

PubMed

Vienneau, Danielle; Infanger, Denis; Feychting, Maria; Schüz, Joachim; Schmidt, Lisbeth Samsø; Poulsen, Aslak Harbo; Tettamanti, Giorgio; Klæboe, Lars; Kuehni, Claudia E; Tynes, Tore; Von der Weid, Nicolas; Lannering, Birgitta; Röösli, Martin

2016-02-01

Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight, length, maternal age), birth characteristics (e.g. vacuum extraction, preterm delivery, birth order) and exposures during pregnancy (e.g. maternal: smoking, working, dietary supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain tumour risk. Agreement between interview and birth registry data ranged from moderate (Kappa=0.54; worked during pregnancy) to almost perfect (Kappa=0.98; birth weight). Neither anthropogenic factors nor birth characteristics were associated with childhood brain tumour risk. Maternal vitamin intake during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube x-ray source array

NASA Astrophysics Data System (ADS)

Zhang, Lei; Yuan, Hong; Burk, Laurel M.; Inscoe, Christy R.; Hadsell, Michael J.; Chtcheprov, Pavel; Lee, Yueh Z.; Lu, Jianping; Chang, Sha; Zhou, Otto

2014-03-01

Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based x-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board x-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 µm measured directly from the histology (537 µm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors.

Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd‐DTPA and USPIO‐enhanced imaging

PubMed Central

Borri, Marco; Jury, Alexa; Popov, Sergey; Box, Gary; Perryman, Lara; Eccles, Suzanne A.; Jones, Chris; Robinson, Simon P.

2016-01-01

Abstract High grade and metastatic brain tumours exhibit considerable spatial variations in proliferation, angiogenesis, invasion, necrosis and oedema. Vascular heterogeneity arising from vascular co‐option in regions of invasive growth (in which the blood–brain barrier remains intact) and neoangiogenesis is a major challenge faced in the assessment of brain tumours by conventional MRI. A multiparametric MRI approach, incorporating native measurements and both Gd‐DTPA (Magnevist) and ultrasmall superparamagnetic iron oxide (P904)‐enhanced imaging, was used in combination with histogram and unsupervised cluster analysis using a k‐means algorithm to examine the spatial distribution of vascular parameters, water diffusion characteristics and invasion in intracranially propagated rat RG2 gliomas and human MDA‐MB‐231 LM2–4 breast adenocarcinomas in mice. Both tumour models presented with higher ΔR 1 (the change in transverse relaxation rate R 1 induced by Gd‐DTPA), fractional blood volume (fBV) and apparent diffusion coefficient than uninvolved regions of the brain. MDA‐MB‐231 LM2–4 tumours were less densely cellular than RG2 tumours and exhibited substantial local invasion, associated with oedema, whereas invasion in RG2 tumours was minimal. These additional features were reflected in the more heterogeneous appearance of MDA‐MB‐231 LM2–4 tumours on T 2‐weighted images and maps of functional MRI parameters. Unsupervised cluster analysis separated subregions with distinct functional properties; areas with a low fBV and relatively impermeable blood vessels (low ΔR 1) were predominantly located at the tumour margins, regions of MDA‐MB‐231 LM2–4 tumours with relatively high levels of water diffusion and low vascular permeability and/or fBV corresponded to histologically identified regions of invasion and oedema, and areas of mismatch between vascular permeability and blood volume were identified. We demonstrate that dual contrast MRI and evaluation of tissue diffusion properties, coupled with cluster analysis, allows for the assessment of heterogeneity within invasive brain tumours and the designation of functionally diverse subregions that may provide more informative predictive biomarkers. PMID:27671990

Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging.

PubMed

Boult, Jessica K R; Borri, Marco; Jury, Alexa; Popov, Sergey; Box, Gary; Perryman, Lara; Eccles, Suzanne A; Jones, Chris; Robinson, Simon P

2016-11-01

High grade and metastatic brain tumours exhibit considerable spatial variations in proliferation, angiogenesis, invasion, necrosis and oedema. Vascular heterogeneity arising from vascular co-option in regions of invasive growth (in which the blood-brain barrier remains intact) and neoangiogenesis is a major challenge faced in the assessment of brain tumours by conventional MRI. A multiparametric MRI approach, incorporating native measurements and both Gd-DTPA (Magnevist) and ultrasmall superparamagnetic iron oxide (P904)-enhanced imaging, was used in combination with histogram and unsupervised cluster analysis using a k-means algorithm to examine the spatial distribution of vascular parameters, water diffusion characteristics and invasion in intracranially propagated rat RG2 gliomas and human MDA-MB-231 LM2-4 breast adenocarcinomas in mice. Both tumour models presented with higher ΔR 1 (the change in transverse relaxation rate R 1 induced by Gd-DTPA), fractional blood volume (fBV) and apparent diffusion coefficient than uninvolved regions of the brain. MDA-MB-231 LM2-4 tumours were less densely cellular than RG2 tumours and exhibited substantial local invasion, associated with oedema, whereas invasion in RG2 tumours was minimal. These additional features were reflected in the more heterogeneous appearance of MDA-MB-231 LM2-4 tumours on T 2 -weighted images and maps of functional MRI parameters. Unsupervised cluster analysis separated subregions with distinct functional properties; areas with a low fBV and relatively impermeable blood vessels (low ΔR 1 ) were predominantly located at the tumour margins, regions of MDA-MB-231 LM2-4 tumours with relatively high levels of water diffusion and low vascular permeability and/or fBV corresponded to histologically identified regions of invasion and oedema, and areas of mismatch between vascular permeability and blood volume were identified. We demonstrate that dual contrast MRI and evaluation of tissue diffusion properties, coupled with cluster analysis, allows for the assessment of heterogeneity within invasive brain tumours and the designation of functionally diverse subregions that may provide more informative predictive biomarkers. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Pooled analysis of two Swedish case-control studies on the use of mobile and cordless telephones and the risk of brain tumours diagnosed during 1997-2003.

PubMed

Mild, Kjell Hansson; Hardell, Lennart; Carlberg, Michael

2007-01-01

Here we present the pooled analysis of 2 case-control studies on the association of brain tumours with mobile phone use. Use of analogue cellular phones increased the risk for acoustic neuroma by 5%, 95% confidence interval (CI) = 2-9% per 100 hrs of use. The risk increased for astrocytoma grade III-IV with latency period with highest estimates using >10-year time period from first use of these phone types. The risk increased per one year of use of analogue phones by 10%, 95% CI = 6-14%, digital phones by 11%, 95% CI = 6-16%, and cordless phones by 8%, 95% CI = 5-12%. For all studied phone types OR for brain tumours, mainly acoustic neuroma and malignant brain tumours, increased with latency period, especially for astrocytoma grade III-IV.

The carbon dioxide laser surgical unit as an instrument for surgery of brain tumours--its advantages and disadvantages.

PubMed

Takizawa, T

1984-01-01

The author started in 1969 his studies on developing the practical models of the carbon dioxide laser surgical units and produced Medilaser-S, Model MEL-42 and MEL-444. By the end of 1982 the author had operated on 143 cases of brain tumour with the laser. Most of those cases were brain tumours which were difficult or impossible to remove by conventional means. The major points of this paper are as follows: The principle of the laser, the mechanism of the CO2 laser, the biomedical features of the CO2 laser, the advantages and disadvantages of the CO2 laser, indications and contraindications for the use of the CO2 laser, development of the CO2 laser surgical units, surgical procedures and techniques of brain tumour laser surgery, adjuvant methods of laser surgery and comparison between the CO2 laser and the Nd-YAG laser.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

PubMed

Arshad, Azeem; Yang, Bin; Bienemann, Alison S; Barua, Neil U; Wyatt, Marcella J; Woolley, Max; Johnson, Dave E; Edler, Karen J; Gill, Steven S

2015-01-01

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma

PubMed Central

Arshad, Azeem; Yang, Bin; Bienemann, Alison S.; Barua, Neil U.; Wyatt, Marcella J.; Woolley, Max; Johnson, Dave E.; Edler, Karen J.; Gill, Steven S.

2015-01-01

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas. PMID:26186224

Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube X-ray source array

PubMed Central

Zhang, Lei; Yuan, Hong; Burk, Laurel M; Inscoe, Christy R; Hadsell, Michael J; Chtcheprov, Pavel; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

2014-01-01

Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based X-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board X-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 μm measured directly from the histology (537 μm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors. PMID:24556798

Analysis of gene expression as relevant to cancer cells and circulating tumour cells.

PubMed

Friel, Anne M; Crown, John; O'Driscoll, Lorraine

2011-01-01

Current literature provides significant evidence to support the concept that there are limited subpopulations of cells within a solid tumour that have increased tumour-initiating potential relative to the total tumour population. Such tumour-initiating cells have been identified in leukaemia and in a variety of solid tumours using different combinations of cell surface markers, suggesting that a tumour-initiating cell heterogeneity exists for each specific tumour. These studies have been extended to endometrial cancer; and herein we present several experimental approaches, both in vitro and in vivo, that can be used to determine whether such populations exist, and if so, to characterize them. These methods are adaptable to the investigation of tumour-initiating cells from other tumour types.

Changes in Cognition and Decision Making Capacity Following Brain Tumour Resection: Illustrated with Two Cases.

PubMed

Veretennikoff, Katie; Walker, David; Biggs, Vivien; Robinson, Gail

2017-09-24

Changes in cognition, behaviour and emotion frequently occur in patients with primary and secondary brain tumours. This impacts the ability to make considered decisions, especially following surgical resection, which is often overlooked in the management of patients. Moreover, the impact of cognitive deficits on decision making ability affects activities of daily living and functional independence. The assessment process to ascertain decision making capacity remains a matter of debate. One avenue for evaluating a patient's ability to make informed decisions in the context of brain tumour resection is neuropsychological assessment. This involves the assessment of a wide range of cognitive abilities on standard measurement tools, providing a robust approach to ascertaining capacity. Evidence has shown that a comprehensive and tailored neuropsychological assessment has greater sensitivity than brief cognitive screening tools to detect subtle and/or specific cognitive deficits in brain tumours. It is the precise nature and severity of any cognitive deficits that determines any implications for decision making capacity. This paper focuses on cognitive deficits and decision making capacity following surgical resection of both benign and malignant, and primary and secondary brain tumours in adult patients, and the implications for patients' ability to consent to future medical treatment and make decisions related to everyday activities.

Changes in Cognition and Decision Making Capacity Following Brain Tumour Resection: Illustrated with Two Cases

PubMed Central

Veretennikoff, Katie; Walker, David; Biggs, Vivien; Robinson, Gail

2017-01-01

Changes in cognition, behaviour and emotion frequently occur in patients with primary and secondary brain tumours. This impacts the ability to make considered decisions, especially following surgical resection, which is often overlooked in the management of patients. Moreover, the impact of cognitive deficits on decision making ability affects activities of daily living and functional independence. The assessment process to ascertain decision making capacity remains a matter of debate. One avenue for evaluating a patient’s ability to make informed decisions in the context of brain tumour resection is neuropsychological assessment. This involves the assessment of a wide range of cognitive abilities on standard measurement tools, providing a robust approach to ascertaining capacity. Evidence has shown that a comprehensive and tailored neuropsychological assessment has greater sensitivity than brief cognitive screening tools to detect subtle and/or specific cognitive deficits in brain tumours. It is the precise nature and severity of any cognitive deficits that determines any implications for decision making capacity. This paper focuses on cognitive deficits and decision making capacity following surgical resection of both benign and malignant, and primary and secondary brain tumours in adult patients, and the implications for patients’ ability to consent to future medical treatment and make decisions related to everyday activities. PMID:28946652

MORPHOLOGICAL PATTERN AND FREQUENCY OF CENTRAL NERVOUS SYSTEM TUMOURS IN CHILDREN.

PubMed

Bilqees, Fatima; Samina, Khaleeq; Mohammad, Tahir; Khaleeq-uz-Zamaan

2016-01-01

Recent studies, including a comprehensive study by National Cancer Institute, have shown that a significant increase in the incidence of childhood brain tumours makes them the most common paediatric tumour. The objectives of this study were to determine the frequency of central nervous system tumours in paediatric age group (0-12 years), and to segregate various morphologic types according to WHO classification. The study included consecutive cases of central nervous system tumours diagnosed in children in the histopathology department at Federal Government Polyclinic, PGMI, Islamabad, during a period of 4.8 years (Jan 2009-Aug 2013). The initial histopathological evaluation of these lesions was performed on H&E stained sections of paraffin embedded tissues. Special stains and immunohistochemistry were performed whenever indicated. Out of 75 cases, 34 (45.3%) were astrocytic tumours, including 16 (47.1%) Pilocytic astrocytomas (WHO Grade-I), 1 (2.9%) diffuse fibrillary astrocytoma (WHO Grade-II), 1 (2.9%) anaplastic astrocytoma (WHO Grade-III) and 16(47.1%) glioblastoma multiforme (WHO Grade-IV); 18 (24%) were embryonal tumours including 17 (94.4%) medulloblastoma (WHO Grade-IV) and 1 (5.6%) neuroblastoma (WHO Grade IV); 10 (13.3%) were craniopharyngiomas (WHO Grade-I) and 5 (6.7%) were ependymal tumours including 1 (20%) myxopapillary ependymoma (WHO Grade-I) and 4 (80%) ependymomas (WHO Grade-II). Miscellaneous entities included 3 (4%) choroid plexus tumours; 1 (2%) anaplastic oligodendroglioma (WHO Grade-III); 1 (2%) atypical meningioma (WHO Grade-II); 1 (2%) schwannoma (WHO Grade-I); 1 (2%) neurofibroma (WHO Grade-I) and 1 (2%) lipoma (WHO Grade-I). Astrocytic tumours are the most common central nervous system tumours in paediatric age group and high grade lesions (WHO Grade-IV) constitute the largest category (45.3%).

Automated brain tumour detection and segmentation using superpixel-based extremely randomized trees in FLAIR MRI.

PubMed

Soltaninejad, Mohammadreza; Yang, Guang; Lambrou, Tryphon; Allinson, Nigel; Jones, Timothy L; Barrick, Thomas R; Howe, Franklyn A; Ye, Xujiong

2017-02-01

We propose a fully automated method for detection and segmentation of the abnormal tissue associated with brain tumour (tumour core and oedema) from Fluid- Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI). The method is based on superpixel technique and classification of each superpixel. A number of novel image features including intensity-based, Gabor textons, fractal analysis and curvatures are calculated from each superpixel within the entire brain area in FLAIR MRI to ensure a robust classification. Extremely randomized trees (ERT) classifier is compared with support vector machine (SVM) to classify each superpixel into tumour and non-tumour. The proposed method is evaluated on two datasets: (1) Our own clinical dataset: 19 MRI FLAIR images of patients with gliomas of grade II to IV, and (2) BRATS 2012 dataset: 30 FLAIR images with 10 low-grade and 20 high-grade gliomas. The experimental results demonstrate the high detection and segmentation performance of the proposed method using ERT classifier. For our own cohort, the average detection sensitivity, balanced error rate and the Dice overlap measure for the segmented tumour against the ground truth are 89.48 %, 6 % and 0.91, respectively, while, for the BRATS dataset, the corresponding evaluation results are 88.09 %, 6 % and 0.88, respectively. This provides a close match to expert delineation across all grades of glioma, leading to a faster and more reproducible method of brain tumour detection and delineation to aid patient management.

Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries.

PubMed

Cardis, E; Armstrong, B K; Bowman, J D; Giles, G G; Hours, M; Krewski, D; McBride, M; Parent, M E; Sadetzki, S; Woodward, A; Brown, J; Chetrit, A; Figuerola, J; Hoffmann, C; Jarus-Hakak, A; Montestruq, L; Nadon, L; Richardson, L; Villegas, R; Vrijheid, M

2011-09-01

The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made.

Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries

PubMed Central

Armstrong, B K; Bowman, J D; Giles, G G; Hours, M; Krewski, D; McBride, M; Parent, M E; Sadetzki, S; Woodward, A; Brown, J; Chetrit, A; Figuerola, J; Hoffmann, C; Jarus-Hakak, A; Montestruq, L; Nadon, L; Richardson, L; Villegas, R; Vrijheid, M

2011-01-01

Objectives The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. Methods Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the ‘tumour location’ of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. Results ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. Conclusions There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made. PMID:21659469

Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use.

PubMed

Hardell, Lennart; Carlberg, Michael; Söderqvist, Fredrik; Mild, Kjell Hansson

2013-12-01

Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the handheld phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a 'possible' human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18-75 years and diagnosed during 2007-2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04‑3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6-6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996-2.7, increasing with latency >15-20 years to an OR=2.1, 95% CI=1.2-3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1-2.9, and, for latency of 15-20 years, the OR=2.1, 95% CI=1.2-3.8. Few participants had used a cordless phone for >20-25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1-5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15-20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis.

Proximal dentatothalamocortical tract involvement in posterior fossa syndrome

PubMed Central

Phillips, Nicholas S.; Laningham, Fred H.; Patay, Zoltan; Gajjar, Amar; Wallace, Dana; Boop, Frederick; Sanford, Robert; Ness, Kirsten K.; Ogg, Robert J.

2009-01-01

Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, –71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates –24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome. PMID:19805491

Mobile phone use and risk of brain tumours: a systematic review of association between study quality, source of funding, and research outcomes.

PubMed

Prasad, Manya; Kathuria, Prachi; Nair, Pallavi; Kumar, Amit; Prasad, Kameshwar

2017-05-01

Mobile phones emit electromagnetic radiations that are classified as possibly carcinogenic to humans. Evidence for increased risk for brain tumours accumulated in parallel by epidemiologic investigations remains controversial. This paper aims to investigate whether methodological quality of studies and source of funding can explain the variation in results. PubMed and Cochrane CENTRAL searches were conducted from 1966 to December 2016, which was supplemented with relevant articles identified in the references. Twenty-two case control studies were included for systematic review. Meta-analysis of 14 case-control studies showed practically no increase in risk of brain tumour [OR 1.03 (95% CI 0.92-1.14)]. However, for mobile phone use of 10 years or longer (or >1640 h), the overall result of the meta-analysis showed a significant 1.33 times increase in risk. The summary estimate of government funded as well as phone industry funded studies showed 1.07 times increase in odds which was not significant, while mixed funded studies did not show any increase in risk of brain tumour. Metaregression analysis indicated that the association was significantly associated with methodological study quality (p < 0.019, 95% CI 0.009-0.09). Relationship between source of funding and log OR for each study was not statistically significant (p < 0.32, 95% CI 0.036-0.010). We found evidence linking mobile phone use and risk of brain tumours especially in long-term users (≥10 years). Studies with higher quality showed a trend towards high risk of brain tumour, while lower quality showed a trend towards lower risk/protection.

Biological effects from electromagnetic field exposure and public exposure standards.

PubMed

Hardell, Lennart; Sage, Cindy

2008-02-01

During recent years there has been increasing public concern on potential health risks from power-frequency fields (extremely low frequency electromagnetic fields; ELF) and from radiofrequency/microwave radiation emissions (RF) from wireless communications. Non-thermal (low-intensity) biological effects have not been considered for regulation of microwave exposure, although numerous scientific reports indicate such effects. The BioInitiative Report is based on an international research and public policy initiative to give an overview of what is known of biological effects that occur at low-intensity electromagnetic fields (EMFs) exposure. Health endpoints reported to be associated with ELF and/or RF include childhood leukaemia, brain tumours, genotoxic effects, neurological effects and neurodegenerative diseases, immune system deregulation, allergic and inflammatory responses, breast cancer, miscarriage and some cardiovascular effects. The BioInitiative Report concluded that a reasonable suspicion of risk exists based on clear evidence of bioeffects at environmentally relevant levels, which, with prolonged exposures may reasonably be presumed to result in health impacts. Regarding ELF a new lower public safety limit for habitable space adjacent to all new or upgraded power lines and for all other new constructions should be applied. A new lower limit should also be used for existing habitable space for children and/or women who are pregnant. A precautionary limit should be adopted for outdoor, cumulative RF exposure and for cumulative indoor RF fields with considerably lower limits than existing guidelines, see the BioInitiative Report. The current guidelines for the US and European microwave exposure from mobile phones, for the brain are 1.6 W/Kg and 2 W/Kg, respectively. Since use of mobile phones is associated with an increased risk for brain tumour after 10 years, a new biologically based guideline is warranted. Other health impacts associated with exposure to electromagnetic fields not summarized here may be found in the BioInitiative Report at www.bioinitiative.org.

Novel mutations target distinct subgroups of medulloblastoma

PubMed Central

Robinson, Giles; Parker, Matthew; Kranenburg, Tanya A.; Lu, Charles; Chen, Xiang; Ding, Li; Phoenix, Timothy N.; Hedlund, Erin; Wei, Lei; Zhu, Xiaoyan; Chalhoub, Nader; Baker, Suzanne J.; Huether, Robert; Kriwacki, Richard; Curley, Natasha; Thiruvenkatam, Radhika; Wang, Jianmin; Wu, Gang; Rusch, Michael; Hong, Xin; Beckford, Jared; Gupta, Pankaj; Ma, Jing; Easton, John; Vadodaria, Bhavin; Onar-Thomas, Arzu; Lin, Tong; Li, Shaoyi; Pounds, Stanley; Paugh, Steven; Zhao, David; Kawauchi, Daisuke; Roussel, Martine F.; Finkelstein, David; Ellison, David W.; Lau, Ching C.; Bouffet, Eric; Hassall, Tim; Gururangan, Sridharan; Cohn, Richard; Fulton, Robert S.; Fulton, Lucinda L.; Dooling, David J.; Ochoa, Kerri; Gajjar, Amar; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Zhang, Jinghui; Gilbertson, Richard J.

2012-01-01

Summary Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. To identify mutations that drive medulloblastoma we sequenced the entire genomes of 37 tumours and matched normal blood. One hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma: several target distinct components of the epigenetic machinery in different disease subgroups, e.g., regulators of H3K27 and H3K4 trimethylation in subgroup-3 and 4 (e.g., KDM6A and ZMYM3), and CTNNB1-associated chromatin remodellers in WNT-subgroup tumours (e.g., SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours, identified genes that maintain this cell lineage (DDX3X) as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumourigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development. PMID:22722829

[Modern Management of Pancoast Tumour].

PubMed

Marra, Alessandro

2018-06-01

Pancoast or superior pulmonary sulcus tumour is a subset of lung carcinoma that invades the structures of the thoracic inlet - first ribs, distal roots of the brachial plexus, stellate ganglion, vertebrae, and subclavian vessels. The first symptom is usually shoulder pain; consequently, most patients are initially treated for osteoarthritis. Late diagnosis is common. Success of therapy depends on an accurate staging: standard imaging with CT scan of the chest, PET-CT scan, brain MRI are needed to rule out distant metastases, endobronchial ultrasound-guided needle biopsy (EBUS-TBNA) or mediastinoscopy are mandatory for reliable nodal staging. An MRI of the thoracic inlet allows to clearly define the boundaries of local invasion. Modern management of Pancoast tumour includes induction concurrent chemoradiotherapy followed by surgical resection. As compared with historical series treated by preoperative radiation, a trimodally approach did enhance complete resection rates and perhaps long-term survival - from about 30% 5-year survival rate to 60% in R0-resected patients. In patients who have unresectable but non-metastatic Pancoast tumours and appropriate performance status, definitive concurrent chemoradiotherapy and radiotherapy are recommended options. Georg Thieme Verlag KG Stuttgart · New York.

Diagnostic, prognostic and predictive relevance of molecular markers in gliomas.

PubMed

Brandner, Sebastian; von Deimling, Andreas

2015-10-01

The advances of genome-wide 'discovery platforms' and the increasing affordability of the analysis of significant sample sizes have led to the identification of novel mutations in brain tumours that became diagnostically and prognostically relevant. The development of mutation-specific antibodies has facilitated the introduction of these convenient biomarkers into most neuropathology laboratories and has changed our approach to brain tumour diagnostics. However, tissue diagnosis will remain an essential first step for the correct stratification for subsequent molecular tests, and the combined interpretation of the molecular and tissue diagnosis ideally remains with the neuropathologist. This overview will help our understanding of the pathobiology of common intrinsic brain tumours in adults and help guiding which molecular tests can supplement and refine the tissue diagnosis of the most common adult intrinsic brain tumours. This article will discuss the relevance of 1p/19q codeletions, IDH1/2 mutations, BRAF V600E and BRAF fusion mutations, more recently discovered mutations in ATRX, H3F3A, TERT, CIC and FUBP1, for diagnosis, prognostication and predictive testing. In a tumour-specific topic, the role of mitogen-activated protein kinase pathway mutations in the pathogenesis of pilocytic astrocytomas will be covered. © 2015 British Neuropathological Society.

Machine learning based brain tumour segmentation on limited data using local texture and abnormality.

PubMed

Bonte, Stijn; Goethals, Ingeborg; Van Holen, Roel

2018-05-07

Brain tumour segmentation in medical images is a very challenging task due to the large variety in tumour shape, position, appearance, scanning modalities and scanning parameters. Most existing segmentation algorithms use information from four different MRI-sequences, but since this is often not available, there is need for a method able to delineate the different tumour tissues based on a minimal amount of data. We present a novel approach using a Random Forests model combining voxelwise texture and abnormality features on a contrast-enhanced T1 and FLAIR MRI. We transform the two scans into 275 feature maps. A random forest model next calculates the probability to belong to 4 tumour classes or 5 normal classes. Afterwards, a dedicated voxel clustering algorithm provides the final tumour segmentation. We trained our method on the BraTS 2013 database and validated it on the larger BraTS 2017 dataset. We achieve median Dice scores of 40.9% (low-grade glioma) and 75.0% (high-grade glioma) to delineate the active tumour, and 68.4%/80.1% for the total abnormal region including edema. Our fully automated brain tumour segmentation algorithm is able to delineate contrast enhancing tissue and oedema with high accuracy based only on post-contrast T1-weighted and FLAIR MRI, whereas for non-enhancing tumour tissue and necrosis only moderate results are obtained. This makes the method especially suitable for high-grade glioma. Copyright © 2018 Elsevier Ltd. All rights reserved.

ICGC PedBrain: Dissecting the genomic complexity underlying medulloblastoma

PubMed Central

Jones, David TW; Jäger, Natalie; Kool, Marcel; Zichner, Thomas; Hutter, Barbara; Sultan, Marc; Cho, Yoon-Jae; Pugh, Trevor J; Hovestadt, Volker; Stütz, Adrian M; Rausch, Tobias; Warnatz, Hans-Jörg; Ryzhova, Marina; Bender, Sebastian; Sturm, Dominik; Pleier, Sabrina; Cin, Huriye; Pfaff, Elke; Sieber, Laura; Wittmann, Andrea; Remke, Marc; Witt, Hendrik; Hutter, Sonja; Tzaridis, Theophilos; Weischenfeldt, Joachim; Raeder, Benjamin; Avci, Meryem; Amstislavskiy, Vyacheslav; Zapatka, Marc; Weber, Ursula D; Wang, Qi; Lasitschka, Bärbel; Bartholomae, Cynthia C; Schmidt, Manfred; von Kalle, Christof; Ast, Volker; Lawerenz, Chris; Eils, Jürgen; Kabbe, Rolf; Benes, Vladimir; van Sluis, Peter; Koster, Jan; Volckmann, Richard; Shih, David; Betts, Matthew J; Russell, Robert B; Coco, Simona; Tonini, Gian Paolo; Schüller, Ulrich; Hans, Volkmar; Graf, Norbert; Kim, Yoo-Jin; Monoranu, Camelia; Roggendorf, Wolfgang; Unterberg, Andreas; Herold-Mende, Christel; Milde, Till; Kulozik, Andreas E; von Deimling, Andreas; Witt, Olaf; Maass, Eberhard; Rössler, Jochen; Ebinger, Martin; Schuhmann, Martin U; Frühwald, Michael C; Hasselblatt, Martin; Jabado, Nada; Rutkowski, Stefan; von Bueren, André O; Williamson, Dan; Clifford, Steven C; McCabe, Martin G; Collins, V. Peter; Wolf, Stephan; Wiemann, Stefan; Lehrach, Hans; Brors, Benedikt; Scheurlen, Wolfram; Felsberg, Jörg; Reifenberger, Guido; Northcott, Paul A; Taylor, Michael D; Meyerson, Matthew; Pomeroy, Scott L; Yaspo, Marie-Laure; Korbel, Jan O; Korshunov, Andrey; Eils, Roland; Pfister, Stefan M; Lichter, Peter

2013-01-01

Summary Medulloblastoma is an aggressively-growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and displays tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently discriminated2,3. WNT tumours, displaying activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 & 4 tumours are molecularly less well-characterised, and also present the greatest clinical challenges2,3,5. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs. Tetraploidy was identified as a frequent early event in Group 3 & 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA-sequencing confirmed these alterations, and revealed the expression of the first medulloblastoma fusion genes. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 & 4 patients. PMID:22832583

Side population in human glioblastoma is non-tumorigenic and characterizes brain endothelial cells

PubMed Central

Golebiewska, Anna; Bougnaud, Sébastien; Stieber, Daniel; Brons, Nicolaas H. C.; Vallar, Laurent; Hertel, Frank; Klink, Barbara; Schröck, Evelin; Bjerkvig, Rolf

2013-01-01

The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the ‘side population’ phenotype based on efflux properties of ATP-binding cassette transporters in freshly isolated human glioblastoma samples and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of endothelial cells are likely to compromise drug availability, transiently targeting ATP-binding cassette transporters may be a valuable therapeutic strategy to improve treatment effects in brain tumours. PMID:23460667

Leukaemia, brain tumours and exposure to extremely low frequency magnetic fields: cohort study of Swiss railway employees

PubMed Central

Röösli, Martin; Lörtscher, Manfred; Egger, Matthias; Pfluger, Dominik; Schreier, Nadja; Lörtscher, Emanuel; Locher, Peter; Spoerri, Adrian; Minder, Christoph

2007-01-01

Aims To investigate the relationship between extremely low frequency magnetic field (ELF‐MF) exposure and mortality from leukaemia and brain tumour in a cohort of Swiss railway workers. Methods 20 141 Swiss railway employees with 464 129 person‐years of follow‐up between 1972 and 2002 were studied. Mortality rates for leukaemia and brain tumour of highly exposed train drivers (21 μT average annual exposure) were compared with medium and low exposed occupational groups (i.e. station masters with an average exposure of 1 μT). In addition, individual cumulative exposure was calculated from on‐site measurements and modelling of past exposures. Results The hazard ratio (HR) for leukaemia mortality of train drivers was 1.43 (95% CI 0.74 to 2.77) compared with station masters. For myeloid leukaemia the HR of train drivers was 4.74 (95% CI 1.04 to 21.60) and for Hodgkin's disease 3.29 (95% CI 0.69 to 15.63). Lymphoid leukaemia, non‐Hodgkin's disease and brain tumour mortality were not associated with magnetic field exposure. Concordant results were obtained from analyses based on individual cumulative exposure. Conclusions Some evidence of an exposure–response association was found for myeloid leukaemia and Hodgkin's disease, but not for other haematopoietic and lymphatic malignancies and brain tumours. PMID:17525094

Protein Kinase CK2 Content in GL261 Mouse Glioblastoma.

PubMed

Ferrer-Font, Laura; Alcaraz, Estefania; Plana, Maria; Candiota, Ana Paula; Itarte, Emilio; Arús, Carles

2016-07-01

Glioblastoma (GBM) is the most prevalent and aggressive human glial tumour with a median survival of 14-15 months. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment. Unfortunately, chemoresistence always ensues with concomitant tumour regrowth. Protein kinase CK2 (CK2) contributes to tumour development, proliferation, and suppression of apoptosis in cancer and it is overexpressed in human GBM. Targeting CK2 in GBM treatment may benefit patients. With this translational perspective in mind, we have studied the CK2 expression level by Western blot analysis in a preclinical model of GBM: GL261 cells growing orthotopically in C57BL/6 mice. The expression level of the CK2 catalytic subunit (CK2α) was higher in tumour (about 4-fold) and in contralateral brain parenchyma (more than 2-fold) than in normal brain parenchyma (p < 0.05). In contrast, no significant changes were found in CK2 regulatory subunit (CK2β) expression, suggesting an increased unbalance of CK2α/CK2β in GL261 tumours with respect to normal brain parenchyma, in agreement with a differential role of these two subunits in tumours.

[Oligodendroglioma with neuronal differentiation in an 8-month-old African hedgehog (Atelerix albiventris)].

PubMed

Völker, Iris; Schwarze, Iris; Brezina, Tina E; Köstlinger, Saskia; Hewicker-Trautwein, Marion

2016-10-12

An 8-month-old, male African hedgehog clinically displayed a wobbly walk, anuria, inappetence and apathy, whereupon the suspected diagnosis wobbly hedgehog syndrome was made. After exacerbation, the hedgehog was euthanized. Histologically, a tumour mainly consisting of medium-sized, oval tumour cells and a smaller number of spindeloid cells was found in the cerebrum. The tumour contained neuropil islets and extracellular myxoid material. Immunohistochemically, the tumour cells expressed oligodendroglial (neurite outgrowth inhibitor, Nogo-A; oligodendrocyte transcription factor, Olig-2) and neuronal (neuron-specific enolase, NSE; microtubule-associated protein-2a, MAP-2a; synaptophysin) cell markers. Based on these findings, an oligodendroglioma with neuronal differentiation was diagnosed. Such a brain tumour has to date not been reported for African hedgehogs. At necropsy, a severely filled and dilated urinary bladder was observed, which was presumably caused by a central blockade of the micturition centre in the brain. In the case of neurological symptoms in young hedgehogs, a primary brain tumour should, as in adults, be considered as a differential diagnosis. As further differentials, inflammatory-infectious (rabies, herpes, baylisascariosis), degenerative (cardiomyopathy, intervertebral-disc disease), traumatic, alimentary (vitamin-B deficiency) and metabolic-toxic (heat-cold-torpor, hepatic encephalopathy) triggers have to be considered.

'This diagnosis can be extremely scary'.

PubMed

Newton-Snow, Tamsin

2017-01-18

Neurofibromatosis type 2 (NF2) is a rare genetic disorder that occurs in an estimated one in 35,000 people. The condition is often life-limiting and involves tumours growing on the nervous system, typically on the hearing nerves, brain and spine. While the tumours are mainly benign, they can lead to hearing loss, deafness and problems with balance and mobility. Most patients will need surgery or other treatments for NF2-related brain or spinal cord tumours at some point in their lives.

Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study.

PubMed

Castelo-Branco, Pedro; Choufani, Sanaa; Mack, Stephen; Gallagher, Denis; Zhang, Cindy; Lipman, Tatiana; Zhukova, Nataliya; Walker, Erin J; Martin, Dianna; Merino, Diana; Wasserman, Jonathan D; Elizabeth, Cynthia; Alon, Noa; Zhang, Libo; Hovestadt, Volker; Kool, Marcel; Jones, David T W; Zadeh, Gelareh; Croul, Sidney; Hawkins, Cynthia; Hitzler, Johann; Wang, Jean C Y; Baruchel, Sylvain; Dirks, Peter B; Malkin, David; Pfister, Stefan; Taylor, Michael D; Weksberg, Rosanna; Tabori, Uri

2013-05-01

Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0.0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site [UTSS]) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0.0001). UTSS had a positive predictive value of 1.00 (95% CI 0.95-1.00) and a negative predictive value of 0.95 (0.87-0.99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31-71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86-100) for 20 with non-hypermethylated tumours (p=0.0008). 5-year progression-free survival was 86% (68-100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10-50) for those with hypermethylated tumours (p=0.0008). Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. The Canadian Institute of Health Research and the Terry Fox Foundation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hybrid MR-PET of brain tumours using amino acid PET and chemical exchange saturation transfer MRI.

PubMed

da Silva, N A; Lohmann, P; Fairney, J; Magill, A W; Oros Peusquens, A-M; Choi, C-H; Stirnberg, R; Stoffels, G; Galldiks, N; Golay, X; Langen, K-J; Jon Shah, N

2018-06-01

PET using radiolabelled amino acids has become a promising tool in the diagnostics of gliomas and brain metastasis. Current research is focused on the evaluation of amide proton transfer (APT) chemical exchange saturation transfer (CEST) MR imaging for brain tumour imaging. In this hybrid MR-PET study, brain tumours were compared using 3D data derived from APT-CEST MRI and amino acid PET using O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET). Eight patients with gliomas were investigated simultaneously with 18 F-FET PET and APT-CEST MRI using a 3-T MR-BrainPET scanner. CEST imaging was based on a steady-state approach using a B 1 average power of 1μT. B 0 field inhomogeneities were corrected a Prametric images of magnetisation transfer ratio asymmetry (MTR asym ) and differences to the extrapolated semi-solid magnetisation transfer reference method, APT# and nuclear Overhauser effect (NOE#), were calculated. Statistical analysis of the tumour-to-brain ratio of the CEST data was performed against PET data using the non-parametric Wilcoxon test. A tumour-to-brain ratio derived from APT# and 18 F-FET presented no significant differences, and no correlation was found between APT# and 18 F-FET PET data. The distance between local hot spot APT# and 18 F-FET were different (average 20 ± 13 mm, range 4-45 mm). For the first time, CEST images were compared with 18 F-FET in a simultaneous MR-PET measurement. Imaging findings derived from 18 F-FET PET and APT CEST MRI seem to provide different biological information. The validation of these imaging findings by histological confirmation is necessary, ideally using stereotactic biopsy.

Iodine-123 alpha-methyl tyrosine single-photon emission tomography of cerebral gliomas: standardised evaluation of tumour uptake and extent.

PubMed

Weckesser, M; Griessmeier, M; Schmidt, D; Sonnenberg, F; Ziemons, K; Kemna, L; Holschbach, M; Langen, K; Müller-Gärtner, H

1998-02-01

Single-photon emission tomography (SPET) with the amino acid analogue l-3-[123I]iodo-alpha-methyl tyrosine (IMT) is helpful in the diagnosis and monitoring of cerebral gliomas. Radiolabelled amino acids seem to reflect tumour infiltration more specifically than conventional methods like magnetic resonance imaging and computed tomography. Automatic tumour delineation based on maximal tumour uptake may cause an overestimation of mean tumour uptake and an underestimation of tumour extension in tumours with circumscribed peaks. The aim of this study was to develop a program for tumour delineation and calculation of mean tumour uptake which takes into account the mean background activity and is thus optimised to the problem of tumour definition in IMT SPET. Using the frequency distribution of pixel intensities of the tomograms a program was developed which automatically detects a reference brain region and draws an isocontour region around the tumour taking into account mean brain radioactivity. Tumour area and tumour/brain ratios were calculated. A three-compartment phantom was simulated to test the program. The program was applied to IMT SPET studies of 20 patients with cerebral gliomas and was compared to the results of manual analysis by three different investigators. Activity ratios and chamber extension of the phantom were correctly calculated by the automatic analysis. A method based on image maxima alone failed to determine chamber extension correctly. Manual region of interest analysis in patient studies resulted in a mean inter-observer standard deviation of 8.7% +/ -6.1% (range 2.7% -25.0%). The mean value of the results of the manual analysis showed a significant correlation to the results of the automatic analysis (r = 0.91, P<0. 0001 for the uptake ratio; r = 0.87, P<0.0001 for the tumour area). We conclude that the algorithm proposed simplifies the calculation of uptake ratios and may be used for observer-independent evaluation of IMT SPET studies. Three-dimensional tumour recognition and transfer to co-registered morphological images based on this program may be useful for the planning of surgical and radiation treatment.

Childhood brain tumour risk and its association with wireless phones: a commentary

PubMed Central

2011-01-01

Case-control studies on adults point to an increased risk of brain tumours (glioma and acoustic neuroma) associated with the long-term use of mobile phones. Recently, the first study on mobile phone use and the risk of brain tumours in children and adolescents, CEFALO, was published. It has been claimed that this relatively small study yielded reassuring results of no increased risk. We do not agree. We consider that the data contain several indications of increased risk, despite low exposure, short latency period, and limitations in the study design, analyses and interpretation. The information certainly cannot be used as reassuring evidence against an association, for reasons that we discuss in this commentary. PMID:22182218

Childhood brain tumour risk and its association with wireless phones: a commentary.

PubMed

Söderqvist, Fredrik; Carlberg, Michael; Hansson Mild, Kjell; Hardell, Lennart

2011-12-19

Case-control studies on adults point to an increased risk of brain tumours (glioma and acoustic neuroma) associated with the long-term use of mobile phones. Recently, the first study on mobile phone use and the risk of brain tumours in children and adolescents, CEFALO, was published. It has been claimed that this relatively small study yielded reassuring results of no increased risk. We do not agree. We consider that the data contain several indications of increased risk, despite low exposure, short latency period, and limitations in the study design, analyses and interpretation. The information certainly cannot be used as reassuring evidence against an association, for reasons that we discuss in this commentary.

Increasing Rates of Brain Tumours in the Swedish National Inpatient Register and the Causes of Death Register

PubMed Central

Hardell, Lennart; Carlberg, Michael

2015-01-01

Radiofrequency emissions in the frequency range 30 kHz–300 GHz were evaluated to be Group 2B, i.e., “possibly”, carcinogenic to humans by the International Agency for Research on Cancer (IARC) at WHO in May 2011. The Swedish Cancer Register has not shown increasing incidence of brain tumours in recent years and has been used to dismiss epidemiological evidence on a risk. In this study we used the Swedish National Inpatient Register (IPR) and Causes of Death Register (CDR) to further study the incidence comparing with the Cancer Register data for the time period 1998–2013 using joinpoint regression analysis. In the IPR we found a joinpoint in 2007 with Annual Percentage Change (APC) +4.25%, 95% CI +1.98, +6.57% during 2007–2013 for tumours of unknown type in the brain or CNS. In the CDR joinpoint regression found one joinpoint in 2008 with APC during 2008–2013 +22.60%, 95% CI +9.68, +37.03%. These tumour diagnoses would be based on clinical examination, mainly CT and/or MRI, but without histopathology or cytology. No statistically significant increasing incidence was found in the Swedish Cancer Register during these years. We postulate that a large part of brain tumours of unknown type are never reported to the Cancer Register. Furthermore, the frequency of diagnosis based on autopsy has declined substantially due to a general decline of autopsies in Sweden adding further to missing cases. We conclude that the Swedish Cancer Register is not reliable to be used to dismiss results in epidemiological studies on the use of wireless phones and brain tumour risk. PMID:25854296

Increasing rates of brain tumours in the Swedish national inpatient register and the causes of death register.

PubMed

Hardell, Lennart; Carlberg, Michael

2015-04-03

Radiofrequency emissions in the frequency range 30 kHz-300 GHz were evaluated to be Group 2B, i.e., "possibly", carcinogenic to humans by the International Agency for Research on Cancer (IARC) at WHO in May 2011. The Swedish Cancer Register has not shown increasing incidence of brain tumours in recent years and has been used to dismiss epidemiological evidence on a risk. In this study we used the Swedish National Inpatient Register (IPR) and Causes of Death Register (CDR) to further study the incidence comparing with the Cancer Register data for the time period 1998-2013 using joinpoint regression analysis. In the IPR we found a joinpoint in 2007 with Annual Percentage Change (APC) +4.25%, 95% CI +1.98, +6.57% during 2007-2013 for tumours of unknown type in the brain or CNS. In the CDR joinpoint regression found one joinpoint in 2008 with APC during 2008-2013 +22.60%, 95% CI +9.68, +37.03%. These tumour diagnoses would be based on clinical examination, mainly CT and/or MRI, but without histopathology or cytology. No statistically significant increasing incidence was found in the Swedish Cancer Register during these years. We postulate that a large part of brain tumours of unknown type are never reported to the Cancer Register. Furthermore, the frequency of diagnosis based on autopsy has declined substantially due to a general decline of autopsies in Sweden adding further to missing cases. We conclude that the Swedish Cancer Register is not reliable to be used to dismiss results in epidemiological studies on the use of wireless phones and brain tumour risk.

Three validation metrics for automated probabilistic image segmentation of brain tumours

PubMed Central

Zou, Kelly H.; Wells, William M.; Kikinis, Ron; Warfield, Simon K.

2005-01-01

SUMMARY The validity of brain tumour segmentation is an important issue in image processing because it has a direct impact on surgical planning. We examined the segmentation accuracy based on three two-sample validation metrics against the estimated composite latent gold standard, which was derived from several experts’ manual segmentations by an EM algorithm. The distribution functions of the tumour and control pixel data were parametrically assumed to be a mixture of two beta distributions with different shape parameters. We estimated the corresponding receiver operating characteristic curve, Dice similarity coefficient, and mutual information, over all possible decision thresholds. Based on each validation metric, an optimal threshold was then computed via maximization. We illustrated these methods on MR imaging data from nine brain tumour cases of three different tumour types, each consisting of a large number of pixels. The automated segmentation yielded satisfactory accuracy with varied optimal thresholds. The performances of these validation metrics were also investigated via Monte Carlo simulation. Extensions of incorporating spatial correlation structures using a Markov random field model were considered. PMID:15083482

Visualisation of brain tumors and quantitation of the protein synthesis rate with L-1-[C-11]-tyrosine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pruim, J.; Willemsen, A.T.M.; Waarde, A. van

1994-05-01

We have developed the tracer L-1-[C-11]-tyrosine (TYR) for the quantitation of the protein synthesis rate (PSR) in tumours. Here the first results with TYR in a group of patients with (suspected) primary or recurrent brain tumours are reported. Twenty-six patients were studied: 12 male, 14 female, age 45{plus_minus}16 (mean{plus_minus}S.D.) years. At the time of the study the diagnosis of a primary tumour or recurrent tumour was considered on the basis of clinical symptoms and CT/MRI. Patients received 237{plus_minus}111 MBq TYR i.v. Seventeen patients were studied in a dynamic mode (frame sequence: 10 x 0.5, 3 x 5, 3 x 10more » minutes). During the studies, arterial blood samples were taken for measurement of the input function, and the assessment of metabolites ([C-11]CO{sub 2}, [C-11]proteins). ROIs were placed over the tumour and using a modified Patlak-analysis the PSR was calculated. In the other 9 patients a static emission scan was made, 20-40 min after injection. All images were corrected for attenuation via a transmission scan. Histology or cytology of the tumour was obtained shortly after the TYR-PET in 20 patients. The calculated PSR of the tumours was 1.0{plus_minus}0.6 nmol/ml/min. This is in range with our animal experiments. The PSR in brain tissue of the contralateral hemisphere was 0.7{plus_minus}0.4 nmol/ml/min. Sixteen of the turnouts were correctly identified with TYR-PET. Also, 2 benign lesions were correctly identified. TYR-PET gave 1 false-positive (infarction) and 1 false-negative (astrocytoma of intermediate malignancy) result. In a few patients with extensive peri-tumoural edema on MRI/CT, additional tumour locations were found with TYR-PET, proven to be malignant on biopsy. In conclusion: TYR is applicable for the visualisation of brain tumours. The possibility of calculating a PSR allows its use in the evaluation of therapy.« less

Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis.

PubMed

Kim, Soo-Hyun; Redvers, Richard P; Chi, Lap Hing; Ling, Xiawei; Lucke, Andrew J; Reid, Robert C; Fairlie, David P; Baptista Moreno Martin, Ana Carolina; Anderson, Robin L; Denoyer, Delphine; Pouliot, Normand

2018-05-21

Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. © 2018. Published by The Company of Biologists Ltd.

Case-control study of the association between malignant brain tumours diagnosed between 2007 and 2009 and mobile and cordless phone use

PubMed Central

HARDELL, LENNART; CARLBERG, MICHAEL; SÖDERQVIST, FREDRIK; MILD, KJELL HANSSON

2013-01-01

Previous studies have shown a consistent association between long-term use of mobile and cordless phones and glioma and acoustic neuroma, but not for meningioma. When used these phones emit radiofrequency electromagnetic fields (RF-EMFs) and the brain is the main target organ for the hand-held phone. The International Agency for Research on Cancer (IARC) classified in May, 2011 RF-EMF as a group 2B, i.e. a ‘possible’ human carcinogen. The aim of this study was to further explore the relationship between especially long-term (>10 years) use of wireless phones and the development of malignant brain tumours. We conducted a new case-control study of brain tumour cases of both genders aged 18–75 years and diagnosed during 2007–2009. One population-based control matched on gender and age (within 5 years) was used to each case. Here, we report on malignant cases including all available controls. Exposures on e.g. use of mobile phones and cordless phones were assessed by a self-administered questionnaire. Unconditional logistic regression analysis was performed, adjusting for age, gender, year of diagnosis and socio-economic index using the whole control sample. Of the cases with a malignant brain tumour, 87% (n=593) participated, and 85% (n=1,368) of controls in the whole study answered the questionnaire. The odds ratio (OR) for mobile phone use of the analogue type was 1.8, 95% confidence interval (CI)=1.04–3.3, increasing with >25 years of latency (time since first exposure) to an OR=3.3, 95% CI=1.6–6.9. Digital 2G mobile phone use rendered an OR=1.6, 95% CI=0.996–2.7, increasing with latency >15–20 years to an OR=2.1, 95% CI=1.2–3.6. The results for cordless phone use were OR=1.7, 95% CI=1.1–2.9, and, for latency of 15–20 years, the OR=2.1, 95% CI=1.2–3.8. Few participants had used a cordless phone for >20–25 years. Digital type of wireless phones (2G and 3G mobile phones, cordless phones) gave increased risk with latency >1–5 years, then a lower risk in the following latency groups, but again increasing risk with latency >15–20 years. Ipsilateral use resulted in a higher risk than contralateral mobile and cordless phone use. Higher ORs were calculated for tumours in the temporal and overlapping lobes. Using the meningioma cases in the same study as reference entity gave somewhat higher ORs indicating that the results were unlikely to be explained by recall or observational bias. This study confirmed previous results of an association between mobile and cordless phone use and malignant brain tumours. These findings provide support for the hypothesis that RF-EMFs play a role both in the initiation and promotion stages of carcinogenesis. PMID:24064953

Primary pleuropulmonary synovial sarcoma with brain metastases in a paediatric patient: an unusual presentation.

PubMed

Chirmade, Pushpak Chandrakant; Parikh, Sonia; Anand, Asha; Panchal, Harsha; Patel, Apurva; Shah, Sandip

2017-01-01

Primary lung neoplasms are rare in children. The most common primary lung malignancies in children are pleuropulmonary blastoma and carcinoid tumour. Synovial sarcoma (SS) accounts for approximately 1% of all childhood malignancies. In absolute terms, the SS of the lungs and pleura are extremely rare and pose a diagnostic difficulty. Soft tissue sarcomas usually have a high potential for metastases, however, metastasis to the brain is rare, even in widely disseminated disease, and it has been described only in 3 case reports previously. Primary pleuropulmonary SS with brain metastases is even rarer. Here we present a case of an 11-year-old boy who presented with respiratory complaints, viz. fever and cough for 20 days. Initial impression was lung abscess, however, on histopathological, immunohistochemical and molecular study, the disorder was diagnosed as synovial sarcoma. After a week from the first consult, the child developed neurological symptoms, viz., an episode of convulsion and gradually worsening power of the lower limb. Computed tomography scan and Magnetic Resonance Spectroscopy was suggestive of brain metastases. Given the rarity of primary lung neoplasms in children, clinical detection remains a challenge. Delayed diagnoses are common as respiratory symptoms may be attributed to inflammatory or infective processes. Primary pleuropulmonary synovial sarcoma is a rare tumour and it is not known to commonly metastasise to the brain. Though rare, primary pleuropulmonary SS should be considered an important differential among peadiatric primary lung neoplasms due to its potential for curability if detected early, and more aggressive metastatic pattern, e.g. brain metastases making early detection imperative.

Primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with carboplatin or toceranib.

PubMed

de Vos, J; Ramos Vega, S; Noorman, E; de Vos, P

2012-09-01

In human medicine, primary frontal sinus squamous cell carcinoma (pFS-SCC) is not frequently reported. In veterinary medicine, frontal sinus SCC is exclusively described as an extension of nasal cavity SCC. To our knowledge, this is the first publication concerning canine pFS-SCC, diagnosed using histology or cytology and medical imaging, in three dogs. The tumours extended into the orbit or brain cavity, without nasal involvement. Treatment was initiated with piroxicam-carboplatin. Prolongation of carboplatin delivery with a low dose intensity was performed on dogs with a favourable initial response. Dog 1 achieved a complete remission (CR), but was euthanized 344 days after start of therapy. Dog 2, still alive 3 years after start of therapy and in CR, received 14 carboplatin deliveries. In dog 3, after changing the treatment protocol into piroxicam-toceranib, a significant tumour reduction occurred, but the dog was euthanized after 195 days because of a relapse. © 2011 Blackwell Publishing Ltd.

Leptin concentration and nutritional status in the course of treatment in children with brain tumours--preliminary report.

PubMed

Musiol, Katarzyna; Sobol, Grazyna; Mizia-Malarz, Agnieszka; Wos, Halina

2014-01-01

To assess the nutritional status in children with central nervous system (CNS) tumours, including concentration of leptin, the neuropeptide responsible for regulation of energetic homeostasis in an organism. The studied group comprised 44 children with brain tumours, aged (4.02-18.7). In all children during the whole therapy (from the start to the period of 1 year and more after the end of therapy), a number of standard deviations (SDs) for the body mass index (SDS BMI) was derived from anthropometric measurements. Concentrations of leptin were assayed simultaneously. The lowest values of the anthropometric indices were found in children during the maintenance therapy. Concentrations of leptin in patients with malignant CNS tumours and significant undernutrition were slightly greater as compared to patients presenting normal nutritional status; however, without statistical significance. In children with tumours of the central nervous system, there are quantitative disorders of the nutritional status which correlate with the period of the treatment. The most significant disorders in the nutritional status are observed during maintenance chemotherapy. There was no statistically significant correlation between the concentration of leptin and nutritional status in children with malignant brain tumours during the course of treatment and after its completion.

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo.

PubMed

Martin, Ana Carolina B M; Fuzer, Angelina M; Becceneri, Amanda B; da Silva, James Almada; Tomasin, Rebeka; Denoyer, Delphine; Kim, Soo-Hyun; McIntyre, Katherine A; Pearson, Helen B; Yeo, Belinda; Nagpal, Aadya; Ling, Xiawei; Selistre-de-Araújo, Heloisa S; Vieira, Paulo Cézar; Cominetti, Marcia R; Pouliot, Normand

2017-09-22

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin ( Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo . We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro . In addition, [10]-gingerol is well tolerated in vivo , induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients.

[10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo

PubMed Central

Becceneri, Amanda B.; da Silva, James Almada; Tomasin, Rebeka; Denoyer, Delphine; Kim, Soo-Hyun; McIntyre, Katherine A.; Pearson, Helen B.; Yeo, Belinda; Nagpal, Aadya; Ling, Xiawei; Selistre-de-Araújo, Heloisa S.; Vieira, Paulo Cézar

2017-01-01

There is increasing interest in the use of non-toxic natural products for the treatment of various pathologies, including cancer. In particular, biologically active constituents of the ginger oleoresin (Zingiber officinale Roscoe) have been shown to mediate anti-tumour activity and to contribute to the anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties of ginger. Here we report on the inhibitory properties of [10]-gingerol against metastatic triple negative breast cancer (TNBC) in vitro and in vivo. We show that [10]-gingerol concentration-dependently induces apoptotic death in mouse and human TNBC cell lines in vitro. In addition, [10]-gingerol is well tolerated in vivo, induces a marked increase in caspase-3 activation and inhibits orthotopic tumour growth in a syngeneic mouse model of spontaneous breast cancer metastasis. Importantly, using both spontaneous and experimental metastasis assays, we show for the first time that [10]-gingerol significantly inhibits metastasis to multiple organs including lung, bone and brain. Remarkably, inhibition of brain metastasis was observed even when treatment was initiated after surgical removal of the primary tumour. Taken together, these results indicate that [10]-gingerol may be a safe and useful complementary therapy for the treatment of metastatic breast cancer and warrant further investigation of its efficacy, either alone or in combination with standard systemic therapies, in pre-clinical models of metastatic breast cancer and in patients. PMID:29069785

Bronchogenic adenocarcinoma presenting as a synchronous solitary lytic skull lesion with ischaemic stroke – case report and literature review

PubMed Central

O’Connell, David; Kaliaperumal, Chandrasekaran; Wyse, Gerald; McCarthy, Julie; Ryan, Aisling

2011-01-01

The authors describe a rare case of metastatic bronchogenic adenocarcinoma in a 55-year-old man presenting with concomittant solitary lytic skull lesion and ischaemic stroke. Metastatic bronchogenic carcinoma is known to present as lytic skull lesions. Primary brain tumours are also known to cause ischaemic brain injury. An underlying stroke risk may be exagerated by cranial tumour surgery. Patients with brain tumours are well known to be predisposed to an increased risk of developing thromboembolic disease. It is unusual to see metastatic bronchogenic adenocarcinoma presenting as ischaemic stroke with a background of concomittant cerebral metastasis. The aetio-pathogenesis of this rare occurrence is discussed with a review of literature. PMID:22669998

Occupational exposure to extremely low frequency magnetic fields and brain tumour risks in the INTEROCC study

PubMed Central

Turner, Michelle C; Benke, Geza; Bowman, Joseph D; Figuerola, Jordi; Fleming, Sarah; Hours, Martine; Kincl, Laurel; Krewski, Daniel; McLean, Dave; Parent, Marie-Elise; Richardson, Lesley; Sadetzki, Siegal; Schlaefer, Klaus; Schlehofer, Brigitte; Schüz, Joachim; Siemiatycki, Jack; van Tongeren, Martie; Cardis, Elisabeth

2014-01-01

Background Occupational exposure to extremely low frequency magnetic fields (ELF) is a suspected risk factor for brain tumours, however the literature is inconsistent. Few studies have assessed whether ELF in different time windows of exposure may be associated with specific histologic types of brain tumours. This study examines the association between ELF and brain tumours in the large-scale INTEROCC study. Methods Cases of adult primary glioma and meningioma were recruited in seven countries (Australia, Canada, France, Germany, Israel, New Zealand, United Kingdom) between 2000 and 2004. Estimates of mean workday ELF exposure based on a job exposure matrix assigned. Estimates of cumulative exposure, average exposure, maximum exposure, and exposure duration were calculated for the lifetime, and 1–4, 5–9, and 10+ years prior to the diagnosis/reference date. Results There were 3,761 included brain tumour cases (1,939 glioma, 1,822 meningioma) and 5,404 population controls. There was no association between lifetime cumulative ELF exposure and glioma or meningioma risk. However, there were positive associations between cumulative ELF 1–4 years prior to the diagnosis/reference date and glioma (odds ratio (OR) ≥ 90th percentile vs < 25th percentile = 1.67, 95% confidence interval (CI) 1.36–2.07, p < 0.0001 linear trend), and, somewhat weaker associations with meningioma (OR ≥ 90th percentile vs < 25th percentile = 1.23, 95% CI 0.97–1.57, p = 0.02 linear trend). Conclusions Results showed positive associations between ELF in the recent past and glioma. Impact Occupational ELF exposure may play a role in the later stages (promotion and progression) of brain tumourigenesis. PMID:24935666

Enriched environment reduces glioma growth through immune and non-immune mechanisms in mice

PubMed Central

Garofalo, Stefano; D’Alessandro, Giuseppina; Chece, Giuseppina; Brau, Frederic; Maggi, Laura; Rosa, Alessandro; Porzia, Alessandra; Mainiero, Fabrizio; Esposito, Vincenzo; Lauro, Clotilde; Benigni, Giorgia; Bernardini, Giovanni; Santoni, Angela; Limatola, Cristina

2015-01-01

Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mφ) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mφ infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment. PMID:25818172

Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster

NASA Astrophysics Data System (ADS)

Jeibmann, Astrid; Eikmeier, Kristin; Linge, Anna; Kool, Marcel; Koos, Björn; Schulz, Jacqueline; Albrecht, Stefanie; Bartelheim, Kerstin; Frühwald, Michael C.; Pfister, Stefan M.; Paulus, Werner; Hasselblatt, Martin

2014-06-01

Atypical teratoid/rhabdoid tumours (AT/RT) are malignant brain tumours. Unlike most other human brain tumours, AT/RT are characterized by inactivation of one single gene, SMARCB1. SMARCB1 is a member of the evolutionarily conserved SWI/SNF chromatin remodelling complex, which has an important role in the control of cell differentiation and proliferation. Little is known, however, about the pathways involved in the oncogenic effects of SMARCB1 inactivation, which might also represent targets for treatment. Here we report a comprehensive genetic screen in the fruit fly that revealed several genes not yet associated with loss of snr1, the Drosophila homologue of SMARCB1. We confirm the functional role of identified genes (including merlin, kibra and expanded, known to regulate hippo signalling pathway activity) in human rhabdoid tumour cell lines and AT/RT tumour samples. These results demonstrate that fly models can be employed for the identification of clinically relevant pathways in human cancer.

Phase congruency map driven brain tumour segmentation

NASA Astrophysics Data System (ADS)

Szilágyi, Tünde; Brady, Michael; Berényi, Ervin

2015-03-01

Computer Aided Diagnostic (CAD) systems are already of proven value in healthcare, especially for surgical planning, nevertheless much remains to be done. Gliomas are the most common brain tumours (70%) in adults, with a survival time of just 2-3 months if detected at WHO grades III or higher. Such tumours are extremely variable, necessitating multi-modal Magnetic Resonance Images (MRI). The use of Gadolinium-based contrast agents is only relevant at later stages of the disease where it highlights the enhancing rim of the tumour. Currently, there is no single accepted method that can be used as a reference. There are three main challenges with such images: to decide whether there is tumour present and is so localize it; to construct a mask that separates healthy and diseased tissue; and to differentiate between the tumour core and the surrounding oedema. This paper presents two contributions. First, we develop tumour seed selection based on multiscale multi-modal texture feature vectors. Second, we develop a method based on a local phase congruency based feature map to drive level-set segmentation. The segmentations achieved with our method are more accurate than previously presented methods, particularly for challenging low grade tumours.

Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours.

PubMed

Makale, Milan T; McDonald, Carrie R; Hattangadi-Gluth, Jona A; Kesari, Santosh

2017-01-01

Standard treatment of primary and metastatic brain tumours includes high-dose megavoltage-range radiation to the cranial vault. About half of patients survive >6 months, and many attain long-term control or cure. However, 50-90% of survivors exhibit disabling cognitive dysfunction. The radiation-associated cognitive syndrome is poorly understood and has no effective prevention or long-term treatment. Attention has primarily focused on mechanisms of disability that appear at 6 months to 1 year after radiotherapy. However, recent studies show that CNS alterations and dysfunction develop much earlier following radiation exposure. This finding has prompted the hypothesis that subtle early forms of radiation-induced CNS damage could drive chronic pathophysiological processes that lead to permanent cognitive decline. This Review presents evidence of acute radiation-triggered CNS inflammation, injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury-related processes initiated soon after irradiation could synergistically alter the signalling microenvironment in progenitor cell niches in the brain and the hippocampus, which is a structure critical to memory and cognition. Progenitor cell niche degradation could cause progressive neuronal loss and cognitive disability. The concluding discussion addresses future directions and potential early treatments that might reverse degenerative processes before they can cause permanent cognitive disability.

The biology and mathematical modelling of glioma invasion: a review

PubMed Central

Talkenberger, K.; Seifert, M.; Klink, B.; Hawkins-Daarud, A.; Swanson, K. R.; Hatzikirou, H.

2017-01-01

Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion. PMID:29118112

Intraoperative probe detecting β- decays in brain tumour radio-guided surgery

NASA Astrophysics Data System (ADS)

Solfaroli Camillocci, E.; Bocci, V.; Chiodi, G.; Collamati, F.; Donnarumma, R.; Faccini, R.; Mancini Terracciano, C.; Marafini, M.; Mattei, I.; Muraro, S.; Recchia, L.; Rucinski, A.; Russomando, A.; Toppi, M.; Traini, G.; Morganti, S.

2017-02-01

Radio-guided surgery (RGS) is a technique to intraoperatively detect tumour remnants, favouring a radical resection. Exploiting β- emitting tracers provides a higher signal to background ratio compared to the established technique with γ radiation, allowing the extension of the RGS applicability range. We developed and tested a detector based on para-terphenyl scintillator with high sensitivity to low energy electrons and almost transparent to γs to be used as intraoperative probe for RGS with β- emitting tracer. Portable read out electronics was customised to match the surgeon needs. This probe was used for preclinical test on specific phantoms and a test on "ex vivo" specimens from patients affected by meningioma showing very promising results for the application of this new technique on brain tumours. In this paper, the prototype of the intraoperative probe and the tests are discussed; then, the results on meningioma are used to make predictions on the performance of the probe detecting residuals of a more challenging and more interesting brain tumour: the glioma.

Ethics roundtable debate: Child with severe brain damage and an underlying brain tumour

PubMed Central

Gunn, Scott; Hashimoto, Satoru; Karakozov, Michael; Marx, Thomas; Tan, Ian KS; Thompson, Dan R; Vincent, Jean-Louis

2004-01-01

A young person presents with a highly malignant brain tumour with hemiparesis and limited prognosis after resection. She then suffers an iatrogenic cardiac and respiratory arrest that results in profound anoxic encephalopathy. A difference in opinion between the treatment team and the parent is based on a question of futile therapy. Opinions from five intensivists from around the world explore the differences in ethical and legal issues. A Physician-ethicist comments on the various approaches. PMID:15312199

Active video gaming improves body coordination in survivors of childhood brain tumours.

PubMed

Sabel, Magnus; Sjölund, Anette; Broeren, Jürgen; Arvidsson, Daniel; Saury, Jean-Michel; Blomgren, Klas; Lannering, Birgitta; Emanuelson, Ingrid

2016-10-01

We investigated whether active video gaming (AVG) could bring about regular, enjoyable, physical exercise in children treated for brain tumours, what level of physical activity could be reached and if the children's physical functioning improved. Thirteen children, aged 7-17 years, were randomised to either AVG or waiting-list. After 10-12 weeks they crossed-over. Weekly Internet coaching sessions were used to sustain motivation and evaluate enjoyment. Energy expenditure (EE) levels were measured as Metabolic Equivalent of Task (MET), using a multisensory activity monitor. Single-blinded assessments of physical functioning were done, using the Bruininks-Osteretsky Test of Motor Performance, second edition, evaluating participants before and after the intervention period, as well as comparing the randomisation groups after the first period. All patients completed the study. AVG sessions (mean duration 47 minutes) were performed on 72% of all days. Mean EE level during AVG sessions was 3.0 MET, corresponding to moderate physical activity. The Body Coordination score improved by 15% (p = 0.021) over the intervention period. In this group of childhood brain tumour survivors, home-based AVG, supported by a coach, was a feasible, enjoyable and moderately intense form of exercise that improved Body Coordination. Implications for Rehabilitation Childhood brain tumour survivors frequently have cognitive problems, inferior physical functioning and are less physically active compared to their healthy peers. Active video gaming (AVG), supported by Internet coaching, is a feasible home-based intervention in children treated for brain tumours, promoting enjoyable, regular physical exercise of moderate intensity. In this pilot study, AVG with Nintendo Wii improved Body Coordination.

Predicting parenting stress in caregivers of children with brain tumours.

PubMed

Bennett, Emily; English, Martin William; Rennoldson, Michael; Starza-Smith, Arleta

2013-03-01

The purpose of the study was to identify factors that contribute to parenting stress in caregivers of children diagnosed with brain tumours. The study was cross-sectional and recruited 37 participants from a clinical database at a specialist children's hospital. Parents were sent questionnaires, which were used to measure factors related to stress in caregivers of children diagnosed with a brain tumour. Stress levels were measured using the Parenting Stress Index-Short Form (PSI/SF). Correlation analysis and multiple linear regression were used to examine the associations between parenting stress and coping styles, locus of control, parent-perceived child disability and time since diagnosis. Results revealed that 51% of parents were experiencing clinically significant levels of stress. The mean stress level of parents in the study was significantly higher than the PSI/SF norms (t = 4.7, p < .001). Regression analysis revealed that external locus of control and coping by accepting responsibility accounted for 67% of the variance in parenting stress. Other styles of coping, child behaviour problems and the amount of time since diagnosis were not found to be predictive of levels of parenting stress. There was a high prevalence of parenting stress in caregivers of children with a brain tumour. An external locus of control and coping by accepting responsibility increased the likelihood of elevated levels of stress. Results emphasised the importance of ongoing support for parents of children with brain tumours. Intervention might helpfully be centred on strategies to increase parents' internal locus of control. Copyright © 2012 John Wiley & Sons, Ltd.

Evaluating the apparent diffusion coefficient in MRI studies as a means of determining paediatric brain tumour stages.

PubMed

Domínguez-Pinilla, N; Martínez de Aragón, A; Diéguez Tapias, S; Toldos, O; Hinojosa Bernal, J; Rigal Andrés, M; González-Granado, L I

2016-09-01

The apparent diffusion coefficient (ADC) in MRI seems to be related to cellularity in brain tumours. Its utility as a tool for distinguishing between histological types and tumour stages remains controversial. We retrospectively evaluated children diagnosed with CNS tumours between January 2008 and December 2013. Data collected were age, sex, histological diagnosis, and location of the tumour. We evaluated the ADC and ADC ratio and correlated those values with histological diagnoses. The study included 55 patients with a median age of 6 years. Histological diagnoses were pilocytic astrocytoma (40%), anaplastic ependymoma (16.4%), ganglioglioma (10.9%), glioblastoma (7.3%), medulloblastoma (5.5%), and other (20%). Tumours could also be classified as low-grade (64%) or high-grade (36%). Mean ADC was 1.3 for low-grade tumours and 0.9 for high-grade tumours (p=.004). Mean ADC ratios were 1.5 and 1.2 for low and high-grade tumours respectively (p=.025). There were no significant differences in ADC/ADC ratio between different histological types. ADC and ADC ratio may be useful in imaging-study based differential diagnosis of low and high-grade tumours, but they are not a substitute for an anatomical pathology study. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Identification of cells initiating human melanomas.

PubMed

Schatton, Tobias; Murphy, George F; Frank, Natasha Y; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M; Weishaupt, Carsten; Fuhlbrigge, Robert C; Kupper, Thomas S; Sayegh, Mohamed H; Frank, Markus H

2008-01-17

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies and solid cancers. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5- bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ subpopulations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5- progeny, whereas ABCB5- tumour populations give rise, at lower rates, exclusively to ABCB5- cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.

Neutron medical treatment of tumours — a survey of facilities

NASA Astrophysics Data System (ADS)

Wagner, F. M.; Loeper-Kabasakal, B.; Breitkreutz, H.

2012-03-01

Neutron therapy has two branches: Fast Neutron Therapy (FNT) and Boron Neutron Capture Therapy (BNCT). The mean neutron energies used for FNT range from 2 MeV to 25 MeV whereas the maximum energy for BNCT is about 10 keV. Neutron generators for FNT have been cyclotrons, accelerators and reactors, whereas BNCT is so far bound to reactors. Both therapies use the effects of high-LET radiation (secondary recoil protons and alpha particles, respectively) and can attack otherwise radioresistant tumours, however, with the hazard of adverse effects for irradiated healthy tissue. FNT has been administered to about 30,000 patients world-wide. From formerly 40 facilities, only eight are operational or stand-by today. The reasons for this development have been, on the one hand, related to technical and economical conditions; on the other hand, strong side effects and insufficient proof of clinical results in the early years as well as increasing competition with new clinical methods have reduced patient numbers. In fact, strict observations of indications, appropriate therapy-planning including low-LET radiation, and consequent treatment of side effects have lead to remarkable results in the meantime. BNCT initially was developed for the treatment of extremely aggressive forms of brain tumour, taking advantage of the action of the blood-brain-barrier which allows for a boronated compound to be selectively enriched in tumour cells. Meanwhile, also malignant melanoma (MM) and Head-and-Neck (H&T) tumours are treated because of their relative radioresistance. At present, epithermal beams with sufficient flux are available only at two facilities. Existing research reactors were indispensable in the development of BNCT, but are to be replaced by hospital-based epithermal neutron sources. Clinical results indicate significantly increased survival times, but the number of patients ever treated is still below 1,000. 3D-dose calculation systems have been developed at several facilities and guarantee a high safety for both therapies, FNT and BNCT.

Simpson grading as predictor of meningioma recurrence.

PubMed

Quddusi, Ayesha; Shamim, Muhammad Shahzad

2018-05-01

Meningimas are one of the commonest primary brain tumours and the commonest extra-axial primary brain tumour. Despite better understanding of the molecular pathogenesis of the tumours, surgical excision remains the treatment of choice, and in a large proportion of cases, complete excision is curative. Simpson grading for the extent of resection of meningiomas, was introduced more than six decades ago, and has stood the test of time. With modern technological advancements, however, the relevance of Simpson grading has been questioned. Herein we review the recent literature on the relevance of Simpson grading more than sixty years after its introduction.

Further aspects on cellular and cordless telephones and brain tumours.

PubMed

Hardell, Lennart; Mild, Kjell Hansson; Carlberg, Michael

2003-02-01

We included in a case-control study on brain tumours and mobile and cordless telephones 1,617 patients aged 20-80 years of both sexes diagnosed during January 1, 1997 to June 30, 2000. They were alive at the study time and had histopathology verified brain tumour. One matched control to each case was selected from the Swedish Population Register. The study area was the Uppsala-Orebro, Stockholm, Linköping and Göteborg medical regions of Sweden. Exposure was assessed by a questionnaire that was answered by 1,429 (88%) cases and 1,470 (91%) controls. In total use of analogue cellular telephones gave an increased risk with odds ratio (OR)=1.3, 95% confidence interval (CI)=1.04-1.6, whereas digital and cordless phones did not overall increase the risk significantly. Ipsilateral use of analogue phones gave OR=1.7, 95% CI=1.2-2.3, digital phones OR=1.3, 95% CI=1.02-1.8 and cordless phones OR=1.2, 95% CI=0.9-1.6. The risk for ipsilateral use was significantly increased for astrocytoma for all studied phone types, analogue phones OR=1.8,95% CI=1.1-3.2, digital phones OR=1.8, 95% CI=1.1-2.8, cordless phones OR=1.8, 95% CI=1.1-2.9. Use of a telephone on the opposite side of the brain was not associated with a significantly increased risk for brain tumours. Regarding anatomical area of the tumour and exposure to microwaves, the risk was increased for tumours located in the temporal area on the same side of the brain that was used during phone calls, significantly so for analogue cellular telephones OR=2.3, 95% CI=1.2-4.1. For acoustic neurinoma OR=4.4, 95% CI=2.1-9.2 was calculated among analogue cellular telephone users. When duration of use was analysed as a continuous variable in the total material, the risk increased per year for analogue phones with OR=1.04, 95% CI=1.01-1.08. For astrocytoma and ipsilateral use the trend was for analogue phones OR=1.10, 95% CI=1.02-1.19, digital phones OR=1.11, 95% CI=1.01-1.22, and cordless phones OR=1.09, 95% CI=1.01-1.19. There was a tendency of a shorter tumour induction period for ipsilateral exposure to microwaves than for contralateral, which may indicate a tumour promotor effect.

The med AUSTRON/OGRO patterns of care study on radiotherapy indications in Austria.

PubMed

Mock, Ulrike; Mayer, Ramona; Potter, Richard; Jäger, Robert; Vutuc, Christian; Eiter, Helmut; Hammer, Josef; Hawliczek, Robert; Hirn, Brigitte; Knocke-Abulesz, Tomas-Henrik; Kogelnik, Hans-Dieter; Lukas, Peter; Nechville, Elisabeth; Pakisch, Brigitte; Papauschek, Michael; Ing Raunik, Wolfgang; Rhomberg, Walter; Sabitzer, Hubert; Schratter-Sehn, Annemarie; Sedlmayer, Felix; Wedrich, Irene; Auberger, Thomas

2004-12-01

In Austria a national survey was conducted by Med AUSTRON/Osterreichische Gesellschaft for Radio--Onkologie, Radiobiologie und Medizinische Radiophysik (OGRO) in order to estimate the indications, patient numbers and radiotherapy treatment planning procedures and performances at all Austrian radiotherapy institutes. Results were correlated with incidence rates (Austrian cancer registry) to determine patterns of radiotherapy practice in Austria. At 12 radiotherapy departments of Austria data of all patients receiving irradiation within a 3 months (2002/2003) period were assessed. On the basis of a questionnaire number of treated patients, indications, and parameters of disease (stage, histology) and treatment modalities were evaluated. Results were analysed with regard to different tumour groups, according to academic and non academic hospitals, and correlated with epidemiological data on cancer incidence. In total, 3783 patients were registered within this period. According to the different tumour entities percentages of patients receiving radiotherapy within initial treatment varied from 3% to 90 % (e.g. brain tumours: 77%, breast cancer: 90%, prostate cancer: 35%). The most frequent indications to radiotherapy per radiotherapy department were breast cancer (range 22%-35%; mean 26%), urological tumours (range 6%-27%; mean 12%) and bone metastases (mean 10%, range 3%-17%). In Austria breast cancer, urological tumours and bone metastases are representing the most common indications to radiotherapy. Among the different departments variations in indications to radiotherapy were observed. Our study is the first evaluation of radiotherapeutic management in Austria.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis.

PubMed

Liu, Yongqing; Lu, Xiaoqin; Huang, Li; Wang, Wei; Jiang, Guomin; Dean, Kevin C; Clem, Brian; Telang, Sucheta; Jenson, Alfred B; Cuatrecasas, Miriam; Chesney, Jason; Darling, Douglas S; Postigo, Antonio; Dean, Douglas C

2014-12-01

Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancer-initiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.

Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study

PubMed Central

Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Craft, Alan W; Parker, Louise; de González, Amy Berrington

2012-01-01

Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain cancer. Because these cancers are relatively rare, the cumulative absolute risks are small: in the 10 years after the first scan for patients younger than 10 years, one excess case of leukaemia and one excess case of brain tumour per 10 000 head CT scans is estimated to occur. Nevertheless, although clinical benefits should outweigh the small absolute risks, radiation doses from CT scans ought to be kept as low as possible and alternative procedures, which do not involve ionising radiation, should be considered if appropriate. Funding US National Cancer Institute and UK Department of Health. PMID:22681860

Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study.

PubMed

Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Sir Craft, Alan W; Parker, Louise; Berrington de González, Amy

2012-08-04

Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. During follow-up, 74 of 178,604 patients were diagnosed with leukaemia and 135 of 176,587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005-0·120; p=0·0097) and brain tumours (0·023, 0·010-0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46-6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50-74 mGy (mean dose 60·42 mGy) was 2·82 (1·33-6·03). Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain cancer. Because these cancers are relatively rare, the cumulative absolute risks are small: in the 10 years after the first scan for patients younger than 10 years, one excess case of leukaemia and one excess case of brain tumour per 10,000 head CT scans is estimated to occur. Nevertheless, although clinical benefits should outweigh the small absolute risks, radiation doses from CT scans ought to be kept as low as possible and alternative procedures, which do not involve ionising radiation, should be considered if appropriate. US National Cancer Institute and UK Department of Health. Copyright © 2012 Elsevier Ltd. All rights reserved.

Identification of cells initiating human melanomas

PubMed Central

Schatton, Tobias; Murphy, George F.; Frank, Natasha Y.; Yamaura, Kazuhiro; Waaga-Gasser, Ana Maria; Gasser, Martin; Zhan, Qian; Jordan, Stefan; Duncan, Lyn M.; Weishaupt, Carsten; Fuhlbrigge, Robert C.; Kupper, Thomas S.; Sayegh, Mohamed H.; Frank, Markus H.

2012-01-01

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3–6. If such minority populations are associated with tumour progression in human patients, specific targeting of tumour-initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant-melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5+ tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCB5+ melanoma cells possess greater tumorigenic capacity than ABCB5− bulk populations and re-establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5+ sub-populations for self-renewal and differentiation, because ABCB5+ cancer cells generate both ABCB5+ and ABCB5− progeny, whereas ABCB5− tumour populations give rise, at lower rates, exclusively to ABCB5− cells. In an initial proof-of-principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5+ MMIC, exerted tumour-inhibitory effects. Identification of tumour-initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy. PMID:18202660

The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy.

PubMed Central

Lilge, L.; Olivo, M. C.; Schatz, S. W.; MaGuire, J. A.; Patterson, M. S.; Wilson, B. C.

1996-01-01

The applicability and limitations of a photodynamic threshold model, used to describe quantitatively the in vivo response of tissues to photodynamic therapy, are currently being investigated in a variety of normal and malignant tumour tissues. The model states that tissue necrosis occurs when the number of photons absorbed by the photosensitiser per unit tissue volume exceeds a threshold. New Zealand White rabbits were sensitised with porphyrin-based photosensitisers. Normal brain or intracranially implanted VX2 tumours were illuminated via an optical fibre placed into the tissue at craniotomy. The light fluence distribution in the tissue was measured by multiple interstitial optical fibre detectors. The tissue concentration of the photosensitiser was determined post mortem by absorption spectroscopy. The derived photodynamic threshold values for normal brain are significantly lower than for VX2 tumour for all photosensitisers examined. Neuronal damage is evident beyond the zone of frank necrosis. For Photofrin the threshold decreases with time delay between photosensitiser administration and light treatment. No significant difference in threshold is found between Photofrin and haematoporphyrin derivative. The threshold in normal brain (grey matter) is lowest for sensitisation by 5 delta-aminolaevulinic acid. The results confirm the very high sensitivity of normal brain to porphyrin photodynamic therapy and show the importance of in situ light fluence monitoring during photodynamic irradiation. Images Figure 1 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8562339

Mobile phone use and brain tumours in the CERENAT case-control study.

PubMed

Coureau, Gaëlle; Bouvier, Ghislaine; Lebailly, Pierre; Fabbro-Peray, Pascale; Gruber, Anne; Leffondre, Karen; Guillamo, Jean-Sebastien; Loiseau, Hugues; Mathoulin-Pélissier, Simone; Salamon, Roger; Baldi, Isabelle

2014-07-01

The carcinogenic effect of radiofrequency electromagnetic fields in humans remains controversial. However, it has been suggested that they could be involved in the aetiology of some types of brain tumours. The objective was to analyse the association between mobile phone exposure and primary central nervous system tumours (gliomas and meningiomas) in adults. CERENAT is a multicenter case-control study carried out in four areas in France in 2004-2006. Data about mobile phone use were collected through a detailed questionnaire delivered in a face-to-face manner. Conditional logistic regression for matched sets was used to estimate adjusted ORs and 95% CIs. A total of 253 gliomas, 194 meningiomas and 892 matched controls selected from the local electoral rolls were analysed. No association with brain tumours was observed when comparing regular mobile phone users with non-users (OR=1.24; 95% CI 0.86 to 1.77 for gliomas, OR=0.90; 95% CI 0.61 to 1.34 for meningiomas). However, the positive association was statistically significant in the heaviest users when considering life-long cumulative duration (≥896 h, OR=2.89; 95% CI 1.41 to 5.93 for gliomas; OR=2.57; 95% CI 1.02 to 6.44 for meningiomas) and number of calls for gliomas (≥18,360 calls, OR=2.10, 95% CI 1.03 to 4.31). Risks were higher for gliomas, temporal tumours, occupational and urban mobile phone use. These additional data support previous findings concerning a possible association between heavy mobile phone use and brain tumours. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Evaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma.

PubMed

Karagianis, G; Hill, J S; Stylli, S S; Kaye, A H; Varadaxis, N J; Reiss, J A; Phillips, D R

1996-02-01

A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.

Segmentation of solid subregion of high grade gliomas in MRI images based on active contour model (ACM)

NASA Astrophysics Data System (ADS)

Seow, P.; Win, M. T.; Wong, J. H. D.; Abdullah, N. A.; Ramli, N.

2016-03-01

Gliomas are tumours arising from the interstitial tissue of the brain which are heterogeneous, infiltrative and possess ill-defined borders. Tumour subregions (e.g. solid enhancing part, edema and necrosis) are often used for tumour characterisation. Tumour demarcation into substructures facilitates glioma staging and provides essential information. Manual segmentation had several drawbacks that include laborious, time consuming, subjected to intra and inter-rater variability and hindered by diversity in the appearance of tumour tissues. In this work, active contour model (ACM) was used to segment the solid enhancing subregion of the tumour. 2D brain image acquisition data using 3T MRI fast spoiled gradient echo sequence in post gadolinium of four histologically proven high-grade glioma patients were obtained. Preprocessing of the images which includes subtraction and skull stripping were performed and then followed by ACM segmentation. The results of the automatic segmentation method were compared against the manual delineation of the tumour by a trainee radiologist. Both results were further validated by an experienced neuroradiologist and a brief quantitative evaluations (pixel area and difference ratio) were performed. Preliminary results of the clinical data showed the potential of ACM model in the application of fast and large scale tumour segmentation in medical imaging.

Multiscale biomechanics of brain tumours favours cancer invasion by cell softening and tissue stiffening

NASA Astrophysics Data System (ADS)

Kas, Josef; Fritsch, Anatol; Grosser, Steffen; Friebe, Sabrina; Reiss-Zimmermann, Martin; Müller, Wolf; Hoffmann, Karl-Titus; Sack, Ingolf

Cancer progression needs two contradictory mechanical prerequisites. For metastasis individual cancer cells or small clusters have to flow through the microenvironment by overcoming the yield stress exerted by the surrounding. On the other hand a tumour has to behave as a solid to permit cell proliferation and spreading of the tumour mass against its surrounding. We determine that the high mechanical adaptability of cancer cells and the scale controlled viscoelastic properties of tissues reconcile both conflicting properties, fluid and solid, simultaneously in brain tumours. We resolve why different techniques that assess cell and tissue mechanics have produced apparently conflicting results by our finding that tumours generate different viscoelastic behaviours on different length scales, which are in concert optimal for tumour spreading and metastasis. Single cancer cells become very soft in their elastic behavior which promotes cell unjamming. On the level of direct cell-to-cell interactions cells feel their micro-environment as rigid elastic substrate that stimulates cancer on the molecular level. All over a tumour has predominately a stiff elastic character in terms of viscoelastic behaviour caused by a solid backbone. Simultaneously, the tumour mass is characterized by a large local variability in the storage and loss modulus that is caused by areas of a more fluid nature.

Seizure characteristics and the use of anti-epileptic drugs in children and young people with brain tumours and epileptic seizures: Analysis of regional paediatric cancer service population.

PubMed

Pilotto, Chiara; Liu, Jo-Fen; Walker, David A; Whitehouse, William P

2018-03-21

Epileptic seizures complicate the management of childhood brain tumours. There are no published standards for clinical practice concerning risk factors, treatment selection or strategies to withdraw treatment with antiepileptic drugs (AED). we undertook a case note review of 120 patients with newly diagnosed brain tumours, referred to a regional paediatric cancer service. data was available on 117/120 (98%) children <18 years: median age at tumour presentation was 8.1 years (IQR 25°-75° : 3.6-12.7), median follow up was 33 months (IQR 25°-75°: 24-56), and 35/117 (29%) experienced seizures. A cortical tumour location was associated with the highest risk of seizures (OR: 7.1; CI 95% 2.9-17.3). At a median follow up of 24 months (IQR 25°-75° : 15-48), 22/35 (63%) with seizures, had a single seizure episode, 15/35 (43%) were seizure free (SF) on AEDs, 13/35 (37%) were SF off AEDs, and 7/35 (20%) experienced continuing epileptic seizures. Overall 34/35 (97%) were treated with AEDs after a seizure, of whom 12/35 (35%) withdrew from AED medication, and although 4/35 (12%) had seizure relapse, all were after further acute events. The median duration of AED before withdrawal was 11 months (IQR 25°-75° 5-14 months), and the median follow up after withdrawal was 15 months (IQR 25°-75° 5-34 months). Seizures affect about 1/3rd of children and young people presenting with and being treated for brain tumours particularly when the tumour is in the cerebral cortex. The low risk of recurrent seizures after AED treatment justifies consideration of early withdrawal of AED after seizure control. Copyright © 2018. Published by Elsevier Ltd.

Information needs and requirements in patients with brain tumours and their relatives.

PubMed

Reinert, Christiane; Rathberger, Katharina; Klinkhammer-Schalke, Monika; Kölbl, Oliver; Proescholdt, Martin; Riemenschneider, Markus J; Schuierer, Gerhard; Hutterer, Markus; Gerken, Michael; Hau, Peter

2018-06-01

Patients with brain tumours face a number of medical and social challenges. Previous studies have shown that these patients and their relatives need a high level of patient-oriented information and counselling. However, these needs are often underestimated. In this single-centre cross-sectional study, we evaluated, for the first time, the information needs of patients with brain tumours and their relatives depending on diagnosis, age and level of education. The participants were interviewed using pre-specified questionnaires. Answers were evaluated descriptively using standard statistical methods. A total of 888 questionnaires were sent out. The return rate was 50.7%. The majority of patients (nP = 103; 59.9%) and a higher proportion of relatives (nR = 103; 72.5%; p = 0.019) wished to receive a maximum of information. The majority (79.7% of patients; 83.1% of relatives) also stated that they preferred a personal, face-to-face meeting as primary source of information. The need for information increased with education (p = 0.015), and decreased with tumour grade (p = 0.025) and age (p = 0.118). Our data indicate that patients with brain tumours and their relatives have high information needs throughout their disease and continuously require information and counselling. Optimal provision of information is based on personal preferences, which needs to be evaluated appropriately. Patient-oriented information and counselling are parts of a successful communication strategy that can improve cancer care significantly.

Double-labelling immunohistochemistry for MGMT and a “cocktail” of non-tumourous elements is a reliable, quick and easy technique for inferring methylation status in glioblastomas and other primary brain tumours

PubMed Central

2013-01-01

Background Our aim was to develop a new protocol for MGMT immunohistochemistry with good agreement between observers and good correlation with molecular genetic tests of tumour methylation. We examined 40 primary brain tumours (30 glioblastomas and 10 oligodendroglial tumours) with our new technique, namely double-labelling immunohistochemistry for MGMT and a "cocktail" of non-tumour antigens (CD34, CD45 and CD68). We compared the results with single-labelling immunohistochemistry for MGMT and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA, a recognised molecular genetic technique which we applied as the gold-standard for the methylation status). Results Double-labelling immunohistochemistry for MGMT produced a visual separation of tumourous and non-tumourous elements on the same histological slide, making it quick and easy to determine whether tumour cell nuclei were MGMT-positive or MGMT-negative (and thereby infer the methylation status of the tumour). We found good agreement between observers (kappa 0.76) and within observer (kappa 0.84). Furthermore, double-labelling showed good specificity (80%), sensitivity (73.33%), positive predictive value (PPV, 83.33%) and negative predictive value (NPV, 68.75%) compared to MS-MLPA. Double-labelling was quicker and easier to assess than single-labelling and it outperformed quantitative computerised image analysis of MGMT single-labelling in terms of sensitivity, specificity, PPV and NPV. Conclusions Double-labelling immunohistochemistry for MGMT and a cocktail of non-tumourous elements provides a "one look" method for determining whether tumour cell nuclei are MGMT-positive or MGMT-negative. This can be used to infer the methylation status of the tumour. There is good observer agreement and good specificity, sensitivity, PPV and NPV compared to a molecular gold-standard. PMID:24252243

Double-labelling immunohistochemistry for MGMT and a "cocktail" of non-tumourous elements is a reliable, quick and easy technique for inferring methylation status in glioblastomas and other primary brain tumours.

PubMed

Burke, Elinor; Grobler, Mariana; Elderfield, Kay; Bond, Frances; Crocker, Matthew; Taylor, Rohan; Bridges, Leslie R

2013-06-10

Our aim was to develop a new protocol for MGMT immunohistochemistry with good agreement between observers and good correlation with molecular genetic tests of tumour methylation. We examined 40 primary brain tumours (30 glioblastomas and 10 oligodendroglial tumours) with our new technique, namely double-labelling immunohistochemistry for MGMT and a "cocktail" of non-tumour antigens (CD34, CD45 and CD68). We compared the results with single-labelling immunohistochemistry for MGMT and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA, a recognised molecular genetic technique which we applied as the gold-standard for the methylation status). Double-labelling immunohistochemistry for MGMT produced a visual separation of tumourous and non-tumourous elements on the same histological slide, making it quick and easy to determine whether tumour cell nuclei were MGMT-positive or MGMT-negative (and thereby infer the methylation status of the tumour). We found good agreement between observers (kappa 0.76) and within observer (kappa 0.84). Furthermore, double-labelling showed good specificity (80%), sensitivity (73.33%), positive predictive value (PPV, 83.33%) and negative predictive value (NPV, 68.75%) compared to MS-MLPA. Double-labelling was quicker and easier to assess than single-labelling and it outperformed quantitative computerised image analysis of MGMT single-labelling in terms of sensitivity, specificity, PPV and NPV. Double-labelling immunohistochemistry for MGMT and a cocktail of non-tumourous elements provides a "one look" method for determining whether tumour cell nuclei are MGMT-positive or MGMT-negative. This can be used to infer the methylation status of the tumour. There is good observer agreement and good specificity, sensitivity, PPV and NPV compared to a molecular gold-standard.

Pooled analysis of two case-control studies on use of cellular and cordless telephones and the risk for malignant brain tumours diagnosed in 1997-2003.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2006-09-01

To study the use of cellular and cordless telephones and the risk for malignant brain tumours. Two case-control studies on malignant brain tumours diagnosed during 1997-2003 included answers from 905 (90%) cases and 2,162 (89%) controls aged 20-80 years. We present pooled analysis of the results in the two studies. Cumulative lifetime use for >2,000 h yielded for analogue cellular phones odds ratio (OR)=5.9, 95% confidence interval (CI)=2.5-14, digital cellular phones OR=3.7, 95% CI=1.7-7.7, and for cordless phones OR=2.3, 95% CI=1.5-3.6. Ipsilateral exposure increased the risk for malignant brain tumours; analogue OR=2.1, 95% CI=1.5-2.9, digital OR=1.8, 95% CI=1.4-2.4, and cordless OR=1.7, 95% CI=1.3-2.2. For high-grade astrocytoma using >10 year latency period analogue phones yielded OR=2.7, 95% CI=1.8-4.2, digital phones OR=3.8, 95% CI=1.8-8.1, and cordless phones OR=2.2, 95% CI=1.3-3.9. In the multivariate analysis all phone types increased the risk. Regarding digital phones OR=3.7, 95% CI=1.5-9.1 and cordless phones OR=2.1, 95% CI=0.97-4.6 were calculated for malignant brain tumours for subjects with first use use <20 years of age, higher than in older persons. Increased risk was obtained for both cellular and cordless phones, highest in the group with >10 years latency period.

Cancer stem cells from human glioblastoma resemble but do not mimic original tumors after in vitro passaging in serum-free media.

PubMed

García-Romero, Noemí; González-Tejedo, Carmen; Carrión-Navarro, Josefa; Esteban-Rubio, Susana; Rackov, Gorjana; Rodríguez-Fanjul, Vanessa; Oliver-De La Cruz, Jorge; Prat-Acín, Ricardo; Peris-Celda, María; Blesa, David; Ramírez-Jiménez, Laura; Sánchez-Gómez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel

2016-10-04

Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.

A Patient-Specific Anisotropic Diffusion Model for Brain Tumour Spread.

PubMed

Swan, Amanda; Hillen, Thomas; Bowman, John C; Murtha, Albert D

2018-05-01

Gliomas are primary brain tumours arising from the glial cells of the nervous system. The diffuse nature of spread, coupled with proximity to critical brain structures, makes treatment a challenge. Pathological analysis confirms that the extent of glioma spread exceeds the extent of the grossly visible mass, seen on conventional magnetic resonance imaging (MRI) scans. Gliomas show faster spread along white matter tracts than in grey matter, leading to irregular patterns of spread. We propose a mathematical model based on Diffusion Tensor Imaging, a new MRI imaging technique that offers a methodology to delineate the major white matter tracts in the brain. We apply the anisotropic diffusion model of Painter and Hillen (J Thoer Biol 323:25-39, 2013) to data from 10 patients with gliomas. Moreover, we compare the anisotropic model to the state-of-the-art Proliferation-Infiltration (PI) model of Swanson et al. (Cell Prolif 33:317-329, 2000). We find that the anisotropic model offers a slight improvement over the standard PI model. For tumours with low anisotropy, the predictions of the two models are virtually identical, but for patients whose tumours show higher anisotropy, the results differ. We also suggest using the data from the contralateral hemisphere to further improve the model fit. Finally, we discuss the potential use of this model in clinical treatment planning.

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

PubMed

Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

2014-08-15

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

Fitness to drive in patients with brain tumours: the influence of mandatory reporting legislation on radiation oncologists in Canada.

PubMed

Louie, A V; D'Souza, D P; Palma, D A; Bauman, G S; Lock, M; Fisher, B; Patil, N; Rodrigues, G B

2012-06-01

Certain jurisdictions in Canada legally require that physicians report unfit drivers. Physician attitudes and patterns of practice have yet to be evaluated in Canada for patients with brain tumours. We conducted a survey of 97 radiation oncologists, eliciting demographics, knowledge of reporting laws, and attitudes on reporting guidelines for unfit drivers. Eight scenarios with varying disability levels were presented to determine the likelihood of a patient being reported as unfit to drive. Statistical comparisons were made using the Fisher exact test. Of physicians approached, 99% responded, and 97 physicians participated. Most respondents (87%) felt that laws in their province governing the reporting of medically unfit drivers were unclear. Of the responding physicians, 23 (24%) were unable to correctly identify whether their province had mandatory reporting legislation. Physicians from provinces without mandatory reporting legislation were significantly less likely to consider reporting patients to provincial authorities (p = 0.001), and for all clinical scenarios, the likelihood of reporting significantly depended on the physician's provincial legal obligations. The presence of provincial legislation is of primary importance in determining whether physicians will report brain tumour patients to drivers' licensing authorities. In Canada, clear guidelines have to be developed to help in the assessment of whether brain tumour patients should drive.

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

PubMed Central

Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

2014-01-01

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro.

PubMed

Rooprai, H K; Kandanearatchi, A; Maidment, S L; Christidou, M; Trillo-Pazos, G; Dexter, D T; Rucklidge, G J; Widmer, W; Pilkington, G J

2001-02-01

Although intrinsic tumours of the brain seldom metastasize to distant sites, their diffuse, infiltrative-invasive growth within the brain generally precludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that include the use of anti-invasive and anti-proliferative agents. The effect of four anti-invasive agents, swainsonine (a locoweed alkaloid), captopril (an anti-hypertensive drug), tangeretin and nobiletin (both citrus flavonoids), were investigated on various parameters of brain tumour invasion such as matrix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A standard cytotoxicity assay was used to optimize working concentrations of the drugs on seven human brain tumour-derived cell lines of various histological type and grade of malignancy. A qualitative assessment by gelatin zymography revealed that the effect of these agents varied between the seven cell lines such that the low grade pilocytic astrocytoma was unaffected by three of the agents. In contrast, downregulation of the two gelatinases, MMP-2 and MMP-9 was seen in the grade 3 astrocytoma irrespective of which agent was used. Generally, swainsonine was the least effective whereas the citrus flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most efficient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astrocytoma and a glioblastoma multiforme). Yet again, the effects of the four agents varied between the four cell lines. Nobiletin was, nevertheless, the most effective agent used in these assays. In conclusion, the differential effects seen on the various parameters studied by these putative anti-invasive agents may be the result of interference with MMPs and other mechanisms underlying the invasive phenotype. From these pilot studies, it is possible that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a larger study.

Brain Tumour Segmentation based on Extremely Randomized Forest with high-level features.

PubMed

Pinto, Adriano; Pereira, Sergio; Correia, Higino; Oliveira, J; Rasteiro, Deolinda M L D; Silva, Carlos A

2015-08-01

Gliomas are among the most common and aggressive brain tumours. Segmentation of these tumours is important for surgery and treatment planning, but also for follow-up evaluations. However, it is a difficult task, given that its size and locations are variable, and the delineation of all tumour tissue is not trivial, even with all the different modalities of the Magnetic Resonance Imaging (MRI). We propose a discriminative and fully automatic method for the segmentation of gliomas, using appearance- and context-based features to feed an Extremely Randomized Forest (Extra-Trees). Some of these features are computed over a non-linear transformation of the image. The proposed method was evaluated using the publicly available Challenge database from BraTS 2013, having obtained a Dice score of 0.83, 0.78 and 0.73 for the complete tumour, and the core and the enhanced regions, respectively. Our results are competitive, when compared against other results reported using the same database.

Oxidative stress specifically downregulates survivin to promote breast tumour formation.

PubMed

Pervin, S; Tran, L; Urman, R; Braga, M; Parveen, M; Li, S A; Chaudhuri, G; Singh, R

2013-03-05

Breast cancer, a heterogeneous disease has been broadly classified into oestrogen receptor positive (ER+) or oestrogen receptor negative (ER-) tumour types. Each of these tumours is dependent on specific signalling pathways for their progression. While high levels of survivin, an anti-apoptotic protein, increases aggressive behaviour in ER- breast tumours, oxidative stress (OS) promotes the progression of ER+ breast tumours. Mechanisms and molecular targets by which OS promotes tumourigenesis remain poorly understood. DETA-NONOate, a nitric oxide (NO)-donor induces OS in breast cancer cell lines by early re-localisation and downregulation of cellular survivin. Using in vivo models of HMLE(HRAS) xenografts and E2-induced breast tumours in ACI rats, we demonstrate that high OS downregulates survivin during initiation of tumourigenesis. Overexpression of survivin in HMLE(HRAS) cells led to a significant delay in tumour initiation and tumour volume in nude mice. This inverse relationship between survivin and OS was also observed in ER+ human breast tumours. We also demonstrate an upregulation of NADPH oxidase-1 (NOX1) and its activating protein p67, which are novel markers of OS in E2-induced tumours in ACI rats and as well as in ER+ human breast tumours. Our data, therefore, suggest that downregulation of survivin could be an important early event by which OS initiates breast tumour formation.

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules.

PubMed

He, Bo; Jabouille, Arnaud; Steri, Veronica; Johansson-Percival, Anna; Michael, Iacovos P; Kotamraju, Venkata Ramana; Junckerstorff, Reimar; Nowak, Anna K; Hamzah, Juliana; Lee, Gabriel; Bergers, Gabriele; Ganss, Ruth

2018-06-01

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.

PubMed

Andrianova, Maria A; Chetan, Ghati Kasturirangan; Sibin, Madathan Kandi; Mckee, Thomas; Merkler, Doron; Narasinga, Rao Kvl; Ribaux, Pascale; Blouin, Jean-Louis; Makrythanasis, Periklis; Seplyarskiy, Vladimir B; Antonarakis, Stylianos E; Nikolaev, Sergey I

2017-11-01

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo - , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo - disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Guideline on brain metastases: not a cookbook].

PubMed

Reijneveld, Jaap C

2011-01-01

The guideline 'Brain Metastases', which was revised on behalf of the Dutch Society for Neuro-Oncology (LWNO), provides an excellent overview of levels of scientific evidence on diagnosis and treatment of patients with parenchymal brain metastases of solid tumours. I would like to emphasize, however, that this guideline is not a cookbook for facilitating individual physicians to treat patients on their own. It is important that every patient suffering from brain metastases is discussed by a multidisciplinary tumour board consisting of at least a neurologist, a neurosurgeon, a medical oncologist, a radiation oncologist, a pathologist and a radiologist, and that several crucial questions need to be explicitly asked and answered about every single patient.

[Awake craniotomy for brain tumours].

PubMed

Milos, Peter; Metcalf, Kerstin; Vigren, Patrick; Lindehammar, Hans; Nilsson, Malin; Boström, Sverre

2016-10-11

Awake craniotomy for brain tumours  Awake neurosurgery is a useful method in lesions near eloquent brain areas, particularly low-grade gliomas.The aim is to maximise tumour resection and preserve neurological function. We performed 40 primary awake surgeries and 8 residual surgeries. Patients were operated awake throughout the procedure or with a laryngeal mask and general anaesthesia during the opening stage and then awake during intracerebral surgery. Language and motor function were mapped with direct cortical stimulation, motor evoked potential and standardised neurological testing. Radiologically, complete resection was achieved in 18 out of 40 patients in the primary surgeries. Full neurological recovery at three months was observed in 29 patients. Of the 11 patients with persisting neurological deficits at three months, symptoms were present preoperatively in 9 patients. We conclude that awake surgery, combined with intraoperative neurophysiological methods, is a safe method to improve treatment for low-grade gliomas.

Assessment of induced rat mammary tumour response to chemotherapy using the apparent diffusion coefficient of tissue water as determined by diffusion-weighted 1H-NMR spectroscopy in vivo.

PubMed

Lemaire, L; Howe, F A; Rodrigues, L M; Griffiths, J R

1999-03-01

Chemosensitivity of N-methyl-N-nitrosourea-induced rat mammary tumours treated with 5-fluorouracil at a dose of 100 mg kg(-1) i.p. was assessed by using diffusion-weighted 1H-MRS to measure the average diffusion coefficient (ADC) of water in the tumour tissue. ADC measurements prior to any therapy correlated positively with necrotic fraction. Tumours with low initial ADC (< 0.95 x 10(9) m2 s(-1)) showed an increase in ADC 7 days after treatment, whereas tumours with a high initial ADC (> 1.2 x 10(9) m2 s(-1)) showed a decrease. All tumours decreased significantly in volume (P < 0.05) 2, 5 and 7 days after treatment. At day 7 post-treatment, tumours with a high pre-treatment ADC started to regrow. The initial ADC value, as well as changes after treatment predict tumour chemosensitivity, which could be clinically relevant.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien

Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cellsmore » leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.« less

Long term reshaping of language, sensory, and motor maps after glioma resection: a new parameter to integrate in the surgical strategy

PubMed Central

Duffau, H; Denvil, D; Capelle, L

2002-01-01

Objectives: To describe cortical reorganisation and the effects of glioma infiltration on local brain function in three patients who underwent two operations 12–24 months apart. Methods: Three patients who had no neurological deficit underwent two operations for low grade glioma, located in functionally important brain regions. During each operation, local brain function was characterised by electrical mapping and awake craniotomy. Results: Language or sensorimotor areas had been invaded by the tumour at the time of the first operation, leading to incomplete glioma removal in all cases. Because of a tumour recurrence, the patients were reoperated on between 12 and 24 months later. Functional reorganisation of the language, sensory, and motor maps was detected by electrical stimulation of the brain, and this allowed total glioma removal without neurological sequelae. Conclusions: These findings show that surgical resection of a glioma can lead to functional reorganisation in the peritumorous and infiltrated brain. It may be that this reorganisation is directly or indirectly caused by the surgical procedure. If this hypothesis is confirmed by other studies, the use of such brain plasticity potential could be used when planning surgical options in some patients with low grade glioma. Such a strategy could extend the limits of tumour resection in gliomas involving eloquent brain areas without causing permanent morbidity. PMID:11909913

Long-term use of cellular phones and brain tumours: increased risk associated with use for > or =10 years.

PubMed

Hardell, Lennart; Carlberg, Michael; Söderqvist, Fredrik; Mild, Kjell Hansson; Morgan, L Lloyd

2007-09-01

To evaluate brain tumour risk among long-term users of cellular telephones. Two cohort studies and 16 case-control studies on this topic were identified. Data were scrutinised for use of mobile phone for > or =10 years and ipsilateral exposure if presented. The cohort study was of limited value due to methodological shortcomings in the study. Of the 16 case-control studies, 11 gave results for > or =10 years' use or latency period. Most of these results were based on low numbers. An association with acoustic neuroma was found in four studies in the group with at least 10 years' use of a mobile phone. No risk was found in one study, but the tumour size was significantly larger among users. Six studies gave results for malignant brain tumours in that latency group. All gave increased odd ratios (OR), especially for ipsilateral exposure. In a meta-analysis, ipsilateral cell phone use for acoustic neuroma was OR = 2.4 (95% CI 1.1 to 5.3) and OR = 2.0, (1.2 to 3.4) for glioma using a tumour latency period of > or =10 years. Results from present studies on use of mobile phones for > or =10 years give a consistent pattern of increased risk for acoustic neuroma and glioma. The risk is highest for ipsilateral exposure.

A 63-year-old man with peripheral facial nerve paralysis and a pulmonary lesion.

PubMed

Yserbyt, J; Wilms, G; Lievens, Y; Nackaerts, K

2009-01-01

Occasionally, malignant neoplasms may cause peripheral facial nerve paralysis as a presenting symptom. A 63-year-old man was referred to the Emergency Department because of a peripheral facial nerve paralysis, lasting for 10 days. Initial diagnostic examinations revealed no apparent cause for this facial nerve paralysis. Chest X-ray, however, showed a suspicious tumoural mass, located in the right hilar region, as confirmed by CAT scan. The diagnosis of an advanced stage lung adenocarcinoma was finally confirmed by bronchial biopsy. MRI scanning showed diffuse brain metastases and revealed a pontine lesion as the most probable underlying cause of this case of peripheral facial nerve paralysis. Platin-based palliative chemotherapy was given, after an initial pancranial irradiation. According to the MRI findings, the pontine lesion was responsible for the peripheral facial nerve paralysis, as an initial presenting symptom in this case of lung adenocarcinoma. This clinical case of a peripheral facial nerve paralysis was caused by a pontine brain metastasis and illustrates a rather rare presenting symptom of metastatic lung cancer.

Essential problems in the interpretation of epidemiologic evidence for an association between mobile phone use and brain tumours

NASA Astrophysics Data System (ADS)

Kundi, Michael

2010-11-01

Due to the close proximity of a mobile phone to the head when placing a call, concerns have been raised that exposure from microwaves during mobile phone use may exert adverse health effects and, in particular, may increase the risk of brain tumours. In response to these concerns epidemiological studies have been conducted, most applying the case-control design. While epidemiology can provide decisive evidence for an association between an exposure and a disease fundamental problems arise if exposure is short compared to the natural history of the disease. For brain tumours latencies of decades have been implicated making special considerations about potential effects of exposures necessary that commence during an already growing tumour. It is shown that measures of disease risk like odds ratios and relative risks can under such circumstances not be interpreted as indicators of a long term effect on incidences in the exposed population. Besides this problem, the issues of a suitable exposure metric and the selection of endpoints are unresolved. It is shown that the solution of these problems affords knowledge about the mechanism of action by which exposure increases the risk of manifest disease.

Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population.

PubMed

Uvirova, Magdalena; Simova, Jarmila; Kubova, Barbora; Dvorackova, Nina; Tomaskova, Hana; Sedivcova, Monika; Dite, Petr

2015-09-01

A germline SNP (rs61764370) is located in a let-7 complementary site (LCS6) in the 3'UTR of KRAS oncogene, and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA. The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer (CRC), breast cancer (BC), non-small cell lung cancer (NSCLC) and brain tumour patient subgroups from the Czech Republic. The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours. DNA of tumour tissues was isolated from 428 colorectal cancer samples, 311 non-small cell lung cancer samples, 195 breast cancer samples and 151 samples with brain tumour. Analysis of SNP (rs61764370) was performed by the PCR+RFLP method and direct sequencing. KRAS, BRAF and EGFR mutation status was assessed using real-time PCR. The status of the HER2 gene was assessed using the FISH method. The KRAS-LCS6 TG genotype has been detected in 16.4% (32/195) of breast cancer cases (in HER2 positive breast cancer 3.3%, in HER2 negative breast cancer 20.1%), in 12.4% (53/428) of CRC cases (KRAS/BRAF wild type CRC in 10.6%, KRAS mutant CRC in 10.1%, BRAF V600E mutant CRC in 18.5%), in 13.2% (41/311) of NSCLC samples, (EGFR mutant NSCLC patients in 8%, EGFR wild type NSCLC in 12.9%), and 17.9% (27/151) of brain tumour cases. The KRAS-LCS6 TG genotype was not significantly different across the studied tumours. In our study, the GG genotype has not been found among the cancer samples. Based on the findings, it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer. Furthermore, significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway (KRAS, BRAF, EGFR) and the KRAS-LCS6 genotype in colorectal cancer and NSCLC has not been established.

Mobile phones, cordless phones and the risk for brain tumours.

PubMed

Hardell, Lennart; Carlberg, Michael

2009-07-01

The Hardell-group conducted during 1997-2003 two case control studies on brain tumours including assessment of use of mobile phones and cordless phones. The questionnaire was answered by 905 (90%) cases with malignant brain tumours, 1,254 (88%) cases with benign tumours and 2,162 (89%) population-based controls. Cases were reported from the Swedish Cancer Registries. Anatomical area in the brain for the tumour was assessed and related to side of the head used for both types of wireless phones. In the current analysis we defined ipsilateral use (same side as the tumour) as >or=50% of the use and contralateral use (opposite side) as <50% of the calling time. We report now further results for use of mobile and cordless phones. Regarding astrocytoma we found highest risk for ipsilateral mobile phone use in the >10 year latency group, OR=3.3, 95% CI=2.0-5.4 and for cordless phone use OR=5.0, 95% CI=2.3-11. In total, the risk was highest for cases with first use <20 years age, for mobile phone OR=5.2, 95% CI=2.2-12 and for cordless phone OR=4.4, 95% CI=1.9-10. For acoustic neuroma, the highest OR was found for ipsilateral use and >10 year latency, for mobile phone OR=3.0, 95% CI=1.4-6.2 and cordless phone OR=2.3, 95% CI=0.6-8.8. Overall highest OR for mobile phone use was found in subjects with first use at age <20 years, OR=5.0, 95% CI 1.5-16 whereas no association was found for cordless phone in that group, but based on only one exposed case. The annual age-adjusted incidence of astrocytoma for the age group >19 years increased significantly by +2.16%, 95% CI +0.25 to +4.10 during 2000-2007 in Sweden in spite of seemingly underreporting of cases to the Swedish Cancer Registry. A decreasing incidence was found for acoustic neuroma during the same period. However, the medical diagnosis and treatment of this tumour type has changed during recent years and underreporting from a single center would have a large impact for such a rare tumour.

Mobile phone use, exposure to radiofrequency electromagnetic field, and brain tumour: a case-control study.

PubMed

Takebayashi, T; Varsier, N; Kikuchi, Y; Wake, K; Taki, M; Watanabe, S; Akiba, S; Yamaguchi, N

2008-02-12

In a case-control study in Japan of brain tumours in relation to mobile phone use, we used a novel approach for estimating the specific absorption rate (SAR) inside the tumour, taking account of spatial relationships between tumour localisation and intracranial radiofrequency distribution. Personal interviews were carried out with 88 patients with glioma, 132 with meningioma, and 102 with pituitary adenoma (322 cases in total), and with 683 individually matched controls. All maximal SAR values were below 0.1 W kg(-1), far lower than the level at which thermal effects may occur, the adjusted odds ratios (ORs) for regular mobile phone users being 1.22 (95% confidence interval (CI): 0.63-2.37) for glioma and 0.70 (0.42-1.16) for meningioma. When the maximal SAR value inside the tumour tissue was accounted for in the exposure indices, the overall OR was again not increased and there was no significant trend towards an increasing OR in relation to SAR-derived exposure indices. A non-significant increase in OR among glioma patients in the heavily exposed group may reflect recall bias.

Integrative genomic analyses identify LIN28 and OLIG2 as markers of survival and metastatic potential in childhood central nervous system primitive neuro-ectodermal brain tumours

PubMed Central

Picard, Daniel; Miller, Suzanne; Hawkins, Cynthia E; Bouffet, Eric; Rogers, Hazel A; Chan, Tiffany SY; Kim, Seung-Ki; Ra, Young-Shin; Fangusaro, Jason; Korshunov, Andrey; Toledano, Helen; Nakamura, Hideo; Hayden, James T; Chan, Jennifer; Lafay-Cousin, Lucie; Hu, Ping X; Fan, Xing; Muraszko, Karin M; Pomeroy, Scott L; Lau, Ching C; Ng, Ho-Keung; Jones, Chris; Meter, Timothy Van; Clifford, Steven C; Eberhart, Charles; Gajjar, Amar; Pfister, Stefan M; Grundy, Richard G; Huang, Annie

2013-01-01

Background Childhood Central Nervous System Primitive Neuro-Ectodermal brain Tumours (CNS-PNETs) are highly aggressive brain tumours for which molecular features and best therapeutic strategy remains unknown. We interrogated a large cohort of these rare tumours in order to identify molecular markers that will enhance clinical management of CNS-PNET. Methods Transcriptional and copy number profiles from primary hemispheric CNS-PNETs were examined using clustering, gene and pathways enrichment analyses to discover tumour sub-groups and group-specific molecular markers. Immuno-histochemical and/or gene expression analyses were used to validate and examine the clinical significance of novel sub-group markers in 123 primary CNS-PNETs. Findings Three molecular sub-groups of CNS-PNETs distinguished by primitive neural (Group 1), oligo-neural (Group 2) and mesenchymal lineage (Group 3) gene expression signature were identified. Tumour sub-groups exhibited differential expression of cell lineage markers, LIN28 and OLIG2, and correlated with distinct demographics, survival and metastatic incidence. Group 1 tumours affected primarily younger females; male: female ratios were respectively 0.61 (median age 2.9 years; 95% CI: 2.4–5.2; p≤ 0.005), 1.25 (median age 7.9 years; 95% CI: 6–9.7) and 1.63 (median age 5.9 years; 95% CI: 4.9–7.8) for group 1, 2 and 3 patients. Overall outcome was poorest in group 1 patients which had a median survival of 0.8 years (95% CI: 0.47–1.2; p=0.019) as compared to 1.8 years (95% CI: 1.4–2.3) and 4.3 years; (95% CI: 0.82–7.8) respectively for group 2 and 3 patients. Group 3 tumours had the highest incidence of metastases at diagnosis; M0: M+ ratio were respectively 0.9 and 3.9 for group 3, versus group 1 and 2 tumours combined (p=0.037). Interpretation LIN28 and OLIG2 represent highly promising, novel diagnostic and prognostic molecular markers for CNS PNET that warrants further evaluation in prospective clinical trials. PMID:22691720

Relationship between paediatric CT scans and subsequent risk of leukaemia and brain tumours: assessment of the impact of underlying conditions.

PubMed

Berrington de Gonzalez, Amy; Salotti, Jane A; McHugh, Kieran; Little, Mark P; Harbron, Richard W; Lee, Choonsik; Ntowe, Estelle; Braganza, Melissa Z; Parker, Louise; Rajaraman, Preetha; Stiller, Charles; Stewart, Douglas R; Craft, Alan W; Pearce, Mark S

2016-02-16

We previously reported evidence of a dose-response relationship between ionising-radiation exposure from paediatric computed tomography (CT) scans and the risk of leukaemia and brain tumours in a large UK cohort. Underlying unreported conditions could have introduced bias into these findings. We collected and reviewed additional clinical information from radiology information systems (RIS) databases, underlying cause of death and pathology reports. We conducted sensitivity analyses excluding participants with cancer-predisposing conditions or previous unreported cancers and compared the dose-response analyses with our original results. We obtained information from the RIS and death certificates for about 40% of the cohort (n∼180 000) and found cancer-predisposing conditions in 4 out of 74 leukaemia/myelodysplastic syndrome (MDS) cases and 13 out of 135 brain tumour cases. As these conditions were unrelated to CT exposure, exclusion of these participants did not alter the dose-response relationships. We found evidence of previous unreported cancers in 2 leukaemia/MDS cases, 7 brain tumour cases and 232 in non-cases. These previous cancers were related to increased number of CTs. Exclusion of these cancers reduced the excess relative risk per mGy by 15% from 0.036 to 0.033 for leukaemia/MDS (P-trend=0.02) and by 30% from 0.023 to 0.016 (P-trend<0.0001) for brain tumours. When we included pathology reports we had additional clinical information for 90% of the cases. Additional exclusions from these reports further reduced the risk estimates, but this sensitivity analysis may have underestimated risks as reports were only available for cases. Although there was evidence of some bias in our original risk estimates, re-analysis of the cohort with additional clinical data still showed an increased cancer risk after low-dose radiation exposure from CT scans in young patients.

TREATMENT OF PROGRESSION OF DIFFUSE ASTROCYTOMA BY HERBAL MEDICINE: CASE REPORT.

PubMed

Trogrlić, Ivo; Trogrlić, Dragan; Trogrlić, Zoran

2016-01-01

The paper presents the results of the use of phytotherapy in a 33-year-old woman who, after finishing the oncological treatment of diffuse astrocytoma, had tumour progression. Phytotherapy was introduced after the tumour had progressed. It consisted of 4 types of herbal medicine which the subject was taking in form of tea once a day at regular intervals. The patient started phytotherapy along with temozolomide, which was the only oncological treatment she was under after the tumour had progressed. Following the finished chemotherapy, the patient continued the treatment with herbal medicine only. She regularly took phytotherapy without interruption and to the fullest extent for 30 months, and the results of treatment were monitored by periodic scanning using nuclear magnetic resonance technique. The control scanning that was conducted after the end of combined treatment with temozolomide and phytotherapy showed tumour regression. The patient continued with phytotherapy after finishing chemotherapy and, during the following 24 months, it was the sole treatment option. In that period, the regression of the tumour continued, until a control examination 30 months after the introduction of phytotherapy showed no clinical and radiological signs of tumour. The results presented in this research paper clearly indicate the potential of phytotherapy in the treatment of some types of brain tumours. A complete regression of tumour following the treatment with nothing but herbal medicine offers support for such claim. Future research should demonstrate the effectiveness of phytotherapy, as a supplementary form of brain tumour treatment, and the results of this research should be compared with the existing information on the effectiveness of the protocols currently used in the treatment of these types of tumour.

Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta‐analysis

PubMed Central

Tsaousi, Georgia; Apostolidou, Eirini; Karakoulas, Konstantinos; Kouvelas, Dimitrios; Amaniti, Ekaterini

2016-01-01

Aims The aim of this study was to perform an up‐to‐date systematic review and meta‐analysis on the efficacy and safety of prophylactic administration of levetiracetam in brain tumour patients. Method A systematic review of studies published until April 2015 was conducted using Scopus/Elsevier, EMBASE and MEDLINE. The search was limited to articles reporting results from adult patients, suffering from brain tumour, undergoing supratentorial craniotomy for tumour resection or biopsy and administered levetiracetam in the perioperative period for seizure prophylaxis. Outcomes included the efficacy and safety of levetiracetam, as well as the tolerability of the specific regimen, defined by the discontinuation of the treatment due to side effects. Results The systematic review included 1148 patients from 12 studies comparing levetiracetam with no treatment, phenytoin and valproate, while only 243 patients from three studies, comparing levetiracetam vs phenytoin efficacy and safety, were included in the meta‐analysis. The combined results from the meta‐analysis showed that levetiracetam administration was followed by significantly fewer seizures than treatment with phenytoin (OR = 0.12 [0.03–0.42]: χ2 = 1.76: I2 = 0%). Analysis also showed significantly fewer side effects in patients receiving levetiracetam, compared to other groups (P < 0.05). The combined results showed fewer side effects in the levetiracetam group compared to the phenytoin group (OR = 0.65 [0.14–2.99]: χ2 = 8.79: I2 = 77%). Conclusions The efficacy of prophylaxis with levetiracetam seems to be superior to that with phenytoin and valproate administration. Moreover, levetiracetam use demonstrates fewer side effects in brain tumour patients. Nevertheless, high risk of bias and moderate methodological quality must be taken into account when considering these results. PMID:26945547

Experimental and clinical standards, and evolution of lasers in neurosurgery.

PubMed

Devaux, B C; Roux, F X

1996-01-01

From initial experiments of ruby, argon and CO2 lasers on the nervous system so far, dramatic progress was made in delivery systems technology as well as in knowledge of laser-tissue interaction effects and hazards through various animal experiments and clinical experience. Most surgical effects of laser light on neural tissue and the central nervous system (CNS) are thermal lesions. Haemostasis, cutting and vaporization depend on laser emission parameters--wavelength, fluence and mode--and on the exposed tissues optical and thermal properties--water and haemoglobin content, thermal conductivity and specific heat. CO2 and Nd-YAG lasers have today a large place in the neurosurgical armamentarium, while new laser sources such as high power diode lasers will have one in the near future. Current applications of these lasers derive from their respective characteristics, and include CNS tumour and vascular malformation surgery, and stereotactic neurosurgery. Intracranial, spinal cord and intra-orbital meningiomas are the best lesions for laser use for haemostasis, dissection and tissue vaporization. Resection of acoustic neuromas, pituitary tumours, spinal cord neuromas, intracerebral gliomas and metastases may also benefit from lasers as accurate, haemostatic, non-contact instruments which reduce surgical trauma to the brain and eloquent structures such as brain stem and cranial nerves. Coagulative lasers (1.06 microns and 1.32 microns Nd-YAG, argon, or diode laser) will find an application for arteriovenous malformations and cavernomas. Any fiberoptic-guided laser will find a use during stereotactic neurosurgical procedures, including image-guided resection of tumours and vascular malformations and endoscopic tumour resection and cysts or entry into a ventricle. Besides these routine applications of lasers, laser interstitial thermotherapy (LITT) and photodynamic therapy (PDT) of brain tumours are still in the experimental stage. The choice of a laser in a neurosurgical operating room implies an evaluation of the laser use (applications, frequency), of the available budget and costs--including purchase, maintenance and staff training--, and material that will be necessary: unit, peripherals, safety devices and measures, training programme. Future applications of lasers in neurosurgery will come from technological advances and refined experimental applications. The availability of new wavelength, tunable, small sized and "smart" laser units, will enlarge the thermal and non-thermal interactions between laser energy and neural tissue leading to new surgical applications. Tissue photo-ablation, photohynamic therapy using second generation of photosensitizers, updated thermotherapy protocols, are current trends for further use of lasers in neurosurgery.

New developments in surgery of malignant gliomas

PubMed Central

Vranic, Andrej

2011-01-01

Background Malignant gliomas account for a high proportion of brain tumours. With new advances in neurooncology, the recurrence-free survival of patients with malignant gliomas has been substantially prolonged. It, however, remains dependent on the thoroughness of the surgical resection. The maximal tumour resection without additional postoperative deficit is the goal of surgery on patients with malignant gliomas. In order to minimize postoperative deficit, several pre- and intraoperative techniques have been developed. Conclusions Several techniques used in malignant glioma surgery have been developed, including microsurgery, neuroendoscopy, stereotactic biopsy and brachytherapy. Imaging and functional techniques allowing for safer tumour resection have a special value. Imaging techniques allow for better preoperative visualization and choice of the approach, while functional techniques help us locate eloquent regions of the brain. PMID:22933950

Recurrence of Phaeochromocytoma and Abdominal Paraganglioma After Initial Surgical Intervention.

PubMed

Johnston, Philip C; Mullan, Karen R; Atkinson, A Brew; Eatock, Fiona C; Wallace, Helen; Gray, Moyra; Hunter, Steven J

2015-05-01

Clinical and biochemical follow up after surgery for phaeochromocytoma is essential with long term studies demonstrating recurrence frequencies between 6% and 23%. To examine the characteristics and frequency of tumour recurrence in a regional endocrine referral centre, in patients with surgical resection of phaeochromocytoma (P) and abdominal paraganglioma (AP). We identified a cohort of 52 consecutive patients who attended our Regional Endocrinology & Diabetes Centre and retrospectively reviewed their clinical, biochemical and radiological data (between 2002 and 2013). After confirmation of early post-operative remission by negative biochemical testing, tumour recurrence was defined by demonstration of catecholamine excess with confirmatory imaging. Phaeochromocytoma was confirmed histologically in all cases (43:P, 9:AP, mean-age:53 years). Open adrenalectomy was performed in 20 cases and laparoscopically in 32. Hereditary phaeochromocytoma was confirmed by genetic analysis in 12 (23%) patients. Median follow up time from initial surgery was 47 months, (range: 12 - 296 months), 49 patients had no evidence of tumour recurrence at latest follow-up. Three patients (6%) demonstrated tumour development, one in a patient with VHL which occurred in a contralateral adrenal gland, one sporadic case had local recurrence, and an adrenal tumour occurred in a patient with a SDHB gene mutation who had a previous bladder tumour. After initial surgery, the tumours occurred at 8.6, 12.0 and 17.7 years respectively. In this study tumour development occurred in 6% of patients. Although tumour rates were low, careful and sustained clinical and biochemical follow up is advocated, as new tumour development or recurrence may occur long after the initial surgery is performed.

Withdrawal of antiepileptic drugs in glioma patients after long-term seizure freedom: design of a prospective observational study.

PubMed

Koekkoek, Johan A F; Kerkhof, Melissa; Dirven, Linda; Heimans, Jan J; Postma, Tjeerd J; Vos, Maaike J; Bromberg, Jacoline E C; van den Bent, Martin J; Reijneveld, Jaap C; Taphoorn, Martin J B

2014-08-15

Epilepsy is common in patients with a glioma. Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment, but may cause side effects and may negatively impact neurocognitive functioning and quality of life. Besides antiepileptic drugs, anti-tumour treatment, which currently consists of surgery, radiotherapy and/or chemotherapy, may contribute to seizure control as well. In glioma patients with seizure freedom after anti-tumour therapy the question emerges whether AEDs should be continued, particularly in the case where anti-tumour treatment has been successful. We propose to explore the possibility of AED withdrawal in glioma patients with long-term seizure freedom after anti-tumour therapy and without signs of tumour progression. We initiate a prospective, observational study exploring the decision-making process on the withdrawal or continuation of AEDs in low-grade and anaplastic glioma patients with stable disease and prolonged seizure freedom after anti-tumour treatment, and the effects of AED withdrawal or continuation on seizure freedom. We recruit participants through the outpatient clinics of three tertiary referral centers for brain tumour patients in The Netherlands. The patient and the treating physician make a shared decision to either withdraw or continue AED treatment. Over a one-year period, we aim to include 100 glioma patients. We expect approximately half of the participants to be willing to withdraw AEDs. The primary outcome measures are: 1) the outcome of the shared-decision making on AED withdrawal or continuation, and decision related arguments, and 2) seizure freedom at 12 months and 24 months of follow-up. We will also evaluate seizure type and frequency in case of seizure recurrence, as well as neurological symptoms, adverse effects related to AED treatment or withdrawal, other anti-tumour treatments and tumour progression. This study addresses two issues that are currently unexplored. First, it will explore the willingness to withdraw AEDs in glioma patients, and second, it will assess the risk of seizure recurrence in case AEDs are withdrawn in this specific patient population. This study aims to contribute to a more tailored AED treatment, and prevent unnecessary and potentially harmful use of AEDs in glioma patients.

Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours

NASA Astrophysics Data System (ADS)

Sakurai, Yoshinori; Ono, Koji; Miyatake, Shin-ichi; Maruhashi, Akira

2006-03-01

Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours.

PubMed

Sakurai, Yoshinori; Ono, Koji; Miyatake, Shin-Ichi; Maruhashi, Akira

2006-03-07

Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells

PubMed Central

Li, Li; Grausam, Katie B.; Wang, Jun; Lun, Melody P.; Ohli, Jasmin; Lidov, Hart G. W.; Calicchio, Monica L.; Zeng, Erliang; Salisbury, Jeffrey L.; Wechsler-Reya, Robert J.; Lehtinen, Maria K.; Schüller, Ulrich; Zhao, Haotian

2016-01-01

Aberrant Notch signaling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly pediatric brain neoplasms. We developed animal models of CP tumours by inducing sustained expression of Notch1 that recapitulate properties of human CP tumours with aberrant NOTCH signaling. Whole transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate diffferentiation. A Shh-driven signaling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from mono-ciliated progenitors in the roof plate characterized by elevated Notch signaling. Abnormal SHH signaling and distinct ciliogenesis are detected in human CP tumours, suggesting SHH pathway and cilia differentiation as potential therapeutic avenues. PMID:26999738

Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.

PubMed

Chen, Qing; Boire, Adrienne; Jin, Xin; Valiente, Manuel; Er, Ekrem Emrah; Lopez-Soto, Alejandro; Jacob, Leni; Patwa, Ruzeen; Shah, Hardik; Xu, Ke; Cross, Justin R; Massagué, Joan

2016-05-26

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

Distribution of RF energy emitted by mobile phones in anatomical structures of the brain.

PubMed

Cardis, E; Deltour, I; Mann, S; Moissonnier, M; Taki, M; Varsier, N; Wake, K; Wiart, J

2008-06-07

The rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in possible carcinogenic effects of radio frequency (RF). Because exposure to RF from phones is localized, if a risk exists it is likely to be greatest for tumours in regions with greatest energy absorption. The objective of the current paper was to characterize the spatial distribution of RF energy in the brain, using results of measurements made in two laboratories on 110 phones used in Europe or Japan. Most (97-99% depending on frequency) appears to be absorbed in the brain hemisphere on the side where the phone is used, mainly (50-60%) in the temporal lobe. The average relative SAR is highest in the temporal lobe (6-15%, depending on frequency, of the spatial peak SAR in the most exposed region of the brain) and the cerebellum (2-10%) and decreases very rapidly with increasing depth, particularly at higher frequencies. The SAR distribution appears to be fairly similar across phone models, between older and newer phones and between phones with different antenna types and positions. Analyses of risk by location of tumour are therefore important for the interpretation of results of studies of brain tumours in relation to mobile phone use.

Whole brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS) versus surgery plus whole brain radiotherapy (OP+WBRT) for 1-3 brain metastases: results of a matched pair analysis.

PubMed

Rades, Dirk; Kueter, Jan-Dirk; Veninga, Theo; Gliemroth, Jan; Schild, Steven E

2009-02-01

This study is the first one to compare WBRT+SRS to OP+WBRT for 1-3 brain metastases. Survival (OS), intracerebral control (IC) and local control (LC) of the treated metastases were retrospectively evaluated in 52 patients undergoing WBRT+SRS and in 52 patients undergoing OP+WBRT. Both groups were matched for WBRT schedule, age, gender, performance status, tumour, number of brain metastases, extracerebral metastases, RPA class and interval from tumour diagnosis to WBRT. One-year OS was 56% after WBRT+SRS and 47% after OP+WBRT (p=0.034). One-year IC was 66% and 50% (p=0.003). One-year LC was 82% and 66% (p=0.006). On multivariate analyses, it was found that improved OS was associated with younger age (p=0.044), no extracerebral metastases (p<0.001), RPA class 1 (p<0.001) and longer interval from tumour diagnosis to WBRT (p=0.001). IC was associated with younger age (p=0.002) and longer interval (p=0.004); WBRT+SRS achieved borderline significance (p=0.052). Improved LC was associated with longer interval (p=0.017); WBRT+SRS showed a trend (p=0.09). WBRT+SRS appears at least as effective as OP+WBRT.

Epidemiology, management and treatment outcome of medulloblastoma in singapore.

PubMed

Chan, Mei-Yoke; Teo, Wan-Yee; Seow, Wan-Tew; Tan, Ah-Moy

2007-05-01

Medulloblastoma/primitive neuroectodermal tumour is the most common type of malignant brain tumour in children. Long-term survival rates have improved over the years with a combination of surgical, radiotherapeutic and chemotherapeutic treatment modalities in the developed world. This paper aims to analyse the epidemiology and outcome of medulloblastoma in Singapore and compare our results with those reported in the literature. A 9-year retrospective study was done using data reported to the Singapore Children's Cancer Registry from June 1997 to June 2005. Only 39 children up to the age of 15 years diagnosed histologically with medulloblastoma or primitive neuroectodermal tumour arising from the cerebellum were included in the study. Follow-up data were collected up to June 2006 and analysed using SPSS v 13.0 software. Medulloblastoma/primitive neuroectodermal tumour was the most common type of brain tumour, accounting for 40.7% of all brain tumours diagnosed in children in Singapore. The 5-year event-free survival rate was 44.5%, while the 5- year overall survival rate was 51.5%. Nearly half (41%) of our patients had spinal metastasis at presentation and this was associated with a worse event-free survival (6.3% vs 71.9%, P = 0). Children under 36 months of age had a significantly poorer overall survival (28.8% vs 52.2%, P = 0.041). The outcome of medulloblastoma in Singapore was inferior to reported figures in the literature. We need to close identified gaps in care, like standardising assessment and treatment protocols, in order to improve our results. Research into molecular and genetic characteristics may also throw light on whether the disease is inherently more aggressive in our population.

Non-negative matrix factorisation methods for the spectral decomposition of MRS data from human brain tumours

PubMed Central

2012-01-01

Background In-vivo single voxel proton magnetic resonance spectroscopy (SV 1H-MRS), coupled with supervised pattern recognition (PR) methods, has been widely used in clinical studies of discrimination of brain tumour types and follow-up of patients bearing abnormal brain masses. SV 1H-MRS provides useful biochemical information about the metabolic state of tumours and can be performed at short (< 45 ms) or long (> 45 ms) echo time (TE), each with particular advantages. Short-TE spectra are more adequate for detecting lipids, while the long-TE provides a much flatter signal baseline in between peaks but also negative signals for metabolites such as lactate. Both, lipids and lactate, are respectively indicative of specific metabolic processes taking place. Ideally, the information provided by both TE should be of use for clinical purposes. In this study, we characterise the performance of a range of Non-negative Matrix Factorisation (NMF) methods in two respects: first, to derive sources correlated with the mean spectra of known tissue types (tumours and normal tissue); second, taking the best performing NMF method for source separation, we compare its accuracy for class assignment when using the mixing matrix directly as a basis for classification, as against using the method for dimensionality reduction (DR). For this, we used SV 1H-MRS data with positive and negative peaks, from a widely tested SV 1H-MRS human brain tumour database. Results The results reported in this paper reveal the advantage of using a recently described variant of NMF, namely Convex-NMF, as an unsupervised method of source extraction from SV1H-MRS. Most of the sources extracted in our experiments closely correspond to the mean spectra of some of the analysed tumour types. This similarity allows accurate diagnostic predictions to be made both in fully unsupervised mode and using Convex-NMF as a DR step previous to standard supervised classification. The obtained results are comparable to, or more accurate than those obtained with supervised techniques. Conclusions The unsupervised properties of Convex-NMF place this approach one step ahead of classical label-requiring supervised methods for the discrimination of brain tumour types, as it accounts for their increasingly recognised molecular subtype heterogeneity. The application of Convex-NMF in computer assisted decision support systems is expected to facilitate further improvements in the uptake of MRS-derived information by clinicians. PMID:22401579

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy

PubMed Central

Miao, L; Fraefel, C; Sia, K C; Newman, J P; Mohamed-Bashir, S A; Ng, W H; Lam, P Y P

2014-01-01

Background: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. Methods: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. Results: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. Conclusion: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers. PMID:24196790

Recent Developments of 18F-FET PET in Neuro-oncology.

PubMed

Muoio, Barbara; Giovanella, Luca; Treglia, Giorgio

2017-11-23

From the past decade to date several studies about O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography (PET) in brain tumours have been published in the literature. Objective The aim of this narrative review is to summarize the recent developments and the current role of 18F-FET PET in brain tumours according to recent literature data. Methods Main findings from selected recently published and relevant articles on the role of 18F-FET PET in neuro-oncology were described. Results 18F-FET PET may be useful in the differential diagnosis between brain tumours and non-neoplastic lesions and between low-grade and high-grade gliomas. Integration of 18F-FET PET into surgical planning allows better delineation of the extent of resection beyond margins visible with standard MRI. For biopsy planning, 18F-FET PET is particularly useful in identifying malignant foci within non-contrast-enhancing gliomas. 18F-FET PET may improve the radiation therapy planning in patients with gliomas. This metabolic imaging method may be useful to evaluate treatment response in patients with gliomas and it improves the differential diagnosis between brain tumours recurrence and post-treatment changes. 18F-FET PET may provide useful prognostic information in high-grade gliomas. Conclusions Based on recent literature data 18F-FET PET may provide additional diagnostic information compared to standard MRI in neuro-oncology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies - how do they arise?

PubMed

Levis, Angelo G; Minicuci, Nadia; Ricci, Paolo; Gennaro, Valerio; Garbisa, Spiridione

2011-06-17

Whether or not there is a relationship between use of mobile phones (analogue and digital cellulars, and cordless) and head tumour risk (brain tumours, acoustic neuromas, and salivary gland tumours) is still a matter of debate; progress requires a critical analysis of the methodological elements necessary for an impartial evaluation of contradictory studies. A close examination of the protocols and results from all case-control and cohort studies, pooled- and meta-analyses on head tumour risk for mobile phone users was carried out, and for each study the elements necessary for evaluating its reliability were identified. In addition, new meta-analyses of the literature data were undertaken. These were limited to subjects with mobile phone latency time compatible with the progression of the examined tumours, and with analysis of the laterality of head tumour localisation corresponding to the habitual laterality of mobile phone use. Blind protocols, free from errors, bias, and financial conditioning factors, give positive results that reveal a cause-effect relationship between long-term mobile phone use or latency and statistically significant increase of ipsilateral head tumour risk, with biological plausibility. Non-blind protocols, which instead are affected by errors, bias, and financial conditioning factors, give negative results with systematic underestimate of such risk. However, also in these studies a statistically significant increase in risk of ipsilateral head tumours is quite common after more than 10 years of mobile phone use or latency. The meta-analyses, our included, examining only data on ipsilateral tumours in subjects using mobile phones since or for at least 10 years, show large and statistically significant increases in risk of ipsilateral brain gliomas and acoustic neuromas. Our analysis of the literature studies and of the results from meta-analyses of the significant data alone shows an almost doubling of the risk of head tumours induced by long-term mobile phone use or latency.

Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies - how do they arise?

PubMed Central

2011-01-01

Background Whether or not there is a relationship between use of mobile phones (analogue and digital cellulars, and cordless) and head tumour risk (brain tumours, acoustic neuromas, and salivary gland tumours) is still a matter of debate; progress requires a critical analysis of the methodological elements necessary for an impartial evaluation of contradictory studies. Methods A close examination of the protocols and results from all case-control and cohort studies, pooled- and meta-analyses on head tumour risk for mobile phone users was carried out, and for each study the elements necessary for evaluating its reliability were identified. In addition, new meta-analyses of the literature data were undertaken. These were limited to subjects with mobile phone latency time compatible with the progression of the examined tumours, and with analysis of the laterality of head tumour localisation corresponding to the habitual laterality of mobile phone use. Results Blind protocols, free from errors, bias, and financial conditioning factors, give positive results that reveal a cause-effect relationship between long-term mobile phone use or latency and statistically significant increase of ipsilateral head tumour risk, with biological plausibility. Non-blind protocols, which instead are affected by errors, bias, and financial conditioning factors, give negative results with systematic underestimate of such risk. However, also in these studies a statistically significant increase in risk of ipsilateral head tumours is quite common after more than 10 years of mobile phone use or latency. The meta-analyses, our included, examining only data on ipsilateral tumours in subjects using mobile phones since or for at least 10 years, show large and statistically significant increases in risk of ipsilateral brain gliomas and acoustic neuromas. Conclusions Our analysis of the literature studies and of the results from meta-analyses of the significant data alone shows an almost doubling of the risk of head tumours induced by long-term mobile phone use or latency. PMID:21679472

Motor deficits correlate with resting state motor network connectivity in patients with brain tumours

PubMed Central

Mikell, Charles B.; Youngerman, Brett E.; Liston, Conor; Sisti, Michael B.; Bruce, Jeffrey N.; Small, Scott A.; McKhann, Guy M.

2012-01-01

While a tumour in or abutting primary motor cortex leads to motor weakness, how tumours elsewhere in the frontal or parietal lobes affect functional connectivity in a weak patient is less clear. We hypothesized that diminished functional connectivity in a distributed network of motor centres would correlate with motor weakness in subjects with brain masses. Furthermore, we hypothesized that interhemispheric connections would be most vulnerable to subtle disruptions in functional connectivity. We used task-free functional magnetic resonance imaging connectivity to probe motor networks in control subjects and patients with brain tumours (n = 22). Using a control dataset, we developed a method for automated detection of key nodes in the motor network, including the primary motor cortex, supplementary motor area, premotor area and superior parietal lobule, based on the anatomic location of the hand-motor knob in the primary motor cortex. We then calculated functional connectivity between motor network nodes in control subjects, as well as patients with and without brain masses. We used this information to construct weighted, undirected graphs, which were then compared to variables of interest, including performance on a motor task, the grooved pegboard. Strong connectivity was observed within the identified motor networks between all nodes bilaterally, and especially between the primary motor cortex and supplementary motor area. Reduced connectivity was observed in subjects with motor weakness versus subjects with normal strength (P < 0.001). This difference was driven mostly by decreases in interhemispheric connectivity between the primary motor cortices (P < 0.05) and between the left primary motor cortex and the right premotor area (P < 0.05), as well as other premotor area connections. In the subjects without motor weakness, however, performance on the grooved pegboard did not relate to interhemispheric connectivity, but rather was inversely correlated with connectivity between the left premotor area and left supplementary motor area, for both the left and the right hands (P < 0.01). Finally, two subjects who experienced severe weakness following surgery for their brain tumours were followed longitudinally, and the subject who recovered showed reconstitution of her motor network at follow-up. The subject who was persistently weak did not reconstitute his motor network. Motor weakness in subjects with brain tumours that do not involve primary motor structures is associated with decreased connectivity within motor functional networks, particularly interhemispheric connections. Motor networks become weaker as the subjects become weaker, and may become strong again during motor recovery. PMID:22408270

Calcified miliary brain metastases with mitochondrial inclusion bodies.

PubMed Central

Yamazaki, T; Harigaya, Y; Noguchi, O; Okamoto, K; Hirai, S

1993-01-01

A patient with calcified miliary brain metastases from lung adenocarcinoma is reported. Electron microscopic study of the metastatic tumour cells showed membranous inclusion bodies in mitochondria. Images PMID:8429312

Imaging brain tumour microstructure.

PubMed

Nilsson, Markus; Englund, Elisabet; Szczepankiewicz, Filip; van Westen, Danielle; Sundgren, Pia C

2018-05-08

Imaging is an indispensable tool for brain tumour diagnosis, surgical planning, and follow-up. Definite diagnosis, however, often demands histopathological analysis of microscopic features of tissue samples, which have to be obtained by invasive means. A non-invasive alternative may be to probe corresponding microscopic tissue characteristics by MRI, or so called 'microstructure imaging'. The promise of microstructure imaging is one of 'virtual biopsy' with the goal to offset the need for invasive procedures in favour of imaging that can guide pre-surgical planning and can be repeated longitudinally to monitor and predict treatment response. The exploration of such methods is motivated by the striking link between parameters from MRI and tumour histology, for example the correlation between the apparent diffusion coefficient and cellularity. Recent microstructure imaging techniques probe even more subtle and specific features, providing parameters associated to cell shape, size, permeability, and volume distributions. However, the range of scenarios in which these techniques provide reliable imaging biomarkers that can be used to test medical hypotheses or support clinical decisions is yet unknown. Accurate microstructure imaging may moreover require acquisitions that go beyond conventional data acquisition strategies. This review covers a wide range of candidate microstructure imaging methods based on diffusion MRI and relaxometry, and explores advantages, challenges, and potential pitfalls in brain tumour microstructure imaging. Copyright © 2018. Published by Elsevier Inc.

Malignant Brain Tumours in Children : Present and Future Perspectives.

PubMed

Rutka, James T

2018-05-01

In contrast to many of the malignant tumors that occur in the central nervous system in adults, the management, responses to therapy, and future perspectives of children with malignant lesions of the brain hold considerable promise. Within the past 5 years, remarkable progress has been made with our understanding of the basic biology of the molecular genetics of several pediatric malignant brain tumors including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumour, and high grade glioma/diffuse intrinsic pontine glioma. The recent literature in pediatric neuro-oncology was reviewed, and a summary of the major findings are presented. Meaningful sub-classifications of these tumors have arisen, placing children into discrete categories of disease with requirements for targeted therapy. While the mainstay of therapy these past 30 years has been a combination of central nervous system irradiation and conventional chemotherapy, now with the advent of high resolution genetic mapping, targeted therapies have emerged, and less emphasis is being placed on craniospinal irradiation. In this article, the present and future perspective of pediatric brain malignancy are reviewed in detail. The progress that has been made offers significant hope for the future for patients with these tumours.

Recurrence of Phaeochromocytoma and Abdominal Paraganglioma After Initial Surgical Intervention

PubMed Central

Mullan, Karen R; Atkinson, A Brew; Eatock, Fiona C; Wallace, Helen; Gray, Moyra; Hunter, Steven J

2015-01-01

Background Clinical and biochemical follow up after surgery for phaeochromocytoma is essential with long term studies demonstrating recurrence frequencies between 6% and 23%. Aim To examine the characteristics and frequency of tumour recurrence in a regional endocrine referral centre, in patients with surgical resection of phaeochromocytoma (P) and abdominal paraganglioma (AP). Methods We identified a cohort of 52 consecutive patients who attended our Regional Endocrinology & Diabetes Centre and retrospectively reviewed their clinical, biochemical and radiological data (between 2002 and 2013). After confirmation of early post-operative remission by negative biochemical testing, tumour recurrence was defined by demonstration of catecholamine excess with confirmatory imaging. Results Phaeochromocytoma was confirmed histologically in all cases (43:P, 9:AP, mean-age:53years). Open adrenalectomy was performed in 20 cases and laparoscopically in 32. Hereditary phaeochromocytoma was confirmed by genetic analysis in 12 (23%) patients. Median follow up time from initial surgery was 47 months, (range: 12 - 296 months), 49 patients had no evidence of tumour recurrence at latest follow-up. Three patients (6%) demonstrated tumour development, one in a patient with VHL which occurred in a contralateral adrenal gland, one sporadic case had local recurrence, and an adrenal tumour occurred in a patient with a SDHB gene mutation who had a previous bladder tumour. After initial surgery, the tumours occurred at 8.6, 12.0 and 17.7 years respectively. Conclusion In this study tumour development occurred in 6% of patients. Although tumour rates were low, careful and sustained clinical and biochemical follow up is advocated, as new tumour development or recurrence may occur long after the initial surgery is performed. PMID:26170485

The INTERPRET Decision-Support System version 3.0 for evaluation of Magnetic Resonance Spectroscopy data from human brain tumours and other abnormal brain masses

PubMed Central

2010-01-01

Background Proton Magnetic Resonance (MR) Spectroscopy (MRS) is a widely available technique for those clinical centres equipped with MR scanners. Unlike the rest of MR-based techniques, MRS yields not images but spectra of metabolites in the tissues. In pathological situations, the MRS profile changes and this has been particularly described for brain tumours. However, radiologists are frequently not familiar to the interpretation of MRS data and for this reason, the usefulness of decision-support systems (DSS) in MRS data analysis has been explored. Results This work presents the INTERPRET DSS version 3.0, analysing the improvements made from its first release in 2002. Version 3.0 is aimed to be a program that 1st, can be easily used with any new case from any MR scanner manufacturer and 2nd, improves the initial analysis capabilities of the first version. The main improvements are an embedded database, user accounts, more diagnostic discrimination capabilities and the possibility to analyse data acquired under additional data acquisition conditions. Other improvements include a customisable graphical user interface (GUI). Most diagnostic problems included have been addressed through a pattern-recognition based approach, in which classifiers based on linear discriminant analysis (LDA) were trained and tested. Conclusions The INTERPRET DSS 3.0 allows radiologists, medical physicists, biochemists or, generally speaking, any person with a minimum knowledge of what an MR spectrum is, to enter their own SV raw data, acquired at 1.5 T, and to analyse them. The system is expected to help in the categorisation of MR Spectra from abnormal brain masses. PMID:21114820

[Liposomal cytarabine for the treatment of leptomeningeal dissemination of central nervous system tumours in children and adolescents].

PubMed

Moreno, Lucas; García Ariza, Miguel Angel; Cruz, Ofelia; Calvo, Carlota; Fuster, Jose Luis; Salinas, Jose Antonio; Moscardo, Cristina; Portugal, Raquel; Merino, Jose Manuel; Madero, Luis

2016-11-01

Leptomeningeal dissemination in paediatric central nervous system (CNS) tumours is associated with a poor outcome, and new therapeutic strategies are desperately needed. One of the main difficulties in the treatment of CNS tumours is blood brain barrier penetration. Intrathecal therapy has shown to be effective in several paediatric tumours. The aim of this article is to review the data available on the use of liposomal cytarabine for paediatric patients with leptomeningeal dissemination of CNS tumours, including the pharmacology, administration route, safety and efficacy data. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis.

PubMed

Eyre, Rachel; Alférez, Denis G; Spence, Kath; Kamal, Mohamed; Shaw, Frances L; Simões, Bruno M; Santiago-Gómez, Angélica; Sarmiento-Castro, Aida; Bramley, Maria; Absar, Mohammed; Saad, Zahida; Chatterjee, Sumohan; Kirwan, Cliona; Gandhi, Ashu; Armstrong, Anne C; Wardley, Andrew M; O'Brien, Ciara S; Farnie, Gillian; Howell, Sacha J; Clarke, Robert B

2016-12-01

Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease.

Clinical and histopathological features of adenomas of the ciliary pigment epithelium.

PubMed

Chang, Ying; Wei, Wen Bin; Shi, Ji Tong; Xian, Jun Fang; Yang, Wen Li; Xu, Xiao Lin; Bai, Hai Xia; Li, Bin; Jonas, Jost B

2016-11-01

Adenomas of the ciliary pigment epithelium (CPE) are rare benign tumours which have mainly to be differentiated from malignant ciliary body melanomas. Here we report on a consecutive series of patients with CPE adenomas and describe their characteristics. The retrospective hospital-based case series study included all patients who were consecutively operated for CPE adenomas. Of the 110 patients treated for ciliary body tumours, five patients (4.5%) had a CPE adenoma. Mean age was 59.0 ± 9.9 years (range: 46-72 years). Mean tumour apical thickness was 6.6 ± 1.7 mm. Tumour colour was mostly homogenously brown to black, and the tumour surface was smooth. The tumour masses pushed the iris tissue forward without infiltrating iris or anterior chamber angle. Sonography revealed an irregular echogram with sharp lesion borders and signs of blood flow in Color Doppler flow imaging. Ultrasonographic biomicroscopy demonstrated medium-low internal reflectivity and acoustic attenuation. In magnetic resonance imaging (MRI), the tumours as compared to brain were hyperintense on T1-weighted images and hypointense on T2-weighted images. Tumour tissue consisted of cords and nests of pigment epithelium cells separated by septa of vascularized fibrous connective tissue, leading to a pseudo-glandular appearance. The melanin granules in the cytoplasm were large and mostly spherical in shape. In four patients, the tumours were hyperpigmented. Tumour cells were large with round or oval nuclei and clearly detectable nucleoli. These clinical characteristics of CPE adenomas, such as homogenous dark brown colour, smooth surface, iris dislocation and anterior chamber angle narrowing but no iris infiltration, segmental cataract, pigment dispersion, and, as compared to brain tissue, hypointensity and, as compared to extraocular muscles or lacrimal gland, hyperintensity on T2-weighted MRI images, may be helpful for the differentiation from ciliary body malignant melanomas. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Distribution of RF energy emitted by mobile phones in anatomical structures of the brain

NASA Astrophysics Data System (ADS)

Cardis, E.; Deltour, I.; Mann, S.; Moissonnier, M.; Taki, M.; Varsier, N.; Wake, K.; Wiart, J.

2008-06-01

The rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in possible carcinogenic effects of radio frequency (RF). Because exposure to RF from phones is localized, if a risk exists it is likely to be greatest for tumours in regions with greatest energy absorption. The objective of the current paper was to characterize the spatial distribution of RF energy in the brain, using results of measurements made in two laboratories on 110 phones used in Europe or Japan. Most (97-99% depending on frequency) appears to be absorbed in the brain hemisphere on the side where the phone is used, mainly (50-60%) in the temporal lobe. The average relative SARSAR is the specific energy absorption rate i.e. energy absorption rate per unit mass (measured in W kg-1). is highest in the temporal lobe (6-15%, depending on frequency, of the spatial peak SAR in the most exposed region of the brain) and the cerebellum (2-10%) and decreases very rapidly with increasing depth, particularly at higher frequencies. The SAR distribution appears to be fairly similar across phone models, between older and newer phones and between phones with different antenna types and positions. Analyses of risk by location of tumour are therefore important for the interpretation of results of studies of brain tumours in relation to mobile phone use.

Pharmaco-thermodynamics of deuterium-induced oedema in living rat brain via 1H2O MRI: implications for boron neutron capture therapy of malignant brain tumours

NASA Astrophysics Data System (ADS)

Medina, Daniel C.; Li, Xin; Springer, Charles S., Jr.

2005-05-01

In addition to its common usage as a tracer in metabolic and physiological studies, deuterium possesses anti-tumoural activity and confers protection against γ-irradiation. A more recent interest in deuterium emanates from the search for alternatives capable of improving neutron penetrance whilst reducing healthy tissue radiation dose deposition in boron neutron capture therapy of malignant brain tumours. Despite this potential clinical application, deuterium induces brain oedema, which is detrimental to neutron capture therapy. In this study, five adult male rats were titrated with deuterated drinking water while brain oedema was monitored via water proton magnetic resonance imaging. This report concludes that deuterium, as well as deuterium-induced brain oedema, possesses a uniform brain bio-distribution. At a steady-state blood fluid deuteration value of 16%, when the deuterium isotope fraction in drinking water was 25%, a mean oedematous volume change of 9 ± 2% (p-value <0.001) was observed in the rat brain—this may account for neurological and behavioural abnormalities found in mammals drinking highly deuterated water. In addition to characterizing the pharmaco-thermodynamics of deuterium-induced oedema, this report also estimates the impact of oedema on thermal neutron enhancement and effective dose reduction factors using simple linear transport calculations. While body fluid deuteration enhances thermal neutron flux penetrance and reduces dose deposition, oedema has the opposite effect because it increases the volume of interest, e.g., the brain volume. Thermal neutron enhancement and effective dose reduction factors could be reduced by as much as ~10% in the presence of a 9% water volume increase (oedema). All three authors have contributed equally to this work.

Radiation injury vs. recurrent brain metastasis: combining textural feature radiomics analysis and standard parameters may increase 18F-FET PET accuracy without dynamic scans.

PubMed

Lohmann, Philipp; Stoffels, Gabriele; Ceccon, Garry; Rapp, Marion; Sabel, Michael; Filss, Christian P; Kamp, Marcel A; Stegmayr, Carina; Neumaier, Bernd; Shah, Nadim J; Langen, Karl-Josef; Galldiks, Norbert

2017-07-01

We investigated the potential of textural feature analysis of O-(2-[ 18 F]fluoroethyl)-L-tyrosine ( 18 F-FET) PET to differentiate radiation injury from brain metastasis recurrence. Forty-seven patients with contrast-enhancing brain lesions (n = 54) on MRI after radiotherapy of brain metastases underwent dynamic 18 F-FET PET. Tumour-to-brain ratios (TBRs) of 18 F-FET uptake and 62 textural parameters were determined on summed images 20-40 min post-injection. Tracer uptake kinetics, i.e., time-to-peak (TTP) and patterns of time-activity curves (TAC) were evaluated on dynamic PET data from 0-50 min post-injection. Diagnostic accuracy of investigated parameters and combinations thereof to discriminate between brain metastasis recurrence and radiation injury was compared. Diagnostic accuracy increased from 81 % for TBR mean alone to 85 % when combined with the textural parameter Coarseness or Short-zone emphasis. The accuracy of TBR max alone was 83 % and increased to 85 % after combination with the textural parameters Coarseness, Short-zone emphasis, or Correlation. Analysis of TACs resulted in an accuracy of 70 % for kinetic pattern alone and increased to 83 % when combined with TBR max . Textural feature analysis in combination with TBRs may have the potential to increase diagnostic accuracy for discrimination between brain metastasis recurrence and radiation injury, without the need for dynamic 18 F-FET PET scans. • Textural feature analysis provides quantitative information about tumour heterogeneity • Textural features help improve discrimination between brain metastasis recurrence and radiation injury • Textural features might be helpful to further understand tumour heterogeneity • Analysis does not require a more time consuming dynamic PET acquisition.

Patients' experiences and care needs during the diagnostic phase of an Integrated Brain Cancer Pathway: A Case Study.

PubMed

Vedelø, Tina Wang; Sørensen, Jens Christian Hedemann; Delmar, Charlotte

2018-03-31

To identify and describe patients' experiences and care needs throughout the diagnostic phase of an Integrated Brain Cancer Pathway. A malignant brain tumour is a devastating diagnosis, which may cause psychical symptoms and cognitive deficits. Studies have shown that the shock of the diagnosis, combined with the multiple symptoms, affect patients' ability to understand information and express needs of care and support. Unmet needs have been reported within this group of patients, however, the experiences and care needs of patients going through the diagnostic phase of a standardised Integrated Brain Cancer Pathway have not previously been explored. A Case Study design was used to provide detailed information of the complex needs of patients being diagnosed with a malignant brain tumour. Research interviews and direct participant observation of four patients during hospital admission, brain surgery and discharge were conducted in a Danish university hospital. Systematic text condensation was used to analyse the data material. Four major themes were identified: information needs, balancing hope and reality while trying to perceive the unknown reality of brain cancer, not knowing what to expect and participants' perceptions of the relationship with the health care providers. The analysis revealed that participants were in risk of having unmet information needs and that contextual factors seemed to cause fragmented care that led to feelings of uncertainty and loss of control. Brain tumour patients have complex care needs and experience a particular state of vulnerability during the diagnostic phase. Through personal relationships based on trust with skilled health care providers, participants experienced an existential recognition and alleviation of emotional distress. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The hypoxia signalling pathway in haematological malignancies

PubMed Central

Irigoyen, Marta; García-Ruiz, Juan Carlos; Berra, Edurne

2017-01-01

Haematological malignancies are tumours that affect the haematopoietic and the lymphatic systems. Despite the huge efforts to eradicate these tumours, the percentage of patients suffering resistance to therapies and relapse still remains significant. The tumour environment favours drug resistance of cancer cells, and particularly of cancer stem/initiating cells. Hypoxia promotes aggressiveness, metastatic spread and relapse in most of the solid tumours. Furthermore, hypoxia is associated with worse prognosis and resistance to conventional treatments through activation of the hypoxia-inducible factors. Haematological malignancies are not considered solid tumours, and therefore, the role of hypoxia in these diseases was initially presumed to be inconsequential. However, hypoxia is a hallmark of the haematopoietic niche. Here, we will review the current understanding of the role of both hypoxia and hypoxia-inducible factors in different haematological tumours. PMID:28415662

Three-dimensional textural features of conventional MRI improve diagnostic classification of childhood brain tumours.

PubMed

Fetit, Ahmed E; Novak, Jan; Peet, Andrew C; Arvanitits, Theodoros N

2015-09-01

The aim of this study was to assess the efficacy of three-dimensional texture analysis (3D TA) of conventional MR images for the classification of childhood brain tumours in a quantitative manner. The dataset comprised pre-contrast T1 - and T2-weighted MRI series obtained from 48 children diagnosed with brain tumours (medulloblastoma, pilocytic astrocytoma and ependymoma). 3D and 2D TA were carried out on the images using first-, second- and higher order statistical methods. Six supervised classification algorithms were trained with the most influential 3D and 2D textural features, and their performances in the classification of tumour types, using the two feature sets, were compared. Model validation was carried out using the leave-one-out cross-validation (LOOCV) approach, as well as stratified 10-fold cross-validation, in order to provide additional reassurance. McNemar's test was used to test the statistical significance of any improvements demonstrated by 3D-trained classifiers. Supervised learning models trained with 3D textural features showed improved classification performances to those trained with conventional 2D features. For instance, a neural network classifier showed 12% improvement in area under the receiver operator characteristics curve (AUC) and 19% in overall classification accuracy. These improvements were statistically significant for four of the tested classifiers, as per McNemar's tests. This study shows that 3D textural features extracted from conventional T1 - and T2-weighted images can improve the diagnostic classification of childhood brain tumours. Long-term benefits of accurate, yet non-invasive, diagnostic aids include a reduction in surgical procedures, improvement in surgical and therapy planning, and support of discussions with patients' families. It remains necessary, however, to extend the analysis to a multicentre cohort in order to assess the scalability of the techniques used. Copyright © 2015 John Wiley & Sons, Ltd.

New technologies to combat malignant tumours of the brain.

PubMed

Heppner, F

1982-01-01

1. The primary problem in an effective treatment of a glioblastoma is the prevention of a recurrence. 2. For that purpose were the following therapeutical procedures undertaken: (a) Temporary implantation of radio cobalt in the brain itself (1957): (b) Clostridium butyricum M 55 was used to render the centre of the tumour fluid (1967): (c) Podophyllin was used to destroy the border of the tumour (1980); (d) The CO2 Laser beam (1975); (e) The electromagnetic heat induction deep in the brain (1973-1978). 3. In order to make the operation and postoperative phase safer for the patient, the following precautions were drawn upon or employed: (a) Hyperbaric oxygenisation in the pressure chamber (1971); (b) The anti-G-suit (1974); (c) the computer controlled automatic infusion pump (1980), and (d) the telemetric measurement of intra-cranial pressure (1975). 4. Apart from the pressure chamber, the mentioned devices were all supervised and developed in the department of the author. 5. The first successful means in the prevention of the recurrence of a glioblastoma multiform seems to be the telethermic method mentioned in 2 (e) above.

Pooled analysis of two case-control studies on the use of cellular and cordless telephones and the risk of benign brain tumours diagnosed during 1997-2003.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2006-02-01

The use of cellular and cordless telephones and the risk of brain tumours is of concern since the brain is a high exposure area. We present the results of a pooled analysis of two case-control studies on benign brain tumours diagnosed during 1997-2003 including answers from 1,254 (88%) cases and 2,162 (89%) controls aged 20-80 years. For acoustic neuroma, the use of analogue cellular phones gave an odds ratio (OR) of 2.9 and a 95% confidence interval (CI) of 2.0-4.3; for digital cellular phones, OR=1.5; 95% CI=1.1-2.1; and for cordless telephones, OR=1.5, 95% CI=1.04-2.0. The highest OR was found for analogue phones with a latency period of >15 years; OR=3.8, 95% CI=1.4-10. Regarding meningioma, the results were as follows: for analogue phones, OR=1.3, 95% CI=0.99-1.7; for digital phones, OR=1.1, 95% CI=0.9-1.3; and for cordless phones, OR=1.1, 95% CI=0.9-1.4. In the multivariate analysis, a significantly increased risk of acoustic neuroma was found with the use of analogue phones.

A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified, DOX-loaded PAMAM dendrimer.

PubMed

Han, Shunping; Zheng, Hongyue; Lu, Yanping; Sun, Yue; Huang, Anhao; Fei, Weidong; Shi, Xiaowei; Xu, Xiuling; Li, Jingjing; Li, Fanzhu

2018-01-01

Glioma is the most common primary malignant brain tumour and the effect of chemotherapy is hampered by low permeability across the blood-brain-barrier (BBB). Borneol is a time-honoured 'Guide' drug in traditional Chinese medicine and has been proved to be capable of promoting free drugs into the brain efficiently, but there are still risks that free drugs, especially anti-glioma drugs, may be disassembled and metabolised before penetrating the BBB and caused the whole brain distribution. The purpose of this paper was to investigate whether borneol intervention could facilitate the BBB penetration and assist glioma treatment by combining with doxorubicin (DOX) loaded PAMAM dendrimers drug delivery system modified with Angiopep-2 (a ligand of the low-density lipoprotein receptor-related protein, which overexpress both in the BBB and gliomas). The results demonstrated that Angiopep-2 modification could actually enhance the affinity between the dendrimers and the targeting cells and finally increase the cell uptake and boost the anti-tumour ability. Borneol physical combination could further enhance the anti-tumour efficiency of this targeting drug delivery system (TDDS) after penetrating BBB. Compared with free DOX solution, this TDDS illustrated obviously sustained and pH-dependent drug release. This suggested that this synergetic strategy provided a promising way for glioma therapy.

A three-dimensional point process model for the spatial distribution of disease occurrence in relation to an exposure source.

PubMed

Grell, Kathrine; Diggle, Peter J; Frederiksen, Kirsten; Schüz, Joachim; Cardis, Elisabeth; Andersen, Per K

2015-10-15

We study methods for how to include the spatial distribution of tumours when investigating the relation between brain tumours and the exposure from radio frequency electromagnetic fields caused by mobile phone use. Our suggested point process model is adapted from studies investigating spatial aggregation of a disease around a source of potential hazard in environmental epidemiology, where now the source is the preferred ear of each phone user. In this context, the spatial distribution is a distribution over a sample of patients rather than over multiple disease cases within one geographical area. We show how the distance relation between tumour and phone can be modelled nonparametrically and, with various parametric functions, how covariates can be included in the model and how to test for the effect of distance. To illustrate the models, we apply them to a subset of the data from the Interphone Study, a large multinational case-control study on the association between brain tumours and mobile phone use. Copyright © 2015 John Wiley & Sons, Ltd.

Tumour exosome integrins determine organotropic metastasis

PubMed Central

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Mark, Milica Tesic; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E.; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M.; Dumont-Cole, Vanessa D.; Kramer, Kimberly; Wexler, Leonard H.; Narendran, Aru; Schwartz, Gary K.; Healey, John H.; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H.; Grandgenett, Paul M.; Hollingsworth, Michael A.; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K.; Jarnagin, William R.; Brady, Mary S.; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J.; Bissell, Mina J.; Garcia, Benjamin A.; Kang, Yibin; Rajasekhar, Vinagolu K.; Ghajar, Cyrus M.; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

2015-01-01

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis. PMID:26524530

Tumour exosome integrins determine organotropic metastasis

DOE PAGES

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; ...

2015-10-28

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6β 4 and α 6β 1 weremore » associated with lung metastasis, while exosomal integrin α vβ 5 was linked to liver metastasis. Targeting the integrins α 6β 4 and α vβ 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.« less

Tumour exosome integrins determine organotropic metastasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6β 4 and α 6β 1 weremore » associated with lung metastasis, while exosomal integrin α vβ 5 was linked to liver metastasis. Targeting the integrins α 6β 4 and α vβ 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.« less

Advances in immunotherapy for the treatment of glioblastoma.

PubMed

Tivnan, Amanda; Heilinger, Tatjana; Lavelle, Ed C; Prehn, Jochen H M

2017-01-01

Glioblastoma (GBM) is an aggressive brain tumour, associated with extremely poor prognosis and although there have been therapeutic advances, treatment options remain limited. This review focuses on the use of immunotherapy, harnessing the power of the host's immune system to reject cancer cells. Key challenges in glioma specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumour. Although specific antigens have been identified in several cancers; brain tumours, such as GBM, are considered poorly immunogenic. However, as detailed in this review, strategies aimed at circumventing these challenges are showing promise for GBM treatment; including identification of glioma specific antigens and endogenous immune cell activation in an attempt to overcome the immunosuppressive environment which is associated with GBM tumours. An up-to-date summary of current Phase I/II and ongoing Phase III GBM immunotherapy clinical trials is provided in addition to insights into promising preclinical approaches which are focused predominantly on increased induction of Type 1 helper T cell (T h 1) immune responses within patients.

Tumour exosome integrins determine organotropic metastasis.

PubMed

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Tesic Mark, Milica; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M; Dumont-Cole, Vanessa D; Kramer, Kimberly; Wexler, Leonard H; Narendran, Aru; Schwartz, Gary K; Healey, John H; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H; Grandgenett, Paul M; Hollingsworth, Michael A; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K; Jarnagin, William R; Brady, Mary S; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J; Bissell, Mina J; Garcia, Benjamin A; Kang, Yibin; Rajasekhar, Vinagolu K; Ghajar, Cyrus M; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

2015-11-19

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Nonlinear modelling of cancer: bridging the gap between cells and tumours

PubMed Central

Lowengrub, J S; Frieboes, H B; Jin, F; Chuang, Y-L; Li, X; Macklin, P; Wise, S M; Cristini, V

2010-01-01

Despite major scientific, medical and technological advances over the last few decades, a cure for cancer remains elusive. The disease initiation is complex, and including initiation and avascular growth, onset of hypoxia and acidosis due to accumulation of cells beyond normal physiological conditions, inducement of angiogenesis from the surrounding vasculature, tumour vascularization and further growth, and invasion of surrounding tissue and metastasis. Although the focus historically has been to study these events through experimental and clinical observations, mathematical modelling and simulation that enable analysis at multiple time and spatial scales have also complemented these efforts. Here, we provide an overview of this multiscale modelling focusing on the growth phase of tumours and bypassing the initial stage of tumourigenesis. While we briefly review discrete modelling, our focus is on the continuum approach. We limit the scope further by considering models of tumour progression that do not distinguish tumour cells by their age. We also do not consider immune system interactions nor do we describe models of therapy. We do discuss hybrid-modelling frameworks, where the tumour tissue is modelled using both discrete (cell-scale) and continuum (tumour-scale) elements, thus connecting the micrometre to the centimetre tumour scale. We review recent examples that incorporate experimental data into model parameters. We show that recent mathematical modelling predicts that transport limitations of cell nutrients, oxygen and growth factors may result in cell death that leads to morphological instability, providing a mechanism for invasion via tumour fingering and fragmentation. These conditions induce selection pressure for cell survivability, and may lead to additional genetic mutations. Mathematical modelling further shows that parameters that control the tumour mass shape also control its ability to invade. Thus, tumour morphology may serve as a predictor of invasiveness and treatment prognosis. PMID:20808719

Nonlinear modelling of cancer: bridging the gap between cells and tumours

NASA Astrophysics Data System (ADS)

Lowengrub, J. S.; Frieboes, H. B.; Jin, F.; Chuang, Y.-L.; Li, X.; Macklin, P.; Wise, S. M.; Cristini, V.

2010-01-01

Despite major scientific, medical and technological advances over the last few decades, a cure for cancer remains elusive. The disease initiation is complex, and including initiation and avascular growth, onset of hypoxia and acidosis due to accumulation of cells beyond normal physiological conditions, inducement of angiogenesis from the surrounding vasculature, tumour vascularization and further growth, and invasion of surrounding tissue and metastasis. Although the focus historically has been to study these events through experimental and clinical observations, mathematical modelling and simulation that enable analysis at multiple time and spatial scales have also complemented these efforts. Here, we provide an overview of this multiscale modelling focusing on the growth phase of tumours and bypassing the initial stage of tumourigenesis. While we briefly review discrete modelling, our focus is on the continuum approach. We limit the scope further by considering models of tumour progression that do not distinguish tumour cells by their age. We also do not consider immune system interactions nor do we describe models of therapy. We do discuss hybrid-modelling frameworks, where the tumour tissue is modelled using both discrete (cell-scale) and continuum (tumour-scale) elements, thus connecting the micrometre to the centimetre tumour scale. We review recent examples that incorporate experimental data into model parameters. We show that recent mathematical modelling predicts that transport limitations of cell nutrients, oxygen and growth factors may result in cell death that leads to morphological instability, providing a mechanism for invasion via tumour fingering and fragmentation. These conditions induce selection pressure for cell survivability, and may lead to additional genetic mutations. Mathematical modelling further shows that parameters that control the tumour mass shape also control its ability to invade. Thus, tumour morphology may serve as a predictor of invasiveness and treatment prognosis.

Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells

PubMed Central

Liu, Chen-Chi; Lin, Shih-Pei; Hsu, Han-Shui; Yang, Shung-Haur; Lin, Chiu-Hua; Yang, Muh-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

2016-01-01

Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis. PMID:27306323

Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells.

PubMed

Liu, Chen-Chi; Lin, Shih-Pei; Hsu, Han-Shui; Yang, Shung-Haur; Lin, Chiu-Hua; Yang, Muh-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

2016-06-16

Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis.

Tumour necrosis factor-α-mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin-6.

PubMed

Rochfort, Keith D; Collins, Laura E; McLoughlin, Alisha; Cummins, Philip M

2016-02-01

The co-involvement of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) during blood-brain barrier (BBB) injury has been reported in various models of neuroinflammation, although the precise functional interplay between these archetypal proinflammatory cytokines remains largely undefined within this context. In the current paper, we tested the hypothesis that TNF-α-mediated BBB disruption is measurably attributable in-part to induction of microvascular endothelial IL-6 production. In initial experiments, we observed that treatment of human brain microvascular endothelial cells (HBMvECs) with TNF-α (0-100 ng/mL, 0-24 h) robustly elicited both time- and dose-dependent induction of IL-6 expression and release, as well as expression of the IL-6 family receptor, GP130. Further experiments demonstrated that the TNF-α-dependent generation of reactive oxygen species, down-regulation of adherens/tight junction proteins, and concomitant elevation of HBMvEC permeability, were all significantly attenuated by blockade of IL-6 signalling using either an anti-IL-6 neutralizing antibody or an IL-6 siRNA. Based on these observations, we conclude that TNF-α treatment of HBMvECs in vitro activates IL-6 production and signalling, events that were shown to synergize with TNF-α actions to elicit HBMvEC permeabilization. These novel findings offer a constructive insight into the specific contribution of downstream cytokine induction to the injurious actions of TNF-α at the BBB microvascular endothelium interface. The co-involvement of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) during blood-brain barrier (BBB) injury has been widely reported. Using human brain microvascular endothelial cells (HBMvEC), we show that TNF-α-mediated BBB disruption is measurably attributable in-part to induction of endothelial IL-6 production and signalling. We demonstrate that the TNF-α-dependent generation of reactive oxygen species (ROS), down-regulation of interendothelial junctions, and concomitant elevation of HBMvEC permeability, could be significantly attenuated by using either an IL-6 neutralizing antibody or an IL-6-specific siRNA. These findings provide insight into the complex nature of proinflammatory cytokine injury at the BBB microvascular endothelium interface. © 2015 International Society for Neurochemistry.

A comparison between surgical resection in combination with WBRT or hypofractionated stereotactic irradiation in the treatment of solitary brain metastases.

PubMed

Lindvall, Peter; Bergström, Per; Löfroth, Per-Olov; Tommy Bergenheim, A

2009-09-01

The standard treatment of solitary brain metastases previously has been tumour resection in combination with whole-brain radiation therapy (WBRT). Stereotactic radiotherapy has emerged as a non-invasive treatment option especially for small brain metastases. We now report our results on resection + WBRT or hypofractionated stereotactic irradiation (HCSRT) in the treatment of solitary brain metastases. Between 1993 and 2004 patients with metastatic cancer and solitary brain metastases were selected for surgical resection + WBRT or HCSRT alone at the Umeå University Hospital. Fifty-nine patients were treated with surgical resection + WBRT (34 male, 25 female, mean age 63.3 years). Forty-seven patients were treated with HCSRT alone (15 male, 32 female, mean age 64.9 years). In patients followed radiologically, 28% treated with resection + WBRT showed a local recurrence after a median time of 8.0 months, whereas there was a lack of local control in 16% in the HCSRT group after a median time of 3.0 months. There was a significantly longer survival time for patients treated with resection + WBRT (median 7.9, mean 12.9 months) compared to HCSRT (median 5.0, mean 7.6 months). Even in patients with a tumour volume <10 cc, there was a significantly longer survival in favour of resection + WBRT (median 8.4, mean 17.4 months) compared to HCSRT (median 5.0, mean 7.9 months). This retrospective and non-randomised study indicates that surgical resection in combination with WBRT may be an option even for small brain metastases suitable for treatment with HCSRT. Since survival and local control following resection + WBRT was at least as favourable as compared to HCSRT alone, tumour location and expected neurological outcome may be the strongest aspect when selecting treatment modality.

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases.

PubMed

Loriot, Y; Pagliaro, L; Fléchon, A; Mardiak, J; Geoffrois, L; Kerbrat, P; Chevreau, C; Delva, R; Rolland, F; Theodore, C; Roubaud, G; Gravis, G; Eymard, J C; Malhaire, J P; Linassier, C; Habibian, M; Martin, A L; Journeau, F; Reckova, M; Logothetis, C; Laplanche, A; Le Teuff, G; Culine, S; Fizazi, K

2017-12-01

The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lost in laterality: interpreting ''preferred side of the head during mobile phone use and risk of brain tumour'' associations.

PubMed

Schüz, Joachim

2009-08-01

Due to the highly localized exposure from mobile phones, the preferred side of the head during their use is important information when investigating a possible link with brain tumour risk, but at the same time, error and bias hamper the assessment of this information in case-control studies. Current studies provide evidence of reporting bias insofar as cases appear to over-report the side of the head where the tumour occurred as the one that they preferred in the past when using mobile phones. More refined methods of analysis among only cases or prospective studies with an assessment of the laterality of mobile phone use before the diagnosis of disease are needed to evaluate whether associations seen in some studies are entirely due to reporting bias or a mixture of reporting bias and a causal effect.

Multimodality imaging and mathematical modelling of drug delivery to glioblastomas.

PubMed

Boujelben, Ahmed; Watson, Michael; McDougall, Steven; Yen, Yi-Fen; Gerstner, Elizabeth R; Catana, Ciprian; Deisboeck, Thomas; Batchelor, Tracy T; Boas, David; Rosen, Bruce; Kalpathy-Cramer, Jayashree; Chaplain, Mark A J

2016-10-06

Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization, and they typically exhibit a disrupted blood-brain barrier (BBB). Although it has been hypothesized that the 'normalization' of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of BBB integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper, we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated-flow rate, vessel permeability and tissue diffusion coefficient-interact nonlinearly to produce the observed average drug concentration in the microenvironment.

High grade glioma mimicking voltage gated potassium channel complex associated antibody limbic encephalitis.

PubMed

Athauda, Dilan; Delamont, R S; Pablo-Fernandez, E De

2014-01-01

Though raised titres of voltage gated potassium channel (VGKC) complex antibodies have been occasionally associated with extracranial tumours, mainly presenting as Morvan's Syndrome or neuromyotonia, they have not yet been reported to be associated with an intracranial malignancy. This is especially important as misdiagnosis of these conditions and delay of the appropriate treatment can have important prognostic implications. We describe a patient with a high grade glioma presenting with clinical, radiological, and serological features consistent with the diagnosis of VGKC antibody associated limbic encephalitis (LE). This is the first association between a primary brain tumour and high titre of VGKC complex antibodies. Clinicoradiological progression despite effective immunosuppressive treatment should prompt clinicians to look for alternative diagnoses. Further studies to elucidate a possible association between VGKC complex and other surface antigen antibodies with primary brain tumours should be carried out.

Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours

PubMed Central

Messal, Hendrik A.; Andersson, Agneta B.; Ruiz, E. Josue; Gerling, Marco; Douagi, Iyadh; Spencer-Dene, Bradley; Musch, Alexandra; Mitter, Richard; Bhaw, Leena; Stone, Richard; Bornhorst, Dorothee; Sesay, Abdul K.; Jonkers, Jos; Stamp, Gordon; Malanchi, Ilaria; Toftgård, Rune; Behrens, Axel

2018-01-01

The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. Here we show that Lgr6 marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lineage tracing analysis showed that Lgr6+ cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. In pregnancy or upon stimulation with ovarian hormones, adult Lgr6+ cells regained proliferative potency and their progeny formed alveoli over repeated pregnancies. Oncogenic mutations in Lgr6+ cells resulted in expansion of luminal cells, culminating in mammary gland tumours. Conversely, depletion of Lgr6+ cells in the MMTV-PyMT model of mammary tumourigenesis significantly impaired tumour growth. Thus, Lgr6 marks mammary gland progenitor cells that can initiate tumours, and cells of luminal breast tumours required for efficient tumour maintenance. PMID:27798604

Retinoblastoma and optic nerve enhancement in a brain magnetic resonance scan: is it always a metastasis?

PubMed

Correa-Acosta, A; González-Alviar, M E; Gaviria-Bravo, M L

2018-05-01

The case is presented on a girl with a unilateral retinoblastoma that required treatment with intra-arterial chemotherapy. In the nuclear magnetic resonance imaging of the brain performed 1 month after intra-arterial chemotherapy treatment, post-laminar optic nerve (ON) enhancement was observed, leading to the suspicion of an ON tumour infiltration. Additional examinations were requested by which a probable optic neuropathy was diagnosed. The ON enhancement in magnetic resonance imaging of the brain in retinoblastoma generally corresponds to tumour invasion of the ON. However, other diagnostic alternatives associated with the use of new treatments, such as intra-arterial chemotherapy, should be considered. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study

NASA Astrophysics Data System (ADS)

Wenger, Cornelia; Salvador, Ricardo; Basser, Peter J.; Miranda, Pedro C.

2015-09-01

Tumor treating fields (TTFields) are a non-invasive, anti-mitotic and approved treatment for recurrent glioblastoma multiforme (GBM) patients. In vitro studies have shown that inhibition of cell division in glioma is achieved when the applied alternating electric field has a frequency in the range of 200 kHz and an amplitude of 1-3 V cm-1. Our aim is to calculate the electric field distribution in the brain during TTFields therapy and to investigate the dependence of these predictions on the heterogeneous, anisotropic dielectric properties used in the computational model. A realistic head model was developed by segmenting MR images and by incorporating anisotropic conductivity values for the brain tissues. The finite element method (FEM) was used to solve for the electric potential within a volume mesh that consisted of the head tissues, a virtual lesion with an active tumour shell surrounding a necrotic core, and the transducer arrays. The induced electric field distribution is highly non-uniform. Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less. A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature. Comparing results to a previously developed head model suggests significant inter-subject variability. This modelling study predicts that during treatment with TTFields the electric field in the tumour exceeds 1 V cm-1, independent of modelling assumptions. In the future, computational models may be useful to optimize delivery of TTFields.

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study.

PubMed

Wenger, Cornelia; Salvador, Ricardo; Basser, Peter J; Miranda, Pedro C

2015-09-21

Tumor treating fields (TTFields) are a non-invasive, anti-mitotic and approved treatment for recurrent glioblastoma multiforme (GBM) patients. In vitro studies have shown that inhibition of cell division in glioma is achieved when the applied alternating electric field has a frequency in the range of 200 kHz and an amplitude of 1-3 V cm(-1). Our aim is to calculate the electric field distribution in the brain during TTFields therapy and to investigate the dependence of these predictions on the heterogeneous, anisotropic dielectric properties used in the computational model. A realistic head model was developed by segmenting MR images and by incorporating anisotropic conductivity values for the brain tissues. The finite element method (FEM) was used to solve for the electric potential within a volume mesh that consisted of the head tissues, a virtual lesion with an active tumour shell surrounding a necrotic core, and the transducer arrays. The induced electric field distribution is highly non-uniform. Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less. A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature. Comparing results to a previously developed head model suggests significant inter-subject variability. This modelling study predicts that during treatment with TTFields the electric field in the tumour exceeds 1 V cm(-1), independent of modelling assumptions. In the future, computational models may be useful to optimize delivery of TTFields.

Occupational risk factors for low grade and high grade glioma: results from an international case control study of adult brain tumours.

PubMed

Schlehofer, Brigitte; Hettinger, Iris; Ryan, Philip; Blettner, Maria; Preston-Martin, Susan; Little, Julian; Arslan, Annie; Ahlbom, Anders; Giles, Graham G; Howe, Geoffrey R; Ménégoz, Francoise; Rodvall, Ylva; Choi, Won N; Wahrendorf, Jürgen

2005-01-01

The majority of suspected occupational risk factors for adult brain tumours have yet to be confirmed as etiologically relevant. Within an international case-control study on brain tumours, lifelong occupational histories and information on exposures to specific substances were obtained by direct interviews to further investigate occupational risk factors for glioma. This is one of the largest studies of brain tumours in adults, including 1,178 cases and 1987 population controls from 8 collaborating study centres matched for age, gender and centre. All occupational information, was aggregated into 16 occupational categories. In a pooled analysis, odds ratios (OR), adjusted for education, were estimated separately for men and women and for high-grade glioma (HGG) and low-grade glioma (LGG), focusing especially on 6 categories defined a priori: agricultural, chemical, construction, metal, electrical/electronic and transport. For men, an elevated OR of glioma associated with the category "metal" (OR = 1.24, 95% CI 0.96-1.62) was seen, which appeared to be largely accounted for by LGG (OR = 1.59, 95% CI 1.00-2.52). For the other 5 occupational categories, no elevated risks for glioma were observed. For women the only noteworthy observation for the 6 a priori categories was an inverse association with the "agriculture" category (OR = 0.60, 95% CI 0.36-0.99). Apart from the 6 major categories, women working in food production or food processing (category "food") showed an increased OR of 1.95 (95% CI 1.04-3.68). None of the 20 substance groups was positively associated with glioma risk. Although some other point estimates were elevated, they lacked statistical significance. The results do not provide evidence of a strong association between occupational exposures and glioma development.

A machine learning approach for real-time modelling of tissue deformation in image-guided neurosurgery.

PubMed

Tonutti, Michele; Gras, Gauthier; Yang, Guang-Zhong

2017-07-01

Accurate reconstruction and visualisation of soft tissue deformation in real time is crucial in image-guided surgery, particularly in augmented reality (AR) applications. Current deformation models are characterised by a trade-off between accuracy and computational speed. We propose an approach to derive a patient-specific deformation model for brain pathologies by combining the results of pre-computed finite element method (FEM) simulations with machine learning algorithms. The models can be computed instantaneously and offer an accuracy comparable to FEM models. A brain tumour is used as the subject of the deformation model. Load-driven FEM simulations are performed on a tetrahedral brain mesh afflicted by a tumour. Forces of varying magnitudes, positions, and inclination angles are applied onto the brain's surface. Two machine learning algorithms-artificial neural networks (ANNs) and support vector regression (SVR)-are employed to derive a model that can predict the resulting deformation for each node in the tumour's mesh. The tumour deformation can be predicted in real time given relevant information about the geometry of the anatomy and the load, all of which can be measured instantly during a surgical operation. The models can predict the position of the nodes with errors below 0.3mm, beyond the general threshold of surgical accuracy and suitable for high fidelity AR systems. The SVR models perform better than the ANN's, with positional errors for SVR models reaching under 0.2mm. The results represent an improvement over existing deformation models for real time applications, providing smaller errors and high patient-specificity. The proposed approach addresses the current needs of image-guided surgical systems and has the potential to be employed to model the deformation of any type of soft tissue. Copyright © 2017 Elsevier B.V. All rights reserved.

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study

PubMed Central

Wenger, Cornelia; Salvador, Ricardo; Basser, Peter J; Miranda, Pedro C

2015-01-01

Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic and approved treatment for recurrent glioblastoma multiforme (GBM) patients. In vitro studies have shown that inhibition of cell division in glioma is achieved when the applied alternating electric field has a frequency in the range of 200 kHz and an amplitude of 1 - 3 V/cm. Our aim is to calculate the electric field distribution in the brain during TTFields therapy and to investigate the dependence of these predictions on the heterogeneous, anisotropic dielectric properties used in the computational model. A realistic head model was developed by segmenting MR images and by incorporating anisotropic conductivity values for the brain tissues. The finite element method (FEM) was used to solve for the electric potential within a volume mesh that consisted of the head tissues, a virtual lesion with an active tumour shell surrounding a necrotic core, and the transducer arrays. The induced electric field distribution is highly non-uniform. Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less. A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature. Comparing results to a previously developed head model suggests significant inter-subject variability. This modelling study predicts that during treatment with TTFields the electric field in the tumour exceeds 1 V/cm, independent of modelling assumptions. In the future, computational models may be useful to optimize delivery of TTFields. PMID:26350296

[The radiobiologycal approaches of the individual prognosis of the radiotherapy efficacy of the tumor deseases].

PubMed

Pelevina, I I; Dar'ialova, S L; Sergeeva, N S; Saenko, A S

2005-01-01

The results of several years standing investigations about the develop of the way to the individual prognosis of tumour sensitivity to radiotherapy are brought. The initial level of proliferative activity of different tumour types of individual patients--carcinoma of oropharingeal zone, stomach, oesophagys, rectum, glioblastoma have been studied. It was shown that for the several tumours the high initial level of proliferative activity is the indication of good prognosis. For the all tumours studied the significant decreasing of proliferative activity in the beginning of the radiation treatment is the good prognostic factor of tumour regression (decreasing of volume on 70-100%) or the strong damages of tumour tissue (III-IV grade of patomorphosis). The data of literature of last years are discussed and the proposal is that for the determination of prognostic factors the multiparameter analysis is need.

R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine.

PubMed

Han, Teng; Schatoff, Emma M; Murphy, Charles; Zafra, Maria Paz; Wilkinson, John E; Elemento, Olivier; Dow, Lukas E

2017-07-11

Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.

Use of mobile phones and risk of brain tumours: update of Danish cohort study.

PubMed

Frei, Patrizia; Poulsen, Aslak H; Johansen, Christoffer; Olsen, Jørgen H; Steding-Jessen, Marianne; Schüz, Joachim

2011-10-19

To investigate the risk of tumours in the central nervous system among Danish mobile phone subscribers. Nationwide cohort study. Denmark. All Danes aged ≥ 30 and born in Denmark after 1925, subdivided into subscribers and non-subscribers of mobile phones before 1995. Risk of tumours of the central nervous system, identified from the complete Danish Cancer Register. Sex specific incidence rate ratios estimated with log linear Poisson regression models adjusted for age, calendar period, education, and disposable income. 358,403 subscription holders accrued 3.8 million person years. In the follow-up period 1990-2007, there were 10,729 cases of tumours of the central nervous system. The risk of such tumours was close to unity for both men and women. When restricted to individuals with the longest mobile phone use--that is, ≥ 13 years of subscription--the incidence rate ratio was 1.03 (95% confidence interval 0.83 to 1.27) in men and 0.91 (0.41 to 2.04) in women. Among those with subscriptions of ≥ 10 years, ratios were 1.04 (0.85 to 1.26) in men and 1.04 (0.56 to 1.95) in women for glioma and 0.90 (0.57 to 1.42) in men and 0.93 (0.46 to 1.87) in women for meningioma. There was no indication of dose-response relation either by years since first subscription for a mobile phone or by anatomical location of the tumour--that is, in regions of the brain closest to where the handset is usually held to the head. In this update of a large nationwide cohort study of mobile phone use, there were no increased risks of tumours of the central nervous system, providing little evidence for a causal association.

Target volume geometric change and/or deviation from the cranium during fractionated stereotactic radiotherapy for brain metastases: potential pitfalls in image guidance based on bony anatomy alignment.

PubMed

Ohtakara, Kazuhiro; Hoshi, Hiroaki

2014-12-01

This study sought to evaluate the potential geometrical change and/or displacement of the target relative to the cranium during fractionated stereotactic radiotherapy (FSRT) for treating newly developed brain metastases. For 16 patients with 21 lesions treated with image-guided frameless FSRT in 5 or 10 fractions using a 6-degree-of-freedom image guidance system-integrated platform, the unenhanced computed tomography or T2-weighted magnetic resonance images acquired until the completion of FSRT were fused to the planning image datasets for comparison. Significant change was defined as ≥3-mm change in the tumour diameter or displacement of the tumour centroid. FSRT was started 1 day after planning image acquisition. Tumour shrinkage, deviation and both were observed in 2, 1 and 1 of the 21 lesions, respectively, over a period of 7-13 days. Tumour shrinkage or deviation resulted in an increase or decrease in the marginal dose to the tumour, respectively, and a substantial increase in the irradiated volume for the surrounding tissue irrespective of the pattern of alteration. No obvious differences in the clinical and treatment characteristics were noted among the populations with or without significant changes in tumour volume or position. Target deformity and/or deviation can unexpectedly occur even during relatively short-course FSRT, inevitably leading to a gradual discrepancy between the planned and actually delivered doses to the tumour and surrounding tissue. To appropriately weigh the treatment outcome against the planned dose distribution, target deformity and/or deviation should also be considered in addition to the immobilisation accuracy, as image guidance with bony anatomy alignment does not necessarily guarantee accurate target localisation until completion of FSRT. © 2014 The Royal Australian and New Zealand College of Radiologists.

Inhibition of formyl peptide receptor in high-grade astrocytoma by CHemotaxis Inhibitory Protein of S. aureus

PubMed Central

Boer, J C; Domanska, U M; Timmer-Bosscha, H; Boer, I G J; de Haas, C J C; Joseph, J V; Kruyt, F A E; de Vries, E G E; den Dunnen, W F A; van Strijp, J A G; Walenkamp, A M E

2013-01-01

Background: High-grade astrocytomas are malignant brain tumours that infiltrate the surrounding brain tissue and have a poor prognosis. Activation of formyl peptide receptor (FPR1) on the human astrocytoma cell line U87 promotes cell motility, growth and angiogenesis. We therefore investigated the FPR1 inhibitor, Chemotaxis Inhibitory Protein of S. aureus (CHIPS), as a potential anti-astrocytoma drug. Methods and results: FPR1 expression was studied immunohistochemically in astrocytomas WHO grades I–IV. With intracellular calcium mobilisation and migration assays, human ligands were tested for their ability to activate FPR1 on U87 cells and on a cell line derived from primary astrocytoma grade IV patient material. Thereafter, we selectively inhibited these ligand-induced responses of FPR1 with an anti-inflammatory compound called Chemotaxis Inhibitory Protein of S. aureus (CHIPS). U87 xenografts in NOD-SCID mice served to investigate the effects of CHIPS in vivo. FPR1 was expressed in 29 out of 32 (90%) of all grades of astrocytomas. Two human mitochondrial-derived formylated peptides, formyl-methionil-leucine-lysine-isoleucine-valine (fMLKLIV) and formyl-methionil-methionil-tyrosine-alanine-leucine-phenylalanine (fMMYALF), were potent activators of FPR1 on tumour cells. Ligand-induced responses of FPR1-expressing tumour cells could be inhibited with FPR1 inhibitor CHIPS. Treatment of tumour-bearing mice with CHIPS slightly reduced tumour growth and improved survival as compared to non-treated animals (P=0.0019). Conclusion: Targeting FPR1 with CHIPS reduces cell motility and tumour cell activation, and prolongs the survival of tumour-bearing mice. This strategy could be explored in future research to improve treatment results for astrocytoma patients. PMID:23322202

P12.105-ALA GUIDED REMOVAL AND COMBINED TREATMENT IN MALIGNANT GLIOMA

PubMed Central

Oppido, P.A.; Carapella, C.M.; Pompili, A.; Vidiri, A.; Pace, A.; Villani, V.

2014-01-01

INTRODUCTION: Malignant gliomas are the most unfavourable brain tumours. Recent evidence suggests that extensive tumour removal is associated with better survival. The current treatment is complete as possible resection of the contrast-enhancing tumour tissue, followed by adjuvant treatment with radiotherapy and chemotherapy. As it appears difficult to distinguish between infiltration tumour and normal tissue, specially in recurrent tumours, the radical removal becomes harmful. Techniques to visualize the borderline tumour intraoperatively are helpful. More recently, fluorescence guidance has taken advantage of intrinsic metabolic and structural changes that occur within malignant glioma by exploiting the eme biosynthetic pathway and a natural biochemical in that pathway, 5-aminolevulinic acid (5-ALA). METHODS: Since the end of 2009, in our Institute 54 patients were operated on using fluorescence guided tumour resection. Preoperatively, all enrolled patients had MRI showing contrast enhancing lesions. MRI within 72 hours after surgery and thereafter at 3-month interval was performed. 32 patients were newly diagnosed tumour, 22 were recurrent malignant glioma. An oral dose of 20 mg 5-ALA /kg body weight was administered to each patient. By a NC4 OPMI Pentero operating microscope (Zeiss), enabled switching from xenon light to violet-blue light for visualizing fluorescence, the surgical resection was performed. Histology was in 48 glioblastoma (1 gliosarcoma), in 4 anaplastic oligodendroglioma, in 1 oligodendroglioma I WHO and in 1 pleomorphic xanthoastrocytoma. All the patients, as first line treatment, were submitted to radiotherapy and chemotherapy; in recurrent tumours second and in some cases third line treatments were administered. The follow-up ranged from 2 years to 8 months. RESULTS: In all cases the yellow fluorescence due to 5-ALA in cortical vessels was seen. In 47 glioblastoma, 4 anaplastic oligodendroglioma and 1 xanthoastrocytoma the tumour tissue showed intraoperative red fluorescence. Specially in recurrent tumours, the fluorescence-guided surgery was helpful to identify, inside the gliotic tissue, some areas with active tumour from perilesional “healthy” brain. Furthermore, after surgery no relevant neurological deficit caused by 5-ALA guided resection were observed. Early postoperative MRI confirmed gross total resection without contrast enhancment in 80 % of patients. At the follow-up 24 patients are still alive. CONCLUSIONS: The 5-ALA was helpful to localize the tumour on the cortex and extended resection of infiltrating tumour, specially in recurrence. Patients affected by glioblastoma are elctive for this technique. Extended resections by 5-ALA fluorescence guide does not impair neurological functions and can impact on the overall survival of patients affected by malignant glioma.

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

PubMed Central

Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

2012-01-01

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes.

PubMed

Tseng, Yuan-Yun; Su, Chen-Hsing; Yang, Shun-Tai; Huang, Yin-Chen; Lee, Wei-Hwa; Wang, Yi-Chuan; Liu, Shou-Cheng; Liu, Shih-Jung

2016-09-13

Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.

Genotyping tumour DNA in cerebrospinal fluid and plasma of a HER2-positive breast cancer patient with brain metastases

PubMed Central

Siravegna, Giulia; Geuna, Elena; Mussolin, Benedetta; Crisafulli, Giovanni; Bartolini, Alice; Galizia, Danilo; Casorzo, Laura; Sarotto, Ivana; Scaltriti, Maurizio; Sapino, Anna; Bardelli, Alberto; Montemurro, Filippo

2017-01-01

Background Central nervous system (CNS) involvement contributes to significant morbidity and mortality in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) and represents a major challenge for clinicians. Liquid biopsy of cerebrospinal fluid (CSF)-derived circulating tumour DNA (ctDNA) harbours clinically relevant genomic alterations in patients with CNS metastases and could be effective in tracking tumour evolution. Methods In a HER2-positive mBC patient with brain metastases, we applied droplet digital PCR (ddPCR) and next-generation whole exome sequencing (WES) analysis to measure ctDNA dynamic changes in CSF and plasma collected during treatment. Results Baseline CSF-derived ctDNA analysis revealed TP53 and PIK3CA mutations as well as ERBB2 and cMYC amplification. Post-treatment ctDNA analysis showed decreased markers level in plasma, consistent with extra-CNS disease control, while increased in the CSF, confirming poor treatment benefit in the CNS. Discussion Analysis of ctDNA in the CSF of HER2-positive mBC is feasible and could represent a useful companion for clinical management of brain metastases. PMID:29067216

Brain-stem hemangioblastomas: The seemingly innocuous lesion in a perilous location.

PubMed

Joseph, Jeena; Behari, Sanjay; Gupta, Shruti; Bhaisora, Kamlesh Singh; Gandhi, Anish; Srivastava, Arun; Jaiswal, Awadhesh K

2018-01-01

Hemangioblastomas [75% sporadic, 25% with Von Hippel Lindau (VHL) disease] are highly vascular, benign lesions. The surgical nuances, management, and complication avoidance in brain-stem hemangioblastomas (BHs) have been studied. Over 18 years, 27(mean age: 29 years; range 15-60 years) consecutive cases of BH underwent microsurgical excision. All patients were assessed clinico-radiologically for neurological deficits and screened for VHL disease. Outcome of the patients was based on Karnofsky Performance Status scale (KPS). 12 out of 19 (70.4%) patients with hydrocephalus underwent a cerebrospinal fluid (CSF) diversion procedure. Lower cranial nerve palsy was present in 10 (37%) patients and motor weakness in 13 (48%). The tumours [mean size 3.34 ± 1.06 cm, range: 1.4-5.5 cm; 11 solid, rest solid-cystic; 18 (66.7%) subpial and 9 (33.33%) intramedullary] were divided into four categories based on size: A: <2 cm (n = 5,18.5%); B: 2-3 cm (n = 10,37%); C: 3-4 cm (n = 6,22.2%); D: >4 cm (n = 6,22.2%). Their location was at posterior cervicomedullary junction (n = 12); pontomedullary junction (n = 7); pons (n = 3), medulla (n = 3) and ponto-mesencephalic region (n = 2). Multiple flow voids were seen in >50% patients with tumour >2 cm. 5 patients had syringomyelia; and, 8 had diffuse cervical cord expansion. Two patients with a large vascular tumour underwent preoperative embolization. Six patients had VHL disease; one underwent bilateral adrenalectomy for refractory hypertension; and, the another, nephrectomy for renal cell carcinoma. Twenty-six patients underwent a midline suboccipital craniectomy; and, 1 with a cerebellopontine angle tumour, a retromastoid craniectomy. 15 patients underwent total excision; 10 patients, near-total (<10% remaining) excision, and 2 patients, a subtotal (>10% remaining)) excision. Three patients (2 with VHL disease) expired due to exsanguinating hemorrhage, spreading venous thrombosis and aspiration pneumonitis, respectively. At follow-up visit (median: 25 ± interquartile range 2-56months), 17 patients had improved KPS, 4 remained in same status and 3 (recently operated, on tracheostomy) had worsened KPS. Significant improvement is achievable in neurological status in patients following successful extirpation of a brain-stem hemangioblastoma, despite a turbulent perioperative period. Leaving tumour capsule adherent to the brain-stem often helps in preserving brain-stem function. Postoperatively, the patients should be monitored for their respiratory and lower cranial nerve status to prevent aspiration pneumonitis.

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo MRS.

PubMed

Candiota, A P; Majós, C; Julià-Sapé, M; Cabañas, M; Acebes, J J; Moreno-Torres, A; Griffiths, J R; Arús, C

2011-01-01

MRI and MRS are established methodologies for evaluating intracranial lesions. One MR spectral feature suggested for in vivo grading of astrocytic tumours is the apparent myo-lnositol (ml) intensity (ca 3.55 ppm) at short echo times, although glycine (gly) may also contribute in vivo to this resonance. The purpose of this study was to quantitatively evaluate the ml + gly contribution to the recorded spectral pattern in vivo and correlate it with in vitro data obtained from perchloric acid extraction of tumour biopsies. Patient spectra (n = 95) at 1.5T at short (20-31 ms) and long (135-136 ms) echo times were obtained from the INTERPRET MRS database (http://gabrmn.uab.eslinterpretvalidateddbl). Phantom spectra were acquired with a comparable protocol. Spectra were automatically processed and the ratios of the (ml + gly) to Cr peak heights ((ml + gly)/Cr) calculated. Perchloric acid extracts of brain tumour biopsies were analysed by high-resolution NMR at 9.4T. The ratio (ml + gly)/Cr decreased significantly with astrocytic grade in vivo between low-grade astrocytoma (A2) and glioblastoma multiforme (GBM). In vitro results displayed a somewhat different tendency, with anaplastic astrocytomas having significantly higher (ml + gly)/Cr than A2 and GBM. The discrepancy between in vivo and in vitro data suggests that the NMR visibility of glycine in glial brain tumours is restricted in vivo.

[Tumor-associated prognostic factors of the plasminogen activator family: determination and clinical value of u-PA, t-PA, PAI-1, and PAI-2].

PubMed

Mengele, K; Harbeck, N; Reuning, U; Magdolen, V; Schmitt, M

2005-08-01

Proteolytic factors belonging t the plasminogen activator family (plasmin, u-PA, t-PA, u-PAR, PAI-1, and PAI-2), which usually are involved in blood clotting and degradation of blood clots, are also present in healthy and diseased tissue of the kidney, lung, liver, gastro-intestinal tract, breast, prostate, ovary, and brain. These factors are engaged in brain development, angiogenesis and vascular invasion, wound healing as well as in placenta development and embryogenesis. Plasminogen activators u-PA and t-PA, their inhibitors PAI-1 and PAI-2, and the u-PA-receptor (u-PAR, CD87) are often elevated in solid malignant tumour tissues compared to their normal counterparts. In breast cancer patients, an elevated tumour tissue extract antigen content of u-PA, PAI-1, and u-PAR is associated with increased tumour aggressiveness and poor prognosis; in contrary, an elevated content of t-PA and PAI-2 indicates a favourable prognosis. For clinical relevant determination of these proteolytic factors in tumour tissue extracts, only enzymo-immunometric tests (ELISA) are recommended. Enzymometric and enzymographic tests are actually conducted only in an experimental, preclinical context.

Inter-hemispheric language functional reorganization in low-grade glioma patients after tumour surgery.

PubMed

Kristo, Gert; Raemaekers, Mathijs; Rutten, Geert-Jan; de Gelder, Beatrice; Ramsey, Nick F

2015-03-01

Despite many claims of functional reorganization following tumour surgery, empirical studies that investigate changes in functional activation patterns are rare. This study investigates whether functional recovery following surgical treatment in patients with a low-grade glioma in the left hemisphere is linked to inter-hemispheric reorganization. Based on literature, we hypothesized that reorganization would induce changes in the spatial pattern of activation specifically in tumour homologue brain areas in the healthy right hemisphere. An experimental group (EG) of 14 patients with a glioma in the left hemisphere near language related brain areas, and a control group of 6 patients with a glioma in the right, non-language dominant hemisphere were scanned before and after resection. In addition, an age and gender matched second control group of 18 healthy volunteers was scanned twice. A verb generation task was used to map language related areas and a novel technique was used for data analysis. Contrary to our hypothesis, we found that functional recovery following surgery of low-grade gliomas cannot be linked to functional reorganization in language homologue brain areas in the healthy, right hemisphere. Although elevated changes in the activation pattern were found in patients after surgery, these were largest in brain areas in proximity to the surgical resection, and were very similar to the spatial pattern of the brain shift following surgery. This suggests that the apparent perilesional functional reorganization is mostly caused by the brain shift as a consequence of surgery. Perilesional functional reorganization can however not be excluded. The study suggests that language recovery after transient post-surgical language deficits involves recovery of functioning of the presurgical language system. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mixed Glioma (Oligoastrocytoma) in the brain of an African Hedgehog (Atelerix albiventris).

PubMed

Benneter, S S; Summers, B A; Schulz-Schaeffer, W J; Härtig, W; Mollidor, J; Schöniger, S

2014-11-01

This report describes an oligoastrocytoma in the brain of a 3.5-year-old female pet African hedgehog (Atelerix albiventris) that showed progressive central nervous system signs for 6 months. Microscopical examination of the brain revealed a widely infiltrative, deep-seated glioma within the white matter of the cerebral hemispheres, basal nuclei, hippocampus, thalamus, midbrain, pons and the medulla of the cerebellum with extension of neoplastic cells into the cerebral cortex and overlying leptomeninges. Morphological features of the neoplastic cells, together with variable immunohistochemical expression of glial fibrillary acidic protein, Olig-2 and Nogo-A, indicated the presence of intermingled astrocytic and oligodendroglial tumour cells with an astrocytic component of approximately 40% consistent with an oligoastrocytoma. The distribution of the tumour is consistent with gliomatosis cerebri. Copyright © 2014 Elsevier Ltd. All rights reserved.

A case report of desmoid tumour-a forgotten aspect of FAP?

PubMed

Xuereb, Sarah; Xuereb, Rachel; Buhagiar, Chiara; Gauci, Jonathan; Magri, Claude

2017-01-01

Desmoid tumours are locally aggressive tumours which are common in Familial Adenomatous Polyposis (FAP). A 20-year old Familial Adenomatous Polyposis (FAP) patient presented with abdominal pain and distention. Abdominal imaging showed small bowel obstruction and hydronephrosis due to a pelvic mass. This mass showed significant enlargement on repeat imaging, and a diagnostic biopsy confirmed desmoid tumour. The mass was deemed unresectable and he was initially started on sulindac and raloxifene. Repeat imaging however showed further enlargement of the tumour, and therefore vinblastine+methotrexate chemotherapy was commenced, with a good response. FAP is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. Gardner's syndrome is also caused by a mutation in the APC gene, and is now considered a different phenotypic presentation of FAP. Desmoid tumours are initially kept under observation while their size remains stable. Treatment options for enlarging desmoids tumours include surgery (first-line), radiotherapy, and systemic therapy with non-cytotoxic and cytotoxic therapy. FAP patients should be examined regularly post-panprocotocolectomy, since desmoid tumours may arise. The presence of epidermal cysts in this FAP patient suggests a diagnosis of Gardner's syndrome. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Ultraviolet carcinogenesis in the hairless mouse skin. Influence of the sunscreen 2-ethylhexyl-p-methoxycinnamate.

PubMed

Gallagher, C H; Greenoak, G E; Reeve, V E; Canfield, P J; Baker, R S; Bonin, A M

1984-10-01

The mutagenicity of some samples of a commonly used sunscreen, 2-ethylhexyl-p-methoxycinnamate (2-EHMC), led to these studies of its potential carcinogenicity in the HRA/Skh hairless mouse. In a daily treatment regime, repeated for 9 weeks, groups of mice were painted on the dorsum with 2-EHMC, and were then exposed to low doses of one of two artificial ultraviolet (UV) light sources. Mice were also treated with UV alone and with 2-EHMC alone. The accumulated UV exposure alone produced tumours in 40-100% of mice. However, 2-EHMC-treated mice were protected. Subsequent treatment of the 2-EHMC-protected mice, and mice previously treated with 2-EHMC alone, with the tumour promoter, croton oil, produced tumours on a significant number of animals. We conclude that 2-EHMC protects from UV tumorigenesis in the absence of a tumour promoter. However, although tumours appeared on only 4 out of 160 2-EHMC-treated mice exposed to UV, the carcinogenic process had been initiated in others, as application of the tumour promoter, croton oil, produced tumours. Statistical analysis of the incidence of promoted tumours inferred that prior irradiation with UV may not have been implicated. Therefore, 2-EHMC itself may initiate tumours in this strain of hairless mouse.

Cerebral Metastases of Lung Cancer Mimicking Multiple Ischaemic Lesions - A Case Report and Review of Literature.

PubMed

Zacharzewska-Gondek, Anna; Maksymowicz, Hanna; Szymczyk, Małgorzata; Sąsiadek, Marek; Bladowska, Joanna

2017-01-01

Restricted diffusion that is found on magnetic resonance diffusion-weighted imaging (DWI) typically indicates acute ischaemic stroke. However, restricted diffusion can also occur in other diseases, like metastatic brain tumours, which we describe in this case report. A 57-year-old male, with a diagnosis of small-cell cancer of the right lung (microcellular anaplastic carcinoma), was admitted with focal neurological symptoms. Initial brain MRI revealed multiple, disseminated lesions that were hyperintense on T2-weighted images and did not enhance after contrast administration; notably, some lesions manifested restricted diffusion on DWI images. Based on these findings, disseminated ischaemic lesions were diagnosed. On follow-up MRI that was performed after 2 weeks, we observed enlargement of the lesions; there were multiple, disseminated, sharply outlined, contrast-enhancing, oval foci with persistent restriction of diffusion. We diagnosed the lesions as disseminated brain metastases due to lung cancer. To our knowledge, this is the first description of a patient with brain metastases that were characterised by restricted diffusion and no contrast enhancement. Multiple, disseminated brain lesions, that are characterised by restricted diffusion on DWI, typically indicate acute or hyperacute ischemic infarcts; however, they can also be due to hypercellular metastases, even if no contrast enhancement is observed. This latter possibility should be considered particularly in patients with cancer.

Isolating dividing neural and brain tumour cells for gene expression profiling.

PubMed

Endaya, Berwini; Cavanagh, Brenton; Alowaidi, Faisal; Walker, Tom; de Pennington, Nicholas; Ng, Jin-Ming A; Lam, Paula Y P; Mackay-Sim, Alan; Neuzil, Jiri; Meedeniya, Adrian C B

2016-01-15

The characterisation of dividing brain cells is fundamental for studies ranging from developmental and stem cell biology, to brain cancers. Whilst there is extensive anatomical data on these dividing cells, limited gene transcription data is available due to technical constraints. We focally isolated dividing cells whilst conserving RNA, from culture, primary neural tissue and xenografted glioma tumours, using a thymidine analogue that enables gene transcription analysis. 5-ethynyl-2-deoxyuridine labels the replicating DNA of dividing cells. Once labelled, cultured cells and tissues were dissociated, fluorescently tagged with a revised click chemistry technique and the dividing cells isolated using fluorescence-assisted cell sorting. RNA was extracted and analysed using real time PCR. Proliferation and maturation related gene expression in neurogenic tissues was demonstrated in acutely and 3 day old labelled cells, respectively. An elevated expression of marker and pathway genes was demonstrated in the dividing cells of xenografted brain tumours, with the non-dividing cells showing relatively low levels of expression. BrdU "immune-labelling", the most frequently used protocol for detecting cell proliferation, causes complete denaturation of RNA, precluding gene transcription analysis. This EdU labelling technique, maintained cell integrity during dissociation, minimized copper exposure during labelling and used a cell isolation protocol that avoided cell lysis, thus conserving RNA. The technique conserves RNA, enabling the definition of cell proliferation-related changes in gene transcription of neural and pathological brain cells in cells harvested immediately after division, or following a period of maturation. Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical carcinogenesis in the nervous system. Preferential accumulation of O6-methylguanine in rat brain deoxyribonucleic acid during repetitive administration of N-methyl-N-nitrosourea.

PubMed Central

Margison, G P; Kleihues, P

1975-01-01

The alkylation of purine bases in DNA of several rat tissues was determined during weekly injections (10 mg/kg) of N-[3H]methyl-N-nitrosourea, a dose schedule known to selectively induce tumours of the nervous system. Each group of animals was killed 1 week after the final injection, and the DNA hydrolysates were analysed by chromatography on Sephadex G-10. After five weekly applications, O6-methylguanine had accumulated in brain DNA to an extent which greatly exceeded that in kidney, spleen and intestine. In the liver, the final O6-methylguanine concentration was less than 1% of that in brain. Between the first and the fifth injection, the O6-methylguanine/7-methylguanine ratio in cerebral DNA increased from 0.28 to 0.68. In addition, 3-methylguanine was found to accumulate in brain DNA whereas in the other organs no significant quantities of this base were detectable. The results are compatible with the hypothesis that O6-alkylation of guanine in DNA plays a major role in the induction of tumours by N-methyl-N-nitrosourea and related carcinogens. The kinetics of the increase of O6-methylguanine in cerebral DNA suggest that there is no major cell fraction in the brain which is capable of excising chemically methylated bases from DNA. This repair deficiency could be a determining factor in the selective induction of nervous-system tumours by N-methyl-N-nitrosourea and other neuro-oncogenic compounds. PMID:1200992

R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine

PubMed Central

Han, Teng; Schatoff, Emma M.; Murphy, Charles; Zafra, Maria Paz; Wilkinson, John E.; Elemento, Olivier; Dow, Lukas E.

2017-01-01

Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E–RSPO2 and PTPRK–RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers. PMID:28695896

Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma.

PubMed

Mario Gonzalez-Meljem, Jose; Haston, Scott; Carreno, Gabriela; Apps, John R; Pozzi, Sara; Stache, Christina; Kaushal, Grace; Virasami, Alex; Panousopoulos, Leonidas; Neda Mousavy-Gharavy, Seyedeh; Guerrero, Ana; Rashid, Mamunur; Jani, Nital; Goding, Colin R; Jacques, Thomas S; Adams, David J; Gil, Jesus; Andoniadou, Cynthia L; Martinez-Barbera, Juan Pedro

2017-11-28

Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2- cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.

The Clinical Significance of Occult Gastrointestinal Primary Tumours in Metastatic Cancer: A Population Retrospective Cohort Study.

PubMed

Hannouf, Malek B; Winquist, Eric; Mahmud, Salaheddin M; Brackstone, Muriel; Sarma, Sisira; Rodrigues, George; Rogan, Peter K; Hoch, Jeffrey S; Zaric, Gregory S

2018-01-01

The purpose of this study was to estimate the incidence of occult gastrointestinal (GI) primary tumours in patients with metastatic cancer of uncertain primary origin and evaluate their influence on treatments and overall survival (OS). We used population heath data from Manitoba, Canada to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients to have "occult" primary tumour if the primary was found at least 6 months after initial diagnosis. Otherwise, we considered primary tumours as "obvious." We used propensity-score methods to match each patient with occult GI tumour to four patients with obvious GI tumour on all known clinicopathologic features. We compared treatments and 2-year survival data between the two patient groups and assessed treatment effect on OS using Cox regression adjustment. Eighty-three patients had occult GI primary tumours, accounting for 17.6% of men and 14% of women with metastatic cancer of uncertain primary. A 1:4 matching created a matched group of 332 patients with obvious GI primary tumour. Occult cases compared to the matched group were less likely to receive surgical interventions and targeted biological therapy, and more likely to receive cytotoxic empiric chemotherapeutic agents. Having an occult GI tumour was associated with reduced OS and appeared to be a nonsignificant independent predictor of OS when adjusting for treatment differences. GI tumours are the most common occult primary tumours in men and the second most common in women. Patients with occult GI primary tumours are potentially being undertreated with available GI site-specific and targeted therapies.

CT fluoroscopy-guided renal tumour cutting needle biopsy: retrospective evaluation of diagnostic yield, safety, and risk factors for diagnostic failure.

PubMed

Iguchi, Toshihiro; Hiraki, Takao; Matsui, Yusuke; Fujiwara, Hiroyasu; Sakurai, Jun; Masaoka, Yoshihisa; Gobara, Hideo; Kanazawa, Susumu

2018-01-01

To evaluate retrospectively the diagnostic yield, safety, and risk factors for diagnostic failure of computed tomography (CT) fluoroscopy-guided renal tumour biopsy. Biopsies were performed for 208 tumours (mean diameter 2.3 cm; median diameter 2.1 cm; range 0.9-8.5 cm) in 199 patients. One hundred and ninety-nine tumours were ≤4 cm. All 208 initial procedures were divided into diagnostic success and failure groups. Multiple variables related to the patients, lesions, and procedures were assessed to determine the risk factors for diagnostic failure. After performing 208 initial and nine repeat biopsies, 180 malignancies and 15 benign tumours were pathologically diagnosed, whereas 13 were not diagnosed. In 117 procedures, 118 Grade I and one Grade IIIa adverse events (AEs) occurred. Neither Grade ≥IIIb AEs nor tumour seeding were observed within a median follow-up period of 13.7 months. Logistic regression analysis revealed only small tumour size (≤1.5 cm; odds ratio 3.750; 95% confidence interval 1.362-10.326; P = 0.011) to be a significant risk factor for diagnostic failure. CT fluoroscopy-guided renal tumour biopsy is a safe procedure with a high diagnostic yield. A small tumour size (≤1.5 cm) is a significant risk factor for diagnostic failure. • CT fluoroscopy-guided renal tumour biopsy has a high diagnostic yield. • CT fluoroscopy-guided renal tumour biopsy is safe. • Small tumour size (≤1.5 cm) is a risk factor for diagnostic failure.

Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis

PubMed Central

Zhou, Chengcheng; Yang, Zixiao; Yao, Zhengwei; Yin, Bo; Pan, Jiawei; Yu, Yang; Zhu, Wei; Mao, Ying

2016-01-01

Objective: Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). Methods: 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS® (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. Results: The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 ± 21.9, 18.45 ± 17.28 and 11.40 ± 5.63 ml, respectively. The corresponding Voedema were 44.08 ± 25.84, 73.20 ± 40.35 and 23.74 ± 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p-value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. Conclusion: Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. Advances in knowledge: This study presents a new method for the quantitation of PTO to differentiate bMET from GBM. PMID:27119727

Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis.

PubMed

Zhou, Chengcheng; Yang, Zixiao; Yao, Zhengwei; Yin, Bo; Pan, Jiawei; Yu, Yang; Zhu, Wei; Hua, Wei; Mao, Ying

2016-07-01

Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS(®) (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 ± 21.9, 18.45 ± 17.28 and 11.40 ± 5.63 ml, respectively. The corresponding Voedema were 44.08 ± 25.84, 73.20 ± 40.35 and 23.74 ± 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p-value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. This study presents a new method for the quantitation of PTO to differentiate bMET from GBM.

Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.

PubMed

Fisusi, Funmilola A; Siew, Adeline; Chooi, Kar Wai; Okubanjo, Omotunde; Garrett, Natalie; Lalatsa, Katerina; Serrano, Dolores; Summers, Ian; Moger, Julian; Stapleton, Paul; Satchi-Fainaro, Ronit; Schätzlein, Andreas G; Uchegbu, Ijeoma F

2016-05-01

The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression. Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg(-1)) or ethanolic lomustine (6.5 mg kg(-1)) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg(-1)) or ethanolic lomustine (daily 1.2 mg kg(-1) - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated. The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes. Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.

Multi-scale spectrally resolved quantitative fluorescence imaging system: towards neurosurgical guidance in glioma resection

NASA Astrophysics Data System (ADS)

Xie, Yijing; Thom, Maria; Miserocchi, Anna; McEvoy, Andrew W.; Desjardins, Adrien; Ourselin, Sebastien; Vercauteren, Tom

2017-02-01

In glioma resection surgery, the detection of tumour is often guided by using intraoperative fluorescence imaging notably with 5-ALA-PpIX, providing fluorescent contrast between normal brain tissue and the gliomas tissue to achieve improved tumour delineation and prolonged patient survival compared with the conventional white-light guided resection. However, the commercially available fluorescence imaging system relies on surgeon's eyes to visualise and distinguish the fluorescence signals, which unfortunately makes the resection subjective. In this study, we developed a novel multi-scale spectrally-resolved fluorescence imaging system and a computational model for quantification of PpIX concentration. The system consisted of a wide-field spectrally-resolved quantitative imaging device and a fluorescence endomicroscopic imaging system enabling optical biopsy. Ex vivo animal tissue experiments as well as human tumour sample studies demonstrated that the system was capable of specifically detecting the PpIX fluorescent signal and estimate the true concentration of PpIX in brain specimen.

When does a strategy intervention overcome a failure of inhibition? Evidence from two left frontal brain tumour cases.

PubMed

Robinson, Gail A; Walker, David G; Biggs, Vivien; Shallice, Tim

2016-06-01

Initiation and inhibition of responses are crucial for appropriate behaviour across different settings. Initiation and inhibition difficulties are well documented following frontal damage, although task differences have limited our understanding. The Hayling Sentence Completion Test was designed to assess verbal initiation and inhibition within the same task. This study investigates the ability of two patients with left frontal tumours (KI: high grade glioma; PM: meningioma) to use a strategy to overcome profound suppression failures on the Hayling Test. KI and PM completed the Hayling Test and two experimental tasks. The Selection Investigation assessed verbal initiation on a sentence completion task that varied selection demands (high/low). The Suppression and Strategy Investigation assessed ability to implement four strategies aimed to override a suppression failure and facilitate production of an unconnected word. On the Hayling Test, KI and PM initiated responses to complete high constraint sentences, in contrast to impaired suppression. KI benefitted minimally from strategies to overcome suppression failure although one strategy (object naming) was partially successful. KI's errors revealed fast suppression errors, in contrast to slow no responses, and selection ability was also impaired for verbal initiation. PM, however, implemented each strategy 100% to overcome a suppression failure and had no difficulty completing sentences meaningfully, regardless of selection demands. This first investigation of strategy implementation to overcome profound suppression impairments provides insights into verbal initiation, inhibition, selection and strategy mechanisms, which has implications for neurorehabilitation. Specifically, both patients had profound inhibition deficits but KI also presented with a selection deficit and was unable to implement a strategy. By contrast, PM's selection ability was intact but she was unable to generate, rather than implement, a strategy. We suggest that KI has both fast, uncontrolled semantic output and response inhibition difficulty, whereas PM's difficulty is underpinned by motivational factors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Contemporary management of low--grade glioma: a paradigm shift in neuro-oncology.

PubMed

Hayhurst, Caroline

2017-06-01

Supratentorial diffuse intrinsic low-grade gliomas represent a distinct but heterogenous group of tumours, with the propensity to grow and to differentiate into malignant tumours. They have been historically viewed in the 'benign' spectrum of intrinsic brain tumours, so a watch-and-wait policy was often adopted. With recent advances in our understanding of the natural history of these tumours, combined with advances in surgical technique, an aggressive approach is now recommended. Increasing quality evidence of the impact of tumour resection and multicentre trials of adjuvant radiotherapy and chemotherapy have led to a new algorithm for low-grade glioma management. This review aims to outline the emerging evidence that has shifted neuro-oncology practice. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Mobile phones and head tumours: it is time to read and highlight data in a proper way].

PubMed

Levis, Angelo G; Minicucci, Nadia; Ricci, Paolo; Gennaro, Valerio; Garbisa, Spiridione

2011-01-01

The uncertainty about the relationship between the use of mobile phones (MPs: analogue and digital cellulars, and cordless) and the increase of head tumour risk can be solved by a critical analysis of the methodological elements of both the positive and the negative studies. Results by Hardell indicate a cause/effect relationship: exposures for or latencies from ≥ 10 years to MPs increase by up to 100% the risk of tumour on the same side of the head preferred for phone use (ipsilateral tumours) - which is the only one significantly irradiated - with statistical significance for brain gliomas, meningiomas and acoustic neuromas. On the contrary, studies published under the Interphone project and others produced negative results and are characterised by the substantial underestimation of the risk of tumour. However, also in the Interphone studies a clear and statistically significant increase of ipsilateral head tumours (gliomas, neuromas and parotid gland tumours) is quite common in people having used MPs since or for ≥ 10 years. And also the metaanalyses by Hardell and other Authors, including only the literature data on ipsilateral tumours in people having used MPs since or for ≥ 10 years - and so also part of the Interphone data - still show statistically significant increases of head tumours.

Functional Magnetic Resonance Imaging for Preoperative Planning in Brain Tumour Surgery.

PubMed

Lau, Jonathan C; Kosteniuk, Suzanne E; Bihari, Frank; Megyesi, Joseph F

2017-01-01

Functional magnetic resonance imaging (fMRI) is being increasingly used for the preoperative evaluation of patients with brain tumours. The study is a retrospective chart review investigating the use of clinical fMRI from 2002 through 2013 in the preoperative evaluation of brain tumour patients. Baseline demographic and clinical data were collected. The specific fMRI protocols used for each patient were recorded. Sixty patients were identified over the 12-year period. The tumour types most commonly investigated were high-grade glioma (World Health Organization grade III or IV), low-grade glioma (World Health Organization grade II), and meningioma. Most common presenting symptoms were seizures (69.6%), language deficits (23.2%), and headache (19.6%). There was a predominance of left hemispheric lesions investigated with fMRI (76.8% vs 23.2% for right). The most commonly involved lobes were frontal (64.3%), temporal (33.9%), parietal (21.4%), and insular (7.1%). The most common fMRI paradigms were language (83.9%), motor (75.0%), sensory (16.1%), and memory (10.7%). The majority of patients ultimately underwent a craniotomy (75.0%), whereas smaller groups underwent stereotactic biopsy (8.9%) and nonsurgical management (16.1%). Time from request for fMRI to actual fMRI acquisition was 3.1±2.3 weeks. Time from fMRI acquisition to intervention was 4.9±5.5 weeks. We have characterized patient demographics in a retrospective single-surgeon cohort undergoing preoperative clinical fMRI at a Canadian centre. Our experience suggests an acceptable wait time from scan request to scan completion/analysis and from scan to intervention.

Multicentre imaging measurements for oncology and in the brain

PubMed Central

Tofts, P S; Collins, D J

2011-01-01

Multicentre imaging studies of brain tumours (and other tumour and brain studies) can enable a large group of patients to be studied, yet they present challenging technical problems. Differences between centres can be characterised, understood and minimised by use of phantoms (test objects) and normal control subjects. Normal white matter forms an excellent standard for some MRI parameters (e.g. diffusion or magnetisation transfer) because the normal biological range is low (<2–3%) and the measurements will reflect this, provided the acquisition sequence is controlled. MR phantoms have benefits and they are necessary for some parameters (e.g. tumour volume). Techniques for temperature monitoring and control are given. In a multicentre study or treatment trial, between-centre variation should be minimised. In a cross-sectional study, all groups should be represented at each centre and the effect of centre added as a covariate in the statistical analysis. In a serial study of disease progression or treatment effect, individual patients should receive all of their scans at the same centre; the power is then limited by the within-subject reproducibility. Sources of variation that are generic to any imaging method and analysis parameters include MR sequence mismatch, B1 errors, CT effective tube potential, region of interest generation and segmentation procedure. Specific tissue parameters are analysed in detail to identify the major sources of variation and the most appropriate phantoms or normal studies. These include dynamic contrast-enhanced and dynamic susceptibility contrast gadolinium imaging, T1, diffusion, magnetisation transfer, spectroscopy, tumour volume, arterial spin labelling and CT perfusion. PMID:22433831

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project.

PubMed

Schültke, E; Bräuer-Krisch, E; Blattmann, H; Requardt, H; Laissue, J A; Hildebrandt, G

2018-05-10

Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time. BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease. The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy. Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31. After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain. In this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy

PubMed Central

Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

2016-01-01

An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors’ knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

Fever as a factor contributing to long-term survival in a patient with metastatic melanoma: A case report.

PubMed

Wrotek, Sylwia; Brycht, Łukasz; Wrotek, Weronika; Kozak, Wiesław

2018-06-01

Malignant melanoma is a cancer that arises from pigment cells in the skin called melanocytes. The long-term survival of a patient with advanced melanoma is rare. We present a unique case of a female patient who has suffered from malignant melanoma for more than 13 years. The disease progressed quickly, and 19 months after diagnosis, the patient was classified as having stage IV melanoma. After several years, the patient had several episodes of fever that were not deliberately treated with medication. After each episode of fever, the patient observed the disappearance of tumours, which was confirmed by medical examination. Interestingly, since her initial diagnosis, the patient has refused most of the proposed medical treatments. Consequently, only some of the surgical procedures were performed. Currently, despite the initially poor prognosis, the patient only suffers symptoms that are the result of surgical resection of brain metastases. Most of her malignant tumours either disappeared or have stabilized without further growth. The onset of fever has altered the typical and unfavourable course of melanoma, causing remission or at least stabilization. This observation, in accordance with others in this field, suggests that fever in cancer patients should not be treated immediately, but should be allowed to develop under the care of a physician. Copyright © 2018 Elsevier Ltd. All rights reserved.

Diagnostic work up for language testing in patients undergoing awake craniotomy for brain lesions in language areas.

PubMed

Bilotta, Federico; Stazi, Elisabetta; Titi, Luca; Lalli, Diana; Delfini, Roberto; Santoro, Antonio; Rosa, Giovanni

2014-06-01

Awake craniotomy is the technique of choice in patients with brain tumours adjacent to primary and accessory language areas (Broca's and Wernicke's areas). Language testing should be aimed to detect preoperative deficits, to promptly identify the occurrence of new intraoperative impairments and to establish the course of postoperative language status. Aim of this case series is to describe our experience with a dedicated language testing work up to evaluate patients with or at risk for language disturbances undergoing awake craniotomy for brain tumour resection. Pre- and intra operative testing was accomplished with 8 tests. Intraoperative evaluation was accomplished when patients were fully cooperative (Ramsey < 3). Postoperative evaluation was scheduled at early (within 21 days) and long-term follow-up (3-6 months). Twenty consecutive patients were prospectively recruited. Preoperative language testings were normal in 9 patients (45%), showed mild to moderate language deficit in 8 (40%) and severe language deficit or aphasic disorders in 3 (15%). Broca's area was identified in 15 patients, in all cases by counting arrest during stimulation and in 12 cases by naming arrest. In this article we describe our experience using a language testing work up to evaluate - pre, intra and postoperatively - patients undergoing awake craniotomy for brain tumour resection with preoperative language disturbances or at risk for postoperative language deficits. This approach allows a systematic evaluation and recording of language function status and can be accomplished even when a neuropsychologist or speech therapist are not involved in the operation crew.

DNA methylation analysis of paediatric low-grade astrocytomas identifies a tumour-specific hypomethylation signature in pilocytic astrocytomas.

PubMed

Jeyapalan, Jennie N; Doctor, Gabriel T; Jones, Tania A; Alberman, Samuel N; Tep, Alexander; Haria, Chirag M; Schwalbe, Edward C; Morley, Isabel C F; Hill, Alfred A; LeCain, Magdalena; Ottaviani, Diego; Clifford, Steven C; Qaddoumi, Ibrahim; Tatevossian, Ruth G; Ellison, David W; Sheer, Denise

2016-05-27

Low-grade gliomas (LGGs) account for about a third of all brain tumours in children. We conducted a detailed study of DNA methylation and gene expression to improve our understanding of the biology of pilocytic and diffuse astrocytomas. Pilocytic astrocytomas were found to have a distinctive signature at 315 CpG sites, of which 312 were hypomethylated and 3 were hypermethylated. Genomic analysis revealed that 182 of these sites are within annotated enhancers. The signature was not present in diffuse astrocytomas, or in published profiles of other brain tumours and normal brain tissue. The AP-1 transcription factor was predicted to bind within 200 bp of a subset of the 315 differentially methylated CpG sites; the AP-1 factors, FOS and FOSL1 were found to be up-regulated in pilocytic astrocytomas. We also analysed splice variants of the AP-1 target gene, CCND1, which encodes cell cycle regulator cyclin D1. CCND1a was found to be highly expressed in both pilocytic and diffuse astrocytomas, but diffuse astrocytomas have far higher expression of the oncogenic variant, CCND1b. These findings highlight novel genetic and epigenetic differences between pilocytic and diffuse astrocytoma, in addition to well-described alterations involving BRAF, MYB and FGFR1.

Provincial development of a patient-reported outcome initiative to guide patient care, quality improvement, and research.

PubMed

Olson, Robert A; Howard, Fuchsia; Lapointe, Vincent; Schellenberg, Devin; Nichol, Alan; Bowering, Gale; Curtis, Susan; Walter, Allison; Brown, Steven; Thompson, Corinne; Bergin, Jackie; Lomas, Sheri; French, John; Halperin, Ross; Tyldesley, Scott; Beckham, Wayne

2018-01-01

The BC Cancer Agency Radiotherapy (RT) program started the Prospective Outcomes and Support Initiative (POSI) at all six centres to utilize patient-reported outcomes for immediate clinical care, quality improvement, and research. Patient-reported outcomes were collected at time of computed tomography simulation via tablet and 2 to 4 weeks post-RT via either tablet or over the phone by a registered nurse. From 2013 to 2016, patients were approached on 20,150 attempts by POSI for patients treated with RT for bone metastases (52%), brain metastases (11%), lung cancer (17%), gynecological cancer (16%), head and neck cancer (2%), and other pilots (2%). The accrual rate for all encounters was 85% (n = 17,101), with the accrual rate varying between the lowest and the highest accruing centre from 78% to 89% ( P < .001) and varying by tumour site ( P < .001). Using the POSI database, we have performed research and quality improvement initiatives that have changed practice.

Impact of dose escalation and adaptive radiotherapy for cervical cancers on tumour shrinkage—a modelling study

NASA Astrophysics Data System (ADS)

Røthe Arnesen, Marius; Paulsen Hellebust, Taran; Malinen, Eirik

2017-03-01

Tumour shrinkage occurs during fractionated radiotherapy and is regulated by radiation induced cellular damage, repopulation of viable cells and clearance of dead cells. In some cases additional tumour shrinkage during external beam therapy may be beneficial, particularly for locally advanced cervical cancer where a small tumour volume may simplify and improve brachytherapy. In the current work, a mathematical tumour model is utilized to investigate how local dose escalation affects tumour shrinkage, focusing on implications for brachytherapy. The iterative two-compartment model is based upon linear-quadratic radiation response, a doubling time for viable cells and a half-time for clearance of dead cells. The model was individually fitted to clinical tumour volume data from fractionated radiotherapy of 25 cervical cancer patients. Three different fractionation patterns for dose escalation, all with an additional dose of 12.2 Gy, were simulated and compared to standard fractionation in terms of tumour shrinkage. An adaptive strategy where dose escalation was initiated after one week of treatment was also considered. For 22 out of 25 patients, a good model fit was achieved to the observed tumour shrinkage. A large degree of inter-patient variation was seen in predicted volume reduction following dose escalation. For the 10 best responding patients, a mean tumour volume reduction of 34  ±  3% (relative to standard treatment) was estimated at the time of brachytherapy. Timing of initiating dose escalation had a larger impact than the number of fractions applied. In conclusion, the model was found useful in evaluating the impact from dose escalation on tumour shrinkage. The results indicate that dose escalation could be conducted from the start of external beam radiotherapy in order to obtain additional tumour shrinkage before brachytherapy.

Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer

PubMed Central

Zhang, Yaqing; Velez-Delgado, Ashley; Mathew, Esha; Li, Dongjun; Mendez, Flor M; Flannagan, Kevin; Rhim, Andrew D; Simeone, Diane M; Beatty, Gregory L; Pasca di Magliano, Marina

2017-01-01

Background Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity. Objective The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment. Methods Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours. Results Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner. Conclusion Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer. PMID:27402485

Endoscopic versus stereotactic procedure for pineal tumour biopsies: Comparative review of the literature and learning from a 25-year experience.

PubMed

Balossier, A; Blond, S; Touzet, G; Lefranc, M; de Saint-Denis, T; Maurage, C-A; Reyns, N

2015-01-01

Pineal tumours account for 1% to 4% of brain tumours in adults and for around 10% in children. Except in a few cases where germ cell markers are elevated, accurate histological samples are mandatory to initiate the treatment. Open surgery still has a high morbidity and is often needless. Biopsies can either be obtained by endoscopic or stereotactic procedures. Following an extensive review of the literature (PubMed 1970-2013; keywords pineal tumour, biopsy; English and French), 33 studies were analysed and relevant data compared regarding the type of procedure, diagnosis rate, cerebrospinal fluid diversion type and rate, perioperative mortality, morbidity. Endoscopic and stereotactic biopsies showed a diagnosis rate of 81.1% (20%-100%) and 93.7% (82%-100%), respectively. Endoscopic biopsies involved 21.0% of minor and 2.0% of major complications whereas stereotactic biopsies involved 6.4% of minor and 1.6% of major complications. The most frequently reported complication was haemorrhage for both endoscopic and stereotactic procedures, accounting for 4.8% and 4.3%, respectively. Mortality rate was low for both endoscopic and stereotactic procedures, equal to 0.4% and 1.3%, respectively. Local experience of stereotactic biopsies was also reported and corroborated the previous data. The difference between both procedures is not statistically significant (p>0.05) across large series (≥20patients). Nevertheless, tissue diagnosis appears less accurate with endoscopic procedures than with stereotactic procedures (81.1% versus 93.7%, weighted mean across all series). In our opinion, the neuroendoscopic approach is the best tool for managing hydrocephalus, whereas stereotactic biopsies remain the best way to obtain a tissue diagnosis with accuracy and low morbidity. Copyright © 2014. Published by Elsevier Masson SAS.

HumanMethylation450K Array–Identified Biomarkers Predict Tumour Recurrence/Progression at Initial Diagnosis of High-risk Non-muscle Invasive Bladder Cancer

PubMed Central

Kitchen, Mark O; Bryan, Richard T; Emes, Richard D; Luscombe, Christopher J; Cheng, KK; Zeegers, Maurice P; James, Nicholas D; Gommersall, Lyndon M; Fryer, Anthony A

2018-01-01

Background: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. Patients and methods: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG) were also assessed by bisulphite Pyrosequencing. Results: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values. Conclusions: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease. PMID:29343995

[Primary pulmonary hemangiopericytoma: 2 new cases].

PubMed

Essola, B; Remmelink, M; Kessler, R; Scillia, P; Rocmans, P

2003-10-01

We describe two new resected cases of primary pulmonary hemangiopericytoma and the review of cases published in the period 1954-2002. The first patient has a large pulmonary mass of the right apex revealed by scapular pain. The right upper lobectomy with free margins reveals hemangiopericytoma. Pelvic and pulmonary metastases appear two years after surgery, treated by two series of chemotherapy without clinical response. After acute nephrotoxicity controlled by hemodialysis, the patient dies with distant metastases three years and an half after thoracotomy. The second patient develops dry cough and thoracic pain with discovery of a cavitary mass in the right pulmonary field. Fine needle aspiration cytology suggests a mesenchymatous lesion. Three months after extended pneumonectomy, the intrathoracic tumour relapses and regresses partially under chemotherapy. Femoral and brain metastases are irradiated. The patient dies 22 months after thoracotomy. Histology and immunohistochemistry of both tumours closely related to solitary fibrous tumour confirm malignant hemangiopericytoma. Primary pulmonary hemangiopericytoma is rare and may be benign or malignant. Radical resection is the best treatment. Chemotherapy and radiotherapy may improve the prognosis. Compared with lung cancer, the tumour is a slow growing mass, often voluminous, with delayed symptoms, very few lymph node dissemination, rare brain metastasis, more frequent cutaneous or retroperitoneal dissemination, often after long-term and requiring indeed a 10 to 20 years follow-up.

Autobiographical memory loss following a right prefrontal lobe tumour resection: a case report and review of the literature.

PubMed

Jamjoom, A A B; Gallo, P; Kandasamy, J; Phillips, J; Sokol, D

2017-07-01

The right prefrontal lobe has not traditionally been considered eloquent brain. Resection of tumours within this region does not typically lead to permanent functional impairment. In this report, we highlight the case of a patient who developed autobiographical memory loss following an uncomplicated resection of a right prefrontal tumour. A previously fit and well 15-year old presented with a persistent right-sided headache. An MRI demonstrated an expanded right mid-frontal gyrus with changes consistent with a low-grade tumour. The patient underwent a right-sided craniotomy and resection of the lesion which was confirmed as a WHO grade II diffuse astrocytoma. Postoperatively, the patient reported profound retrograde amnesia for a range of memory components, in particular autobiographical memory and semantic memory. Postoperative imaging showed a good resection margin with no evidence of underlying brain injury. Over an 18-month period, the patient showed no improvement in autobiographical memory; however, significant relearning of semantic knowledge took place and her academic performance was found to be in line with expectations for her age. In this report, we discuss a case and review the literature on the role of the right prefrontal cortex in memory and caution on the perception of right prefrontal non-eloquence.

[Guidelines for the radiotherapy of gliomas].

PubMed

Feuvret, L; Antoni, D; Biau, J; Truc, G; Noël, G; Mazeron, J-J

2016-09-01

Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Mobile Phone Radiation: Physiological & Pathophysiologcal Considerations.

PubMed

K Sri, Nageswari

2015-01-01

It is documented that electromagnetic emissions from mobile phones can interfere with brain's signal processing activity due to their oscillatory similitude to the inherent rhythms of the brain, akin to "electromagnetic interference" observed while using mobile phones in aeroplanes. At high power density levels, thermal effects occur, some of which can be attributed to heat induced stress mechanisms. The less understood non-thermal effects occur at low radio frequency/microwave power density levels and are not accompanied by any body temperature rise. The safety standards set by international agencies are based on thermal effects. For the mobile phones, ICNIRP 1998 guidelines restrict spatial peak of microwave exposure to 2 W/Kg SAR values averaged over 10 g of tissue for 6 minutes. Some of the reported electromagnetic radiation (EMR) induced adverse effects are brain tumours, male infertility and immune dysfunction with increased susceptibility to infections. Pathophysiological mechanisms of interaction of EMR at plasma membrane are calcium efflux from cell membranes, increased expression of stress proteins, influence on channels/gap junctions in cell membrane, overproduction of reactive oxygen species, ornithine decarboxylase activation, reduction in melatonin levels, decrease in protein kinase C activity, damage to DNA and change in gene expression in brain cells and altered blood-brain barrier. There are equal number of conflicting reports in literature regarding EMR exposure and brain tumours. A comprehensive review concludes "overall the studies published to date do not demonstrate an increased risk within approximately 10 years of use for any tumour of the brain or any other head tumour." Another review summarises that there is "enough data to convince that long-term exposure to low intensity EMR below the ICNIRP guidelines can promote cancer development". However the time limit for exposure has been suggested as more than 10 years. For conducting epidemiological studies, some of the difficulties experienced are obtaining unexposed controls or cohorts, follow up of the cohorts, actual dose measurement for exposure assessment in case-control studies, inaccuracy, recall bias and selective non response in recall of phone use by mobile phone users, long induction times, long latencies (the effects we observe now are of analogue phones that are no longer used ) and the rarity of observed malignancies, variable ways of using the phone by the user i.e. left or right ear, head sets/speaker/blue tooth etc. Large-scale epidemiological studies should employ personal MW dosimeters for strict dose measurement and for interpreting actual tissue exposure.

Dependence of normal brain integral dose and normal tissue complication probability on the prescription isodose values for γ-knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun

2001-11-01

A recent multi-institutional clinical study suggested possible benefits of lowering the prescription isodose lines for stereotactic radiosurgery procedures. In this study, we investigate the dependence of the normal brain integral dose and the normal tissue complication probability (NTCP) on the prescription isodose values for γ-knife radiosurgery. An analytical dose model was developed for γ-knife treatment planning. The dose model was commissioned by fitting the measured dose profiles for each helmet size. The dose model was validated by comparing its results with the Leksell gamma plan (LGP, version 5.30) calculations. The normal brain integral dose and the NTCP were computed and analysed for an ensemble of treatment cases. The functional dependence of the normal brain integral dose and the NCTP versus the prescribing isodose values was studied for these cases. We found that the normal brain integral dose and the NTCP increase significantly when lowering the prescription isodose lines from 50% to 35% of the maximum tumour dose. Alternatively, the normal brain integral dose and the NTCP decrease significantly when raising the prescribing isodose lines from 50% to 65% of the maximum tumour dose. The results may be used as a guideline for designing future dose escalation studies for γ-knife applications.

Cervical embryonal rhabdomyosarcoma and ovarian Sertoli–Leydig cell tumour: a more than coincidental association of two rare neoplasms?

PubMed Central

McClean, Gareth E; Kurian, Susy; Walter, Noel; Kekre, A; McCluggage, W Glenn

2007-01-01

A case in which an embryonal rhabdomyosarcoma of the cervix and an ovarian Sertoli–Leydig cell tumour of intermediate differentiation occurred in a 13‐year‐old girl is described. Although initially considered as a chance association, a review of the literature showed the co‐occurrence of these two uncommon neoplasms in three previous cases. The reason for this association, which is thought to be more than coincidental, is not known, although an underlying genetic abnormality is a possibility. The ovarian tumour in this case was characterised by the presence of foci of cells with extremely pleomorphic nuclei, which initially raised the possibility of metastatic rhabdomyosarcoma. These were interpreted as foci of bizarre nuclei within the Sertoli–Leydig cell tumour. PMID:17347287

The pathobiology of collagens in glioma

PubMed Central

Payne, Leo S.; Huang, Paul H.

2013-01-01

Malignant gliomas are characterised by diffuse infiltration into the surrounding brain parenchyma. Infiltrating glioma cells exist in close proximity with components of the tumour microenvironment, including the extracellular matrix (ECM). While levels of collagens in the normal adult brain are low, in glioma, collagen levels are elevated and play an important role in driving the tumor progression. In this review, we provide a comprehensive overview of the nature of collagens found in gliomas and offer insights into the mechanisms by which cancer cells interact with this ECM via receptors including the integrins, discoidin domain receptors and Endo180. We further describe the major remodelling pathways of brain tumour collagen mediated by the matrix metalloproteinases and highlight the reciprocal relationship between these enzymes and the collagen receptors. Finally, we conclude by offering a perspective on how the biophysical properties of the collagen ECM, in particular, mechanical stiffness and compliance may influence malignant outcome. Understanding the complex interactions between glioma cells and the collagen ECM may provide new avenues to combat the rampant tumor progression and chemoresistance in brain cancer patients. PMID:23861322

The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment.

PubMed

Nota, Nienke M; Wiepjes, Chantal M; de Blok, Christel J M; Gooren, Louis J G; Peerdeman, Saskia M; Kreukels, Baudewijntje P C; den Heijer, Martin

2018-04-23

Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23-41) and 1373 transmen (median age 23 years, interquartile range 18-31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9-7.7) and male population (11.9, 5.5-22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1-7.9) and males (26.5, 12.9-48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7-73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary.

Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome.

PubMed

Kratz, C P; Holter, S; Etzler, J; Lauten, M; Pollett, A; Niemeyer, C M; Gallinger, S; Wimmer, K

2009-06-01

Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases. We analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumour this strongly suggests an underlying PMS2 alteration in family 2 also. Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumours, such as neuroblastoma and Wilm tumour, belong to the tumour spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will lead to a definitive diagnosis of the underlying disorder.

Immunological cross-reactivity between acid extracts of myelin, liver and neoplastic tissues: studies in immunized guinea-pigs.

PubMed Central

Flavell, D. J.; Goepel, J.; Wilson, A. P.; Potter, C. W.

1979-01-01

Groups of 4 guinea-pigs were immunized with acid extracts prepared from bovine myelin (EF), normal human liver tissue and malignant or benign neoplastic tissues in Freund's complete adjuvant (FCA1. The animals were weighed daily and examined for clinical signs of experimental allergic encephalomyelitis (EAE). All the animals immunized with EF developed clinical symptoms of EAE within 21 days of the initial immunization, whilst some of the animals immunized with certain tumour extracts developed symptoms which closely resembled those of EAE. Control animals immunized with FCA only remained asymptomatic. Cellular immunity to the various extracts in immunized animals was assessed 20 days after immunization by i.d. skin testing, and upon killing at Day 21 with the direct peritoneal-exudate macrophage migration inhibition (MMI) test. Brains and spinal cords were removed at killing, fixed in formalin and processed for histological examination. I.d. skin testing was shown to be most consistent in demonstrating positive delayed hypersensitivity, whilst the MMI test frequently gave negative results in the presence of pronounced skin responses to specific extracts. Thus it was shown that 3/4 animals immunized with basic proteins extracted from an adenocarcinoma of the lung or related hepatic metastases, and 1/2 animals immunized with an extract of a carcinoma of the breast, gave intense erythema and induration responses 5 mm in diameter 24 h after i.d. challenge with EF. No such response was obtained in animals immunized with basic proteins extracted from normal human liver, any of the other neoplastic tissues, or in control animals immunized with FCA only. Examination of brains and spinal cords from animals immunized with EF revealed dense infiltration by mononuclear cells in the ependyma and choroid plexus of levels in the spinal cord. Examination of brains and spinal cords from animals immunized with the lung-tumour extract or related hepatic metastases which showed demonstrable immunological cross-reactivity with EF in immunized animals, revealed a number of inflammatory changes characterized by dense infiltrates of mononuclear cells sub-ependymally, and perivascular cuffing in the cortex. However, no significant lesions were seen in the spinal cords of these animals. Polyacrylamide-gel electrophoresis of the 2 tumour extracts exerting this apparent encephalitogenic effect did not reveal proteins within the mol. wt range of EF. Thus the observed pathological effects and cross-reactivity with EF were probably not due to contamination with nervous-tissue components. It is suggested that these tumour extracts may have contained a component or components other than EF, immunologically cross-reactive with EF, and capable of inducing the observed encephalitis. Images Fig. 2 Fig. 3a, b Fig. 3c, d PMID:92328

[Low field intra-operative magnetic resonance imaging for brain tumour surgery: preliminary experience].

PubMed

Roldán, Pedro; García, Sergio; González, Josep; Reyes, Luis Alberto; Torales, Jorge; Valero, Ricard; Oleaga, Laura; Enseñat, Joaquim

Intra-operative magnetic resonance imaging (iMRI) is a recently introduced tool in the most advanced neurosurgical operating rooms worldwide. We present our preliminary experience in brain tumour surgery with low field PoleStar N30® intraoperative MRI since its introduction in 2013 in the Barcelona Clinic Hospital. A prospective non-randomised study was conducted on cases operated on using iMRI and intention of complete removal up to October 2015. A record was made of the data as regards surgical times, resection rates, histological diagnosis, hospital stay, and survival rates during follow-up. The study included 50 patients, with a mean age of 55 years (±13.7), a preoperative mean Karnofsky of 92 (being 81 post-operatively), and a mean follow-up of 10.5 months (±6.5). There were 26% re-operations due to recurrence. High-grade gliomas were reported in 56%, low-grade gliomas in 24%, and 20% "Other" tumours. Overall hospital stay was 10 days (±4.5). Depending on the histologiacl diagnosis, the "Others" group had a longer hospital stay. Overall, there were 52% complete removal, 18% of maximum removals, and 30% of partial removals. The overall survival rates during follow-up was 84%. iMRI is a safe and effective tool for brain tumour surgery. Its use allows an increase in resection rates, and minimises post-operative complications. Its implementation involves an increase in surgical time, which improves with the characteristic learning curve. More studies are needed to establish its role in the long-term survival of patients. Copyright © 2016 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

Context aware decision support in neurosurgical oncology based on an efficient classification of endomicroscopic data.

PubMed

Li, Yachun; Charalampaki, Patra; Liu, Yong; Yang, Guang-Zhong; Giannarou, Stamatia

2018-06-13

Probe-based confocal laser endomicroscopy (pCLE) enables in vivo, in situ tissue characterisation without changes in the surgical setting and simplifies the oncological surgical workflow. The potential of this technique in identifying residual cancer tissue and improving resection rates of brain tumours has been recently verified in pilot studies. The interpretation of endomicroscopic information is challenging, particularly for surgeons who do not themselves routinely review histopathology. Also, the diagnosis can be examiner-dependent, leading to considerable inter-observer variability. Therefore, automatic tissue characterisation with pCLE would support the surgeon in establishing diagnosis as well as guide robot-assisted intervention procedures. The aim of this work is to propose a deep learning-based framework for brain tissue characterisation for context aware diagnosis support in neurosurgical oncology. An efficient representation of the context information of pCLE data is presented by exploring state-of-the-art CNN models with different tuning configurations. A novel video classification framework based on the combination of convolutional layers with long-range temporal recursion has been proposed to estimate the probability of each tumour class. The video classification accuracy is compared for different network architectures and data representation and video segmentation methods. We demonstrate the application of the proposed deep learning framework to classify Glioblastoma and Meningioma brain tumours based on endomicroscopic data. Results show significant improvement of our proposed image classification framework over state-of-the-art feature-based methods. The use of video data further improves the classification performance, achieving accuracy equal to 99.49%. This work demonstrates that deep learning can provide an efficient representation of pCLE data and accurately classify Glioblastoma and Meningioma tumours. The performance evaluation analysis shows the potential clinical value of the technique.

Modelling glioma invasion using 3D bioprinting and scaffold-free 3D culture.

PubMed

van Pel, Derek M; Harada, Kaori; Song, Dandan; Naus, Christian C; Sin, Wun Chey

2018-06-16

Glioma is a highly aggressive form of brain cancer, with some subtypes having 5-year survival rates of less than 5%. Tumour cell invasion into the surrounding parenchyma seems to be the primary driver of these poor outcomes, as most gliomas recur within 2 cm of the original surgically-resected tumour. Many current approaches to the development of anticancer therapy attempt to target genetic weaknesses in a particular cancer, but may not take into account the microenvironment experienced by a tumour and the patient-specific genetic differences in susceptibility to treatment. Here we demonstrate the use of complementary approaches, 3D bioprinting and scaffold-free 3D tissue culture, to examine the invasion of glioma cells into neural-like tissue with 3D confocal microscopy. We found that, while both approaches were successful, the use of 3D tissue culture for organoid development offers the advantage of broad accessibility. As a proof-of-concept of our approach, we developed a system in which we could model the invasion of human glioma cells into mouse neural progenitor cell-derived spheroids. We show that we can follow invasion of human tumour cells using cell-tracking dyes and 3D laser scanning confocal microscopy, both in real time and in fixed samples. We validated these results using conventional cryosectioning. Our scaffold-free 3D approach has broad applicability, as we were easily able to examine invasion using different neural progenitor cell lines, thus mimicking differences that might be observed in patient brain tissue. These results, once applied to iPSC-derived cerebral organoids that incorporate the somatic genetic variability of patients, offer the promise of truly personalized treatments for brain cancer.

Depression, anxiety and positive affect in people diagnosed with low-grade tumours: the role of illness perceptions.

PubMed

Keeling, Melanie; Bambrough, Jacki; Simpson, Jane

2013-06-01

People with low-grade brain tumour experience a range of emotional, behavioural and psychosocial consequences. Using Leventhal's self-regulation model to explore biopsychosocial factors associated with distress, we examine the relationships between illness perceptions, coping and depression, anxiety and positive affect. A cross-sectional, self-report study in which 74 people (54% women) diagnosed with a low-grade brain tumour completed the Illness Perceptions Questionnaire-Revised was conducted. Mean time since diagnosis was 27.69 months (SD = 19.79). Mean age was 38.30 years (SD = 10.67). The Illness Perceptions Questionnaire-Revised, in addition to clinical, demographic and coping variables previously associated with psychological distress, was used to predict three psychological outcomes: depression, anxiety and positive affect. Hierarchical multiple regression analyses demonstrated that a biopsychosocial causal attribution was a significant predictor of anxiety and depression. Illness identity also emerged as a significant predictor of depression scores. Coping through self-blame was the only coping variable to emerge as a significant predictor of anxiety scores. A combination of coping through venting, acceptance, positive reframing, denial, behavioural disengagement and self-blame contributed to the variance in all three psychological outcome scores. No illness perception variables significantly predicted positive affect. Illness perceptions play a significant role in emotional distress experienced by people with low-grade brain tumours. Illness perceptions did not play a significant role in positive affect. Coping variables were shown to significantly contribute to the scores on all three psychological outcomes. Results suggest interventions targeted at modifying illness perceptions and enhancing problem-focused coping strategies may reduce psychological distress. Copyright © 2012 John Wiley & Sons, Ltd.

Intraoperative β{sup -} detecting probe for radio-guided surgery in tumour resection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Solfaroli Camillocci, Elena; Bellini, Fabio; Bocciy, Valerio

The development of the β{sup -} based radio-guided surgery aims to extend the technique to those tumours where surgery is the only possible treatment and the assessment of the resection would most profit from the low background around the lesion, as for brain tumours. Feasibility studies on meningioma and gliomas already estimated the potentiality of this new treatment. To validate the technique, a prototype of the intraoperative probe detecting β{sup -} decays and specific phantoms simulating tumour remnant patterns embedded in healthy tissue have been realized. The response of the probe in this simulated environment is tested with dedicated procedures.more » This document discusses the innovative aspects of the method, the status of the developed intraoperative β{sup -} detecting probe and the results of the preclinical tests. (authors)« less

History of myeloid derived suppressor cells (MDSCs) in the macro- and micro-environment of tumour-bearing hosts

PubMed Central

Talmadge, James E.; Gabrilovich, Dmitry I.

2015-01-01

Tumour-induced granulocytic hyperplasia is associated with tumour vasculogenesis and escape from immunity via T-cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, recent studies revealed that this hyperplasia was associated with populations of multi-potent progenitor cells identified as myeloid-derived suppressor cells (MDSCs). The discovery and study of MDSCs have provided a wealth of information regarding tumour pathobiology, extended our understanding of neoplastic progression, and modified our approaches to immune adjuvant therapy. In this perspective, we discuss the history of MDSCs, their influence on tumour progression and metastasis, and the crosstalk between tumour cells, MDSCs, and the host macroenvironment. PMID:24060865

HELICoiD project: a new use of hyperspectral imaging for brain cancer detection in real-time during neurosurgical operations

NASA Astrophysics Data System (ADS)

Fabelo, Himar; Ortega, Samuel; Kabwama, Silvester; Callico, Gustavo M.; Bulters, Diederik; Szolna, Adam; Pineiro, Juan F.; Sarmiento, Roberto

2016-05-01

Hyperspectral images allow obtaining large amounts of information about the surface of the scene that is captured by the sensor. Using this information and a set of complex classification algorithms is possible to determine which material or substance is located in each pixel. The HELICoiD (HypErspectraL Imaging Cancer Detection) project is a European FET project that has the goal to develop a demonstrator capable to discriminate, with high precision, between normal and tumour tissues, operating in real-time, during neurosurgical operations. This demonstrator could help the neurosurgeons in the process of brain tumour resection, avoiding the excessive extraction of normal tissue and unintentionally leaving small remnants of tumour. Such precise delimitation of the tumour boundaries will improve the results of the surgery. The HELICoiD demonstrator is composed of two hyperspectral cameras obtained from Headwall. The first one in the spectral range from 400 to 1000 nm (visible and near infrared) and the second one in the spectral range from 900 to 1700 nm (near infrared). The demonstrator also includes an illumination system that covers the spectral range from 400 nm to 2200 nm. A data processing unit is in charge of managing all the parts of the demonstrator, and a high performance platform aims to accelerate the hyperspectral image classification process. Each one of these elements is installed in a customized structure specially designed for surgical environments. Preliminary results of the classification algorithms offer high accuracy (over 95%) in the discrimination between normal and tumour tissues.

Variable methylation of the imprinted gene, SNRPN, supports a relationship between intracranial germ cell tumours and neural stem cells.

PubMed

Lee, Shih-Han; Appleby, Vanessa; Jeyapalan, Jennie N; Palmer, Roger D; Nicholson, James C; Sottile, Virginie; Gao, Erning; Coleman, Nicholas; Scotting, Paul J

2011-02-01

Germ cell tumours (GCTs) are a diverse group of neoplasms all of which are generally believed to arise from germ cell progenitors (PGCs). Even those that form in the nervous system are likewise believed to be PGC-derived, despite being found a great distance from the normal location of germ cells. The primary evidence in favour of this model for the origins of intracranial GCTs is that they share molecular features with other GCTs. Those features include shared gene expression and a lack of methylation of imprinted genes, including SNRPN. Contrary to this model, we have proposed that endogenous neural stem cells of the brain are a more likely origin for these tumours. We show here that the lack of methylation of SNRPN that has previously been taken to indicate an origin for GCTs from PGCs is also seen in neural stem cells of mice and humans. We believe that, in the light of these and other recent observations, endogenous neural precursors of the brain are a more plausible origin for intracranial GCTs than are misplaced PGCs.

A small-molecule dye for NIR-II imaging

NASA Astrophysics Data System (ADS)

Antaris, Alexander L.; Chen, Hao; Cheng, Kai; Sun, Yao; Hong, Guosong; Qu, Chunrong; Diao, Shuo; Deng, Zixin; Hu, Xianming; Zhang, Bo; Zhang, Xiaodong; Yaghi, Omar K.; Alamparambil, Zita R.; Hong, Xuechuan; Cheng, Zhen; Dai, Hongjie

2016-02-01

Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (~90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)--a clinically approved NIR-I dye--in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ~4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery.

Aquaporin-4 in brain and spinal cord oedema.

PubMed

Saadoun, S; Papadopoulos, M C

2010-07-28

Brain oedema is a major clinical problem produced by CNS diseases (e.g. stroke, brain tumour, brain abscess) and systemic diseases that secondarily affect the CNS (e.g. hyponatraemia, liver failure). The swollen brain is compressed against the surrounding dura and skull, which causes the intracranial pressure to rise, leading to brain ischaemia, herniation, and ultimately death. A water channel protein, aquaporin-4 (AQP4), is found in astrocyte foot processes (blood-brain border), the glia limitans (subarachnoid cerebrospinal fluid-brain border) and ependyma (ventricular cerebrospinal fluid-brain border). Experiments using mice lacking AQP4 or alpha syntrophin (which secondarily downregulate AQP4) showed that AQP4 facilitates oedema formation in diseases causing cytotoxic (cell swelling) oedema such as cerebral ischaemia, hyponatraemia and meningitis. In contrast, AQP4 facilitates oedema elimination in diseases causing vasogenic (vessel leak) oedema and therefore AQP4 deletion aggravates brain oedema produced by brain tumour and brain abscess. AQP4 is also important in spinal cord oedema. AQP4 deletion was associated with less cord oedema and improved outcome after compression spinal cord injury in mice. Here we consider the possible routes of oedema formation and elimination in the injured cord and speculate about the role of AQP4. Finally we discuss the role of AQP4 in neuromyelitis optica (NMO), an inflammatory demyelinating disease that produces oedema in the spinal cord and optic nerves. NMO patients have circulating AQP4 IgG autoantibody, which is now used for diagnosing NMO. We speculate how NMO-IgG might produce CNS inflammation, demyelination and oedema. Since AQP4 plays a key role in the pathogenesis of CNS oedema, we conclude that AQP4 inhibitors and activators may reduce CNS oedema in many diseases. Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Heterogeneity of circulating epithelial tumour cells from individual patients with respect to expression profiles and clonal growth (sphere formation) in breast cancer.

PubMed

Pizon, M; Zimon, D; Carl, S; Pachmann, U; Pachmann, K; Camara, O

2013-01-01

The detection of tumour cells circulating in the peripheral blood of patients with breast cancer is a sign that cells have been able to leave the primary tumour and survive in the circulation. However, in order to form metastases, they require additional properties such as the ability to adhere, self-renew, and grow. Here we present data that a variable fraction among the circulating tumour cells detected by the Maintrac(®) approach expresses mRNA of the stem cell gene NANOG and of the adhesion molecule vimentin and is capable of forming tumour spheres, a property ascribed to tumour-initiating cells (TICs). Between ten and 50 circulating epithelial antigen-positive cells detected by the Maintrac approach were selected randomly from each of 20 patients with breast cancer before and after surgery and were isolated using automated capillary aspiration and deposited individually onto slides for expression profiling. In addition, the circulating tumour cells were cultured without isolation among the white blood cells from 39 patients with breast cancer in different stages of disease using culture methods favouring growth of epithelial cells. Although no epithelial cell adhesion molecule (EpCAM)-positive cells expressing stem cell genes or the adhesion molecule vimentin was detected before surgery, 10%-20% of the cells were found to be positive for mRNA of these genes after surgery. Tumour spheres from circulating cells of 39 patients with different stages of breast cancer were grown without previous isolation in a fraction increasing with the aggressivity of the tumour. Here we show that among the peripherally circulating tumour cells, a variable fraction is able to express stem cell and adhesion properties and can be grown into tumour spheres, a property ascribed to cells capable of initiating tumours and metastases.

Nanoparticle-triggered in situ catalytic chemical reactions for tumour-specific therapy.

PubMed

Lin, Han; Chen, Yu; Shi, Jianlin

2018-03-21

Tumour chemotherapy employs highly cytotoxic chemodrugs, which kill both cancer and normal cells by cellular apoptosis or necrosis non-selectively. Catalysing/triggering the specific chemical reactions only inside tumour tissues can generate abundant and special chemicals and products locally to initiate a series of unique biological and pathologic effects, which may enable tumour-specific theranostic effects to combat cancer without bringing about significant side effects on normal tissues. Nevertheless, chemical reaction-initiated selective tumour therapy strongly depends on the advances in chemistry, materials science, nanotechnology and biomedicine. This emerging cross-disciplinary research area is substantially different from conventional cancer-theranostic modalities in clinics. In response to the fast developments in cancer theranostics based on intratumoural catalytic chemical reactions, this tutorial review summarizes the very-recent research progress in the design and synthesis of representative nanoplatforms with intriguing nanostructures, compositions, physiochemical properties and biological behaviours for versatile catalytic chemical reaction-enabled cancer treatments, mainly by either endogenous tumour microenvironment (TME) triggering or exogenous physical irradiation. These unique intratumoural chemical reactions can be used in tumour-starving therapy, chemodynamic therapy, gas therapy, alleviation of tumour hypoxia, TME-responsive diagnostic imaging and stimuli-responsive drug release, and even externally triggered versatile therapeutics. In particular, the challenges and future developments of such a novel type of cancer-theranostic modality are discussed in detail to understand the future developments and prospects in this research area as far as possible. It is highly expected that this kind of unique tumour-specific therapeutics by triggering specific in situ catalytic chemical reactions inside tumours would provide a novel but efficient methodology for benefiting personalized biomedicine in combating cancer.

Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms.

PubMed

Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

2013-10-01

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called 'leukaemia of the brain', given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Activation of blood coagulation in cancer: implications for tumour progression

PubMed Central

Lima, Luize G.; Monteiro, Robson Q.

2013-01-01

Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies. PMID:23889169

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib

NASA Astrophysics Data System (ADS)

Collier, Thomas Lee; Normandin, Marc D.; Stephenson, Nickeisha A.; Livni, Eli; Liang, Steven H.; Wooten, Dustin W.; Esfahani, Shadi A.; Stabin, Michael G.; Mahmood, Umar; Chen, Jianqing; Wang, Wei; Maresca, Kevin; Waterhouse, Rikki N.; El Fakhri, Georges; Richardson, Paul; Vasdev, Neil

2017-06-01

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.

Biodistribution of boron after intravenous 4-dihydroxyborylphenylalanine-fructose (BPA-F) infusion in meningioma and schwannoma patients: A feasibility study for boron neutron capture therapy.

PubMed

Kulvik, Martti; Kallio, Merja; Laakso, Juha; Vähätalo, Jyrki; Hermans, Raine; Järviluoma, Eija; Paetau, Anders; Rasilainen, Merja; Ruokonen, Inkeri; Seppälä, Matti; Jääskeläinen, Juha

2015-12-01

We studied the uptake of boron after 100 mg/kg BPA infusion in three meningioma and five schwannoma patients as a pre-BNCT feasibility study. With average tumour-to-whole blood boron concentrations of 2.5, we discuss why BNCT could, and probably should, be developed to treat severe forms of the studied tumours. However, analysing 72 tumour and 250 blood samples yielded another finding: the plasma-to-whole blood boron concentrations varied with time, suggesting that the assumed constant boron ratio of 1:1 between normal brain tissue and whole blood deserves re-assessment. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Tumour lysis syndrome in small-cell lung cancer].

PubMed

Boshuizen, R C; Smit, A A J; Moons-Pasic, A; Bresser, P

2016-01-01

Small-cell lung cancer (SCLC) is a rapidly proliferating malignancy. Dramatic response to chemotherapy can therefore be expected. Unfortunately, tumour lysis prophylaxis is not mentioned in the current Dutch guidelines on SCLC treatment. A 64-year-old female was diagnosed with extensive SCLC and metastases. Shortly after diagnosis, chemotherapy was initiated. Based on Dutch guidelines, no tumour lysis prophylaxis was given. In addition to paraplegia, the patient also developed a clinical tumour lysis syndrome (TLS), and she passed away 5 days after start of treatment. Although tumour lysis prophylaxis is not mentioned in SCLC guidelines, tumour lysis in SCLC can occur as reported previously. Retrospectively, based on parameters applied to haematological malignancies, our patient was assessed as being at high risk of developing TLS.

Stem cells and cancer of the stomach and intestine.

PubMed

Vries, Robert G J; Huch, Meritxell; Clevers, Hans

2010-10-01

Cancer in the 21st century has become the number one cause of death in developed countries. Although much progress has been made in improving patient survival, tumour relapse is one of the important causes of cancer treatment failure. An early observation in the study of cancer was the heterogeneity of tumours. Traditionally, this was explained by a combination of genomic instability of tumours and micro environmental factors leading to diverse phenotypical characteristics. It was assumed that cells in a tumour have an equal capacity to propagate the cancer. This model is currently known as the stochastic model. Recently, the Cancer stem cell model has been proposed to explain the heterogeneity of a tumour and its progression. According to this model, the heterogeneity of tumours is the result of aberrant differentiation of tumour cells into the cells of the tissue the tumour originated from. Tumours were suggested to contain stem cell-like cells, the cancer stem cells or tumour-initiating cells, which are uniquely capable of propagating a tumour much like normal stem cells fuel proliferation and differentiation in normal tissue. In this review we discuss the normal stem cell biology of the stomach and intestine followed by both the stochastic and cancer stem cell models in light of recent findings in the gastric and intestinal systems. The molecular pathways underlying normal and tumourigenic growth have been well studied, and recently the stem cells of the stomach and intestine have been identified. Furthermore, intestinal stem cells were identified as the cells-of-origin of colon cancer upon loss of the tumour suppressor APC. Lastly, several studies have proposed the positive identification of a cancer stem cell of human colon cancer. At the end we compare the cancer stem cell model and the stochastic model. We conclude that clonal evolution of tumour cells resulting from genetic mutations underlies tumour initiation and progression in both cancer models. This implies that at any point during tumour development any tumour cell can revert to a cancer stem cell after having gained a clonal advantage over the original cancer stem cell. Therefore, these models represent two sides of the same coin. Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

In vivo PET evaluation in tumour-bearing rats of 2-[ 18F]fluoromethyl- L-phenylalanine as a new potential tracer for molecular imaging of brain and extra-cranial tumours in humans with PET

NASA Astrophysics Data System (ADS)

Kersemans, Ken; Bauwens, Matthias; Lahoutte, Tony; Bossuyt, Axel; Mertens, John

2007-02-01

The Na +-independent L-type LAT1 amino acid transport system for large and neutral amino acids has been shown to be expressed higher in tumour tissue relative to normal tissue and has been regarded as a key point for the development of new amino acid based tumour tracers for molecular imaging. We developed a new fluorinated phenylalanine analogue, 2-[ 18F]fluoromethyl- L-phenylalanine, considering that the spatial volume of FCH 3 is comparable with that of the iodine atom in 2-I- L-phenylalanine, of which we have proven that it is taken up excellently in tumours by the LAT1 system. The substrate molecule for radiolabeling, Boc-2-bromomethyl- L-phenylalanine- tButylester, was prepared by radical bromination of Boc-2-methyl- L-phenylalanine- tButylester. [ 18F -] for bromine exchange is performed within 3 min in conditions comparable to the [ 18F]FDG synthesis with a radiochemical yield of at least 85%. After deprotection and semi-preparative HPLC purification, the 2-[ 18F]fluoromethyl- L-phenylalanine is recovered n.c.a. (57%) with a high purity and 3.7 MBq were injected into R1M rhabdomyosarcoma tumour-bearing rats. Imaging was performed with a human PET camera from 5 to 45 min p.i. The tumour/background and tumour/blood ratios obtained from PET acquisition were at least 2.5. DUR values for the tumours were at least about 5. Furthermore, a small tumour implanted near a kidney could be well visualized completely separated from this kidney. Moreover in all tumours the "active" tumour tissue can clearly be differentiated from less active tumour tissue. This proves that 2-[ 18F]fluoromethyl- L-phenylalanine has a great potential as a new tracer for specific tumour diagnosis with PET.

REAL-TIME INTRAVITAL IMAGING ESTABLISHES TUMOUR-ASSOCIATED MACROPHAGES AS THE EXTRASKELETAL TARGET OF BISPHOSPHONATE ACTION IN CANCER

PubMed Central

Junankar, Simon; Shay, Gemma; Jurczyluk, Julie; Ali, Naveid; Down, Jenny; Pocock, Nicholas; Parker, Andrew; Nguyen, Akira; Sun, Shuting; Kashemirov, Boris; McKenna, Charles E.; Croucher, Peter I.; Swarbrick, Alexander; Weilbaecher, Katherine; Phan, Tri Giang; Rogers, Michael J.

2014-01-01

Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their anti-resorptive effects on the skeleton. However, since bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their anti-tumour action, particularly on cells outside of bone, remain unknown. Here we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumours, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumour-associated macrophages (TAMs), but not tumour cells. Importantly, we also observed uptake of radiolabeled bisphosphonate in the primary breast tumour of a patient and showed the resected tumour to be infiltrated with TAMs and to contain similar granular microcalcifications. These data represent the first compelling in vivo evidence that bisphosphonates can target cells in tumours outside the skeleton and that their anti-tumour activity is likely to be mediated via TAMs. PMID:25312016

History of myeloid-derived suppressor cells.

PubMed

Talmadge, James E; Gabrilovich, Dmitry I

2013-10-01

Tumour-induced granulocytic hyperplasia is associated with tumour vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, recent studies have revealed that this hyperplasia is associated with populations of multipotent progenitor cells that have been identified as myeloid-derived suppressor cells (MDSCs). The study of MDSCs has provided a wealth of information regarding tumour pathobiology, has extended our understanding of neoplastic progression and has modified our approaches to immune adjuvant therapy. In this Timeline article, we discuss the history of MDSCs, their influence on tumour progression and metastasis, and the crosstalk between tumour cells, MDSCs and the host macroenvironment.

Multiple cortical brain abscesses due to Listeria monocytogenes in an immunocompetent patient.

PubMed

Khan, Sadia; Kumar, Anil; Kale, Satyajit; Kurkure, Nitin; Nair, Gulsiv; Dinesh, Kavitha

2018-04-01

Listeria monocytogenes is an intracellular organism which is well recognised for its ability to cause meningeal infections in neonates, immunosuppressed, debilitated and elderly individuals. 1 Other less common central nervous system (CNS) infections caused by Listeria spp. include rhomboencephalitis, cerebritis and abscesses in the brain, brain stem and spinal cord. The neuroradiological appearance of Listeria brain abscesses is similar to other types and may also mimic primary or metastatic brain tumours. 2 , 3 We report a case of Listeria brain abscesses in a patient who was being treated for atypical parkinsonism. A good clinical outcome was achieved after appropriate antimicrobial therapy.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koger, B; Kirkby, C; Dept. of Oncology, Dept. Of Medical Physics, Jack Ady Cancer Centre, Lethbridge, Alberta

Introduction: The use of gold nanoparticles (GNPs) in radiotherapy has shown promise for therapeutic enhancement. In this study, we explore the feasibility of enhancing radiotherapy with GNPs in an arc-therapy context. We use Monte Carlo simulations to quantify the macroscopic dose-enhancement ratio (DER) and tumour to normal tissue ratio (TNTR) as functions of photon energy over various tumour and body geometries. Methods: GNP-enhanced arc radiotherapy (GEART) was simulated using the PENELOPE Monte Carlo code and penEasy main program. We simulated 360° arc-therapy with monoenergetic photon energies 50 – 1000 keV and several clinical spectra used to treat a spherical tumourmore » containing uniformly distributed GNPs in a cylindrical tissue phantom. Various geometries were used to simulate different tumour sizes and depths. Voxel dose was used to calculate DERs and TNTRs. Inhomogeneity effects were examined through skull dose in brain tumour treatment simulations. Results: Below 100 keV, DERs greater than 2.0 were observed. Compared to 6 MV, tumour dose at low energies was more conformai, with lower normal tissue dose and higher TNTRs. Both the DER and TNTR increased with increasing cylinder radius and decreasing tumour radius. The inclusion of bone showed excellent tumour conformality at low energies, though with an increase in skull dose (40% of tumour dose with 100 keV compared to 25% with 6 MV). Conclusions: Even in the presence of inhomogeneities, our results show promise for the treatment of deep-seated tumours with low-energy GEART, with greater tumour dose conformality and lower normal tissue dose than 6 MV.« less

A mathematical model describes the malignant transformation of low grade gliomas: Prognostic implications.

PubMed

Bogdańska, Magdalena U; Bodnar, Marek; Piotrowska, Monika J; Murek, Michael; Schucht, Philippe; Beck, Jürgen; Martínez-González, Alicia; Pérez-García, Víctor M

2017-01-01

Gliomas are the most frequent type of primary brain tumours. Low grade gliomas (LGGs, WHO grade II gliomas) may grow very slowly for the long periods of time, however they inevitably cause death due to the phenomenon known as the malignant transformation. This refers to the transition of LGGs to more aggressive forms of high grade gliomas (HGGs, WHO grade III and IV gliomas). In this paper we propose a mathematical model describing the spatio-temporal transition of LGGs into HGGs. Our modelling approach is based on two cellular populations with transitions between them being driven by the tumour microenvironment transformation occurring when the tumour cell density grows beyond a critical level. We show that the proposed model describes real patient data well. We discuss the relationship between patient prognosis and model parameters. We approximate tumour radius and velocity before malignant transformation as well as estimate the onset of this process.

Role of 5-ALA in improving extent of tumour resection in patients with Glioblastoma Multiforme.

PubMed

Waqas, Muhammad; Khan, Inamullah; Shamim, Muhammad Shahzad

2017-10-01

Goal of surgery for patients with Glioblastoma Multiforme (GBM) is gross total resection with no new neurological deficits. Surgical resection is often restricted due the difficulty in differentiating the tumour from surrounding normal brain using either naked eye, or standard intra-operative white light microscopy. GBM uptakes orally administered 5-ALA becomes fluorescent when viewed by a special light, and this property has been used to improve intra-operative tumour identification. This technique should therefore allow better extent of tumour resection. The hypothesis has been tested through several studies and even though most studies are of low quality, they strongly favour the use of 5- ALA in improving the extent of resection when compared to white light microscopy. A systematic review on the topic had a similar conclusion. Few studies have also hinted on a high false negative rate with the use of this technique..

Long-term supratentorial brain structure and cognitive function following cerebellar tumour resections in childhood.

PubMed

Moberget, T; Andersson, S; Lundar, T; Due-Tønnessen, B J; Heldal, A; Endestad, T; Westlye, L T

2015-03-01

The cerebellum is connected to extensive regions of the cerebrum, and cognitive deficits following cerebellar lesions may thus be related to disrupted cerebello-cerebral connectivity. Moreover, early cerebellar lesions could affect distal brain development, effectively inducing long-term changes in brain structure and cognitive function. Here, we characterize supratentorial brain structure and cognitive function in 20 adult patients treated for cerebellar tumours in childhood (mean age at surgery: 7.1 years) and 26 matched controls. Relative to controls, patients showed reduced cognitive function and increased grey matter density in bilateral cingulum, left orbitofrontal cortex and the left hippocampus. Within the patient group, increased grey matter density in these regions was associated with decreased performance on tests of processing speed and executive function. Further, diffusion tensor imaging revealed widespread alterations in white matter microstructure in patients. While current ventricle volume (an index of previous hydrocephalus severity it patients) was associated with grey matter density and white matter microstructure in patients, this could only partially account for the observed group differences in brain structure and cognitive function. In conclusion, our results show distal effects of cerebellar lesions on cerebral integrity and wiring, likely caused by a combination of neurodegenerative processes and perturbed neurodevelopment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy.

PubMed

Waragai, M; Chiba, A; Uchibori, A; Fukushima, T; Anno, M; Tanaka, K

2006-01-01

A 36 year old man with a history of testicular germ cell tumour presented six months after bilateral orchidectomy with progressive amnesia, irritability, vertical gaze palsy, and generalised seizures. Eight months after initial onset of symptoms, he demonstrated a head drop with muscular atrophy of the upper limbs, shoulder girdle, and posterior neck. He reported no sensory disturbances and his sensory examination was normal. The overall clinical presentation was consistent with motor neurone disease. Cerebrospinal fluid analysis revealed mild pleocytosis and increased protein concentration. Serum and cerebrospinal fluid were positive for the anti-Ma2 antibody by western blot analysis and immunostaining. Abnormal high signal in the grey matter was noted in the cervical spinal cord and brain by T2 weighted magnetic resonance imaging (MRI). The patient was treated with corticosteroids, intravenous immunoglobulin, and antiepileptic medication. The patient improved clinically and symptom progression ceased after initiation of treatment. There was complete resolution of the abnormal brain MRI lesions; however, the cervical spinal cord MRI lesion and muscular atrophy remained unchanged. It is suggested that the anti-Ma2 antibody is involved not only in encephalitis, but may also play a role in the cervical spinal cord lesions resulting in a motor neurone disease-like presentation.

Anti‐Ma2 associated paraneoplastic neurological syndrome presenting as encephalitis and progressive muscular atrophy

PubMed Central

Waragai, M; Chiba, A; Uchibori, A; Fukushima, T; Anno, M; Tanaka, K

2006-01-01

A 36 year old man with a history of testicular germ cell tumour presented six months after bilateral orchidectomy with progressive amnesia, irritability, vertical gaze palsy, and generalised seizures. Eight months after initial onset of symptoms, he demonstrated a head drop with muscular atrophy of the upper limbs, shoulder girdle, and posterior neck. He reported no sensory disturbances and his sensory examination was normal. The overall clinical presentation was consistent with motor neurone disease. Cerebrospinal fluid analysis revealed mild pleocytosis and increased protein concentration. Serum and cerebrospinal fluid were positive for the anti‐Ma2 antibody by western blot analysis and immunostaining. Abnormal high signal in the grey matter was noted in the cervical spinal cord and brain by T2 weighted magnetic resonance imaging (MRI). The patient was treated with corticosteroids, intravenous immunoglobulin, and antiepileptic medication. The patient improved clinically and symptom progression ceased after initiation of treatment. There was complete resolution of the abnormal brain MRI lesions; however, the cervical spinal cord MRI lesion and muscular atrophy remained unchanged. It is suggested that the anti‐Ma2 antibody is involved not only in encephalitis, but may also play a role in the cervical spinal cord lesions resulting in a motor neurone disease‐like presentation. PMID:16361608

A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord

PubMed Central

Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

2015-01-01

The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. PMID:26123466

Use of mobile phones and risk of brain tumours: update of Danish cohort study

PubMed Central

Poulsen, Aslak H; Johansen, Christoffer; Olsen, Jørgen H; Steding-Jessen, Marianne; Schüz, Joachim

2011-01-01

Objective To investigate the risk of tumours in the central nervous system among Danish mobile phone subscribers. Design Nationwide cohort study. Setting Denmark. Participants All Danes aged ≥30 and born in Denmark after 1925, subdivided into subscribers and non-subscribers of mobile phones before 1995. Main outcome measures Risk of tumours of the central nervous system, identified from the complete Danish Cancer Register. Sex specific incidence rate ratios estimated with log linear Poisson regression models adjusted for age, calendar period, education, and disposable income. Results 358 403 subscription holders accrued 3.8 million person years. In the follow-up period 1990-2007, there were 10 729 cases of tumours of the central nervous system. The risk of such tumours was close to unity for both men and women. When restricted to individuals with the longest mobile phone use—that is, ≥13 years of subscription—the incidence rate ratio was 1.03 (95% confidence interval 0.83 to 1.27) in men and 0.91 (0.41 to 2.04) in women. Among those with subscriptions of ≥10 years, ratios were 1.04 (0.85 to 1.26) in men and 1.04 (0.56 to 1.95) in women for glioma and 0.90 (0.57 to 1.42) in men and 0.93 (0.46 to 1.87) in women for meningioma. There was no indication of dose-response relation either by years since first subscription for a mobile phone or by anatomical location of the tumour—that is, in regions of the brain closest to where the handset is usually held to the head. Conclusions In this update of a large nationwide cohort study of mobile phone use, there were no increased risks of tumours of the central nervous system, providing little evidence for a causal association. PMID:22016439

A dynamic model for tumour growth and metastasis formation.

PubMed

Haustein, Volker; Schumacher, Udo

2012-07-05

A simple and fast computational model to describe the dynamics of tumour growth and metastasis formation is presented. The model is based on the calculation of successive generations of tumour cells and enables one to describe biologically important entities like tumour volume, time point of 1st metastatic growth or number of metastatic colonies at a given time. The model entirely relies on the chronology of these successive events of the metastatic cascade. The simulation calculations were performed for two embedded growth models to describe the Gompertzian like growth behaviour of tumours. The initial training of the models was carried out using an analytical solution for the size distribution of metastases of a hepatocellular carcinoma. We then show the applicability of our models to clinical data from the Munich Cancer Registry. Growth and dissemination characteristics of metastatic cells originating from cells in the primary breast cancer can be modelled thus showing its ability to perform systematic analyses relevant for clinical breast cancer research and treatment. In particular, our calculations show that generally metastases formation has already been initiated before the primary can be detected clinically.

A dynamic model for tumour growth and metastasis formation

PubMed Central

2012-01-01

A simple and fast computational model to describe the dynamics of tumour growth and metastasis formation is presented. The model is based on the calculation of successive generations of tumour cells and enables one to describe biologically important entities like tumour volume, time point of 1st metastatic growth or number of metastatic colonies at a given time. The model entirely relies on the chronology of these successive events of the metastatic cascade. The simulation calculations were performed for two embedded growth models to describe the Gompertzian like growth behaviour of tumours. The initial training of the models was carried out using an analytical solution for the size distribution of metastases of a hepatocellular carcinoma. We then show the applicability of our models to clinical data from the Munich Cancer Registry. Growth and dissemination characteristics of metastatic cells originating from cells in the primary breast cancer can be modelled thus showing its ability to perform systematic analyses relevant for clinical breast cancer research and treatment. In particular, our calculations show that generally metastases formation has already been initiated before the primary can be detected clinically. PMID:22548735

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).

PubMed

Wimmer, Katharina; Kratz, Christian P; Vasen, Hans F A; Caron, Olivier; Colas, Chrystelle; Entz-Werle, Natacha; Gerdes, Anne-Marie; Goldberg, Yael; Ilencikova, Denisa; Muleris, Martine; Duval, Alex; Lavoine, Noémie; Ruiz-Ponte, Clara; Slavc, Irene; Burkhardt, Brigit; Brugieres, Laurence

2014-06-01

Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2. The tumour spectrum is very broad, including mainly haematological, brain and intestinal tract tumours. Patients show a variety of non-malignant features that are indicative of CMMRD. However, currently no criteria that should entail diagnostic evaluation of CMMRD exist. We present a three-point scoring system for the suspected diagnosis CMMRD in a paediatric/young adult cancer patient. Tumours highly specific for CMMRD syndrome are assigned three points, malignancies overrepresented in CMMRD two points and all other malignancies one point. According to their specificity for CMMRD and their frequency in the general population, additional features are weighted with 1-2 points. They include multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity. According to the scoring system, CMMRD should be suspected in any cancer patient who reaches a minimum of three points by adding the points of the malignancy and the additional features. The diagnostic steps to confirm or refute the suspected diagnosis are outlined. We expect that application of the suggested strategy for CMMRD diagnosis will increase the number of patients being identified at the time when they develop their first tumour. This will allow adjustment of the treatment modalities, offering surveillance strategies for second malignancies and appropriate counselling of the entire family. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas.

PubMed

Portnow, Jana; Badie, Behnam; Markel, Susan; Liu, An; D'Apuzzo, Massimo; Frankel, Paul; Jandial, Rahul; Synold, Timothy W

2013-05-01

The primary objective of this study was to use intracerebral microdialysis (ICMD) to determine the neuropharmacokinetics of bafetinib, a dual BCR-Abl/Lyn tyrosine kinase inhibitor that may have activity against gliomas. A microdialysis catheter was placed into either peritumoural or enhancing brain tissue of seven patients at the time of tumour resection or biopsy. Twenty-four hours later, bafetinib was administered, 240 or 360 mg po, repeating the same dose 12 h later. Dialysate samples were continuously collected for 24h, with plasma samples obtained in parallel. One to two weeks after finishing ICMD, patients were allowed to resume taking bafetinib continuously while being observed for toxicity and tumour response. Twenty-six dialysate samples per patient were collected (n=6) and analysed for bafetinib by tandem mass spectrometry. Bafetinib concentrations in the brain were below the lower limit of detection of the assay (0.1 ng/ml) in all samples except one from a single subject that was 0.52 ng/ml. The mean plasma bafetinib maximum concentrations after dose 1 and 2 were 143±99 and 247±73 ng/ml, respectively. Only one patient remained on treatment past two cycles, and no radiographic responses were seen. Bafetinib does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours. ICMD can be a valuable research tool in early drug development. Lead-in ICMD studies can be performed relatively quickly, requiring only a small number of patients, and without significantly disrupting standard cancer care. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Academic future of children treated for brain tumors. Single-center study of 27 children].

PubMed

Zucchinelli, V; Bouffet, E

2000-09-01

Brain tumours constitute the most common type of solid malignancy in childhood. Despite intensive efforts developed since the mid-1970s in paediatric neuro-oncology, survivors still have a wide range of sequelae leading to frequent failure in academic achievements. Very few studies have detailed the educational outcome of these children. The study was based on a questionnaire sent to the parents of children diagnosed with a brain tumour and treated at the Centre Léon-Bérard between 1987 and 1993. Children had to be under 12 years old at the time of diagnosis and with at least three years of follow-up since diagnosis. Questions focused on the child's education before diagnosis, his progress during and after treatment, the measures taken when the child experienced learning difficulties and their consequences on the child's socioprofessional integration. Twenty-seven responses were obtained out of 34 questionnaires. Twenty-six children were reported to experience learning difficulties. Only four children had a normal education. The main problems are associated with slowness, memory and comprehension difficulties. The main disciplines affected are mathematics, reading and spelling. Fifteen children did benefit from extra support, with large interindividual variations in the amount and the quality of this support. Half of the parents play an active role in their child's extra support. This study provides additional information to previous reports on progressive I.Q. decline following the treatment of a brain tumour in childhood. Learning difficulties are nearly constant and adversely influence the child's curriculum. They also affect the parents who experience questions about the future of their ideal child. The severity and complexity of these learning difficulties urge for an early multidisciplinary educational and psychological management. The main characteristics of these remedial efforts should be assessed in prospective studies.

Use of diffusion-weighted MRI to modify radiosurgery planning in brain metastases may reduce local recurrence.

PubMed

Zakaria, Rasheed; Pomschar, Andreas; Jenkinson, Michael D; Tonn, Jörg-Christian; Belka, Claus; Ertl-Wagner, Birgit; Niyazi, Maximilian

2017-02-01

Stereotactic radiosurgery (SRS) is an effective and well tolerated treatment for selected brain metastases; however, local recurrence still occurs. We investigated the use of diffusion weighted MRI (DWI) as an adjunct for SRS treatment planning in brain metastases. Seventeen consecutive patients undergoing complete surgical resection of a solitary brain metastasis underwent image analysis retrospectively. SRS treatment plans were generated based on standard 3D post-contrast T1-weighted sequences at 1.5T and then separately using apparent diffusion coefficient (ADC) maps in a blinded fashion. Control scans immediately post operation confirmed complete tumour resection. Treatment plans were compared to one another and with volume of local recurrence at progression quantitatively and qualitatively by calculating the conformity index (CI), the overlapping volume as a proportion of the total combined volume, where 1 = identical plans and 0 = no conformation whatsoever. Gross tumour volumes (GTVs) using ADC and post-contrast T1-weighted sequences were quantitatively the same (related samples Wilcoxon signed rank test = -0.45, p = 0.653) but showed differing conformations (CI 0.53, p < 0.001). The diffusion treatment volume (DTV) obtained by combining the two target volumes was significantly greater than the treatment volume based on post contrast T1-weighted MRI alone, both quantitatively (median 13.65 vs. 9.52 cm 3 , related samples Wilcoxon signed rank test p < 0.001) and qualitatively (CI 0.74, p = 0.001). This DTV covered a greater volume of subsequent tumour recurrence than the standard plan (median 3.53 cm 3 vs. 3.84 cm 3 , p = 0.002). ADC maps may be a useful tool in addition to the standard post-contrast T1-weighted sequence used for SRS planning.

The 2016 revision of the WHO Classification of Central Nervous System Tumours: retrospective application to a cohort of diffuse gliomas.

PubMed

Rogers, Te Whiti; Toor, Gurvinder; Drummond, Katharine; Love, Craig; Field, Kathryn; Asher, Rebecca; Tsui, Alpha; Buckland, Michael; Gonzales, Michael

2018-03-01

The classification of central nervous system tumours has more recently been shaped by a focus on molecular pathology rather than histopathology. We re-classified 82 glial tumours according to the molecular-genetic criteria of the 2016 revision of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Initial diagnoses and grading were based on the morphological criteria of the 2007 WHO scheme. Because of the impression of an oligodendroglial component on initial histological assessment, each tumour was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH-1 and 2) genes. Additionally, expression of proteins encoded by alpha-thalassemia X-linked mental retardation (ATRX) and TP53 genes was assessed by immunohistochemistry. We found that all but two tumours could be assigned to a specific category in the 2016 revision. The most common change in diagnosis was from oligoastrocytoma to specifically astrocytoma or oligodendroglioma. Analysis of progression free survival (PFS) for WHO grade II and III tumours showed that the objective criteria of the 2016 revision separated diffuse gliomas into three distinct molecular categories: chromosome 1p/19q co-deleted/IDH mutant, intact 1p/19q/IDH mutant and IDH wild type. No significant difference in PFS was found when comparing IDH mutant grade II and III tumours suggesting that IDH status is more informative than tumour grade. The segregation into distinct molecular sub-types that is achieved by the 2016 revision provides an objective evidence base for managing patients with grade II and III diffuse gliomas based on prognosis.

Initial diagnosis of small lymphocytic lymphoma in parotidectomy for Warthin tumour, a rare collision tumour

PubMed Central

Saxena, A; Memauri, B; Hasegawa, W

2005-01-01

Warthin tumours (WT) and malignant lymphomas are only rarely associated, and most are examples of involvement of the lymphoid stroma of WT by a disseminated lymphoma. This report describes a case where excision of a parotid mass led to the initial diagnosis of WT and small lymphocytic lymphoma (SLL). The diagnosis of SLL was confirmed by immunohistochemistry and molecular studies. The patient had stage IV A disease and is currently in chemotherapy induced complete remission. This case highlights the extremely rare association of SLL with WT and the importance of evaluation of the WT stroma, where the pale proliferation centres of SLL may mimic germinal centres of reactive lymphoid nodules. PMID:15735173

A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord.

PubMed

Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

2015-06-29

The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. 2015 BMJ Publishing Group Ltd.

Tumour suppressor TRIM33 targets nuclear β-catenin degradation

PubMed Central

Xue, Jianfei; Chen, Yaohui; Wu, Yamei; Wang, Zhongyong; Zhou, Aidong; Zhang, Sicong; Lin, Kangyu; Aldape, Kenneth; Majumder, Sadhan; Lu, Zhimin; Huang, Suyun

2014-01-01

Aberrant activation of β-catenin in the nucleus has been implicated in a variety of human cancers but the fate of nuclear β-catenin is unknown. Here we demonstrate that tripartite motif-containing protein 33 (TRIM33), acting as an E3 ubiquitin ligase, reduces the abundance of nuclear β-catenin protein. TRIM33-mediated β-catenin is destabilized and is GSK-3β or β-TrCP independent. TRIM33 interacts with and ubiquitylates nuclear β-catenin. Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. The function of TRIM33 in suppressing tumour cell proliferation and brain tumour development depends on TRIM33-promoted β-catenin degradation. In human glioblastoma specimens, endogenous TRIM33 levels are inversely correlated with β-catenin. In summary, our findings identify TRIM33 as a tumour suppressor that can abolish tumour cell proliferation and tumorigenesis by degrading nuclear β-catenin. This work suggests a new therapeutic strategy against human cancers caused by aberrant activation of β-catenin. PMID:25639486

Short term outcomes following surgery in brain tumours sans neuronavigation.

PubMed

Rashid, Mamoon Ur; Junaid, Muhammad; Bukhari, Syed Sarmad; Afsheen, Afeera

2018-02-01

To determine the presentation and frequency of various intracranial neoplasms and assess outcomes for patients who underwent surgery without neuronavigation. This retrospective study was conducted at Combined Military Hospital, Peshawar, Pakistan, and comprised medical records related to the period from August 2011 to July 2014. Patient histories, examination reports and preoperative and post-operative radiological scans were reviewed and extent of excision was determined based on these coupled with recurrence rates. Intraoperatively, tumour excision was determined largely by the experience of the surgeon and preoperative planning using bony landmarks and radiological scans as an objective guide to resection. SPSS 21 was used for data analysis. Of the 143 patients, 83(57.9%) were males and 60(42.1%)were females. Gliomas were the most common tumours, occurring in 20(33.3%) females and 35(42.2%) males. One-year survival rate for grade 4 astrocytomas was poor (39.4%) and was excellent for meningiomas (100%) and pituitary tumours (100%). Time-tested methods of careful neurological examination and knowledge of neuroanatomy can allow a surgeon with limited resources to plan and accommodate for accurate tumour resection with adequate margins.

Spinal cord gliomas: management and outcome with reference to adjuvant therapy.

PubMed

Nishio, S; Morioka, T; Fujii, K; Inamura, T; Fukui, M

2000-01-01

The authors review their experience with 19 consecutive cases with either astrocytic tumour (glioblastoma multiforme one, anaplastic astrocytoma one, astrocytoma 4, pilocytic astrocytoma 4) or ependymoma (10 tumours in 9 patients) of the spinal cord who were treated during the period from 1982 to 1996. The patients included 10 male and 9 female patients with a median age of 38 years. The main tumour locations included the cervicomedullary region 5 the cervical cord (8), the thoracic cord (5) and one each in the thoracolumbar region and conus medullaris. While a total removal of the tumour was achieved in 8 out of 10 ependymomas, the initial treatment for astrocytic tumours was a partial resection in 5, and biopsy in the remaining 5. As adjuvant treatment, 8 patients received radiation therapy and 2 received chemotherapy. Two patients with an astrocytic tumour received chemotherapy only, while the remaining 9 received neither radiation therapy nor chemotherapy initially. After these treatments, 6 out of the 8 patients with low grade astrocytoma have remained alive for 1.3-12.6 years, while 2 patients with high grade astrocytic tumours died within 15 months following surgery. Eight out of 9 patients with an ependymoma have remained alive for 3.0-12.3 years, while one committed suicide 2 years after surgery. As a result, 14 patients are still alive; half of them are accompanied by a mild neurological dysfunction, while the remaining one has a moderate deficit. The postoperative results and the rationale for surgery is discussed, and an approach for utilising adjuvant therapy for high grade tumours is also suggested.

A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

NASA Astrophysics Data System (ADS)

Spring, Bryan Q.; Bryan Sears, R.; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

2016-04-01

Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

NASA Astrophysics Data System (ADS)

Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang

2016-10-01

A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

Cellular phones and their hazards: the current evidence.

PubMed

Munshi, Anusheel; Jalali, Rakesh

2002-01-01

The past decade has seen an exponential increase globally in the use of cellular phones (popularly known as mobile or cell phones). These phones are convenient and trendy. Discarding the wire means that the communication is through electromagnetic waves, which could have potential hazards. Alarmist reports in the lay press and high profile lawsuits, particularly in the West, have attracted attention to the possible harmful effects of cellular phones. Adverse effects investigated by various clinical trials include the possible link to increased risk of vehicular accidents, leukaemias, sleep disturbances and the more serious brain tumours. Available level II evidence suggests that the only proven side-effect is an increased risk of vehicular accidents. So far, all studies have consistently negated any association between cellular phones and brain tumours. Yet, the final word remains to be said.

Photodynamic application in neurosurgery: present and future

NASA Astrophysics Data System (ADS)

Kostron, Herwig

2009-06-01

Photodynamic techniques such as photodynamic diagnosis (PDD), fluorescence guided tumor resection (FGR) and photodynamic therapy (PDT) are currently undergoing intensive clinical investigations as adjunctive treatment for malignant brain tumours. This review provides an overview on the current clinical data and trials as well as on photosensitisers, technical developments and indications for photodynamic application in Neurosurgery. Furthermore new developments and clinical significance of FGR for neurosurgery will be discussed. Over 1000 patients were enrolled in various clinical phase I/II trials for PDT for malignant brain tumours. Despite various treatment protocols, variation of photosensitisers and light dose there is a clear trend towards prolonging median survival after one single PDT as compared to conventional therapeutic modalities. The median survival after PDT for primary glioblastoma multiforme WHO IV was 19 months and for recurrent GBM 9 months as compared to standard convential treatment which is 15 months and 3 months, respectively. FGR in combination with adjunctive radiation was significantly superior to standard surgical resection followed by radiation. The combination of FGR/PDD and intraoperative PDT increased significantly survival in recurrent glioblastoma patients. The combination of PDD/ FGR and PDT offers an exciting approach to the treatment of malignant brain tumours "to see and to treat." PDT was generally well tolerated and side effects consisted of occasionally increased intracranial pressure and prolonged skin sensitivity against direct sunlight. This review covers the current available data and draws the future potential of PDD and PDT for its application in neurosurgery.

Lesser-known myelin-related disorders: focal tumour-like demyelinating lesions.

PubMed

Jiménez Arango, J A; Uribe Uribe, C S; Toro González, G

2015-03-01

Focal tumour-like demyelinating lesions are defined as solitary demyelinating lesions with a diameter greater than 2 cm. In imaging studies, these lesions may mimic a neoplasm or brain abscess; as a result, invasive diagnostic and therapeutic measures may be performed that will in some cases increase morbidity. Our aim was to analyse and characterise these lesions according to their clinical, radiological, and pathological characteristics, and this data in addition to our literature review will contribute to a better understanding of these lesions. This descriptive study includes 5 cases with pathological diagnoses. We provide subject characteristics gathered through reviewing their clinical, radiology, and pathology reports. Patients' ages ranged from 12 to 60 years; 3 patients were female. The time delay between symptom onset and hospital admission was 3 to 120 days. Clinical manifestations were diverse and dependent on the location of the lesion, pyramidal signs were found in 80% of patients, there were no clinical or radiological signs of spinal cord involvement, and follow-up times ranged from 1 to 15 years. Brain biopsy is the gold standard for the diagnosis of demyelinating tumour-like lesions; however, their clinical features, along with several magnetic resonance imaging features such as open ring enhancement, venular enhancement, the presence of glutamate in spectroscopy, and others, may be sufficient to differentiate neoplastic lesions from focal tumour-like demyelinating lesions. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome.

PubMed

Caswell, Deborah R; Swanton, Charles

2017-07-18

The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes. Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability. We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens.

Late presentation of canine nasal tumours in a UK referral hospital and treatment outcomes.

PubMed

Mason, S L; Maddox, T W; Lillis, S M; Blackwood, L

2013-07-01

To determine the computed tomographic stage of dogs with nasal tumours in a UK referral population, and whether stage, time to referral and treatment correlates with outcome. Retrospective review of clinical records and computed tomography scans of dogs with nasal tumours. Dogs (n=78) presented to a referral practice in the UK with suspected nasal tumours are presented with more late stage tumours than dogs in the USA and Japan. Length of time from initial presentation to referral did not correlate with tumour stage at diagnosis. Median survival times for radiotherapy-treated dogs in this population are equivalent to those previously reported for late stage nasal tumours. Dogs with nasal tumours are presented late in the course of disease in the North West of England. Dogs with clinical signs consistent with a nasal tumour should have timely imaging and biopsy, in order to make prompt treatment decisions. Although survival times are comparable with previous reports and radiotherapy is a valid treatment option for dogs with late stage disease, better outcomes are likely to be achievable with earlier treatment. © 2013 British Small Animal Veterinary Association.

Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice.

PubMed

Henke, Guido; Meier, Verena; Lindner, Lars H; Eibl, Hansjörg; Bamberg, Michael; Belka, Claus; Budach, Wilfried; Jendrossek, Verena

2012-10-18

Erufosine is a promising anticancer drug that increases the efficacy of radiotherapy in glioblastoma cell lines in vitro. Moreover, treatment of nude mice with repeated intraperitoneal or subcutaneous injections of Erufosine is well tolerated and yields drug concentrations in the brain tissue that are higher than the concentrations required for cytotoxic drug effects on glioblastoma cell lines in vitro. In the present study we aimed to evaluate the effects of a combined treatment with radiotherapy and Erufosine on growth and local control of T98G subcutaneous glioblastoma xenograft-tumours in NMRI nu/nu mice. We show that repeated intraperitoneal injections of Erufosine resulted in a significant drug accumulation in T98G xenograft tumours on NMRI nu/nu mice. Moreover, short-term treatment with 5 intraperitoneal Erufosine injections caused a transient decrease in the growth of T98G tumours without radiotherapy. Furthermore, an increased radiation-induced growth delay of T98G xenograft tumours was observed when fractionated irradiation was combined with short-term Erufosine-treatment. However, no beneficial drug effects on fractionated radiotherapy in terms of local tumour control were observed. We conclude that short-term treatment with Erufosine is not sufficient to significantly improve local control in combination with radiotherapy in T98G glioblastoma xenograft tumours. Further studies are needed to evaluate efficacy of extended drug treatment schedules.

[Radio and microwave frequency radiation and health--an analysis of the literature].

PubMed

Röösli, M; Rapp, R; Braun-Fahrländer, C

2003-06-01

This paper gives an overview of present scientific knowledge in health research on the effects from radio and microwave frequency radiation, at levels to which the general population is typically exposed. The review is based on human experimental and epidemiological studies investigating the effects of radiation in the frequency range between 100 kHz and 10 GHz. The relevant studies were identified via systematic searches of the databases Medline and ISI Web of Science. The review concludes that the existing scientific knowledge base is too limited to draw final conclusions on the health risk from exposure in the low-dose range. Only few studies have investigated the effect of long-term exposure on the general population in the normal environment. Accordingly, little can be predicted regarding long-term health risks. Various studies observed an increased risk for tumours in the hematopoietic and lymphatic tissue of people living in the proximity of TV and radio broadcast transmitters. However, methodological limitations to these studies have been identified and their findings are controversial. In studies of a possible association between brain tumours and mobile phone use, the average period mobile phones use was short compared to the known latency period of brain tumours. Although these studies did not establish an overall increased risk of brain tumours associated with mobile phone use, there were some indications of an association. Immediate effects associated with mobile phone use have been observed in human experimental studies that cannot be explained by conventional thermal mechanisms. The observed effects are within the normal physiological range and are therefore hard to interpret with respect to an increased risk to health. However, it can be concluded that mechanisms other than the established thermal mechanisms exist. Because of the present fragmentary scientific database, a precautionary approach when dealing with radio and microwave frequency radiation is recommended for the individual and the general population.

PubMed Central

BARBIERI, M.; MUSIZZANO, Y.; BOGGIO, M.; CARCUSCIA, C.

2011-01-01

SUMMARY Granular cell tumour is a rare soft tissue neoplasm that can virtually affect any site of the body. Its histological origin is controversial, since several studies have shown that different cells are involved. Granular cell tumour was initially described as myoblastoma, but, at present, a neural origin is supported by most Authors, due to the immunohistochemical pattern. Even if the biological behaviour of granular cell tumours is usually benign, accurate histological examination is mandatory, because in a small number of cases they can be malignant. Here, a case is described of granular cell tumour in a 14-year-old boy, which is a very rare occurrence, since these tumours typically manifest in subjects between the third and sixth decade. Histopathological features, differential diagnosis and therapeutic implications of granular cell tumour are discussed, together with a brief review of the recent literature. PMID:22058595

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis.

PubMed

Tichet, Mélanie; Prod'Homme, Virginie; Fenouille, Nina; Ambrosetti, Damien; Mallavialle, Aude; Cerezo, Michael; Ohanna, Mickaël; Audebert, Stéphane; Rocchi, Stéphane; Giacchero, Damien; Boukari, Fériel; Allegra, Maryline; Chambard, Jean-Claude; Lacour, Jean-Philippe; Michiels, Jean-François; Borg, Jean-Paul; Deckert, Marcel; Tartare-Deckert, Sophie

2015-04-30

Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.

Nasopharyngeal carcinoma presented as cavernous sinus tumour.

PubMed

Moona, Mohammad Shafi; Mehdi, Itrat

2011-12-01

A 32 year Libyan male presented with the complaints of headache and diplopia. He was diagnosed with a cavernous sinus meningioma on the basis of MRI findings but no initial biopsy was taken. Depending on the radiologic diagnosis the patient was treated with gamma knife surgery twice, abroad. During follow up he developed left ear deafness and left cervical lymph adenopathy. An ENT evaluation with biopsy from the nasopharynx and cervical lymph node was taken. The histopathologic diagnosis of the resected tumour showed a nasopharyngeal carcinoma with cervical lymph node metastasis (poorly differentiated lympho-epithelial carcinoma). The cavernous sinus tumour which was initially treated as a meningioma was in fact metastasis from the nasopharyngeal carcinoma, making this an interesting and rare occurrence.

Assessing emotional status following acquired brain injury: the clinical potential of the depression, anxiety and stress scales.

PubMed

Ownsworth, Tamara; Little, Trudi; Turner, Ben; Hawkes, Anna; Shum, David

2008-10-01

To investigate the clinical potential of the Depression, Anxiety and Stress Scales (DASS 42) and its shorter version (DASS 21) for assessing emotional status following acquired brain injury. Participants included 23 individuals with traumatic brain injury (TBI), 25 individuals with brain tumour and 29 non-clinical controls. Investigations of internal consistency, test-re-test reliability, theory-consistent differences, sensitivity to change and concurrent validity were conducted. Internal consistency of the DASS was generally acceptable (r > 0.70), with the exception of the anxiety scale for the TBI sample. Test-re-test reliability (1-3 weeks) was sound for the depression scale (r > 0.75) and significant but comparatively lower for other scales (r = 0.60-0.73, p < 0.01). Theory-consistent differences were only evident between the brain tumour sample and non-clinical control sample on the anxiety scale (p < 0.01). Sensitivity to change of the DASS in the context of hospital discharge was demonstrated for depression and stress (p < 0.01), but not for anxiety (p > 0.05). Concurrent validity with the Hospital Anxiety and Depression Scale was significant for all scales of the DASS (p < 0.05). While the results generally support the clinical application of the DASS following ABI, further research examining the factor structure of existing and modified versions of the DASS is recommended.

Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights.

PubMed

Alfonso, J C L; Köhn-Luque, A; Stylianopoulos, T; Feuerhake, F; Deutsch, A; Hatzikirou, H

2016-11-23

Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.

Secretory meningioma: clinicopathologic features of eight cases.

PubMed

Nishio, S; Morioka, T; Suzuki, S; Hirano, K; Fukui, M

2001-07-01

The clinical and morphological features of eight patients with meningothelial meningiomas with numerous pseudopsammoma bodies (secretory meningiomas) are presented. The six female and two male patients ranged in age from 43 to 68 years. Tumours were located at the petroclival region in two, the lateral parasellar region in two, the petrous apex in one and the sphenoid ridge in three patients. On magnetic resonance imaging, they were iso or hypointense on T1-weighted images, and hyper or isointense on T 2-weighted images. Peritumoral brain edema was absent in five cases, and was mild to moderate in three cases. Serum carcinoembryonic antigen (CEA) levels were measured preoperatively in three patients, with one having an elevated serum CEA level which re turned to normal following tumour resection. Immunohistochemical analysis on the resected tumour tissues, pseudopsammoma bodies and surrounding tumour cells were shown to be CEA-positive. Ultrastructurally, pseudopsammoma bodies were composed of granular and filamentous materials located predominantly in the intracellular lumina, which were lined by microvilli. While these morphological features of focal epithelial and secretory differentiation of tumour cells call attention to the broad spectrum of differentiation properties of meningiomas, the biological behavior of the eight tumours reported herein corresponded to those of meningiomas in general. Copyright 2001 Harcourt Publishers Ltd.

Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights

NASA Astrophysics Data System (ADS)

Alfonso, J. C. L.; Köhn-Luque, A.; Stylianopoulos, T.; Feuerhake, F.; Deutsch, A.; Hatzikirou, H.

2016-11-01

Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.

Significance of perivascular tumour cells defined by CD109 expression in progression of glioma.

PubMed

Shiraki, Yukihiro; Mii, Shinji; Enomoto, Atsushi; Momota, Hiroyuki; Han, Yi-Peng; Kato, Takuya; Ushida, Kaori; Kato, Akira; Asai, Naoya; Murakumo, Yoshiki; Aoki, Kosuke; Suzuki, Hiromichi; Ohka, Fumiharu; Wakabayashi, Toshihiko; Todo, Tomoki; Ogawa, Seishi; Natsume, Atsushi; Takahashi, Masahide

2017-12-01

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Skull and cerebrospinal fluid effects on microwave radiation propagation in human brain

NASA Astrophysics Data System (ADS)

Ansari, M. A.; Zarei, M.; Akhlaghipour, N.; Niknam, A. R.

2017-12-01

The determination of microwave absorption distribution in the human brain is necessary for the detection of brain tumors using thermo-acoustic imaging and for removing them using hyperthermia treatment. In contrast to ionizing radiation, hyperthermia treatment can be applied to remove tumors inside the brain without the concern of including secondary malignancies, which typically form from the neuronal cells of the septum pellucidum. The aim of this study is to determine the microwave absorption distribution in an adult human brain and to study the effects of skull and cerebrospinal fluid on the propagation of microwave radiation inside the brain. To this end, we simulate the microwave absorption distribution in a realistic adult brain model (Colin 27) using the mesh-based Monte Carlo (MMC) method. This is because in spite of there being other numerical methods, the MMC does not require a large memory, even for complicated geometries, and its algorithm is simple and easy to implement with low computational cost. The brain model is constructed using high-resolution (1 mm isotropic voxel) and low noise magnetic resonance imaging (MRI) scans and its volume contains 181×217×181 voxels, covering the brain completely. Using the MMC method, the radiative transport equation is solved and the absorbed microwave energy distribution in different brain regions is obtained without any fracture or anomaly. The simulation results show that the skull and cerebrospinal fluid guide the microwave radiation and suppress its penetration through deep brain compartments as a shielding factor. These results reveal that the MMC can be used to predict the amount of required energy to increase the temperature inside the tumour during hyperthermia treatment. Our results also show why a deep tumour inside an adult human brain cannot be efficiently treated using hyperthermia treatment. Finally, the accuracy of the presented numerical method is verified using the signal flow graph technique.

Patterns of initial management of node-negative breast cancer in two Canadian provinces

PubMed Central

Goel, V; Olivotto, I; Hislop, T G; Sawka, C; Coldman, A; Holowaty, E J

1997-01-01

OBJECTIVE: To describe the patterns of initial management of node-negative breast cancer in Ontario and British Columbia and to compare the characteristics of the patients and tumours and of the physicians and hospitals involved in management. DESIGN: Retrospective, population-based, cohort study. PARTICIPANTS: All 942 newly diagnosed cases of node-negative breast cancer in 1991 in British Columbia and a random sample of 938 newly diagnosed cases in Ontario in the same year. OUTCOME MEASURES: Number and proportion of patients with newly diagnosed node-negative breast cancer who received breast-conserving surgery (BCS) or mastectomy and who received radiation therapy after BCS. RESULTS: BCS was used in 413 cases (43.8%) in British Columbia and in 634 cases (67.6%) in Ontario (p < 0.001). After BCS, radiation therapy was received by 378 patients (91.5% of those who had undergone BCS) in British Columbia and 479 patients (75.6% of those who had undergone BCS) in Ontario (p < 0.001). In both provinces, lower patient age, smaller tumour size, a noncentral unifocal tumour, absence of extensive ductal carcinoma in situ and initial surgery by a surgeon with an academic affiliation were associated with greater use of BCS. Lower patient age and larger tumour size were associated with greater use of radiation therapy after BCS in both provinces. CONCLUSION: Patient, tumour and physician factors are associated with the choice of initial management of breast cancer in these two Canadian provinces. However, the differences in management between the two provinces are only partly explained by these factors. Other possible explanations, such as the presence of provincial guidelines, differences in the organization of the health care system or differences in patient preference, require further research. PMID:9006561

Dynamics of fertility impairment in childhood brain tumour survivors.

PubMed

Pfitzer, C; Chen, C-M; Wessel, T; Keil, T; Sörgel, A; Langer, T; Steinmann, D; Borgmann-Staudt, A

2014-10-01

Fertility impairment and recovery after chemo- and radiotherapy have been reported in both male and female childhood cancer survivors, but little is known about the dynamics. Our aim, therefore, was to describe the development of fertility impairment and possible recovery in childhood brain tumour survivors. In this longitudinal study, we included 144 survivors, who were treated in two German paediatric oncology centres between 2000 and 2005. Fertility parameters were retrieved from medical records up to 12 years after diagnosis. Participants with age ≥13 years and formerly cranial irradiation ≥30 Gray (n = 23), including 83 % (n = 19) with craniospinal irradiation ≥30 Gray, had a higher median FSH concentration compared to 29 patients without chemoradiotherapy: 8.3 IU/l (IQR 6.5-11.2) versus 4.1 IU/l (IQR 3.2-5.1) 2 years after initial treatment; 8.9 IU/l (IQR 8.5-10.8) versus 4.2 IU/l (IQR 2.4-6.7) after 8 years; and 7.1 IU/l (IQR 6.7-7.7) versus 3.5 IU/l (IQR 2.8-4.2) after 10 years. Altogether, 11/65 women reported the occurrence of amenorrhoea 6.0 years (range 1-10) after diagnosis. Five of these women later developed a regular menstrual cycle without hormone replacement therapy. Patients' chance of recovery from fertility impairment was increased with time since diagnosis (p = 0.074). Signs of fertility impairment such as amenorrhoea and elevated FSH levels were observed at variable time points between 1 and 12 years after chemoradiotherapy. Decreasing FSH levels were observed 1-7 years after elevation and were interpreted either as an atrophy of the pituitary gland or as recovery from fertility impairment.

Direct comparison of (68)Ga-DOTA-TOC and (18)F-FDG PET/CT in the follow-up of patients with neuroendocrine tumour treated with the first full peptide receptor radionuclide therapy cycle.

PubMed

Nilica, Bernhard; Waitz, Dietmar; Stevanovic, Vlado; Uprimny, Christian; Kendler, Dorota; Buxbaum, Sabine; Warwitz, Boris; Gerardo, Llanos; Henninger, Benjamin; Virgolini, Irene; Rodrigues, Margarida

2016-08-01

To determine the value of (68)Ga-DOTA-TOC and (18)F-FDG PET/CT for initial and follow-up evaluation of patients with neuroendocrine tumour (NET) treated with peptide receptor radionuclide therapy (PRRT). We evaluated 66 patients who had histologically proven NET and underwent both PRRT and three combined (68)Ga-DOTA-TOC and (18)F-FDG PET/CT studies. (68)Ga-DOTA-TOC PET/CT was performed before PRRT, 3 months after completion of PRRT and after a further 6 - 9 months. (18)F-FDG PET/CT was done within 2 months of (68)Ga-DOTA-TOC PET/CT. Follow-up ranged from 11.8 to 80.0 months (mean 34.5 months). All patients were (68)Ga-DOTA-TOC PET-positive initially and at follow-up after the first full PRRT cycle. Overall, 62 of the 198 (18)F-FDG PET studies (31 %) were true-positive in 38 of the 66 patients (58 %). Of the 66 patients, 28 (5 grade 1, 23 grade 2) were (18)F-FDG-negative initially and during follow-up (group 1), 24 (5 grade 1, 13 grade 2, 6 grade 3) were (18)F-FDG-positive initially and during follow-up (group 2), 9 patients (2 grade 1, 6 grade 2, 1 grade 3) were (18)F-FDG-negative initially but (18)F-FDG-positive during follow-up (group 3), and 5 patients (all grade 2) were (18)F-FDG-positive initially but (18)F-FDG-negative during follow-up (group 4).(18)F-FDG PET showed more and/or larger metastases than (68)Ga-DOTA-TOC PET in five patients of group 2 and four patients of group 3, all with progressive disease. In three patients with progressive disease who died during follow-up tumour SUVmax increased by 41 - 82 % from the first to the last follow-up investigation. In NET patients, the presence of (18)F-FDG-positive tumours correlates strongly with a higher risk of progression. Initially, patients with (18)F-FDG-negative NET may show (18)F-FDG-positive tumours during follow-up. Also patients with grade 1 and grade 2 NET may have (18)F-FDG-positive tumours. Therefore, (18)F-FDG PET/CT is a complementary tool to (68)Ga-DOTA-TOC PET/CT with clinical relevance for molecular investigation.

Development of a transplantable glioma tumour model from genetically engineered mice: MRI/MRS/MRSI characterisation.

PubMed

Ciezka, Magdalena; Acosta, Milena; Herranz, Cristina; Canals, Josep M; Pumarola, Martí; Candiota, Ana Paula; Arús, Carles

2016-08-01

The initial aim of this study was to generate a transplantable glial tumour model of low-intermediate grade by disaggregation of a spontaneous tumour mass from genetically engineered models (GEM). This should result in an increased tumour incidence in comparison to GEM animals. An anaplastic oligoastrocytoma (OA) tumour of World Health Organization (WHO) grade III was obtained from a female GEM mouse with the S100β-v-erbB/inK4a-Arf (+/-) genotype maintained in the C57BL/6 background. The tumour tissue was disaggregated; tumour cells from it were grown in aggregates and stereotactically injected into C57BL/6 mice. Tumour development was followed using Magnetic Resonance Imaging (MRI), while changes in the metabolomics pattern of the masses were evaluated by Magnetic Resonance Spectroscopy/Spectroscopic Imaging (MRS/MRSI). Final tumour grade was evaluated by histopathological analysis. The total number of tumours generated from GEM cells from disaggregated tumour (CDT) was 67 with up to 100 % penetrance, as compared to 16 % in the local GEM model, with an average survival time of 66 ± 55 days, up to 4.3-fold significantly higher than the standard GL261 glioblastoma (GBM) tumour model. Tumours produced by transplantation of cells freshly obtained from disaggregated GEM tumour were diagnosed as WHO grade III anaplastic oligodendroglioma (ODG) and OA, while tumours produced from a previously frozen sample were diagnosed as WHO grade IV GBM. We successfully grew CDT and generated tumours from a grade III GEM glial tumour. Freezing and cell culture protocols produced progression to grade IV GBM, which makes the developed transplantable model qualify as potential secondary GBM model in mice.

The impact of diagnostic imaging wait times on the prognosis of lung cancer.

PubMed

Byrne, Suzanne C; Barrett, Brendan; Bhatia, Rick

2015-02-01

This study was performed to determine whether gaps in patient flow from initial lung imaging to computed tomography (CT) guided lung biopsy in patients with non-small cell lung cancer (NSCLC) was associated with a change in tumour size, stage, and thus prognosis. All patients who had a CT-guided lung biopsy in 2009 (phase I) and in 2011 (phase II) with a pathologic diagnosis of primary lung cancer (NSCLC) at Eastern Health, Newfoundland, were identified. Dates of initial abnormal imaging, confirmatory CT (if performed), and CT-guided biopsy were recorded, along with tumour size and resulting T stage at each time point. In 2010, wait times for diagnostic imaging at Eastern Health were reduced. The stage and prognosis of NSCLC in 2009 was compared with 2011. In phase 1, there was a statistically significant increase in tumour size (mean difference, 0.67 cm; P < .0001) and stage (P < .0001) from initial image to biopsy. There was a moderate correlation between the time (in days) between the images and change in size (r = 0.33, P = .008) or stage (r = 0.26, P = .036). In phase II, the median wait time from initial imaging to confirmatory CT was reduced to 7.5 days (from 19 days). At this reduced wait time, there was no statistically significant increase in tumour size (mean difference, 0.02; P > .05) or stage (P > .05) from initial imaging to confirmatory CT. Delays in patient flow through diagnostic imaging resulted in an increase in tumour size and stage, with a negative impact on prognosis of NSCLC. This information contributed to the hiring of additional CT technologists and extended CT hours to decrease the wait time for diagnostic imaging. With reduced wait times, the prognosis of NSCLC was not adversely impacted as patients navigated through diagnostic imaging. Copyright © 2015 Canadian Association of Radiologists. All rights reserved.

Randomized pilot study and qualitative evaluation of a clinical decision support system for brain tumour diagnosis based on SV ¹H MRS: evaluation as an additional information procedure for novice radiologists.

PubMed

Sáez, Carlos; Martí-Bonmatí, Luis; Alberich-Bayarri, Angel; Robles, Montserrat; García-Gómez, Juan M

2014-02-01

The results of a randomized pilot study and qualitative evaluation of the clinical decision support system Curiam BT are reported. We evaluated the system's feasibility and potential value as a radiological information procedure complementary to magnetic resonance (MR) imaging to assist novice radiologists in diagnosing brain tumours using MR spectroscopy (1.5 and 3.0T). Fifty-five cases were analysed at three hospitals according to four non-exclusive diagnostic questions. Our results show that Curiam BT improved the diagnostic accuracy in all the four questions. Additionally, we discuss the findings of the users' feedback about the system, and the further work to optimize it for real environments and to conduct a large clinical trial. © 2013 Published by Elsevier Ltd.

An improved monomeric infrared fluorescent protein for neuronal and tumour brain imaging.

PubMed

Yu, Dan; Gustafson, William Clay; Han, Chun; Lafaye, Céline; Noirclerc-Savoye, Marjolaine; Ge, Woo-Ping; Thayer, Desiree A; Huang, Hai; Kornberg, Thomas B; Royant, Antoine; Jan, Lily Yeh; Jan, Yuh Nung; Weiss, William A; Shu, Xiaokun

2014-05-15

Infrared fluorescent proteins (IFPs) are ideal for in vivo imaging, and monomeric versions of these proteins can be advantageous as protein tags or for sensor development. In contrast to GFP, which requires only molecular oxygen for chromophore maturation, phytochrome-derived IFPs incorporate biliverdin (BV) as the chromophore. However, BV varies in concentration in different cells and organisms. Here we engineered cells to express the haeme oxygenase responsible for BV biosynthesis and a brighter monomeric IFP mutant (IFP2.0). Together, these tools improve the imaging capabilities of IFP2.0 compared with monomeric IFP1.4 and dimeric iRFP. By targeting IFP2.0 to the plasma membrane, we demonstrate robust labelling of neuronal processes in Drosophila larvae. We also show that this strategy improves the sensitivity when imaging brain tumours in whole mice. Our work shows promise in the application of IFPs for protein labelling and in vivo imaging.

Identification of a neuronal transcription factor network involved in medulloblastoma development.

PubMed

Lastowska, Maria; Al-Afghani, Hani; Al-Balool, Haya H; Sheth, Harsh; Mercer, Emma; Coxhead, Jonathan M; Redfern, Chris P F; Peters, Heiko; Burt, Alastair D; Santibanez-Koref, Mauro; Bacon, Chris M; Chesler, Louis; Rust, Alistair G; Adams, David J; Williamson, Daniel; Clifford, Steven C; Jackson, Michael S

2013-07-11

Medulloblastomas, the most frequent malignant brain tumours affecting children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1, SUFU) are observed in many of these tumours, high throughput genomic analyses have identified few other recurring mutations. Here, we have mutagenised the Ptch+/- murine tumour model using the Sleeping Beauty transposon system to identify additional genes and pathways involved in SHH subgroup medulloblastoma development. Mutagenesis significantly increased medulloblastoma frequency and identified 17 candidate cancer genes, including orthologs of genes somatically mutated (PTEN, CREBBP) or associated with poor outcome (PTEN, MYT1L) in the human disease. Strikingly, these candidate genes were enriched for transcription factors (p=2x10-5), the majority of which (6/7; Crebbp, Myt1L, Nfia, Nfib, Tead1 and Tgif2) were linked within a single regulatory network enriched for genes associated with a differentiated neuronal phenotype. Furthermore, activity of this network varied significantly between the human subgroups, was associated with metastatic disease, and predicted poor survival specifically within the SHH subgroup of tumours. Igf2, previously implicated in medulloblastoma, was the most differentially expressed gene in murine tumours with network perturbation, and network activity in both mouse and human tumours was characterised by enrichment for multiple gene-sets indicating increased cell proliferation, IGF signalling, MYC target upregulation, and decreased neuronal differentiation. Collectively, our data support a model of medulloblastoma development in SB-mutagenised Ptch+/- mice which involves disruption of a novel transcription factor network leading to Igf2 upregulation, proliferation of GNPs, and tumour formation. Moreover, our results identify rational therapeutic targets for SHH subgroup tumours, alongside prognostic biomarkers for the identification of poor-risk SHH patients.

A novel murine model for evaluating bovine papillomavirus prophylactics/therapeutics for equine sarcoid-like tumours

PubMed Central

Bogaert, Lies; Woodham, Andrew W.; Da Silva, Diane M.; Martens, Ann; Meyer, Evelyne

2015-01-01

Equine sarcoids are highly recurrent bovine papillomavirus (BPV)-induced fibroblastic neoplasms that are the most common skin tumours in horses. In order to facilitate the study of potential equine sarcoid prophylactics or therapeutics, which can be a slow and costly process in equines, a murine model for BPV-1 protein-expressing equine sarcoid-like tumours was developed in mice through stable transfection of BPV-1 E5 and E6 in a murine fibroblast tumour cell line (K-BALB). Like equine sarcoids, these murine tumour cells (BPV-KB) were of fibroblast origin, were tumorigenic and expressed BPV-1 proteins. As an initial investigation of the preclinical potential of this tumour model for equine sarcoids prophylactics, mice were immunized with BPV-1 E5E6 Venezuelan equine encephalitis virus replicon particles, prior to BPV-KB challenge, which resulted in an increased tumour-free period compared with controls, indicating that the BPV-KB murine model may be a valuable preclinical alternative to equine clinical trials. PMID:26044793

A novel murine model for evaluating bovine papillomavirus prophylactics/therapeutics for equine sarcoid-like tumours.

PubMed

Bogaert, Lies; Woodham, Andrew W; Da Silva, Diane M; Martens, Ann; Meyer, Evelyne; Kast, W Martin

2015-09-01

Equine sarcoids are highly recurrent bovine papillomavirus (BPV)-induced fibroblastic neoplasms that are the most common skin tumours in horses. In order to facilitate the study of potential equine sarcoid prophylactics or therapeutics, which can be a slow and costly process in equines, a murine model for BPV-1 protein-expressing equine sarcoid-like tumours was developed in mice through stable transfection of BPV-1 E5 and E6 in a murine fibroblast tumour cell line (K-BALB). Like equine sarcoids, these murine tumour cells (BPV-KB) were of fibroblast origin, were tumorigenic and expressed BPV-1 proteins. As an initial investigation of the preclinical potential of this tumour model for equine sarcoids prophylactics, mice were immunized with BPV-1 E5E6 Venezuelan equine encephalitis virus replicon particles, prior to BPV-KB challenge, which resulted in an increased tumour-free period compared with controls, indicating that the BPV-KB murine model may be a valuable preclinical alternative to equine clinical trials.

Validation of DWI pre-processing procedures for reliable differentiation between human brain gliomas.

PubMed

Vellmer, Sebastian; Tonoyan, Aram S; Suter, Dieter; Pronin, Igor N; Maximov, Ivan I

2018-02-01

Diffusion magnetic resonance imaging (dMRI) is a powerful tool in clinical applications, in particular, in oncology screening. dMRI demonstrated its benefit and efficiency in the localisation and detection of different types of human brain tumours. Clinical dMRI data suffer from multiple artefacts such as motion and eddy-current distortions, contamination by noise, outliers etc. In order to increase the image quality of the derived diffusion scalar metrics and the accuracy of the subsequent data analysis, various pre-processing approaches are actively developed and used. In the present work we assess the effect of different pre-processing procedures such as a noise correction, different smoothing algorithms and spatial interpolation of raw diffusion data, with respect to the accuracy of brain glioma differentiation. As a set of sensitive biomarkers of the glioma malignancy grades we chose the derived scalar metrics from diffusion and kurtosis tensor imaging as well as the neurite orientation dispersion and density imaging (NODDI) biophysical model. Our results show that the application of noise correction, anisotropic diffusion filtering, and cubic-order spline interpolation resulted in the highest sensitivity and specificity for glioma malignancy grading. Thus, these pre-processing steps are recommended for the statistical analysis in brain tumour studies. Copyright © 2017. Published by Elsevier GmbH.

Seizure outcomes in children with epilepsy after resective brain surgery.

PubMed

Nagarajan, Lakshmi; Lee, Michael; Palumbo, Linda; Lee, Sharon; Shah, Snehal; Walsh, Peter; Cannell, Patricia; Ghosh, Soumya

2015-09-01

To assess the role of resective brain surgery in childhood epilepsy. We retrospectively analysed the seizure outcomes in 55 children with epilepsy who had resective brain surgery between 1997 and 2012, at our centre. The children were 1.5-18 years at the time of surgery; their seizure onset was between 0.2 andto 15 years of age. 48 had refractory epilepsy. One child died of tumour progression. Follow-up duration in the survivors ranged from 2 to -16 years (mean: 9).Presurgical evaluation included clinical profiles, non-invasive V-EEG monitoring, neuroimaging with MRIs in all; SPECT and PET in selected patients. 54 had intraoperative ECoG. An Engel Class 1 outcome was seen in 78% of the cohort, with 67% being off all AEDs at the most recent follow-up. Children with tumours constituted the majority (56%), with 87% of this group showing a Class 1 outcome and 84% being off AEDs. Children with cortical dysplasia had a Class 1 outcome in 56%. Resective brain surgery is an efficacious option in some children with epilepsy. We found ECoG useful to tailor the cortical resection and in our opinion ECoG contributed to the good seizure outcomes. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.

PubMed

Bakry, Doua; Aronson, Melyssa; Durno, Carol; Rimawi, Hala; Farah, Roula; Alharbi, Qasim Kholaif; Alharbi, Musa; Shamvil, Ashraf; Ben-Shachar, Shay; Mistry, Matthew; Constantini, Shlomi; Dvir, Rina; Qaddoumi, Ibrahim; Gallinger, Steven; Lerner-Ellis, Jordan; Pollett, Aaron; Stephens, Derek; Kelies, Steve; Chao, Elizabeth; Malkin, David; Bouffet, Eric; Hawkins, Cynthia; Tabori, Uri

2014-03-01

Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development of an autofluorescent probe designed to help brain tumor removal: study on an animal model

NASA Astrophysics Data System (ADS)

Siebert, R.; Leh, B.; Charon, Y.; Collado-Hilly, M.; Duval, M.-A.; Menard, L.; Monnet, F. P.; Varlet, P.

2010-02-01

The complete resection of the brain tumour is crucial to the patient life quality and prognosis. An autofluorescence probe aiming at helping the surgeon to improve the completeness of the removal is being developed. Autofluorescence spectroscopy is a promising approach to define whether the tissue is cancerous or not. First ex vivo measurements have been realised on an animal model. After tumorous cell injection in rat brain, autofluorescence intensity is revealed from the extracted brain. These autofluorescence data are compared to results from a histological analysis of same brains. First indicators are identified that may have the ability to differentiate tumorous and healthy tissues.

Endometrial endometrioid adenocarcinoma associated with primitive neuroectodermal tumour of the uterus: a poor prognostic subtype of uterine tumours.

PubMed

Bartosch, Carla; Vieira, Joana; Teixeira, Manuel R; Lopes, José Manuel

2011-12-01

Uterine primitive neuroectodermal tumours are extremely rare tumours. They can occur in pure form or combined with another component including endometrioid adenocarcinoma. We aimed to review the clinical impact of neuroectodermal phenotype in uterine tumours, after we recently diagnosed one such case. A 58-year-old female presented with irregular vaginal bleeding. Ultrasonography and CT showed the presence of a large uterine mass with irregular contours. At laparotomy it was found to extend to the right ureter, sigmoid colon and some small intestinal loops. Microscopic examination revealed that the tumour consisted of an endometrioid adenocarcinoma component merging with an extensive neuroectodermal component. No EWSR1 or FUS rearrangement was found in the two tumour components. The patient received two courses of chemotherapy but died 11 months after the initial diagnosis. We reviewed the morphological and molecular criteria for the diagnosis of uterine primitive neuroectodermal tumours published in the literature. We conclude that regardless of the detection of an EWSR1 rearrangement, the presence of a neuroectodermal differentiation component in these rare uterine tumours is a marker of aggressive behaviour, and its presence should be highlighted in the diagnosis.

Short-term dietary copper deficiency does not inhibit angiogenesis in tumours implanted in striated muscle.

PubMed Central

Schuschke, D. A.; Reed, M. W.; Saari, J. T.; Olson, M. D.; Ackermann, D. M.; Miller, F. N.

1992-01-01

The effect of dietary copper deficiency on tumour growth, neovascularisation and microvascular integrity was studied in the rat cremaster muscle. Male, weanling Sprague-Dawley rats were fed purified diets which were copper deficient (< 0.5 micrograms g-1 of diet) or copper adequate (5 micrograms g-1 of diet). Seven days after initiation of diets, a chondrosarcoma was implanted in the cremaster muscle of each rat. Five, 10 or 20 days after tumour implantation, rats were anesthetised and their cremasters prepared for observation by intravital microscopy. Intraarterial injection of fluorescein isothiocyanate-conjugated albumin and subsequent observation of fluorescence in the perivascular space indicated no difference in microvascular albumin leakage between the tumour vasculature of copper deficient and copper adequate rats. Neither tumour growth (assessed by wet weight), vascular density (assessed by light microscopy), nor any ultrastructural characteristics of the tumour or its vasculature (assessed by electron microscopy) were affected by copper deficiency. In view of findings by others which indicate changes in tumour characteristics with copper deficiency, we conclude that the copper dependency of tumour growth and vascularisation is a function of the type of tumour, the host tissue, or the conditions of copper depletion. PMID:1280989

Volumetric brain tumour detection from MRI using visual saliency.

PubMed

Mitra, Somosmita; Banerjee, Subhashis; Hayashi, Yoichi

2017-01-01

Medical image processing has become a major player in the world of automatic tumour region detection and is tantamount to the incipient stages of computer aided design. Saliency detection is a crucial application of medical image processing, and serves in its potential aid to medical practitioners by making the affected area stand out in the foreground from the rest of the background image. The algorithm developed here is a new approach to the detection of saliency in a three dimensional multi channel MR image sequence for the glioblastoma multiforme (a form of malignant brain tumour). First we enhance the three channels, FLAIR (Fluid Attenuated Inversion Recovery), T2 and T1C (contrast enhanced with gadolinium) to generate a pseudo coloured RGB image. This is then converted to the CIE L*a*b* color space. Processing on cubes of sizes k = 4, 8, 16, the L*a*b* 3D image is then compressed into volumetric units; each representing the neighbourhood information of the surrounding 64 voxels for k = 4, 512 voxels for k = 8 and 4096 voxels for k = 16, respectively. The spatial distance of these voxels are then compared along the three major axes to generate the novel 3D saliency map of a 3D image, which unambiguously highlights the tumour region. The algorithm operates along the three major axes to maximise the computation efficiency while minimising loss of valuable 3D information. Thus the 3D multichannel MR image saliency detection algorithm is useful in generating a uniform and logistically correct 3D saliency map with pragmatic applicability in Computer Aided Detection (CADe). Assignment of uniform importance to all three axes proves to be an important factor in volumetric processing, which helps in noise reduction and reduces the possibility of compromising essential information. The effectiveness of the algorithm was evaluated over the BRATS MICCAI 2015 dataset having 274 glioma cases, consisting both of high grade and low grade GBM. The results were compared with that of the 2D saliency detection algorithm taken over the entire sequence of brain data. For all comparisons, the Area Under the receiver operator characteristic (ROC) Curve (AUC) has been found to be more than 0.99 ± 0.01 over various tumour types, structures and locations.

Treatment Outcome in Patients with Primary Central Nervous System Germ Cell Tumour: Clinical Experience from a Regional Cancer Centre in North India.

PubMed

Biswas, Ahitagni; Julka, Pramod Kumar; Bakhshi, Sameer; Singh, Manmohan; Rath, Goura Kishor

2017-01-01

Primary intracranial germ cell tumour is a rare entity and constitutes 2-3% of all paediatric brain tumours in Western countries. We herein intend to report the clinical features and treatment outcome of patients with primary central nervous system germ cell tumour treated at our institute. Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed and relevant immunohistochemistry stains were done. Overall survival (OS) and progression-free survival (PFS) were analysed by the Kaplan-Meier product-limit method. Twenty patients met the study criterion (male:female = 7:3). Median age at presentation was 13 years. Tumour location was pineal in 10 patients, suprasellar in 6, thalamic in 2, basal ganglion in 1, and spinal in 1. Leptomeningeal spread was noted in 1 patient at presentation. Surgical resection was gross-total in 7 patients (35%), near-total in 2 (10%), subtotal in 4 (20%), and limited to biopsy in 6 (30%). The tumours were germinomatous, non-germinomatous, and of mixed germ cell subtype in 17 patients (85%), 2 patients (10%), and 1 patient (5%), respectively. Systemic chemotherapy (median of 4 cycles) was given to 19 patients (95%). The common regimens used were a combination of bleomycin, etoposide and cisplatin (BEP) in 14 patients (70%) and etoposide and cisplatin (EP) in 5 patients (25%). Radiation therapy (40-50 Gy in conventional fractionation; median of 42 Gy) was delivered to 17 patients (85%): local radiation in 6 and whole ventricular, whole brain, and craniospinal irradiation followed by a boost in 5, 3, and 3 patients, respectively. After a median follow-up of 44.52 months, 17 patients (85%) were in complete response and 3 (15%) had progressive disease. Death and disease recurrence were noted in 6 patients (30%) and 1 patient, respectively. Median OS and PFS were not reached. The actuarial rates of OS at 3 and 5 years were 75.8 and 68.9%, respectively. The actuarial rates of PFS at both 3 and 5 years were 81.6%. Multimodality treatment consisting of limited resection followed by platinum-based systemic chemotherapy and radiotherapy (40-50 Gy) is a reasonable treatment strategy in patients of primary central nervous system germ cell tumour in a developing nation. © 2017 S. Karger AG, Basel.

On the association between glioma, wireless phones, heredity and ionising radiation.

PubMed

Carlberg, Michael; Hardell, Lennart

2012-09-01

We performed two case-control studies on brain tumours diagnosed during 1 January 1997 to 30 June 2000 and 1 July 2000 to 31 December 2003, respectively. Living cases and controls aged 20-80 years were included. An additional study was performed on deceased cases with a malignant brain tumour using deceased controls. Pooled results for glioma yielded for ipsilateral use of mobile phone odds ratio (OR)=2.9, 95% confidence interval (CI)=1.8-4.7 in the >10 years latency group. The corresponding result for cordless phone was OR=3.8, 95% CI=1.8-8.1. OR increased statistically significant for cumulative use of wireless phones per 100h and per year of latency. For high-grade glioma ipsilateral use of mobile phone gave OR=3.9, 95% CI=2.3-6.6 and cordless phone OR=5.5, 95% CI=2.3-13 in the >10 years latency group. Heredity for brain tumour gave OR=3.4, 95% CI=2.1-5.5 for glioma. There was no interaction with use of wireless phones. X-ray investigation of the head gave overall OR=1.3, 95% CI=1.1-1.7 for glioma without interaction with use of wireless phones or heredity. In conclusion use of mobile and cordless phone increased the risk for glioma with highest OR for ipsilateral use, latency >10 years and third tertile of cumulative use in hours. In total, the risk was highest in the age group <20 years for first use of a wireless phone. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pooled analysis of case-control studies on malignant brain tumours and the use of mobile and cordless phones including living and deceased subjects.

PubMed

Hardell, Lennart; Carlberg, Michael; Hansson Mild, Kjell

2011-05-01

We studied the association between use of mobile and cordless phones and malignant brain tumours. Pooled analysis was performed of two case-control studies on patients with malignant brain tumours diagnosed during 1997-2003 and matched controls alive at the time of study inclusion and one case-control study on deceased patients and controls diagnosed during the same time period. Cases and controls or relatives to deceased subjects were interviewed using a structured questionnaire. Replies were obtained for 1,251 (85%) cases and 2,438 (84%) controls. The risk increased with latency period and cumulative use in hours for both mobile and cordless phones. Highest risk was found for the most common type of glioma, astrocytoma, yielding in the >10 year latency group for mobile phone use odds ratio (OR) = 2.7, 95% confidence interval (CI) = 1.9-3.7 and cordless phone use OR = 1.8, 95% CI = 1.2-2.9. In a separate analysis, these phone types were independent risk factors for glioma. The risk for astrocytoma was highest in the group with first use of a wireless phone before the age of 20; mobile phone use OR = 4.9, 95% CI = 2.2-11, cordless phone use OR = 3.9, 95% CI = 1.7-8.7. In conclusion, an increased risk was found for glioma and use of mobile or cordless phone. The risk increased with latency time and cumulative use in hours and was highest in subjects with first use before the age of 20.

Radioisotope scanning of brain, liver, lung and bone with a note on tumour localizing agents

PubMed Central

Lavender, J. P.

1973-01-01

Radioisotopic scanning of brain, liver, lungs and the skeleton is briefly reviewed with a survey of recent developments of clinical significance. In brain scanning neoplasm detection rates of greater than 90% are claimed. The true figure is probably 70-80%. Autopsy data shows a number of false negatives, particularly with vascular lesions. Attempts to make scanning more specific in differentiating neoplasm from vascular lesions by rapid sequence blood flow studies are reviewed. In liver scanning by means of colloids again high success rate is claimed but small metastases are frequently missed and the false negative scan rate is probably quite high. Lung scanning still has its main place in investigating pulmonary embolic disease. Ventilation studies using Xenon 133 are useful, particularly combined with perfusion studies. The various radiopharmaceuticals for use in bone scanning are reviewed. The appearance of technetium labelled phosphate compounds will probably allow much wider use of total skeletal scanning. Research into tumour localizing agents continues, the most recent and interesting being Gallium citrate and labelled bleomycin. Neither agent is predictable however although Gallium may have a place in Hodgkins disease and bronchogenic neoplasm and both may have a place in the detection of cerebral tumours. ImagesFig. 1Fig. 2Fig. 3p452-bFig. 3bFig. 4Fig. 5Fig. 5bFig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 12c & 12dFig. 13Fig. 13 b,c,dFig. 14Fig. 14bFig. 15Fig. 15bFig. 16Fig. 17Fig. 18 PMID:4602127

Impact of the primary aetiology upon the clinical outcome of adults with childhood-onset GH deficiency.

PubMed

Hoybye, Charlotte; Jönsson, Peter; Monson, John P; Koltowska-Häggström, Maria; Hána, Václav; Geffner, Mitchell; Abs, Roger

2007-11-01

The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy. Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement. GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement. The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

Coupled modelling of tumour angiogenesis, tumour growth and blood perfusion.

PubMed

Cai, Yan; Xu, Shixiong; Wu, Jie; Long, Quan

2011-06-21

We propose a mathematical modelling system to investigate the dynamic process of tumour cell proliferation, death and tumour angiogenesis by fully coupling the vessel growth, tumour growth and blood perfusion. Tumour growth and angiogenesis are coupled by the chemical microenvironment and the cell-matrix interaction. The haemodynamic calculation is carried out on the updated vasculature. The domains of intravascular, transcapillary and interstitial fluid flow were coupled in the model to provide a comprehensive solution of blood perfusion variables. An estimation of vessel collapse is made according to the wall shear stress criterion to provide feedback on vasculature remodelling. The simulation can show the process of tumour angiogenesis and the spatial distribution of tumour cells for periods of up to 24 days. It can show the major features of tumour and tumour microvasculature during the period such as the formation of a large necrotic core in the tumour centre with few functional vessels passing through, and a well circulated tumour periphery regions in which the microvascular density is high and associated with more aggressive proliferating cells of the growing tumour which are all consistent with physiological observations. The study also demonstrated that the simulation results are not dependent on the initial tumour and networks, which further confirms the application of the coupled model feedback mechanisms. The model enables us to examine the interactions between angiogenesis and tumour growth, and to study the dynamic response of a solid tumour to the changes in the microenvironment. This simulation framework can be a foundation for further applications such as drug delivery and anti-angiogenic therapies. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Mobile phones and brain tumours: a review of epidemiological research.

PubMed

Croft, R J; McKenzie, R J; Inyang, I; Benke, G P; Anderson, V; Abramson, M J

2008-12-01

There has been a great deal of public concern regarding the possibility that the use of mobile phone-related technologies might result in adverse health effects. Corresponding to this, there has been substantial epidemiological research designed to determine whether the use of mobile phones (MP) has any effect on health, and in particular whether it increases the risk of developing head and neck tumours. Such literature is particularly heterogeneous, which makes it difficult to pool in a meta-analysis. This paper thus reviews the epidemiological literature pertaining to the use of mobile phones and mobile phone-related technologies, and head and neck tumours, in an attempt to consolidate the various reports. Although there have been individual reports of associations between MP-use and tumours, this research is not consistent and on balance does not provide evidence of an association. There are reports of small associations between MP-use ipsilateral to the tumour for greater than 10 years, for both acoustic neuroma and glioma, but the present paper argues that these are especially prone to confounding by recall bias. The reported associations are in need of replication with methods designed to minimise such bias before they can be treated as more than suggestive.

Advance statement of consent from patients with primary CNS tumours to organ donation and elective ventilation.

PubMed

Patel, Umang Jash

2013-03-01

A deficit in the number of organs available for transplantation persists even with an increase in donation rates. One possible choice of donor for organs that appears under-referred and/or unaccepted is patients with primary brain tumours. In spite of advances in the treatment of high-grade primary central nervous system (CNS) tumours, the prognosis remains dire. A working group on organs from donors with primary CNS tumours showed that the risk of transmission is small and outweighs the benefits of waiting for a normal donor, in survival and organ life-years, with caveats. This paper explores the possibility that, if information on organ donation were made available to patients and their families with knowledge of their inevitable fate, perhaps some will choose to donate. It would be explained that to achieve this, elective ventilation would be performed in their final moments. This would obviate the consent question because of an advance statement. It is accepted that these are sensitive matters and there will be logistic issues. This will need discussion with the public and other professionals, but it could increase the number of donors and can be extrapolated to encompass other primary CNS tumours.

Irinotecan-loaded double-reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration.

PubMed

Din, Fakhar Ud; Kim, Dong Wuk; Choi, Ju Yeon; Thapa, Raj Kumar; Mustapha, Omer; Kim, Dong Shik; Oh, Yu-Kyoung; Ku, Sae Kwang; Youn, Yu Seok; Oh, Kyung Taek; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon

2017-05-01

Intramuscularly administered, anti-tumour drugs induce severe side effects due to their direct contact with body tissues and initial burst effect. In this study, to solve this problem, a novel double-reversible thermogel system (DRTG) for the intramuscular administration of irinotecan was developed. This irinotecan-loaded DRTG was prepared by dispersing the irinotecan-loaded thermoreversible solid lipid nanoparticles (SLNs) in the thermoreversible hydrogel. In DRTG, the former was solid at 25°C but converted to liquid at 36.5°C; in contrast, the latter existed in a liquid form but transformed to gel state in the body. The DRTG was easily administered intramuscularly. Its particle size and drug content were not noticeably changeable, resulting that it was stable at 40°C for at least 6months. Compared to the irinotecan-loaded solution and conventional hydrogel, the DRTG significantly delayed drug release, leading to a reduced burst effect. Moreover, it showed decreased C max and maintained the sustained plasma concentrations at a relatively low level for the long period of 60h in rats, resulting in ameliorated side effects of the anti-tumour drug. Furthermore, it gave significantly improved anti-tumour efficacy in tumour-bearing mice compared to the hydrogel but, unlike the conventional hydrogel, induced no body weight loss and local damage to the muscle. Thus, this DRTG with improved antitumor efficacy without initial burst effect and toxicity could provide a potential pharmaceutical system for the intramuscular administration of irinotecan. Intramuscularly administered, anti-tumour drugs induce severe side effects due to their direct contact with body tissues and initial burst effect. To solve this problem, we developed a novel double-reversible thermogel system (DRTG) for the intramuscular administration of irinotecan. Unlike the conventional hydrogel, the DRTG is a dispersion of the irinotecan-loaded thermoreversible solid lipid nanoparticles in the thermoreversible hydrogel. In DRTG, the former was solid at 25°C but converted to liquid at 36.5°C; in contrast, the latter existed in a liquid form but transformed to gel state in the body. This DRTG gave significantly improved anti-tumour efficacy in tumour-bearing mice compared to the hydrogel but, unlike the conventional hydrogel, induced no body weight loss and local damage to the muscle. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Combined texture feature analysis of segmentation and classification of benign and malignant tumour CT slices.

PubMed

Padma, A; Sukanesh, R

2013-01-01

A computer software system is designed for the segmentation and classification of benign from malignant tumour slices in brain computed tomography (CT) images. This paper presents a method to find and select both the dominant run length and co-occurrence texture features of region of interest (ROI) of the tumour region of each slice to be segmented by Fuzzy c means clustering (FCM) and evaluate the performance of support vector machine (SVM)-based classifiers in classifying benign and malignant tumour slices. Two hundred and six tumour confirmed CT slices are considered in this study. A total of 17 texture features are extracted by a feature extraction procedure, and six features are selected using Principal Component Analysis (PCA). This study constructed the SVM-based classifier with the selected features and by comparing the segmentation results with the experienced radiologist labelled ground truth (target). Quantitative analysis between ground truth and segmented tumour is presented in terms of segmentation accuracy, segmentation error and overlap similarity measures such as the Jaccard index. The classification performance of the SVM-based classifier with the same selected features is also evaluated using a 10-fold cross-validation method. The proposed system provides some newly found texture features have an important contribution in classifying benign and malignant tumour slices efficiently and accurately with less computational time. The experimental results showed that the proposed system is able to achieve the highest segmentation and classification accuracy effectiveness as measured by jaccard index and sensitivity and specificity.

Management of synchronous tumours of the oesophagus and pancreatic head: a novel approach.

PubMed

Gyorki, D E; Clarke, N E; Hii, M W; Banting, S W; Cade, R J

2011-09-01

Synchronous tumours of the oesophagus and pancreatic head are very rare. This report describes a unique case of an adenocarcinoma of the distal oesophagus and a neuroendocrine tumour of the pancreatic head diagnosed synchronously but successfully managed metachronously. Initially, the patient underwent an oesophagectomy, with a colonic reconstruction following some months later by pylorus-preserving pancreaticoduodenectomy. A staged resection was performed after a review of the literature suggested increased morbidity with synchronous major abdominal operations.

Neutrophil-mediated experimental metastasis is enhanced by VEGFR inhibition in a zebrafish xenograft model

PubMed Central

He, Shuning; Lamers, Gerda EM; Beenakker, Jan-Willem M; Cui, Chao; Ghotra, Veerander PS; Danen, Erik HJ; Meijer, Annemarie H; Spaink, Herman P; Snaar-Jagalska, B Ewa

2012-01-01

Inhibition of VEGF signalling effectively suppresses localized tumour growth but accelerates tumour invasiveness and micrometastasis by unknown mechanisms. To study the dynamic and reciprocal interactions between tumour cells and their microenvironment during these processes, we established a xenograft model by injecting tumour cells into the blood circulation of transparent zebrafish embryos. This reproducibly results in rapid simultaneous formation of a localized tumour and experimental micrometastasis, allowing time-resolved imaging of both processes at single-cell resolution within 1 week. The tumour vasculature was initiated de novo by remodelling of primitive endothelial cells into a functional network. Roles of myeloid cells in critical tumourigenesis steps such as vascularization and invasion were revealed by genetic and pharmaceutical approaches. We discovered that the physiological migration of neutrophils controlled tumour invasion by conditioning the collagen matrix and forming the metastatic niche, as detected by two-photon confocal microscopy and second harmonic generation. Administration of VEGFR inhibitors blocked tumour vascularization and a localized tumour growth but enhanced migration of neutrophils, which in turn promoted tumour invasion and formation of micrometastasis. This demonstrates the in vivo cooperation between VEGF signalling and myeloid cells in metastasis and provides a new mechanism underlying the recent findings that VEGFR targeting can promote tumour invasiveness. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:22374800

Retrieval with Clustering in a Case-Based Reasoning System for Radiotherapy Treatment Planning

NASA Astrophysics Data System (ADS)

Khussainova, Gulmira; Petrovic, Sanja; Jagannathan, Rupa

2015-05-01

Radiotherapy treatment planning aims to deliver a sufficient radiation dose to cancerous tumour cells while sparing healthy organs in the tumour surrounding area. This is a trial and error process highly dependent on the medical staff's experience and knowledge. Case-Based Reasoning (CBR) is an artificial intelligence tool that uses past experiences to solve new problems. A CBR system has been developed to facilitate radiotherapy treatment planning for brain cancer. Given a new patient case the existing CBR system retrieves a similar case from an archive of successfully treated patient cases with the suggested treatment plan. The next step requires adaptation of the retrieved treatment plan to meet the specific demands of the new case. The CBR system was tested by medical physicists for the new patient cases. It was discovered that some of the retrieved cases were not suitable and could not be adapted for the new cases. This motivated us to revise the retrieval mechanism of the existing CBR system by adding a clustering stage that clusters cases based on their tumour positions. A number of well-known clustering methods were investigated and employed in the retrieval mechanism. Results using real world brain cancer patient cases have shown that the success rate of the new CBR retrieval is higher than that of the original system.

In-phantom two-dimensional thermal neutron distribution for intraoperative boron neutron capture therapy of brain tumours

NASA Astrophysics Data System (ADS)

Yamamoto, T.; Matsumura, A.; Yamamoto, K.; Kumada, H.; Shibata, Y.; Nose, T.

2002-07-01

The aim of this study was to determine the in-phantom thermal neutron distribution derived from neutron beams for intraoperative boron neutron capture therapy (IOBNCT). Gold activation wires arranged in a cylindrical water phantom with (void-in-phantom) or without (standard phantom) a cylinder styrene form placed inside were irradiated by using the epithermal beam (ENB) and the mixed thermal-epithermal beam (TNB-1) at the Japan Research Reactor No 4. With ENB, we observed a flattened distribution of thermal neutron flux and a significantly enhanced thermal flux delivery at a depth compared with the results of using TNB-1. The thermal neutron distribution derived from both the ENB and TNB-1 was significantly improved in the void-in-phantom, and a double high dose area was formed lateral to the void. The flattened distribution in the circumference of the void was observed with the combination of ENB and the void-in-phantom. The measurement data suggest that the ENB may provide a clinical advantage in the form of an enhanced and flattened dose delivery to the marginal tissue of a post-operative cavity in which a residual and/or microscopically infiltrating tumour often occurs. The combination of the epithermal neutron beam and IOBNCT will improve the clinical results of BNCT for brain tumours.

A GPU-based computer-assisted microscopy system for assessing the importance of different families of histological characteristics in cancer diagnosis

NASA Astrophysics Data System (ADS)

Glotsos, Dimitris; Kostopoulos, Spiros; Sidiropoulos, Konstantinos; Ravazoula, Panagiota; Kalatzis, Ioannis; Asvestas, Pantelis; Cavouras, Dionisis

2014-01-01

In this study a Computer-Aided Microscopy (CAM) system is proposed for investigating the importance of the histological criteria involved in diagnosing of cancers in microscopy in order to suggest the more informative features for discriminating low from high-grade brain tumours. Four families of criteria have been examined, involving the greylevel variations (i.e. texture), the morphology (i.e. roundness), the architecture (i.e. cellularity) and the overall tumour qualities (expert's ordinal scale). The proposed CAM system was constructed using a modified Seeded Region Growing algorithm for image segmentation, and the Probabilistic Neural Network classifier for image classification. The implementation was designed on a commercial Graphics Processing Unit card using parallel programming. The system's performance using textural, morphological, architectural and ordinal information was 90.8%, 87.0%, 81.2% and 88.9% respectively. Results indicate that nuclei texture is the most important family of features regarding the degree of malignancy, and, thus, may guide more accurate predictions for discriminating low from high grade gliomas. Considering that nuclei texture is almost impractical to be encoded by visual observation, the need to incorporate computer-aided diagnostic tools as second opinion in daily clinical practice of diagnosing rare brain tumours may be justified.

Initial assessment of a model relating intratumoral genetic heterogeneity to radiological morphology

PubMed Central

Noterdaeme, O; Kelly, M; Friend, P; Soonowalla, Z; Steers, G; Brady, M

2010-01-01

Tumour heterogeneity has major implications for tumour development and response to therapy. Tumour heterogeneity results from mutations in the genes responsible for mismatch repair or maintenance of chromosomal stability. Cells with different genetic properties may grow at different rates and exhibit different resistance to therapeutic interventions. To date, there exists no approach to non-invasively assess tumour heterogeneity. Here we present a biologically inspired model of tumour growth, which relates intratumoral genetic heterogeneity to gross morphology visible on radiological images. The model represents the development of a tumour as a set of expanding spheres, each sphere representing a distinct clonal centre, with the sprouting of new spheres corresponding to new clonal centres. Each clonal centre may possess different characteristics relating to genetic composition, growth rate and response to treatment. We present a clinical example for which the model accurately tracks tumour growth and shows the correspondence to genetic variation (as determined by array comparative genomic hybridisation). One clinical implication of our work is that the assessment of heterogeneous tumours using Response Evaluation Criteria In Solid Tumours (RECIST) or volume measurements may not accurately reflect tumour growth, stability or the response to treatment. We believe that this is the first model linking the macro-scale appearance of tumours to their genetic composition. We anticipate that our model will provide a more informative way to assess the response of heterogeneous tumours to treatment, which is of increasing importance with the development of novel targeted anti-cancer treatments. PMID:19690073

A comparison of digitized frozen section and smear preparations for intraoperative neurotelepathology.

PubMed

Gould, Peter V; Saikali, Stephan

2012-01-01

Intraoperative consultations in neuropathology are often assessed by smear preparations rather than by frozen sections. Both techniques are standard practice for light microscopic examination on site, but there is little data comparing these techniques in a telepathology setting. Thirty cases of brain tumours submitted for intraoperative consultation at our institution between July and December 2010 were identified in which both frozen section and tissue smear preparations were available for digitization at 20× magnification. Slides were digitized using a Hamamatsu Nanozoomer 2.0 HT whole slide scanner, and resulting digital images were visualized at 1680 × 1050 pixel resolution with NDP. view software. The original intraoperative diagnosis was concordant with the sign out diagnosis in 29/30 cases; one tumeur was initially interpreted as a high grade glioma but proved to be a lymphoma at sign out. Digitized frozen section slides were sufficient for diagnosis at 10× magnification in 27/30 cases. Digitized tissue smears were sufficient for diagnosis at 10× magnification in 28/30 cases. In two cases tumour was present on the tissue smear but not the frozen section (one case of recurrent astrocytoma, one case of meningeal carcinomatosis). In one case of lymphoma, tumour was present on frozen section only. These discrepancies were attributed to tissue sampling rather than image quality. Examination of digitized slides at higher magnfication (20×) permitted confirmation of mitoses and Rosenthal fibers on tissue smear preparations, but did not change the primary diagnosis. Intra-slide variations in tissue thickness on smear preparations led to variable loss of focus in digitized images, but did not affect image quality in thinner areas of the smear or impede diagnosis. Digitized tissue smears are suitable for intraoperative neurotelepathology and provide comparable information to digitized frozen sections at medium power magnification.

IDH mutation is paradoxically associated with higher 18F-FDOPA PET uptake in diffuse grade II and grade III gliomas.

PubMed

Verger, A; Metellus, Ph; Sala, Q; Colin, C; Bialecki, E; Taieb, D; Chinot, O; Figarella-Branger, D; Guedj, E

2017-08-01

The World Health Organization Classification of Tumors of the Central Nervous System has recently been updated by the integration of diagnostic and prognostic molecular parameters, giving pivotal attention to IDH mutation as a favourable factor. Amino acid PET is increasingly used in the management of gliomas, but its prognostic value is a matter of debate. The aim of this study was to assess the relationship between IDH mutation and 18 F-FDOPA uptake on PET in newly diagnosed gliomas. A total of 43 patients, presenting with diffuse astrocytic and oligodendroglial grade II and III gliomas, reclassified according to the 2016 WHO classification of tumours of the CNS, were retrospectively included. They had all undergone 18 F-FDOPA PET at an initial stage before surgery and histological diagnosis. 18 F-FDOPA uptake values were compared between patients with and without IDH mutation in terms of maximum standardized uptake value (SUVmax) ratios between tumour and normal contralateral brain (T/N), and between tumour and striatum (T/S). Patients with IDH mutation showed higher 18 F-FDOPA T/N SUVmax ratios (1.6 vs. 1.2) and T/S SUVmax ratios (0.9 vs. 0.6) than patients without IDH mutation (p < 0.05). This study showed paradoxically higher 18 F-FDOPA uptake in diffuse grade II and III gliomas with IDH mutation. Despite evident interest in the management of gliomas, and especially in relation to posttherapy evaluation, our findings raise the question of the prognostic value of 18 F-FDOPA uptake on PET uptake in this group of patients. This may be related to differences in amino acid integration, metabolism, or cell differentiation.

Biological imaging in radiation therapy: role of positron emission tomography.

PubMed

Nestle, Ursula; Weber, Wolfgang; Hentschel, Michael; Grosu, Anca-Ligia

2009-01-07

In radiation therapy (RT), staging, treatment planning, monitoring and evaluation of response are traditionally based on computed tomography (CT) and magnetic resonance imaging (MRI). These radiological investigations have the significant advantage to show the anatomy with a high resolution, being also called anatomical imaging. In recent years, so called biological imaging methods which visualize metabolic pathways have been developed. These methods offer complementary imaging of various aspects of tumour biology. To date, the most prominent biological imaging system in use is positron emission tomography (PET), whose diagnostic properties have clinically been evaluated for years. The aim of this review is to discuss the valences and implications of PET in RT. We will focus our evaluation on the following topics: the role of biological imaging for tumour tissue detection/delineation of the gross tumour volume (GTV) and for the visualization of heterogeneous tumour biology. We will discuss the role of fluorodeoxyglucose-PET in lung and head and neck cancer and the impact of amino acids (AA)-PET in target volume delineation of brain gliomas. Furthermore, we summarize the data of the literature about tumour hypoxia and proliferation visualized by PET. We conclude that, regarding treatment planning in radiotherapy, PET offers advantages in terms of tumour delineation and the description of biological processes. However, to define the real impact of biological imaging on clinical outcome after radiotherapy, further experimental, clinical and cost/benefit analyses are required.

TOPICAL REVIEW: Biological imaging in radiation therapy: role of positron emission tomography

NASA Astrophysics Data System (ADS)

Nestle, Ursula; Weber, Wolfgang; Hentschel, Michael; Grosu, Anca-Ligia

2009-01-01

In radiation therapy (RT), staging, treatment planning, monitoring and evaluation of response are traditionally based on computed tomography (CT) and magnetic resonance imaging (MRI). These radiological investigations have the significant advantage to show the anatomy with a high resolution, being also called anatomical imaging. In recent years, so called biological imaging methods which visualize metabolic pathways have been developed. These methods offer complementary imaging of various aspects of tumour biology. To date, the most prominent biological imaging system in use is positron emission tomography (PET), whose diagnostic properties have clinically been evaluated for years. The aim of this review is to discuss the valences and implications of PET in RT. We will focus our evaluation on the following topics: the role of biological imaging for tumour tissue detection/delineation of the gross tumour volume (GTV) and for the visualization of heterogeneous tumour biology. We will discuss the role of fluorodeoxyglucose-PET in lung and head and neck cancer and the impact of amino acids (AA)-PET in target volume delineation of brain gliomas. Furthermore, we summarize the data of the literature about tumour hypoxia and proliferation visualized by PET. We conclude that, regarding treatment planning in radiotherapy, PET offers advantages in terms of tumour delineation and the description of biological processes. However, to define the real impact of biological imaging on clinical outcome after radiotherapy, further experimental, clinical and cost/benefit analyses are required.

[Combined palliative hypofractionated radiation and carboplatin chemotherapy of intranasal tumours in dogs].

PubMed

Schwietzer, A; Kessler, M; Kandel-Tschiederer, B

2012-10-17

Combination therapy of intranasal tumours in dogs with palliative 60 cobalt radiation and carboplatin chemotherapy. Twenty-five dogs with intranasal tumours were treated in the Hofheim Veterinary Hospital (Germany) from 2004 to 2006 with a total radiation dose of 24Gy (3 fractions of 8 Gy on days 0, 7 and 21) and five doses of Carboplatin (270-300 mg/m² BSA i.v. every 21-28 days). In 88% patients, clinical symptoms subsided partially or completely resulting in improvement in quality of life. Computed tomography revealed partial (5/25) or complete (5/25) tumour remissions. Chemotherapy was well tolerated. Radiation therapy caused no or minimal side effects except for 3 dogs (12%), which experienced serious ocular side effects resulting in loss of vision of the affected eye and one dog with epileptic seizures. Survival times ranged from 10-639 days with a median of 156 days. There was no statistically significant correlation between the parameters breed, age, sex, brain invasion or tumour stage and survival time or progression free interval. Survival time and progression free interval were significantly correlated with the degree of tumour remission. It can be concluded from this study that palliative radiation therapy combined with chemotherapy results in excellent palliation of clinical symptoms and acceptable survival times. There was no advantage of combined therapy (radiation with carboplatin) when compared to literature data on results of radiation therapy alone.

HER2 expression identifies dynamic functional states within circulating breast cancer cells.

PubMed

Jordan, Nicole Vincent; Bardia, Aditya; Wittner, Ben S; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K; Licausi, Joseph A; Desai, Rushil; O'Keefe, Ryan M; Ebright, Richard Y; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela L; Iafrate, Anthony J; Kapur, Ravi; Sgroi, Dennis; Ting, David T; Toner, Mehmet; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, Daniel A

2016-09-01

Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER + /HER2 - primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2 + and HER2 - subpopulations: HER2 + circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2 - circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2 + and HER2 - circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2 + and HER2 - circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2 + state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2 - phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance.

A neurosurgical presentation of patent foramen ovale with atrial septal aneurysm

PubMed Central

Walsh, Katie; Kaliaperumal, Chandrasekaran; Wyse, Gerry; Kaar, George

2011-01-01

We describe a case of cerebral abscess in a 53-year-old lady with a background of congenital heart defect. She has an atrial septal defect with atrial septal aneurysm, which remained undiagnosed until this clinical presentation. She presented with a short history of right-sided hemiplaegia and neuroimaging revealed a heterogeneous lesion in the left frontoparietal region. Neuronavigation-guided left frontoparietal craniotomy was performed to debulk the lesion and preoperatively frank pus was drained, which grew Streptococcus constellatus. She was successfully treated with antibiotics for 6 weeks and her clinical condition improved. We believe that the patients’ previous dental extraction has possibly resulted in a paradoxical embolism through the atrial septal defect bypassing the pulmonary circulation. The MRI scan picture was misleading, as it was initially thought to be a high-grade brain tumour. PMID:22689610

Improved nTMS- and DTI-derived CST tractography through anatomical ROI seeding on anterior pontine level compared to internal capsule

PubMed Central

Weiss, Carolin; Tursunova, Irada; Neuschmelting, Volker; Lockau, Hannah; Nettekoven, Charlotte; Oros-Peusquens, Ana-Maria; Stoffels, Gabriele; Rehme, Anne K.; Faymonville, Andrea Maria; Shah, N. Jon; Langen, Karl Josef; Goldbrunner, Roland; Grefkes, Christian

2015-01-01

Imaging of the course of the corticospinal tract (CST) by diffusion tensor imaging (DTI) is useful for function-preserving tumour surgery. The integration of functional localizer data into tracking algorithms offers to establish a direct structure–function relationship in DTI data. However, alterations of MRI signals in and adjacent to brain tumours often lead to spurious tracking results. We here compared the impact of subcortical seed regions placed at different positions and the influences of the somatotopic location of the cortical seed and clinical co-factors on fibre tracking plausibility in brain tumour patients. The CST of 32 patients with intracranial tumours was investigated by means of deterministic DTI and neuronavigated transcranial magnetic stimulation (nTMS). The cortical seeds were defined by the nTMS hot spots of the primary motor area (M1) of the hand, the foot and the tongue representation. The CST originating from the contralesional M1 hand area was mapped as intra-individual reference. As subcortical region of interests (ROI), we used the posterior limb of the internal capsule (PLIC) and/or the anterior inferior pontine region (aiP). The plausibility of the fibre trajectories was assessed by a-priori defined anatomical criteria. The following potential co-factors were analysed: Karnofsky Performance Scale (KPS), resting motor threshold (RMT), T1-CE tumour volume, T2 oedema volume, presence of oedema within the PLIC, the fractional anisotropy threshold (FAT) to elicit a minimum amount of fibres and the minimal fibre length. The results showed a higher proportion of plausible fibre tracts for the aiP-ROI compared to the PLIC-ROI. Low FAT values and the presence of peritumoural oedema within the PLIC led to less plausible fibre tracking results. Most plausible results were obtained when the FAT ranged above a cut-off of 0.105. In addition, there was a strong effect of somatotopic location of the seed ROI; best plausibility was obtained for the contralateral hand CST (100%), followed by the ipsilesional hand CST (>95%), the ipsilesional foot (>85%) and tongue (>75%) CST. In summary, we found that the aiP-ROI yielded better tracking results compared to the IC-ROI when using deterministic CST tractography in brain tumour patients, especially when the M1 hand area was tracked. In case of FAT values lower than 0.10, the result of the respective CST tractography should be interpreted with caution with respect to spurious tracking results. Moreover, the presence of oedema within the internal capsule should be considered a negative predictor for plausible CST tracking. PMID:25685709

Iron and cancer: more ore to be mined

PubMed Central

Torti, Suzy V.; Torti, Frank M.

2014-01-01

Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy. PMID:23594855

mRNA expression levels of hypoxia-induced and stem cell-associated genes in human glioblastoma.

PubMed

Bache, Matthias; Rot, Swetlana; Keßler, Jacqueline; Güttler, Antje; Wichmann, Henri; Greither, Thomas; Wach, Sven; Taubert, Helge; Söling, Ariane; Bilkenroth, Udo; Kappler, Matthias; Vordermark, Dirk

2015-06-01

The roles of hypoxia-induced and stem cell-associated genes in the development of malignancy and tumour progression are well known. However, there are a limited number of studies analysing the impact of mRNA expression levels of hypoxia-induced and stem cell-associated genes in the tissues of brain tumours and glioblastoma patients. In this study, tumour tissues from patients with glioblastoma multiforme and tumour adjacent tissues were analysed. We investigated mRNA expression levels of hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), carbonic anhydrase 9 (CA9), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT-1) and osteopontin (OPN), and stem cell-associated genes survivin, epidermal growth factor receptor (EGFR), human telomerase reverse transcriptase (hTERT), Nanog and octamer binding transcription factor 4 (OCT4) using quantitative real-time polymerase chain reaction (qRT-PCR). Our data revealed higher mRNA expression levels of hypoxia-induced and stem cell-associated genes in tumour tissue than levels in the tumour adjacent tissues in patients with glioblastoma multiforme. A strong positive correlation between the mRNA expression levels of HIF-2α, CA9, VEGF, GLUT-1 and OPN suggests a specific hypoxia-associated profile of mRNA expression in glioblastoma multiforme. Additionally, the results indicate the role of stem-cell-related genes in tumour hypoxia. Kaplan-Maier analysis revealed that high mRNA expression levels of hypoxia-induced markers showed a trend towards shorter overall survival in glioblastoma patients (P=0.061). Our data suggest that mRNA expression levels of hypoxia-induced genes are important tumour markers in patients with glioblastoma multiforme.

[Genetic Syndromes Predisposing to Tumors of Central Nervous System in Children].

PubMed

Krutílková, V

2016-01-01

The overall incidence of childhood malignancies is rather low. Central nervous system tumours constitute the largest group of solid tumours among children. In contrast to adult population, a genetic predisposition is frequently associated with these malignancies (it is assumed to occur in approximately 15-25% of all childhood tumours) and there is also a number of monogenic hereditary syndromes known to be associated with brain tumours. The purpose of this article is to present an overview of genetic syndromes reported to increase the risk of childhood central nervous system tumours. The outlined tumour predispositions are divided into two groups. Firstly, syndromes with multisystem manifestation, where neoplasia is one of the components, whereas the distinguishing symptom is usually non-oncological. Secondly, there are syndromes that are diagnosed by the associated neoplasm withou any other noticeable phenotypic manifestation. A brief description of particular diseases is provided with a focus on associated central nervous system tumours. Detection of a tumour predisposition in a child is important not only for the child itself, but also for its family relatives. Often, a modification of treatment is necessary in regards to a genetic diagnosis. With the evolution of personalised medicine the possibility of "tailored" therapy will probably be a demanded solution. Last but not least, it is crucial to provide the child with a specialised preventive care owing to the risk of another potential malignancy. The diagnosis of hereditary cancer predisposition has also a big impact on the relatives of the patient. It enables to specify their oncological risk and arrange a specialised preventive care program, if needed. For high-risk parents planning another pregnancy there is a possibility to prevent the transfer of a certain disposition with the aid of preimplantation and prenatal genetic testing.

High Resolution Imaging of Viscoelastic Properties of Intracranial Tumours by Multi-Frequency Magnetic Resonance Elastography.

PubMed

Reiss-Zimmermann, M; Streitberger, K-J; Sack, I; Braun, J; Arlt, F; Fritzsch, D; Hoffmann, K-T

2015-12-01

In recent years Magnetic Resonance Elastography (MRE) emerged into a clinically applicable imaging technique. It has been shown that MRE is capable of measuring global changes of the viscoelastic properties of cerebral tissue. The purpose of our study was to evaluate a spatially resolved three-dimensional multi-frequent MRE (3DMMRE) for assessment of the viscoelastic properties of intracranial tumours. A total of 27 patients (63 ± 13 years) were included. All examinations were performed on a 3.0 T scanner, using a modified phase-contrast echo planar imaging sequence. We used 7 vibration frequencies in the low acoustic range with a temporal resolution of 8 dynamics per wave cycle. Post-processing included multi-frequency dual elasto-visco (MDEV) inversion to generate high-resolution maps of the magnitude |G*| and the phase angle φ of the complex valued shear modulus. The tumour entities included in this study were: glioblastoma (n = 11), anaplastic astrocytoma (n = 3), meningioma (n = 7), cerebral metastasis (n = 5) and intracerebral abscess formation (n = 1). Primary brain tumours and cerebral metastases were not distinguishable in terms of |G*| and φ. Glioblastoma presented the largest range of |G*| values and a trend was delineable that glioblastoma were slightly softer than WHO grade III tumours. In terms of φ, meningiomas were clearly distinguishable from all other entities. In this pilot study, while analysing the viscoelastic constants of various intracranial tumour entities with an improved spatial resolution, it was possible to characterize intracranial tumours by their mechanical properties. We were able to clearly delineate meningiomas from intraaxial tumours, while for the latter group an overlap remains in viscoelastic terms.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response.

PubMed

Ming, Louise; Byrne, Niall M; Camac, Sarah Nicole; Mitchell, Christopher A; Ward, Claire; Waugh, David J; McKeown, Stephanie R; Worthington, Jenny

2013-03-15

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment, hypoxia is known to drive malignant progression. Our study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold (DSF) chambers were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide-treated and vehicle-only-treated tumours were re-established in vitro, and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2 mg/kg/day) decreased tumour oxygenation by 45% within 24 hr, reaching a nadir of 0.09% oxygen (0.67 ± 0.06 mmHg) by Day 7; this persisted until Day 14 when it increased up to Day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at Days 7 and 14 with revascularisation occurring by Day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50 mg/kg, single dose) caused greater tumour growth delay than bicalutamide alone. Our study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit. Copyright © 2012 UICC.

Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer

PubMed Central

Kitchen, Mark O.; Bryan, Richard T.; Haworth, Kim E.; Emes, Richard D.; Luscombe, Christopher; Gommersall, Lyndon; Cheng, K. K.; Zeegers, Maurice P.; James, Nicholas D.; Devall, Adam J.; Fryer, Anthony A.; Farrell, William E.

2015-01-01

Introduction Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis. Methods Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases. Results The ISL1 genes’ promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM). Conclusions In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC. PMID:26332997

Functional magnetic resonance imaging in clinical practice: State of the art and science.

PubMed

Barras, Christen D; Asadi, Hamed; Baldeweg, Torsten; Mancini, Laura; Yousry, Tarek A; Bisdas, Sotirios

2016-11-01

Functional magnetic resonance imaging (fMRI) has become a mainstream neuroimaging modality in the assessment of patients being evaluated for brain tumour and epilepsy surgeries. Thus, it is important for doctors in primary care settings to be well acquainted with the present and potential future applications, as well as limitations, of this modality. The objective of this article is to introduce the theoretical principles and state-of-the-art clinical applications of fMRI in brain tumour and epilepsy surgery, with a focus on the implications for clinical primary care. fMRI enables non-invasive functional mapping of specific cortical tasks (eg motor, language, memory-based, visual), revealing information about functional localisation, anatomical variation in cortical function, and disease effects and adaptations, including the fascinating phenomenon of brain plasticity. fMRI is currently ordered by specialist neurologists and neurosurgeons for the purposes of pre-surgical assessment, and within the context of an experienced multidisciplinary team to prepare, conduct and interpret the scan. With an increasing number of patients undergoing fMRI, general practitioners can expect questions about the current and emerging role of fMRI in clinical care from these patients and their families.

The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation

PubMed Central

Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; Fata, Giorgio La; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

2013-01-01

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

Newly-derived neuroblastoma cell lines propagated in serum-free media recapitulate the genotype and phenotype of primary neuroblastoma tumours.

PubMed

Bate-Eya, Laurel T; Ebus, Marli E; Koster, Jan; den Hartog, Ilona J M; Zwijnenburg, Danny A; Schild, Linda; van der Ploeg, Ida; Dolman, M Emmy M; Caron, Huib N; Versteeg, Rogier; Molenaar, Jan J

2014-02-01

Recently protocols have been devised for the culturing of cell lines from fresh tumours under serum-free conditions in defined neural stem cell medium. These cells, frequently called tumour initiating cells (TICs) closely retained characteristics of the tumours of origin. We report the isolation of eight newly-derived neuroblastoma TICs from six primary neuroblastoma tumours and two bone marrow metastases. The primary tumours from which these TICs were generated have previously been fully typed by whole genome sequencing (WGS). Array comparative genomic hybridisation (aCGH) analysis showed that TIC lines retained essential characteristics of the primary tumours and exhibited typical neuroblastoma chromosomal aberrations such as MYCN amplification, gain of chromosome 17q and deletion of 1p36. Protein analysis showed expression for neuroblastoma markers MYCN, NCAM, CHGA, DBH and TH while haematopoietic markers CD19 and CD11b were absent. We analysed the growth characteristics and confirmed tumour-forming potential using sphere-forming assays, subcutaneous and orthotopic injection of these cells into immune-compromised mice. Affymetrix mRNA expression profiling of TIC line xenografts showed an expression pattern more closely mimicking primary tumours compared to xenografts from classical cell lines. This establishes that these neuroblastoma TICs cultured under serum-free conditions are relevant and useful neuroblastoma tumour models. Copyright © 2013 Elsevier Ltd. All rights reserved.

The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy.

PubMed

Moore, Colin; Kosgodage, Uchini; Lange, Sigrun; Inal, Jameel M

2017-08-01

There is an urgent need to develop new combination therapies beyond existing surgery, radio- and chemo-therapy, perhaps initially combining chemotherapy with the targeting specificities of immunotherapy. For this, strategies to limit inflammation and immunosuppression and evasion in the tumour microenvironment are also needed. To devise effective new immunotherapies we must first understand tumour immunology, including the roles of T cells, macrophages, myeloid suppressor cells and of exosomes and microvesicles (EMVs) in promoting angiogenesis, tumour growth, drug resistance and metastasis. One promising cancer immunotherapy discussed uses cationic liposomes carrying tumour RNA (RNA-lipoplexes) to provoke a strong anti-viral-like (cytotoxic CD8 + ) anti-tumour immune response. Mesenchymal stem cell-derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumours, have also been used. As tumour EMVs clearly exacerbate the tumour microenvironment, another therapy option could involve EMV removal. Affinity-based methods to deplete EMVs, including an immunodepletion, antibody-based affinity substrate, are therefore considered. Finally EMV and exosome-mimetic nanovesicles (NVs) delivery of siRNA or chemotherapeutic drugs that target tumours using peptide ligands for cognate receptors on the tumour cells are discussed. We also touch upon the reversal of drug efflux in EMVs from cancer cells which can sensitize cells to chemotherapy. The use of immunotherapy in combination with the advent of EMVs provides potent therapies to various cancers. © 2017 UICC.

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance.

PubMed

Funck-Brentano, E; Alvarez, J C; Longvert, C; Abe, E; Beauchet, A; Funck-Brentano, C; Saiag, P

2015-07-01

Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression. We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects. PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Variation, "evolution", immortality and genetic instabilities in tumour cells.

PubMed

Bignold, L P

2007-08-18

The pathological characteristics of tumour cells often include variation of their histopathological features (i.e. "degrees of de-differentiation") between cases of the same tumour type and between different foci within individual tumours. Usually, only a few cell lines from tumours are immortal. Currently, somatic mutation, replicative infidelity of DNA and aneuploidy are suggested as alternative mechanisms of genomic disturbance underlying tumours. Nevertheless, apart from Hansemann's ideas of "anaplasia" and "de-differentiation" (proposed in the 1890s), and supposed "evolutionary themes" in cancer cell biology, little has been published concerning how histopathologic variation and immortality in tumour cells might arise. This paper reviews applications of the concepts of "variation" to tumours, including concepts of "evolution" and "cellular Darwinism". It is proposed that combinations of somatic mutation, DNA replicative infidelity and aneuploidy may explain the variabilities in tumours, and provide immortality in occasional tumour cells. A possible model involves (i) an initial somatic mutation causing reduced replicative fidelity of DNA, which could be variable in intensity, and thus give rise to variations between cases; (ii) a phase of replicative infidelity of DNA causing daughter cells lines to develop various abnormalities to different degrees, and hence provide for variation between areas of the same tumour. As a last event (iii) occasional asymmetric chromosomal distributions (aneuploidy) might "refresh" the ability of a daughter cell to replicate DNA faithfully causing them to become immortal. Thus extensively mutant and variable, hyperploid, and occasionally immortal cells might arise.

Heterogeneity of hypoxia in solid tumours and mechanochemical reactions with oxygen nanobubbles.

PubMed

Orel, V B; Zabolotny, M A; Orel, V E

2017-05-01

Tumour hypoxia leads to radio and chemotherapy resistance among cancer patients. The aim of this paper is to formulate a hypothesis on the heterogeneity of hypoxia in solid tumours. Tumour vasculature is known to be significantly variable. The great structural and functional abnormalities of tumour microcirculation cause spatial and temporal heterogeneity in its perfusion. Tumours have constantly been under the influence of pulsatile blood perfusion with variable pressure that initiates inhomogeneous erythrocyte deformation and following impact on oxygen disorder release from red blood cells into plasma within the blood vessel. Furthermore, stochastically released oxygen in tumour vessel, plasma and interstitial fluid may lead to heterogeneity of hypoxia. Under the influence of increased heterogeneity of hemodynamic force, the oxygen molecules dissolved in blood plasma are inclined to form nanobubbles (NBs) in tumour vessels. Considering the fact that tumour interstitial fluid pressure is increased compared to normal tissues, we assume that oxygen NBs may burst under the impact of shear stress. During the course of mechanochemical reaction, when a nanobubble (NB) bursts, both reactive oxygen species and ions form in various charged states. In consequence of a chain reaction, free radical oxygen molecules bind to proteins and lipids, thus reducing oxygen molecules in a chaotic manner within the tumour. The proposed hypothesis should be used as a methodical approach based on the simultaneous ultrasound imaging diagnostic techniques and therapy, regarding the mechanochemical effect on NB conglomerates with drugs in the tumour. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeting the tumour microenvironment in ovarian cancer.

PubMed

Hansen, Jean M; Coleman, Robert L; Sood, Anil K

2016-03-01

The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Haemangioma in the oesophagus of a red-eared slider (Trachemys scripta elegans).

PubMed

Gál, János; Jakab, Csaba; Szabó, Zoltán; Pazár, Péter; Psáder, Roland; Roeber, Florian; Hegyi, Arpád; Lefler, Kinga Katalin; Farkas, Balázs; Mándoki, Míra

2009-12-01

A haemangioma developing in the wall of the oesophagus and protruding into its cavity is reported for the first time from a Red-eared Slider (Trachemys scripta elegans). As the tumour mechanically hampered swallowing, the animal was unable to eat and consequently developed a poor condition. Histopathology of the tumour revealed all characteristics of a haemangioma: the blood-filled blood-vessels having an irregular cross-section were lined with endothelial cells. Claudin-5 immunohistochemical antibodies were employed for characterising the tumour, and this examination confirmed our initial diagnosis of a haemangioma.

Pleuropulmonary blastoma--case report of a patient presenting in a moribund state.

PubMed

Chauke, Risenga Frank; Muthuphei, M Nelson

2003-11-01

A 4-year-old girl presented with an intrathoracic tumour that was pleural in origin, invading the right lower lobe. The patient underwent urgent right thoracotomy and surgical excision of the tumour and right lower lobectomy as the tumour was invading that lobe. The histological report initially reported it as a rhabdomyosarcoma, embryonal type, but after consultation it was changed to type III pleuropulmonary blastoma. The patient was treated with chemotherapy but succumbed to the disease 12 months after the diagnosis. Relevant literature on pleuropulmonary blastoma is reviewed.

Welfare Assessment following Heterotopic or Orthotopic Inoculation of Bladder Cancer in C57BL/6 Mice.

PubMed

Miller, Amy; Burson, Hannah; Söling, Ariane; Roughan, Johnny

2016-01-01

Few studies have assessed whether mice used as cancer models experience pain. Despite this possibility, the usual practice is to withhold analgesics as these are generally viewed as confounding. However, pain also alters cancer progression, so preventing it might not only be beneficial to welfare but also to study validity. Establishing the extent to which different cancer models result in pain is an important first step towards their refinement. We used conditioned place preference (CPP) testing and body-weight and behaviour analyses to evaluate the assumption that heterotopically implanted tumours result in less pain and fewer welfare concerns than those implanted orthotopically. C57Bl/6 mice received MB49Luc luciferase expressing bladder cancer cells or saline implanted subcutaneously or into the bladder. These tumour-bearing or control groups underwent 2 daily 45 minute conditioning trials to saline or morphine (2mg/kg) and then a 15 minute drug-free preference test on day 3 of a 3 day cycle, continuing until the study ended. Tumours were imaged and behaviour data obtained following preference tests. Development of preference for the morphine-paired chamber (morphine-seeking) was determined over time. Heterotopic tumour development had no effect on morphine-seeking, and although the restraint used for heterotopic inoculation caused greater initial weight losses than anaesthesia, these mice steadily gained weight and behaved comparatively normally throughout the study. Orthotopic tumour inoculation caused no initial weight losses, but over the final 7 days these mice became less active and lost more body weight than cancer-free controls. This indicated orthotopic implantation probably caused a more negative impact on welfare or conceivably pain; but only according to the current test methods. Pain could not be confirmed because morphine-seeking in the tumour-bearing groups was similar to that seen in controls. Imaging was not found to be an effective method of monitoring tumour development surpassing manual tumour inspection.

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer.

PubMed

Cicchelero, L; Denies, S; Haers, H; Vanderperren, K; Stock, E; Van Brantegem, L; de Rooster, H; Sanders, N N

2017-12-01

Interleukin 12 (IL-12) is a powerful immunostimulatory cytokine with a strong antitumoural activity. In this work, the immunological, anti-angiogenic and clinical effects of three consecutive intratumoural IL-12 electrogene therapy (EGT) treatments were evaluated in nine dogs with spontaneous cancer. In all the dogs, tumour biopsies and blood samples were taken prior, during and after the intratumoural IL-12 EGT (on days 1, 8, 35 and 1, 3, 8, 15, 35, respectively). An initial decrease in immune cells was followed by an increase above baseline 1-3 weeks after treatment initiation. Interestingly, the decrease in peripheral leukocytes 2 days after the first intratumoural IL-12 EGT coincided with erythema and tumour swelling. Transient increases of IL-12 and interferon γ were measured in the serum and the tumour tissue, whereas IL-10 transiently increased only in the serum. The effect of intratumoural IL-12 EGT on the levels of IL-24 and vascular endothelial growth factor in the sera and tumour biopsies differed per dog. Via contrast-enhanced ultrasound (US) (on days 1, 8 and 35), we demonstrated that intratumoural IL-12 EGT resulted in a significant decrease of the relative blood volume and blood flow speed in the tumour compared with baseline. Metastases were present in two dogs. In one of these dogs, IL-12 EGT of the primary tumour caused a transient partial regression of the metastases, but not of the primary tumour. The second dog with metastases did not survive long enough to complete the entire treatment cycle. Despite encouraging immunostimulatory and anti-angiogenic effects after intratumoural IL-12 EGT, no clinically relevant outcomes were observed in this study, as persistent tumour regression could not be obtained. On the other hand, the laboratory and US results hold great promise for combinatorial strategies of intratumoural IL-12 EGT with conventional antitumour (immuno)therapies. © 2016 John Wiley & Sons Ltd.

The role of PET in target localization for radiotherapy treatment planning.

PubMed

Rembielak, Agata; Price, Pat

2008-02-01

Positron emission tomography (PET) is currently accepted as an important tool in oncology, mostly for diagnosis, staging and restaging purposes. It provides a new type of information in radiotherapy, functional rather than anatomical. PET imaging can also be used for target volume definition in radiotherapy treatment planning. The need for very precise target volume delineation has arisen with the increasing use of sophisticated three-dimensional conformal radiotherapy techniques and intensity modulated radiation therapy. It is expected that better delineation of the target volume may lead to a significant reduction in the irradiated volume, thus lowering the risk of treatment complications (smaller safety margins). Better tumour visualisation also allows a higher dose of radiation to be applied to the tumour, which may lead to better tumour control. The aim of this article is to review the possible use of PET imaging in the radiotherapy of various cancers. We focus mainly on non-small cell lung cancer, lymphoma and oesophageal cancer, but also include current opinion on the use of PET-based planning in other tumours including brain, uterine cervix, rectum and prostate.

Interactions between occupational exposure to extremely low frequency magnetic fields and chemicals for brain tumour risk in the INTEROCC study.

PubMed

Turner, Michelle C; Benke, Geza; Bowman, Joseph D; Figuerola, Jordi; Fleming, Sarah; Hours, Martine; Kincl, Laurel; Krewski, Daniel; McLean, Dave; Parent, Marie-Elise; Richardson, Lesley; Sadetzki, Siegal; Schlaefer, Klaus; Schlehofer, Brigitte; Schüz, Joachim; Siemiatycki, Jack; Tongeren, Martie van; Cardis, Elisabeth

2017-11-01

In absence of clear evidence regarding possible effects of occupational chemical exposures on brain tumour aetiology, it is worthwhile to explore the hypothesis that such exposures might act on brain tumour risk in interaction with occupational exposure to extremely low frequency magnetic fields (ELF). INTEROCC is a seven-country (Australia, Canada, France, Germany, Israel, New Zealand and UK), population-based, case-control study, based on the larger INTERPHONE study. Incident cases of primary glioma and meningioma were ascertained from 2000 to 2004. Job titles were coded into standard international occupational classifications and estimates of ELF and chemical exposures were assigned based on job-exposure matrices. Dichotomous indicators of cumulative ELF (≥50th vs <50th percentile, 1-4 year exposure time window) and chemical exposures (ever vs never, 5-year lag) were created. Interaction was assessed on both the additive and multiplicative scales. A total of 1939 glioma cases, 1822 meningioma cases and 5404 controls were included in the analysis, using conditional logistic regression. There was no clear evidence for interactions between ELF and any of the chemical exposures assessed for either glioma or meningioma risk. For glioma, subjects in the low ELF/metal exposed group had a lower risk than would be predicted from marginal effects. Results were similar according to different exposure time windows, to cut-points of exposure or in exposed-only analyses. There was no clear evidence for interactions between occupational ELF and chemical exposures in relation to glioma or meningioma risk observed. Further research with more refined estimates of occupational exposures is recommended. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of an alveolar recruitment maneuver on subdural pressure, brain swelling, and mean arterial pressure in patients undergoing supratentorial tumour resection: a randomized crossover study.

PubMed

Flexman, Alana M; Gooderham, Peter A; Griesdale, Donald E; Argue, Ruth; Toyota, Brian

2017-06-01

Although recruitment maneuvers have been advocated as part of a lung protective ventilation strategy, their effects on cerebral physiology during elective neurosurgery are unknown. Our objectives were to determine the effects of an alveolar recruitment maneuver on subdural pressure (SDP), brain relaxation score (BRS), and cerebral perfusion pressure among patients undergoing supratentorial tumour resection. In this prospective crossover study, patients scheduled for resection of a supratentorial brain tumour were randomized to undergo either a recruitment maneuver (30 cm of water for 30 sec) or a "sham" maneuver (5 cm of water for 30 sec), followed by the alternative intervention after a 90-sec equilibration period. Subdural pressure was measured through a dural perforation following opening of the cranium. Subdural pressure and mean arterial pressure (MAP) were recorded continuously. The blinded neurosurgeon provided a BRS at baseline and at the end of each intervention. During each treatment, the changes in SDP, BRS, and MAP were compared. Twenty-one patients underwent the study procedure. The increase in SDP was higher during the recruitment maneuver than during the sham maneuver (difference, 3.9 mmHg; 95% confidence interval [CI], 2.2 to 5.6; P < 0.001). Mean arterial pressure decreased further in the recruitment maneuver than in the sham maneuver (difference, -9.0 mmHg; 95% CI, -12.5 to -5.6; P < 0.001). Cerebral perfusion pressure decreased 14 mmHg (95% CI, 4 to 24) during the recruitment maneuver. The BRS did not change with either maneuver. Our results suggest that recruitment maneuvers increase subdural pressure and reduce cerebral perfusion pressure, although the clinical importance of these findings is thus far unknown. This trial was registered with ClinicalTrials.gov, NCT02093117.

Pairwise mixture model for unmixing partial volume effect in multi-voxel MR spectroscopy of brain tumour patients

NASA Astrophysics Data System (ADS)

Olliverre, Nathan; Asad, Muhammad; Yang, Guang; Howe, Franklyn; Slabaugh, Gregory

2017-03-01

Multi-Voxel Magnetic Resonance Spectroscopy (MV-MRS) provides an important and insightful technique for the examination of the chemical composition of brain tissue, making it an attractive medical imaging modality for the examination of brain tumours. MRS, however, is affected by the issue of the Partial Volume Effect (PVE), where the signals of multiple tissue types can be found within a single voxel and provides an obstacle to the interpretation of the data. The PVE results from the low resolution achieved in MV-MRS images relating to the signal to noise ratio (SNR). To counteract PVE, this paper proposes a novel Pairwise Mixture Model (PMM), that extends a recently reported Signal Mixture Model (SMM) for representing the MV-MRS signal as normal, low or high grade tissue types. Inspired by Conditional Random Field (CRF) and its continuous variant the PMM incorporates the surrounding voxel neighbourhood into an optimisation problem, the solution of which provides an estimation to a set of coefficients. The values of the estimated coefficients represents the amount of each tissue type (normal, low or high) found within a voxel. These coefficients can then be visualised as a nosological rendering using a coloured grid representing the MV-MRS image overlaid on top of a structural image, such as a Magnetic Resonance Image (MRI). Experimental results show an accuracy of 92.69% in classifying patient tumours as either low or high grade compared against the histopathology for each patient. Compared to 91.96% achieved by the SMM, the proposed PMM method demonstrates the importance of incorporating spatial coherence into the estimation as well as its potential clinical usage.

O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction.

PubMed

Brell, Marta; Ibáñez, Javier; Tortosa, Avelina

2011-01-26

The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP. A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974-October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance. Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value. Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably.

Glioblastoma and ABO blood groups: further evidence of an association between the distribution of blood group antigens and brain tumours.

PubMed

Allouh, Mohammed Z; Al Barbarawi, Mohammed M; Hiasat, Mohammad Y; Al-Qaralleh, Mohammed A; Ababneh, Emad I

2017-10-01

Glioblastoma is a highly malignant brain tumour that usually leads to death. Several studies have reported a link between the distribution of ABO blood group antigens and a risk of developing specific types of cancer, although no consensus has been reached. This study aims to investigate the relationship between the distribution of ABO blood group antigens and the incidence of glioblastoma. The study cohort consisted of 115 glioblastoma patients who were diagnosed at King Abdullah University Hospital, Jordan, between 2004 and 2015. Three different patient populations made up three control groups and these were selected from among patients at the same institution between 2014 and 2015 as follows: 3,847 healthy blood donors, 654 accidental trauma patients admitted to the Departments of Neurosurgery and Orthopaedics, and 230 age- and sex-matched control subjects recruited blindly from the Departments of Paediatrics and Internal Medicine. There was a significant association between the distribution of ABO blood group antigens and the incidence of glioblastoma. Post hoc residual analysis revealed that individuals with group A had a higher than expected chance of developing glioblastoma, while individuals with group O had a lower than expected chance. Furthermore, individuals with group A were found to be at a 1.62- to 2.28-fold increased risk of developing glioblastoma compared to individuals with group O. In the present study, we demonstrate that, in Jordan, individuals with group A have an increased risk of developing glioblastoma, while individuals with group O have a reduced risk. These findings suggest that the distribution of ABO blood group antigens is associated with a risk of brain tumours and may play an important role in their development. However, further clinical and experimental investigations are required to confirm this association.

The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: A case series in general practice.

PubMed

Jansen, Natalie; Walach, Harald

2016-01-01

Since the initial observations by Warburg in 1924, it has become clear in recent years that tumour cells require a high level of glucose to proliferate. Therefore, a ketogenic diet that provides the body with energy mainly through fat and proteins, but contains a reduced amount of carbohydrates, has become a dietary option for supporting tumour treatment and has exhibited promising results. In the present study, the first case series of such a treatment in general practice is presented, in which 78 patients with tumours were treated within a time window of 10 months. The patients were monitored regarding their levels of transketolase-like-1 (TKTL1), a novel tumour marker associated with aerobic glycolysis of tumour cells, and the patients' degree of adherence to a ketogenic diet. Tumour progression was documented according to oncologists' reports. Tumour status was correlated with TKTL1 expression (Kruskal-Wallis test, P<0.0001), indicating that more progressed and aggressive tumours may require a higher level of aerobic glycolysis. In palliative patients, a clear trend was observed in patients who adhered strictly to a ketogenic diet, with one patient experiencing a stagnation in tumour progression and others an improvement in their condition. The adoption of a ketogenic diet was also observed to affect the levels of TKTL1 in those patients. In conclusion, the results from the present case series in general practice suggest that it may be beneficial to advise tumour patients to adopt a ketogenic diet, and that those who adhere to it may have positive results from this type of diet. Thus, the use of a ketogenic diet as a complementary treatment to tumour therapy must be further studied in rigorously controlled trials.

The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: A case series in general practice

PubMed Central

JANSEN, NATALIE; WALACH, HARALD

2016-01-01

Since the initial observations by Warburg in 1924, it has become clear in recent years that tumour cells require a high level of glucose to proliferate. Therefore, a ketogenic diet that provides the body with energy mainly through fat and proteins, but contains a reduced amount of carbohydrates, has become a dietary option for supporting tumour treatment and has exhibited promising results. In the present study, the first case series of such a treatment in general practice is presented, in which 78 patients with tumours were treated within a time window of 10 months. The patients were monitored regarding their levels of transketolase-like-1 (TKTL1), a novel tumour marker associated with aerobic glycolysis of tumour cells, and the patients' degree of adherence to a ketogenic diet. Tumour progression was documented according to oncologists' reports. Tumour status was correlated with TKTL1 expression (Kruskal-Wallis test, P<0.0001), indicating that more progressed and aggressive tumours may require a higher level of aerobic glycolysis. In palliative patients, a clear trend was observed in patients who adhered strictly to a ketogenic diet, with one patient experiencing a stagnation in tumour progression and others an improvement in their condition. The adoption of a ketogenic diet was also observed to affect the levels of TKTL1 in those patients. In conclusion, the results from the present case series in general practice suggest that it may be beneficial to advise tumour patients to adopt a ketogenic diet, and that those who adhere to it may have positive results from this type of diet. Thus, the use of a ketogenic diet as a complementary treatment to tumour therapy must be further studied in rigorously controlled trials. PMID:26870251

P16.31THERANOSTIC APPLICATION OF WATER-SOLUBLE GADOLINIUM FULLERENE (GD@FUL) IN EXPERIMENTAL GLIOMA MODEL

PubMed Central

Shevtsov, M.; Nikolaev, B.; Marchenko, Y.; Yakovleva, L.; Dobrodumov, A.; Török, G.; Pitkin, E.; Lebedev, V.

2014-01-01

Glioblastoma multiforme (GMB) is a highly invasive brain tumour with poor prognosis. Alternative treatments offering a better outcome are needed. Novel approach could be based on gadofullerenes that can be used as diagnostic MR imaging contrast agent and as a therapeutic drug. Water soluble gadofullerene Gd@Ful with composition Gd@C82(OH)x x ≥20 was synthesized for theranostic study. Nanosuspensions of Gd@Ful were used for magnetic relaxation measurements in vitro and for MR imaging of a rat with intracranially implanted C6 glioma. Gd@Ful was shown to reduce proton relaxation times in vitro, and provide dual contrast of T1- and T2-weighted images in a rat brain tumour model after paramagnetic intravenous delivery. Magnetic relaxation times and relaxivity of water protons under action of Gd@Ful were strongly shortened due to cluster formation and increase of motional correlation times of protons in the vicinity of the fulleren cage. The Gd@Ful administration promoted the improvement of glioma contrast enhancement at T2-weighted images due to accumulation of paramagnetic substance at the tumour site. The contrast efficiency of Gd@Ful corresponds to the characteristics of negative contrast agent. Retention of the Gd@Ful in the C6 glioma provides not only the tumor contrast enhancement but also has a high therapeutic relevance. We observed the increased survival rates in animals that were intravenously administered with Gd@Ful. Thus, in experimental group the survival was 75% higher then in the control group, constituting 34.2 ± 9.94 and 19.5 ± 3.02 days respectively (P < 0.001). The Gd@Ful solution is shown to be a contrast enhancer with high anti-tumour therapeutic potency.

Decreased circulation time offsets increased efficacy of PEGylated nanocarriers targeting folate receptors of glioma

NASA Astrophysics Data System (ADS)

McNeeley, Kathleen M.; Annapragada, Ananth; Bellamkonda, Ravi V.

2007-09-01

Liposomal and other nanocarrier based drug delivery vehicles can localize to tumours through passive and/or active targeting. Passively targeted liposomal nanocarriers accumulate in tumours via 'leaky' vasculature through the enhanced permeability and retention (EPR) effect. Passive accumulation depends upon the circulation time and the degree of tumour vessel 'leakiness'. After extravasation, actively targeted liposomal nanocarriers efficiently deliver their payload by receptor-mediated uptake. However, incorporation of targeting moieties can compromise circulation time in the blood due to recognition and clearance by the reticuloendothelial system, decreasing passive accumulation. Here, we compare the efficacy of passively targeted doxorubicin-loaded PEGylated liposomal nanocarriers to that of actively targeted liposomal nanocarriers in a rat 9L brain tumour model. Although folate receptor (FR)-targeted liposomal nanocarriers had significantly reduced blood circulation time compared to PEGylated liposomal nanocarriers; intratumoural drug concentrations both at 20 and 50 h after administration were equal for both treatments. Both treatments significantly increased tumour inoculated animal survival by 60-80% compared to non-treated controls, but no difference in survival was observed between FR-targeted and passively targeted nanocarriers. Therefore, alternate approaches allowing for active targeting without compromising circulation time may be important for fully realizing the benefits of receptor-mediated active targeting of gliomas.

Imaging of cerebellopontine angle lesions: an update. Part 2: intra-axial lesions, skull base lesions that may invade the CPA region, and non-enhancing extra-axial lesions.

PubMed

Bonneville, Fabrice; Savatovsky, Julien; Chiras, Jacques

2007-11-01

Computed tomography (CT) and magnetic resonance (MR) imaging reliably demonstrate typical features of vestibular schwannomas or meningiomas in the vast majority of mass lesions responsible for cerebellopontine angle (CPA) syndrome. However, a large variety of unusual lesions can also be encountered in the CPA. Covering the entire spectrum of lesions potentially found in the CPA, these articles explain the pertinent neuroimaging features that radiologists need to know to make clinically relevant diagnoses in these cases, including data from diffusion- and perfusion-weighted imaging or MR spectroscopy, when available. A diagnostic algorithm based on the lesion's site of origin, shape and margins, density, signal intensity and contrast material uptake is also proposed. Non-enhancing extra-axial CPA masses are cystic (epidermoid cyst, arachnoid cyst, neurenteric cyst) or contain fat (dermoid cyst, lipoma). Tumours can also extend into the CPA by extension from the skull base (paraganglioma, chondromatous tumours, chordoma, cholesterol granuloma, endolymphatic sac tumour). Finally, brain stem or ventricular tumours can present with a significant exophytic component in the CPA that may be difficult to differentiate from an extra-axial lesion (lymphoma, hemangioblastoma, choroid plexus papilloma, ependymoma, glioma, medulloblastoma, dysembryoplastic neuroepithelial tumour).

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells.

PubMed

Lim, Yi Chieh; Roberts, Tara L; Day, Bryan W; Stringer, Brett W; Kozlov, Sergei; Fazry, Shazrul; Bruce, Zara C; Ensbey, Kathleen S; Walker, David G; Boyd, Andrew W; Lavin, Martin F

2014-12-01

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival. Copyright © 2014. Published by Elsevier B.V.

Giant fibroadenoma presenting like fungating breast cancer in a Nigerian teenager.

PubMed

Arowolo, O A; Akinkuolie, A A; Adisa, A O; Obonna, G C; Olasode, B J

2013-03-01

Giant fibroadenoma of the breast is a rare benign breast tumour which seldom grows to a giant size, it is even rarer for this benign tumour to grow rapidly, ulcerate spontaneously and present like a fungating breast tumour in a way mimicking breast cancer. This is a presentation of a 14 year old premenarchal girl with a massive ulcerating and fungating left breast mass that was initially thought to be a fungating locally advanced breast carcinoma on clinical examination. Further examination of the morphology of the resected surgical specimen and histological examination confirmed it to be giant fibroadenoma of the breast. It was successfully managed by partial mastectomy and breast reconstruction with an excellent result and a high degree of patient satisfaction was achieved. Though a rare clinical entity benign breast tumour can present like a fungating breast cancer and this must be bore in mind especially in young adolescent patients presenting with ulcerating breast tumour.

Identification of a neuronal transcription factor network involved in medulloblastoma development

PubMed Central

2013-01-01

Background Medulloblastomas, the most frequent malignant brain tumours affecting children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1, SUFU) are observed in many of these tumours, high throughput genomic analyses have identified few other recurring mutations. Here, we have mutagenised the Ptch+/- murine tumour model using the Sleeping Beauty transposon system to identify additional genes and pathways involved in SHH subgroup medulloblastoma development. Results Mutagenesis significantly increased medulloblastoma frequency and identified 17 candidate cancer genes, including orthologs of genes somatically mutated (PTEN, CREBBP) or associated with poor outcome (PTEN, MYT1L) in the human disease. Strikingly, these candidate genes were enriched for transcription factors (p=2x10-5), the majority of which (6/7; Crebbp, Myt1L, Nfia, Nfib, Tead1 and Tgif2) were linked within a single regulatory network enriched for genes associated with a differentiated neuronal phenotype. Furthermore, activity of this network varied significantly between the human subgroups, was associated with metastatic disease, and predicted poor survival specifically within the SHH subgroup of tumours. Igf2, previously implicated in medulloblastoma, was the most differentially expressed gene in murine tumours with network perturbation, and network activity in both mouse and human tumours was characterised by enrichment for multiple gene-sets indicating increased cell proliferation, IGF signalling, MYC target upregulation, and decreased neuronal differentiation. Conclusions Collectively, our data support a model of medulloblastoma development in SB-mutagenised Ptch+/- mice which involves disruption of a novel transcription factor network leading to Igf2 upregulation, proliferation of GNPs, and tumour formation. Moreover, our results identify rational therapeutic targets for SHH subgroup tumours, alongside prognostic biomarkers for the identification of poor-risk SHH patients. PMID:24252690

Quantification of gross tumour volume changes between simulation and first day of radiotherapy for patients with locally advanced malignancies of the lung and head/neck.

PubMed

Kishan, Amar U; Cui, Jing; Wang, Pin-Chieh; Daly, Megan E; Purdy, James A; Chen, Allen M

2014-10-01

To quantify changes in gross tumour volume (GTV) between simulation and initiation of radiotherapy in patients with locally advanced malignancies of the lung and head/neck. Initial cone beam computed tomography (CT) scans from 12 patients with lung cancer and 12 with head/neck cancer (head and neck squamous cell carcinoma (HNSCC)) treated with intensity-modulated radiotherapy with image guidance were rigidly registered to the simulation CT scans. The GTV was demarcated on both scans. The relationship between percent GTV change and variables including time interval between simulation and start, tumour (T) stage, and absolute weight change was assessed. For lung cancer patients, the GTV increased a median of 35.06% (range, -16.63% to 229.97%) over a median interval of 13 days (range, 7-43), while for HNSCC patients, the median GTV increase was 16.04% (range, -8.03% to 47.41%) over 13 days (range, 7-40). These observed changes are statistically significant. The magnitude of this change was inversely associated with the size of the tumour on the simulation scan for lung cancer patients (P < 0.05). However, the observed changes in GTV did not correlate with the duration of the interval for either disease site. Similarly, T stage, absolute weight change and histologic type (the latter for lung cancer cases) did not correlate with degree of GTV change (P > 0.1). While the observed changes in GTV were moderate from the time of simulation to start of radiotherapy, these findings underscore the importance of image guidance for target localisation and verification, particularly for smaller tumours. Minimising the delay between simulation and treatment initiation may also be beneficial. © 2014 The Royal Australian and New Zealand College of Radiologists.

Catalytic nanomedicine: a new field in antitumor treatment using supported platinum nanoparticles. In vitro DNA degradation and in vivo tests with C6 animal model on Wistar rats.

PubMed

López, T; Figueras, F; Manjarrez, J; Bustos, J; Alvarez, M; Silvestre-Albero, J; Rodríguez-Reinoso, F; Martínez-Ferre, A; Martínez, E

2010-05-01

Novel nanostructured TiO2 and SiO2 based biocatalysts, with 3-4 wt. % of Pt have been developed. The obtained materials exhibit a high surface area together with a broad pore size distribution. The method of synthesis allowed obtaining high dispersed platinum metal nanoparticles. In vitro DNA reactivity test of the biocatalysts were carried out by electrophoresis and formation of DNA adducts was observed. The most active biocatalyst was H2PtCl6/SiO2. These biocatalysts were also tested in an experimental model of C6 brain tumours in Wistar rats. Administration of the material was made by stereotactic brain surgery to place it directly in the malignant tissue. A significant decrease in tumour size and weight as well as morphologic changes in cancer cells were observed. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Perfluorocarbon emulsions radiosensitise brain tumors in carbogen breathing mice with orthotopic GL261 gliomas

PubMed Central

Feldman, Lisa A.; Fabre, Marie-Sophie; Grasso, Carole; Reid, Dana; Broaddus, William C.; Lanza, Gregory M.; Spiess, Bruce D.; Garbow, Joel R.; McConnell, Melanie J.

2017-01-01

Background Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy. Aim To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2). Results PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone. Conclusion IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors. PMID:28873460

Quality and readability of information materials for people with brain tumours and their families.

PubMed

Langbecker, Danette; Janda, Monika

2012-12-01

Written information is commonly used to inform patients about their disease and treatment but must be evidence-based and understandable to be useful. This study assessed the quality of the content and the readability of information brochures for people affected by brain tumours. We randomly selected 18 publicly available brochures. Brochures were assessed by criteria to assess the quality of content using the DISCERN instrument. Readability was tested using three commonly used formulas, which yield the reading grade level required to comprehend the brochure (sixth grade level recommended). The mean overall DISCERN score was 3.17 out of a maximum of 5 (moderate quality); only one achieved a rating greater than 4 (high quality). Only one brochure met the sixth grade readability criteria. Although brochures may have accurate content, few satisfied all of the recommended criteria to evaluate their content. Existing brochures need to be critically reviewed and simplified and consumer-focused brochures, produced.

Gastric marginal zone lymphoma of mucosa-associated lymphoid tissue and signet ring cell carcinoma, synchronous collision tumour of the stomach: a case report.

PubMed

George, Smiley Annie; Junaid, T A

2014-01-01

To report a rare case of synchronous marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) signet ring cell carcinoma occurring as a collision tumour in the stomach. A 53-year-old man was diagnosed initially with signet ring cell carcinoma of the stomach. The microscopy of the subsequent total gastrectomy revealed a collision tumour of MALT lymphoma and signet ring cell carcinoma associated with Helicobacter pylori gastritis. This case highlighted the importance of a careful evaluation of the accompanying lymphoid population in the biopsy samples of gastric adenocarcinoma and underlined the need for multiple endoscopic biopsies to detect these rare synchronous tumours. © 2013 S. Karger AG, Basel.

Gastric Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue and Signet Ring Cell Carcinoma, Synchronous Collision Tumour of the Stomach: A Case Report

PubMed Central

George, Smiley Annie; Junaid, T.A.

2014-01-01

Objective To report a rare case of synchronous marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) signet ring cell carcinoma occurring as a collision tumour in the stomach. Clinical Presentation and Intervention A 53-year-old man was diagnosed initially with signet ring cell carcinoma of the stomach. The microscopy of the subsequent total gastrectomy revealed a collision tumour of MALT lymphoma and signet ring cell carcinoma associated with Helicobacter pylori gastritis. Conclusion This case highlighted the importance of a careful evaluation of the accompanying lymphoid population in the biopsy samples of gastric adenocarcinoma and underlined the need for multiple endoscopic biopsies to detect these rare synchronous tumours. PMID:24247357

DOE Office of Scientific and Technical Information (OSTI.GOV)

Espinoza, I; Peschke, P; Karger, C

Purpose: In radiotherapy, it is important to predict the response of tumour to irradiation prior to the treatment. Mathematical modelling of tumour control probability (TCP) based on the dose distribution, medical imaging and other biological information may help to improve this prediction and to optimize the treatment plan. The aim of this work is to develop an image based 3D multiscale radiobiological model, which describes the growth and the response to radiotherapy of hypoxic tumors. Methods: The computer model is based on voxels, containing tumour, normal (including capillary) and dead cells. Killing of tumour cells due to irradiation is calculatedmore » by the Linear Quadratic Model (extended for hypoxia), and the proliferation and resorption of cells are modelled by exponential laws. The initial shape of the tumours is taken from CT images and the initial vascular and cell density information from PET and/or MR images. Including the fractionation regime and the physical dose distribution of the radiation treatment, the model simulates the spatial-temporal evolution of the tumor. Additionally, the dose distribution may be biologically optimized. Results: The model describes the appearance of hypoxia during tumour growth and the reoxygenation processes during radiotherapy. Among other parameters, the TCP is calculated for different dose distributions. The results are in accordance with published results. Conclusion: The simulation model may contribute to the understanding of the influence of biological parameters on tumor response during treatment, and specifically on TCP. It may be used to implement dose-painting approaches. Experimental and clinical validation is needed. This study is supported by a grant from the Ministry of Education of Chile, Programa Mece Educacion Superior (2)« less

The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5.

PubMed

Guaita-Esteruelas, S; Gumà, J; Masana, L; Borràs, J

2018-02-15

The adipose tissue microenvironment plays a key role in tumour initiation and progression because it provides fatty acids and adipokines to tumour cells. The fatty acid-binding protein (FABP) family is a group of small proteins that act as intracellular fatty acid transporters. Adipose-derived FABPs include FABP4 and FABP5. Both have an important role in lipid-related metabolic processes and overexpressed in many cancers, such as breast, prostate, colorectal and ovarian. Moreover, their expression in peritumoural adipose tissue is deregulated, and their circulating levels are upregulated in some tumours. In this review, we discuss the role of the peritumoural adipose tissue and the related adipokines FABP4 and FABP5 in cancer initiation and progression and the possible pathways implicated in these processes. Copyright © 2017 Elsevier B.V. All rights reserved.

Training for planning tumour resection: augmented reality and human factors.

PubMed

Abhari, Kamyar; Baxter, John S H; Chen, Elvis C S; Khan, Ali R; Peters, Terry M; de Ribaupierre, Sandrine; Eagleson, Roy

2015-06-01

Planning surgical interventions is a complex task, demanding a high degree of perceptual, cognitive, and sensorimotor skills to reduce intra- and post-operative complications. This process requires spatial reasoning to coordinate between the preoperatively acquired medical images and patient reference frames. In the case of neurosurgical interventions, traditional approaches to planning tend to focus on providing a means for visualizing medical images, but rarely support transformation between different spatial reference frames. Thus, surgeons often rely on their previous experience and intuition as their sole guide is to perform mental transformation. In case of junior residents, this may lead to longer operation times or increased chance of error under additional cognitive demands. In this paper, we introduce a mixed augmented-/virtual-reality system to facilitate training for planning a common neurosurgical procedure, brain tumour resection. The proposed system is designed and evaluated with human factors explicitly in mind, alleviating the difficulty of mental transformation. Our results indicate that, compared to conventional planning environments, the proposed system greatly improves the nonclinicians' performance, independent of the sensorimotor tasks performed ( ). Furthermore, the use of the proposed system by clinicians resulted in a significant reduction in time to perform clinically relevant tasks ( ). These results demonstrate the role of mixed-reality systems in assisting residents to develop necessary spatial reasoning skills needed for planning brain tumour resection, improving patient outcomes.

A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models

PubMed Central

2009-01-01

Background Over the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect. Methods The in-vitro activities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity on in-vitro microtubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compound in vivo. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours. Results In the four human and the murine glioblastoma cell lines tested, 10 μM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 × 105 M-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. These in vitro studies were reinforced by our in vivo investigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB. Conclusion These in vitro and in vivo data suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model. PMID:19619277

The evolution of the histology in pleomorphic xanthoastrocytomas in children: a study of 15 cases.

PubMed

Wu, Xiangru; Bandopadhayay, Pratiti; Ng, Jessica; Ashley, David; Chow, C W

2011-01-01

To review the clinicopathological spectrum and evolution of the histology of pleomorphic xanthoastrocytomas (PXAs) seen at a single children's hospital. PXAs were selected from the Royal Children's Hospital archives over 30 years. The clinical features and pathology were reviewed, specifically checking the histological variation between areas, and the changes between biopsies. Fifteen patients were identified. Ten had repeat biopsies. Eleven patients did not show histological features of anaplasia. Of these eleven, three did not show the characteristic histological features, which developed 3 and 11 years later in repeat biopsies in two. Seven showed uncommon potentially confusing histology. One died, one had stable disease and one had progressive disease. Three with incomplete initial surgery remained in complete remission following more surgery, radiotherapy and chemotherapy when the tumours progressed, up to 11 years later. Four patients did show anaplasia, with abrupt change from typical PXA in two, and years following initial biopsy in one. Of these four patients, three died, one with extensive metastasis. PXA should be considered in superficial cerebral tumours composed only of compact bundles of glial fibrillary acidic protein positive spindle cells with inconspicuous mitosis, even when the highly characteristic features of this tumour are not seen. The prominent variation in histology makes small biopsies difficult for diagnosis and assessing anaplasia. Patients with non-anaplastic tumours can often be salvaged by more treatment for tumour progression.

High folic acid diet enhances tumour growth in PyMT-induced breast cancer

PubMed Central

Hansen, Mariann Fagernæs; Jensen, Sarah Østrup; Füchtbauer, Ernst-Martin; Martensen, Pia M

2017-01-01

Background: The B-vitamin folate is among the most studied bioactive food compound, and a dietary intake meeting the daily requirements has been found to reduce the risk of cancer and cardiovascular diseases as well as preventing neural tube defects during fetal development. Several countries have therefore introduced dietary fortification with folic acid. However, clinical and animal studies suggest that folic acid has a dual role in cancer development. Methods: During the period of initial tumour progression, MMTV-PyMT (MMTV-polyoma virus middle T) transgenic mice were fed with normal diet and high folic acid diet. Results: We found that PyMT-induced breast tumours highly express the cancer-specific folate receptor (FR), a feature they share with several human epithelial cancers in which expression of FRα correlates with tumour grade. Mice receiving a high folic acid diet displayed a significantly increased tumour volume compared with mice receiving normal diet. In the largest tumours, only found in mice on high folic acid diet, STAT3 was activated. In primary cells from PyMT tumours, STAT3 was activated upon treatment with folic acid in culture. Conclusions: Our results offer a novel molecular explanation for folic acid-induced growth of existing tumours. PMID:28152548

Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

PubMed Central

Stephens, T. C.; Peacock, J. H.

1977-01-01

The relationship between tumour volume response and cell kill in B16 melanoma following treatment in vivo with cyclophosphamide (CY) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was investigated. Tumour volume response, expressed as growth delay, was estimated from measurements of tumour dimensions. Depression of in vitro colony-forming ability of cells from treated tumours was used as the measure of tumour cell kill. The relationship between these parameters was clearly different for the two agents studied. CY produced more growth delay (7.5 days) per decade of tumour cell kill than CCNU (2 to 3.5 days). The possibility that this was due to a technical artefact was rejected in favour of an alternative explanation that different rates of cellular repopulation in tumours treated with CY and CCNU might be responsible. Cellular repopulation was measured directly, by performing cell-survival assays at various times after treatment with doses of CY and CCNU which produced about 3 decades of cell kill. The rate of repopulation by clonogenic cells was much slower after treatment with CY than with CCNU, and this appears to account for the longer duration of the growth delay obtained with CY. PMID:921888

Estimation of RF energy absorbed in the brain from mobile phones in the Interphone Study.

PubMed

Cardis, E; Varsier, N; Bowman, J D; Deltour, I; Figuerola, J; Mann, S; Moissonnier, M; Taki, M; Vecchia, P; Villegas, R; Vrijheid, M; Wake, K; Wiart, J

2011-09-01

The objective of this study was to develop an estimate of a radio frequency (RF) dose as the amount of mobile phone RF energy absorbed at the location of a brain tumour, for use in the Interphone Epidemiological Study. We systematically evaluated and quantified all the main parameters thought to influence the amount of specific RF energy absorbed in the brain from mobile telephone use. For this, we identified the likely important determinants of RF specific energy absorption rate during protocol and questionnaire design, we collected information from study subjects, network operators and laboratories involved in specific energy absorption rate measurements and we studied potential modifiers of phone output through the use of software-modified phones. Data collected were analysed to assess the relative importance of the different factors, leading to the development of an algorithm to evaluate the total cumulative specific RF energy (in joules per kilogram), or dose, absorbed at a particular location in the brain. This algorithm was applied to Interphone Study subjects in five countries. The main determinants of total cumulative specific RF energy from mobile phones were communication system and frequency band, location in the brain and amount and duration of mobile phone use. Though there was substantial agreement between categorisation of subjects by cumulative specific RF energy and cumulative call time, misclassification was non-negligible, particularly at higher frequency bands. Factors such as adaptive power control (except in Code Division Multiple Access networks), discontinuous transmission and conditions of phone use were found to have a relatively minor influence on total cumulative specific RF energy. While amount and duration of use are important determinants of RF dose in the brain, their impact can be substantially modified by communication system, frequency band and location in the brain. It is important to take these into account in analyses of risk of brain tumours from RF exposure from mobile phones.

Estimation of RF energy absorbed in the brain from mobile phones in the Interphone Study

PubMed Central

Varsier, N; Bowman, J D; Deltour, I; Figuerola, J; Mann, S; Moissonnier, M; Taki, M; Vecchia, P; Villegas, R; Vrijheid, M; Wake, K; Wiart, J

2011-01-01

Objectives The objective of this study was to develop an estimate of a radio frequency (RF) dose as the amount of mobile phone RF energy absorbed at the location of a brain tumour, for use in the Interphone Epidemiological Study. Methods We systematically evaluated and quantified all the main parameters thought to influence the amount of specific RF energy absorbed in the brain from mobile telephone use. For this, we identified the likely important determinants of RF specific energy absorption rate during protocol and questionnaire design, we collected information from study subjects, network operators and laboratories involved in specific energy absorption rate measurements and we studied potential modifiers of phone output through the use of software-modified phones. Data collected were analysed to assess the relative importance of the different factors, leading to the development of an algorithm to evaluate the total cumulative specific RF energy (in joules per kilogram), or dose, absorbed at a particular location in the brain. This algorithm was applied to Interphone Study subjects in five countries. Results The main determinants of total cumulative specific RF energy from mobile phones were communication system and frequency band, location in the brain and amount and duration of mobile phone use. Though there was substantial agreement between categorisation of subjects by cumulative specific RF energy and cumulative call time, misclassification was non-negligible, particularly at higher frequency bands. Factors such as adaptive power control (except in Code Division Multiple Access networks), discontinuous transmission and conditions of phone use were found to have a relatively minor influence on total cumulative specific RF energy. Conclusions While amount and duration of use are important determinants of RF dose in the brain, their impact can be substantially modified by communication system, frequency band and location in the brain. It is important to take these into account in analyses of risk of brain tumours from RF exposure from mobile phones. PMID:21659468

A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme

PubMed Central

Morris, E J A; Whitehouse, L E; Farrell, T; Nickerson, C; Thomas, J D; Quirke, P; Rutter, M D; Rees, C; Finan, P J; Wilkinson, J R; Patnick, J

2012-01-01

Background: Colorectal cancer is common in England and, with long-term survival relatively poor, improving outcomes is a priority. A major initiative to reduce mortality from the disease has been the introduction of the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP). Combining data from the BCSP with that in the National Cancer Data Repository (NCDR) allows all tumours diagnosed in England to be categorised according to their involvement with the BCSP. This study sought to quantify the characteristics of the tumours diagnosed within and outside the BCSP and investigate its impact on outcomes. Methods: Linkage of the NCDR and BCSP data allowed all tumours diagnosed between July 2006 and December 2008 to be categorised into four groups; screen-detected tumours, screening-interval tumours, tumours diagnosed in non-participating invitees and tumours diagnosed in those never invited to participate. The characteristics, management and outcome of tumours in each category were compared. Results: In all, 76 943 individuals were diagnosed with their first primary colorectal cancer during the study period. Of these 2213 (2.9%) were screen-detected, 623 (0.8%) were screening-interval cancers, 1760 (2.3%) were diagnosed in individuals in non-participating invitees and 72 437 (94.1%) were diagnosed in individuals not invited to participate in the programme due to its ongoing roll-out over the time period studied. Screen-detected tumours were identified at earlier Dukes' stages, were more likely to be managed with curative intent and had significantly better outcomes than tumours in other categories. Conclusion: Screen-detected cancers had a significantly better prognosis than other tumours and this would suggest that the BCSP should reduce mortality from colorectal cancer in England. PMID:22850549

LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma.

PubMed

Strazisar, Mojca; Mlakar, Vid; Glavac, Damjan

2009-06-01

LATS2 is a new member of the LATS tumour suppressor family. The human LATS2 gene is located at chromosome 13q11-12, a hot spot (67%) for loss of heterozygosity (LOH) in non-small cell lung cancer (NSCLC). We screened 129 non-small cell lung cancer samples and 13 lung cancer cell lines, initially for mutations in the LATS2 gene and subsequently for mutations in P53 and K-RAS genes. Either polymorphisms or mutations were identified in over 50 percent of analysed tumours. A novel missense mutation, S1073R, and a large deletion of 8 amino acids in the PAPA-repeat region were detected in 9 and 2 NSCLC tumours, respectively. Those mutations were not identified in the 13 lung cancer cell lines. Mutations were tumour specific and were absent from adjacent normal tissue and healthy controls. Down-regulation of the LATS2 gene was observed in most NSCLC tumours but was not related to any mutation or polymorphism. Tumours with a LATS2 mutation often also harbour a P53 but not K-RAS gene mutation and were mostly in an advanced stage of development, with regional lymph node involvement.

Temporally separated bilateral anal sac gland carcinomas in four dogs.

PubMed

Bowlt, K L; Friend, E J; Delisser, P; Murphy, S; Polton, G

2013-08-01

Anal sac gland carcinoma arising from the apocrine secretory epithelium in the anal sac wall, is locally invasive and highly metastatic. The majority of anal sac gland carcinomas are unilateral on presentation, but bilateral tumours have been identified. This case series presents the outcome of four unique cases of unilateral anal sac gland carcinoma which subsequently developed contralateral anal sac gland carcinoma 50 to 390 days after removal of the initial tumour. Median survival was 1035 days after initial diagnosis and 807 days after diagnosis of the second anal sac gland carcinoma. © 2013 British Small Animal Veterinary Association.

Spontaneous renal hemorrhage secondary to choriocarcinoma in a man with congenital hypospadias and cryptorchidism: a case report and literature review.

PubMed

Li, Yi; Chen, Gang; Chen, Han; Wen, Shuang; Xiong, Chao-Yu; Yang, Zi-Yi; Zhu, Yun-Xiao; Jeffreys, Nathan

2018-05-08

Choriocarcinoma is a rare malignant germ-cell tumour, most commonly found in adult women. It infrequently presents as spontaneous renal haemorrhage (SRH). Genital malformation and SRH secondary to choriocarcinoma has previously been only reported in females. We present what we believe to be the first case of a male patient with genital malformation (hypospadias and cryptorchidism) and SRH at presentation of choriocarcinoma. A 25-year-old man presented to the department with intense pain in the right flank region and lower back. Initial investigations showed spontaneous renal haemorrhage, for which an emergency partial nephrectomy was performed. Clinical, radiological, and pathological investigations suggested a diagnosis of testicular choriocarcinoma with metastases to the right kidney, both lungs, and brain. Initial treatment was with a chemotherapy regimen of cisplatin, etoposide and bleomycin and whole brain radiotherapy; however, 6 months after diagnosis the patient developed liver metastasis, after which time the BEP protocol was switched to ITP with oral apatinib. Despite best efforts, the liver and lung metastasis continued to grow and a decision was made to discontinue active treatment and provide only palliative care until the patient passed away. Choriocarcinoma is a difficult cancer to diagnose pre-operatively. In male patients with early metastasis, prognosis may be much poorer than in the commoner gestational choriocarcinoma. A multidisciplinary with comprehensive post-surgical intervention is of great importance in the treatment of these patients.

Impact of brain tumour location on emotion and personality: a voxel-based lesion-symptom mapping study on mentalization processes.

PubMed

Campanella, Fabio; Shallice, Tim; Ius, Tamara; Fabbro, Franco; Skrap, Miran

2014-09-01

Patients affected by brain tumours may show behavioural and emotional regulation deficits, sometimes showing flattened affect and sometimes experiencing a true 'change' in personality. However, little evidence is available to the surgeon as to what changes are likely to occur with damage at specific sites, as previous studies have either relied on single cases or provided only limited anatomical specificity, mostly reporting associations rather than dissociations of symptoms. We investigated these aspects in patients undergoing surgery for the removal of cerebral tumours. We argued that many of the problems described can be ascribed to the onset of difficulties in one or more of the different levels of the process of mentalizing (i.e. abstracting and reflecting upon) emotion and intentions, which impacts on everyday behaviour. These were investigated in terms of (i) emotion recognition; (ii) Theory of Mind; (iii) alexithymia; and (iv) self-maturity (personality disorder). We hypothesized that temporo/limbic areas would be critical for processing emotion and intentions at a more perceptual level, while frontal lobe structures would be more critical when higher levels of mentalization/abstraction are required. We administered four different tasks, Task 1: emotion recognition of Ekman faces; Task 2: the Eyes Test (Theory of Mind); Task 3: Toronto Alexithymia Scale; and Task 4: Temperament and Character Inventory (a personality inventory), both immediately before and few days after the operation for the removal of brain tumours in a series of 71 patients (age range: 18-75 years; 33 female) with lesions located in the left or right frontal, temporal and parietal lobes. Lobe-based and voxel-based analysis confirmed that tasks requiring interpretation of emotions and intentions at more basic (less mentalized) levels (Tasks 1 and 2) were more affected by temporo/insular lesions, with emotion recognition (Task 1) being maximally impaired by anterior temporal and amygdala lesions and Task 2 (found to be a 'basic' Theory of Mind task involving only limited mentalization) being mostly impaired by posterior temporoparietal lesions. Tasks relying on higher-level mentalization (Tasks 3 and 4) were maximally affected by prefrontal lesions, with the alexithymia scale (Task 3) being mostly associated with anterior/medial lesions and the self-maturity measure (Task 4) with lateral prefrontal ones. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Real-time surgical simulation for deformable soft-tissue objects with a tumour using Boundary Element techniques

NASA Astrophysics Data System (ADS)

Wang, P.; Becker, A. A.; Jones, I. A.; Glover, A. T.; Benford, S. D.; Vloeberghs, M.

2009-08-01

A virtual-reality real-time simulation of surgical operations that incorporates the inclusion of a hard tumour is presented. The software is based on Boundary Element (BE) technique. A review of the BE formulation for real-time analysis of two-domain deformable objects, using the pre-solution technique, is presented. The two-domain BE software is incorporated into a surgical simulation system called VIRS to simulate the initiation of a cut on the surface of the soft tissue and extending the cut deeper until the tumour is reached.

Pulmonary Embolism as the Initial Presentation of Testicular Carcinoma

PubMed Central

Berber, Ilhami; Erkurt, Mehmet Ali; Ulutas, Ozkan; Ediz, Caner; Nizam, Ilknur; Kırıcı Berber, Nurcan; Unlu, Serkan; Koroglu, Reyhan; Koroglu, Mustafa; Akpolat, Nusret

2013-01-01

Objective. The risk of pulmonary embolism is well recognized as showing an increase in oncological patients. We report a case presenting with pulmonary embolism initially, which was then diagnosed with testicular cancer. Clinical Presentation and Intervention. A 25-year-old man was admitted to the emergency department with a complaint of dyspnoea. Thoracic tomography, lung ventilation/perfusion scintigraphy, and an increased D-dimer level revealed pulmonary embolism. For the aetiology of pulmonary embolism, a left orchiectomy was performed and the patient was diagnosed with a germinal cell tumour of the testicle. Conclusion. In this paper, we present a patient for whom pulmonary embolism was the initial presentation, and a germinal cell tumour was diagnosed later during the search for the aetiology. PMID:24383024

Novel somatic and germline mutations in intracranial germ cell tumours.

PubMed

Wang, Linghua; Yamaguchi, Shigeru; Burstein, Matthew D; Terashima, Keita; Chang, Kyle; Ng, Ho-Keung; Nakamura, Hideo; He, Zongxiao; Doddapaneni, Harshavardhan; Lewis, Lora; Wang, Mark; Suzuki, Tomonari; Nishikawa, Ryo; Natsume, Atsushi; Terasaka, Shunsuke; Dauser, Robert; Whitehead, William; Adekunle, Adesina; Sun, Jiayi; Qiao, Yi; Marth, Gábor; Muzny, Donna M; Gibbs, Richard A; Leal, Suzanne M; Wheeler, David A; Lau, Ching C

2014-07-10

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

PubMed

Farías, Rubén O; Bortolussi, Silva; Menéndez, Pablo R; González, Sara J

2014-12-01

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options. Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

High levels of sFas and PBMC apoptosis before and after excision of malignant melanoma--case report.

PubMed

Alecu, M; Coman, Gabriela; Dănăilă, L

2002-01-01

In our study we investigated the level of apoptosis in PBMCs and the serological level of sFas (CD95/APO-1) in 22 patients with malignant melanoma (12 patients with unique cutaneous primary tumour and 10 patients with unique brain metastasis). The first determination was performed before tumour excision and the second at 6-7 months after excision. Results in patients with primary tumour in the first determination: 6 patients with over normal values in PBMCs apoptosis and 5 patients with increased values of sFas. In the second determination: apoptosis was increased in 5 patients and sFas level was increased in 4 cases. In patients with metastases in the first determination apoptosis of PBMC was increased in 7 cases and sFas in 5 cases. In the second determination apoptosis was increased in 4 cases and sFas was increased in 4 cases. Our results show that half of the investigated patients presented elevated values of PBMCs apoptosis and Fas receptor both before and 6-7 months after tumour excision. Apoptosis values for PBMCs and sFas values were with 1/4 higher than normals. There was no difference in clinical evolution of the patients with normal or increased values for studied parameters. Clinical evolution was performed for 1 year. The presence of increased values for PBMCs and sFas after tumour excision, primary or metastasis is surprising and hard to explain. It is possible that tumoral evolution induces a disregulation at PBMCs level or other cells level that persists unexpectedly, after tumour excision or apoptotic processes, in a certain level to be independent and anterior to tumour development.

Semi-automated and automated glioma grading using dynamic susceptibility-weighted contrast-enhanced perfusion MRI relative cerebral blood volume measurements.

PubMed

Friedman, S N; Bambrough, P J; Kotsarini, C; Khandanpour, N; Hoggard, N

2012-12-01

Despite the established role of MRI in the diagnosis of brain tumours, histopathological assessment remains the clinically used technique, especially for the glioma group. Relative cerebral blood volume (rCBV) is a dynamic susceptibility-weighted contrast-enhanced perfusion MRI parameter that has been shown to correlate to tumour grade, but assessment requires a specialist and is time consuming. We developed analysis software to determine glioma gradings from perfusion rCBV scans in a manner that is quick, easy and does not require a specialist operator. MRI perfusion data from 47 patients with different histopathological grades of glioma were analysed with custom-designed software. Semi-automated analysis was performed with a specialist and non-specialist operator separately determining the maximum rCBV value corresponding to the tumour. Automated histogram analysis was performed by calculating the mean, standard deviation, median, mode, skewness and kurtosis of rCBV values. All values were compared with the histopathologically assessed tumour grade. A strong correlation between specialist and non-specialist observer measurements was found. Significantly different values were obtained between tumour grades using both semi-automated and automated techniques, consistent with previous results. The raw (unnormalised) data single-pixel maximum rCBV semi-automated analysis value had the strongest correlation with glioma grade. Standard deviation of the raw data had the strongest correlation of the automated analysis. Semi-automated calculation of raw maximum rCBV value was the best indicator of tumour grade and does not require a specialist operator. Both semi-automated and automated MRI perfusion techniques provide viable non-invasive alternatives to biopsy for glioma tumour grading.

The novel WHO 2010 classification for gastrointestinal neuroendocrine tumours correlates well with the metastatic potential of rectal neuroendocrine tumours.

PubMed

Jernman, Juha; Välimäki, Matti J; Louhimo, Johanna; Haglund, Caj; Arola, Johanna

2012-01-01

Approximately 10-15% of gastroenteropancreatic neuroendocrine tumours (NETs, carcinoids) occur in the rectum, some of which are potentially able to metastasize. The new WHO 2010 classification of NETs applies to all gastroenteropancreatic NETs, but no reports have studied its correlation with the prognosis of rectal NETs. We retrospectively classified 73 rectal NETs according to the novel WHO 2010 and the previous WHO 2000 classifications. The aim was to assess the validity of the classifications in distinguishing indolent rectal NETs from metastasising tumours. Using the WHO 2010 criteria, we identified 61 G1 tumours, none of which had metastasised during follow-up. Of 11 G2 tumours, 9 had shown distant metastases. The only G3 neuroendocrine carcinoma that occurred had been disseminated at initial presentation. Our results show that rectal NETs classified as G1 according to the WHO 2010 classification have an indolent clinical course, whereas G2 NETs often metastasise. The WHO 2010 classification of NETs predicts the metastatic potential of rectal NETs better than the WHO 2000 classification. Copyright © 2011 S. Karger AG, Basel.

On a nonlinear model for tumour growth with drug application

NASA Astrophysics Data System (ADS)

Donatelli, Donatella; Trivisa, Konstantina

2015-05-01

We investigate the dynamics of a nonlinear system modelling tumour growth with drug application. The tumour is viewed as a mixture consisting of proliferating, quiescent and dead cells as well as a nutrient in the presence of a drug. The system is given by a multi-phase flow model: the densities of the different cells are governed by a set of transport equations, the density of the nutrient and the density of the drug are governed by rather general diffusion equations, while the velocity of the tumour is given by Brinkman's equation. The domain occupied by the tumour in this setting is a growing continuum Ω with boundary ∂Ω both of which evolve in time. Global-in-time weak solutions are obtained using an approach based on penalization of the boundary behaviour, diffusion and viscosity in the weak formulation. Both the solutions and the domain are rather general, no symmetry assumption is required and the result holds for large initial data. This article is part of a research programme whose aim is the investigation of the effect of drug application in tumour growth.

Genomic aberrations in spitzoid tumours and their implications for diagnosis, prognosis and therapy

PubMed Central

Wiesner, Thomas; Kutzner, Heinz; Cerroni, Lorenzo; Mihm, Martin J.; Busam, Klaus J.; Murali, Rajmohan

2016-01-01

Summary Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas conventional naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion, may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or reduce and alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour genomics and progression will refine the classification of melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy. PMID:27020384

The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

PubMed

Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

2013-10-01

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Brain metastasization of breast cancer.

PubMed

Custódio-Santos, Tânia; Videira, Mafalda; Brito, Maria Alexandra

2017-08-01

Central nervous system metastases have been reported in 15-25% of breast cancer patients, and the incidence is increasing. Moreover, the survival of these patients is generally poor, with reports of a 1-year survival rate of 20%. Therefore, a better knowledge about the determinants of brain metastasization is essential for the improvement of the clinical outcomes. Here, we summarize the current data about the metastatic cascade, ranging from the output of cancer cells from the primary tumour to their colonization in the brain, which involves the epithelial-mesenchymal transition, invasion of mammary tissue, intravasation into circulation, and homing into and extravasation towards the brain. The phenotypic change in malignant cells, and the importance of the microenvironment in the formation of brain metastases are also inspected. Finally, the importance of genetic and epigenetic changes, and the recently disclosed effects of microRNAs in brain metastasization of breast cancer are highlighted. Copyright © 2017 Elsevier B.V. All rights reserved.

A less invasive surgical concept for the resection of spinal meningiomas.

PubMed

Boström, A; Bürgel, U; Reinacher, P; Krings, T; Rohde, V; Gilsbach, J M; Hans, F J

2008-06-01

The surgical strategy for spinal meningiomas usually consists of laminectomy, initial tumour debulking, identification of the interface between tumour and spinal cord, resection of the dura including the matrix of the tumour, and duroplasty. The objective of this study was to investigate whether a less invasive surgical strategy consisting of hemilaminectomy or laminectomy, tumour removal and coagulation of the tumour matrix allows comparable surgical and clinical results to be obtained, especially without an increase of the recurrence rate as reported in the literature. Between 1990 and 2005, 61 patients (11 men, 50 women) underwent surgery for spinal meningioma. All patients were treated microsurgically by a posterior approach. In 56 of the 61 patients, the above outlined - less invasive - surgical technique with tumour removal and coagulation of the tumour matrix was performed. In 5 patients, dura resection and duroplasty was additionally performed. Electrophysiological monitoring was routinely used since 1996. Recurrence was defined as new onset or worsening of symptoms and radiological confirmation of tumour growth. The pre-and post-operative clinical status was measured by the Frankel grading system. Pre-operatively, 40 patients were in Frankel grade D, 13 patients in grade C, 6 patients in grade E and 1 patient each in grade A and B. Following surgery no patient presented a permanent worsening of clinical symptoms. All patients who initially presented with a Frankel grades A-C (n = 15) recovered to a better grade at the time of follow-up. Patients who presented with Frankel grade D remained in stable condition (n = 27) or recovered to a better neurological status (n = 13). Two patients experienced a temporary worsening of their symptoms, but subsequently improved to a better state than pre-operatively. Two (3.3%) complications (pseudomeningocele, wound infection) requiring surgery, were encountered. The pseudomeningocele developed in a patient who underwent durotomy. During the follow-up period of 2 months to 10 years (mean 31.3 months), 3 patients (5%) required surgery for symptomatic recurrence: 1 patient had 2 recurrences that occurred 4 and 7 years after first tumour removal and matrix coagulation, 1 recurrence occurred 1 year after tumour removal that was accompanied by matrix coagulation in a patient with a diffuse anterocranial tumour extension and 1 occurred 3 years after tumour removal and durotomy. Two patients showed a small recurrence on MRI during follow-up after 2 and 5 years, respectively, without any symptoms requiring surgery. The high rate of favourable clinical results combined with the low rate of recurrences supports our less invasive surgical concept, which does not aim for resection of the dural matrix of the spinal meningioma.

Evaluation of dissemination studies with FDG whole-body positron emission tomography in patients with suspected metastatic tumours of brain and spine.

PubMed

Go, K G; Pruim, J; Que, T H; Vaalburg, W; Haaxma-Reiche, H

2000-01-01

In the preoperative diagnosis of malignant brain tumours there is often uncertainty regarding their metastatic or primary nature, requiring dissemination studies. Currently FDG-wbPET is being used for the efficient detection of systemic tumours. It therefore may become a substitute for the conventional dissemination studies if it allows an earlier diagnosis. In this descriptive and preliminary study a population of 14 patients with suspected or proven metastatic lesions, [18F]-fluoro-2-deoxy-D-glucose whole body positron emission tomography (FDG-wbPET) was conducted and verified by additional conventional dissemination studies. FINDINGS AND THEIR INTERPRETATION: The entire series of dissemination studies required an average of 30 days with a range of 4-73 days. The FDG-wbPET was corroborated by the other dissemination studies in 10 of the 14 patients. In 7 of these 10 patients both PET and dissemination studies showed systemic abnormal findings, but in one case the presence of high pulmonary activity on the FDG-wbPET and the abnormal findings on the chest X-rays proved to be Aspergillus infection at autopsy. In the other 2 cases the negative PET findings corresponded to the absence of systemic dissemination. In 5 cases there was disagreement of the results of the FDG-wbPET with other evidence, among which there were 2 cases of glioblastoma in which systemic metastases were most unlikely, and the foci of activity on the FDG-wbPET had to be considered as false positives. In the remaining 3 cases the systemic presence of high activity on the FDG-wbPET indicated the systemic presence of tumour, whereas the other dissemination studies disclosed no tumour. The results warrant the use of FDG-wbPET as a screening method for the search of metastases, allowing other studies to be focussed on the lesion. But from the cost/benefit point of view this would make the method less suitable as a substitute for dissemination studies in general, although it may speed up the diagnostic process.

High-risk gastrointestinal stromal tumour (GIST) and synovial sarcoma display similar angiogenic profiles: a nude mice xenograft study.

PubMed

Giner, Francisco; Machado, Isidro; Lopez-Guerrero, Jose Antonio; Mayordomo-Aranda, Empar; Llombart-Bosch, Antonio

2017-01-01

Gastrointestinal stromal tumour (GIST) is the most common primary mesenchymal tumour of the gastrointestinal tract. Spindle cell monophasic synovial sarcoma (SS) can be morphologically similar. Angiogenesis is a major factor for tumour growth and metastasis. Our aim was to compare the angiogenic expression profiles of high-risk GIST and spindle cell monophasic SS by histological, immunohistochemical and molecular characterisation of the neovascularisation established between xenotransplanted tumours and the host during the initial phases of growth in nude mice. The angiogenic profile of two xenotransplanted human soft-tissue tumours were evaluated in 15 passages in nude mice using tissue microarrays (TMA). Tumour pieces were also implanted subcutaneously on the backs of 14 athymic Balb-c nude mice. The animals were sacrificed at 24, 48, and 96 h; and 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularisation experiments). Morphological similarities were apparent in the early stages of neoplastic growth of these two soft-tissue tumours throughout the passages in nude mice and in the two neovascularisation experiments. Immunohistochemistry demonstrated overexpression of pro-angiogenic factors between 24 h and 96 h after xenotransplantation in both tumours. Additionally, neoplastic cells coexpressed chemokines (CXCL9, CXCL10, GRO, and CXCL12) and their receptors in both tumours. Molecular studies showed two expression profiles, revealing an early and a late phase in the angiogenic process. This model could provide information on the early stages of the angiogenic process in monophasic spindle cell SS and high-risk GIST and offers an excellent way to study possible tumour response to antiangiogenic drugs.

Mathematical modelling of radiotherapy strategies for early breast cancer.

PubMed

Enderling, Heiko; Anderson, Alexander R A; Chaplain, Mark A J; Munro, Alastair J; Vaidya, Jayant S

2006-07-07

Targeted intraoperative radiotherapy (Targit) is a new concept of partial breast irradiation where single fraction radiotherapy is delivered directly to the tumour bed. Apart from logistic advantages, this strategy minimizes the risk of missing the tumour bed and avoids delay between surgery and radiotherapy. It is presently being compared with the standard fractionated external beam radiotherapy (EBRT) in randomized trials. In this paper we present a mathematical model for the growth and invasion of a solid tumour into a domain of tissue (in this case breast tissue), and then a model for surgery and radiation treatment of this tumour. We use the established linear-quadratic (LQ) model to compute the survival probabilities for both tumour cells and irradiated breast tissue and then simulate the effects of conventional EBRT and Targit. True local recurrence of the tumour could arise either from stray tumour cells, or the tumour bed that harbours morphologically normal cells having a predisposition to genetic changes, such as a loss of heterozygosity (LOH) in genes that are crucial for tumourigenesis, e.g. tumour suppressor genes (TSGs). Our mathematical model predicts that the single high dose of radiotherapy delivered by Targit would result in eliminating all these sources of recurrence, whereas the fractionated EBRT would eliminate stray tumour cells, but allow (by virtue of its very schedule) the cells with LOH in TSGs or cell-cycle checkpoint genes to pass on low-dose radiation-induced DNA damage and consequently mutations that may favour the development of a new tumour. The mathematical model presented here is an initial attempt to model a biologically complex phenomenon that has until now received little attention in the literature and provides a 'proof of principle' that it is possible to produce clinically testable hypotheses on the effects of different approaches of radiotherapy for breast cancer.

A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET

PubMed Central

Rockne, Russell C.; Trister, Andrew D.; Jacobs, Joshua; Hawkins-Daarud, Andrea J.; Neal, Maxwell L.; Hendrickson, Kristi; Mrugala, Maciej M.; Rockhill, Jason K.; Kinahan, Paul; Krohn, Kenneth A.; Swanson, Kristin R.

2015-01-01

Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient's disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [18F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model–data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning. PMID:25540239

CD44 in cancer progression: adhesion, migration and growth regulation.

PubMed

Marhaba, R; Zöller, M

2004-03-01

It is well established that the large array of functions that a tumour cell has to fulfil to settle as a metastasis in a distant organ requires cooperative activities between the tumour and the surrounding tissue and that several classes of molecules are involved, such as cell-cell and cell-matrix adhesion molecules and matrix degrading enzymes, to name only a few. Furthermore, metastasis formation requires concerted activities between tumour cells and surrounding cells as well as matrix elements and possibly concerted activities between individual molecules of the tumour cell itself. Adhesion molecules have originally been thought to be essential for the formation of multicellular organisms and to tether cells to the extracellular matrix or to neighbouring cells. CD44 transmembrane glycoproteins belong to the families of adhesion molecules and have originally been described to mediate lymphocyte homing to peripheral lymphoid tissues. It was soon recognized that the molecules, under selective conditions, may suffice to initiate metastatic spread of tumour cells. The question remained as to how a single adhesion molecule can fulfil that task. This review outlines that adhesion is by no means a passive task. Rather, ligand binding, as exemplified for CD44 and other similar adhesion molecules, initiates a cascade of events that can be started by adherence to the extracellular matrix. This leads to activation of the molecule itself, binding to additional ligands, such as growth factors and matrix degrading enzymes, complex formation with additional transmembrane molecules and association with cytoskeletal elements and signal transducing molecules. Thus, through the interplay of CD44 with its ligands and associating molecules CD44 modulates adhesiveness, motility, matrix degradation, proliferation and cell survival, features that together may well allow a tumour cell to proceed through all steps of the metastatic cascade.

Simian virus 40, poliovirus vaccines, and human cancer: research progress versus media and public interests

NASA Technical Reports Server (NTRS)

Butel, J. S.

2000-01-01

From 1955 through early 1963, millions of people were inadvertently exposed to simian virus 40 (SV40) as a contaminant of poliovirus vaccines; the virus had been present in the monkey kidney cultures used to prepare the vaccines and had escaped detection. SV40 was discovered in 1960 and subsequently eliminated from poliovirus vaccines. This article reviews current knowledge about SV40 and considers public responses to reports in the media. SV40 is a potent tumour virus with broad tissue tropism that induces tumours in rodents and transforms cultured cells from many species. It is also an important laboratory model for basic studies of molecular processes in eukaryotic cells and mechanisms of neoplastic transformation. SV40 neutralizing antibodies have been detected in individuals not exposed to contaminated poliovirus vaccines. There have been many reports of detection of SV40 DNA in human tumours, especially mesotheliomas, brain tumours and osteosarcomas; and DNA sequence analyses have ruled out the possibility that the viral DNA in tumours was due to laboratory contamination or that the virus had been misidentified. However, additional studies are necessary to prove that SV40 is the cause of certain human cancers. A recently published review article evaluated the status of the field and received much media attention. The public response emphasized that there is great interest in the possibility of health risks today from vaccinations received in the past.

MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma

PubMed Central

McIntyre, Alan; Smith, Stuart

2017-01-01

Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease. PMID:28804724

Anaesthesia for awake craniotomy is safe and well-tolerated.

PubMed

Andersen, Jakob Hessel; Olsen, Karsten Skovgaard

2010-10-01

Awake craniotomy for tumour resection has been performed at Glostrup Hospital since 2004. We describe and discuss the various anaesthetic approaches for such surgery and retrospectively analyse the 44 planned awake craniotomies performed at Glostrup Hospital. The surgery falls into four phases: craniotomy, mapping, tumour resection and closing. Three methods are being used: monitored anaesthetic care, asleep-awake-asleep and asleep-awake (AA). Anaesthesia is induced and maintained with propofol and remifentanil. A laryngeal mask (LM) is used as an airway during the craniotomy phase. In the AA method, patients are mapped and the tumour is resected while the patient is awake. A total of 41 of 44 planned AA craniotomies were performed. Three had to be converted into general anaesthesia (GA) due to tight brain, leaking LM and tumour haemorrhage, respectively. The following complications were observed: bradycardia 10%, leaking LM 5%, nausea 10%, vomiting 5%, focal seizures 28%, generalized seizures 10%, hypoxia 2%, hypotension 5% and hypertension 2%. Our results comply well with the international literature in terms of complications related to haemodynamics, respiration, seizures, vomiting and nausea and in terms of patient satisfaction. Awake craniotomy is a well-tolerated procedure with potential benefits. More prospective randomized studies are required.

Segmental Schwannomatosis of the Spine: Report of a Rare Case and Brief Review of Literature.

PubMed

Baruah, Ranjit Kumar; Bora, Suresh; Haque, Russel

2016-01-01

To report a case of segmental schwannomatosis involving the dorsal and lumbar spine and describe its excision as well as review of literature on schwannomatosis involving the spine. Schwannomas are nerve sheath tumours which usually occur as solitary lesions. Presence of multiple schwannomas suggests a genetic predisposition to tumorogenesis and possible association with neurofibromatosis. However, in very rare cases multiple schwannomas exist without typical features of neurofibromatosis and constitute a clinically and genetically distinct rare syndrome termed schwannomatosis. A 31-year-old female presented with low back pain with left lower limb radiculopathy and sensory deficit over the L4-L5 dermatome. Auditory and ophthalmologic examinations were normal. MRI showed two discrete intradural masses at D12-L2 and L3-L5. MRI of the brain was negative for any vestibular schwannoma. The tumours were excised discretely through a single midline incision to improve the symptoms. HPE of both the tumours revealed them to be schwannomas. Karyotyping from lymphocyte DNA revealed no abnormality. This is the 3rd case of schwannomatosis involving the dorsal and lumbar spine, in which excision of the tumours led to resolution of symptoms.

[Cancers in children in the Auvergne area: retrospective study from 1986 to 1991].

PubMed

Gembara, P; Dechelotte, P; Chauvin, F; Malpuech, G; Chazal, J; Carla, H; Chopard, P; Foulon, E; Goddon, R; Goumy, P

1995-07-01

The specificity of childhood cancers led to the creation of regional childhood cancer registries. An epidemiological study of childhood cancers in the Auvergne area was carried out over a 6 year-period (1986-1991) in order to create a registry. The population of our study was 252,820 children (0-15 years old), living in the Auvergne region. All malignant neoplasms were included together with brain tumours (whatever grading). Data were collected from medical and administrative sources. The data of 153 cases were collected during this period. World age standardized overall incidence rate was 120.5 cases/milion/year. Age standardized incidence rates were: leukemias 37.6 (ALL 28.01), central nervous system tumours 18.34 (medulloblastomas 4.6, astrocytomas 4.6, ependymomas 3.8), lymphomas 10.0, neuroblastomas 18.6, soft tissue tumors 8.3, bone tumours 6.1 (Ewing's sarcomas 4.1, osteosarcomas 2.0), nephroblastomas 5.5, retinoblastomas 3.1, liver tumours 0.5 and others 0.5. Our data base in the Auvergne area might be a source of information for epidemiological studies on the role of etiological factors, the survival, the sequelae and the incidence trends.

Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

PubMed Central

Grivennikov, Sergei I.; Wang, Kepeng; Mucida, Daniel; Stewart, C. Andrew; Schnabl, Bernd; Jauch, Dominik; Taniguchi, Koji; Yu, Guann-Yi; Osterreicher, Christoph H.; Hung, Kenneth E.; Datz, Christian; Feng, Ying; Fearon, Eric R.; Oukka, Mohamed; Tessarollo, Lino; Coppola, Vincenzo; Yarovinsky, Felix; Cheroutre, Hilde; Eckmann, Lars; Trinchieri, Giorgio; Karin, Michael

2013-01-01

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier10. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth. PMID:23034650

Health economic evaluation of a serum-based blood test for brain tumour diagnosis: exploration of two clinical scenarios.

PubMed

Gray, Ewan; Butler, Holly J; Board, Ruth; Brennan, Paul M; Chalmers, Anthony J; Dawson, Timothy; Goodden, John; Hamilton, Willie; Hegarty, Mark G; James, Allan; Jenkinson, Michael D; Kernick, David; Lekka, Elvira; Livermore, Laurent J; Mills, Samantha J; O'Neill, Kevin; Palmer, David S; Vaqas, Babar; Baker, Matthew J

2018-05-24

To determine the potential costs and health benefits of a serum-based spectroscopic triage tool for brain tumours, which could be developed to reduce diagnostic delays in the current clinical pathway. A model-based health pre-trial economic assessment. Decision tree models were constructed based on simplified diagnostic pathways. Models were populated with parameters identified from rapid reviews of the literature and clinical expert opinion. Explored as a test in both primary and secondary care (neuroimaging) in the UK health service, as well as application to the USA. Calculations based on an initial cohort of 10 000 patients. In primary care, it is estimated that the volume of tests would approach 75 000 per annum. The volume of tests in secondary care is estimated at 53 000 per annum. The primary outcome measure was quality-adjusted life-years (QALY), which were employed to derive incremental cost-effectiveness ratios (ICER) in a cost-effectiveness analysis. Results indicate that using a blood-based spectroscopic test in both scenarios has the potential to be highly cost-effective in a health technology assessment agency decision-making process, as ICERs were well below standard threshold values of £20 000-£30 000 per QALY. This test may be cost-effective in both scenarios with test sensitivities and specificities as low as 80%; however, the price of the test would need to be lower (less than approximately £40). Use of this test as triage tool in primary care has the potential to be both more effective and cost saving for the health service. In secondary care, this test would also be deemed more effective than the current diagnostic pathway. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Prostate cancer microenvironment: Its structure, functions and therapeutic applications].

PubMed

Lorion, R; Bladou, F; Spatz, A; van Kempen, L; Irani, J

2016-06-01

In the field of prostate cancer there is a growing tendency for more and more studies to emphasise the predominant role of the zone situated between the tumour and the host: the tumour microenvironment. The aim of this article is to describe the structure and the functions of the prostate cancer microenvironment as well as the principal treatments that are being applied to it. PubMed and ScienceDirect databases have been interrogated using the association of keywords "tumour microenvironment" and "neoplasm therapy" along with "microenvironnement tumoral" and "traitements". Of the 593 articles initially found, 50 were finally included. The tumour microenvironment principally includes host elements that are diverted from their primary functions and encourage the development of the tumour. In it we find immunity cells, support tissue as well as vascular and lymphatic neovascularization. Highlighting the major role played by this microenvironment has led to the development of specific treatments, notably antiangiogenic therapy and immunotherapy. The tumour microenvironment, the tumour and the host influence themselves mutually and create a variable situation over time. Improvement of the knowledge of the prostate cancer microenvironment gradually enables us to pass from an approach centred on the tumour to a broader approach to the whole tumoral ecosystem. This enabled the emergence of new treatments whose place in the therapeutic arsenal still need to be found. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Tumour regression of uveal melanoma after ruthenium-106 brachytherapy or stereotactic radiotherapy with gamma knife or linear accelerator.

PubMed

Georgopoulos, Michael; Zehetmayer, Martin; Ruhswurm, Irene; Toma-Bstaendig, Sabine; Ségur-Eltz, Nikolaus; Sacu, Stefan; Menapace, Rupert

2003-01-01

This study assesses differences in relative tumour regression and internal acoustic reflectivity after 3 methods of radiotherapy for uveal melanoma: (1) brachytherapy with ruthenium-106 radioactive plaques (RU), (2) fractionated high-dose gamma knife stereotactic irradiation in 2-3 fractions (GK) or (3) fractionated linear-accelerator-based stereotactic teletherapy in 5 fractions (Linac). Ultrasound measurements of tumour thickness and internal reflectivity were performed with standardised A scan pre-operatively and 3, 6, 9, 12, 18, 24 and 36 months postoperatively. Of 211 patients included in the study, 111 had a complete 3-year follow-up (RU: 41, GK: 37, Linac: 33). Differences in tumour thickness and internal reflectivity were assessed with analysis of variance, and post hoc multiple comparisons were calculated with Tukey's honestly significant difference test. Local tumour control was excellent with all 3 methods (>93%). At 36 months, relative tumour height reduction was 69, 50 and 30% after RU, GK and Linac, respectively. In all 3 treatment groups, internal reflectivity increased from about 30% initially to 60-70% 3 years after treatment. Brachytherapy with ruthenium-106 plaques results in a faster tumour regression as compared to teletherapy with gamma knife or Linac. Internal reflectivity increases comparably in all 3 groups. Besides tumour growth arrest, increasing internal reflectivity is considered as an important factor indicating successful treatment. Copyright 2003 S. Karger AG, Basel

Cancer stem cells (CSCs), cervical CSCs and targeted therapies.

PubMed

Huang, Ruixia; Rofstad, Einar K

2017-05-23

Accumulating evidence has shown that cancer stem cells (CSCs) have a tumour-initiating capacity and play crucial roles in tumour metastasis, relapse and chemo/radio-resistance. As tumour propagation initiators, CSCs are considered to be promising targets for obtaining a better therapeutic outcome. Cervical carcinoma is the most common gynaecological malignancy and has a high cancer mortality rate among females. As a result, the investigation of cervical cancer stem cells (CCSCs) is of great value. However, the numbers of cancer cells and corresponding CSCs in malignancy are dynamically balanced, and CSCs may reside in the CSC niche, about which little is known to date. Therefore, due to their complicated molecular phenotypes and biological behaviours, it remains challenging to obtain "purified" CSCs and continuously culture CSCs for further in vitro studies without the cells losing their stem properties. At present, CSC-related markers and functional assays are used to purify, identify and therapeutically target CSCs both in vitro and in vivo. Nevertheless, CSC-related markers are not universal to all tumour types, although some markers may be valid in multiple tumour types. Additionally, functional identifications based on CSC-specific properties are usually limited in in vivo studies. Furthermore, an optimal method for identifying potential CCSCs in CCSC studies has not been previously published, and these techniques are currently of great importance. This article updates our knowledge on CSCs and CCSCs, reviews potential stem cell markers and functional assays for identifying CCSCs, and describes the potential of targeting CCSCs in the treatment of cervical carcinoma.

The novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis

PubMed Central

Singh, Shree Ram; Liu, Ying; Zhao, Jiangsha; Zeng, Xiankun; Hou, Steven X.

2016-01-01

Stem cell competition has emerged as a mechanism for selecting fit stem cells/progenitors and controlling tumourigenesis. However, little is known about the underlying molecular mechanism. Here we identify Mlf1-adaptor molecule (Madm), a novel tumour suppressor that regulates the competition between germline stem cells (GSCs) and somatic cyst stem cells (CySCs) for niche occupancy. Madm knockdown results in overexpression of the EGF receptor ligand vein (vn), which further activates EGF receptor signalling and integrin expression non-cell autonomously in CySCs to promote their overproliferation and ability to outcompete GSCs for niche occupancy. Conversely, expressing a constitutively activated form of the Drosophila JAK kinase (hopTum−l) promotes Madm nuclear translocation, and suppresses vn and integrin expression in CySCs that allows GSCs to outcompete CySCs for niche occupancy and promotes GSC tumour formation. Tumour suppressor-mediated stem cell competition presented here could be a mechanism of tumour initiation in mammals. PMID:26792023

The novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis.

PubMed

Singh, Shree Ram; Liu, Ying; Zhao, Jiangsha; Zeng, Xiankun; Hou, Steven X

2016-01-21

Stem cell competition has emerged as a mechanism for selecting fit stem cells/progenitors and controlling tumourigenesis. However, little is known about the underlying molecular mechanism. Here we identify Mlf1-adaptor molecule (Madm), a novel tumour suppressor that regulates the competition between germline stem cells (GSCs) and somatic cyst stem cells (CySCs) for niche occupancy. Madm knockdown results in overexpression of the EGF receptor ligand vein (vn), which further activates EGF receptor signalling and integrin expression non-cell autonomously in CySCs to promote their overproliferation and ability to outcompete GSCs for niche occupancy. Conversely, expressing a constitutively activated form of the Drosophila JAK kinase (hop(Tum-l)) promotes Madm nuclear translocation, and suppresses vn and integrin expression in CySCs that allows GSCs to outcompete CySCs for niche occupancy and promotes GSC tumour formation. Tumour suppressor-mediated stem cell competition presented here could be a mechanism of tumour initiation in mammals.

Oncolytic viruses: a new class of immunotherapy drugs.

PubMed

Kaufman, Howard L; Kohlhapp, Frederick J; Zloza, Andrew

2015-09-01

Oncolytic viruses represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumour cell killing and the induction of systemic anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been developed as oncolytic agents, and the approval of the first oncolytic virus by the US Food and Drug Administration (FDA) is anticipated in the near future. This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncolytic viruses in advanced clinical trials and discusses the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.

A unified model of the hierarchical and stochastic theories of gastric cancer

PubMed Central

Song, Yanjing; Wang, Yao; Tong, Chuan; Xi, Hongqing; Zhao, Xudong; Wang, Yi; Chen, Lin

2017-01-01

Gastric cancer (GC) is a life-threatening disease worldwide. Despite remarkable advances in treatments for GC, it is still fatal to many patients due to cancer progression, recurrence and metastasis. Regarding the development of novel therapeutic techniques, many studies have focused on the biological mechanisms that initiate tumours and cause treatment resistance. Tumours have traditionally been considered to result from somatic mutations, either via clonal evolution or through a stochastic model. However, emerging evidence has characterised tumours using a hierarchical organisational structure, with cancer stem cells (CSCs) at the apex. Both stochastic and hierarchical models are reasonable systems that have been hypothesised to describe tumour heterogeneity. Although each model alone inadequately explains tumour diversity, the two models can be integrated to provide a more comprehensive explanation. In this review, we discuss existing evidence supporting a unified model of gastric CSCs, including the regulatory mechanisms of this unified model in addition to the current status of stemness-related targeted therapy in GC patients. PMID:28301871

STAT3 signaling mediates tumour resistance to EGFR targeted therapeutics.

PubMed

Zulkifli, Ahmad A; Tan, Fiona H; Putoczki, Tracy L; Stylli, Stanley S; Luwor, Rodney B

2017-08-15

Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC). In this mini-review, we specifically focus on the role of the STAT3 signaling axis in providing both intrinsic and acquired resistance to inhibitors of the EGFR. We also focus on STAT3 pathway targeting in an attempt to overcome resistance to anti-EGFR therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

Induction of nasal and nasopharyngeal tumours in Sprague-Dawley rats fed with Chinese salted fish.

PubMed

Zheng, X; Luo, Y; Christensson, B; Drettner, B

1994-01-01

Epidemiological studies have implied that Chinese salted fish is a human nasopharyngeal carcinogen. In the present study, 162 Sprague-Dawley rats were randomly assigned to one of four experimental groups. Rats in groups 1 (n = 41) and 3 (n = 40) were exposed to salted fish from birth through the breast feeding period by giving the maternal rats a diet containing 10% and 5% salted fish, respectively, later feeding the rats with pellets containing 10% and 5% of salted fish respectively. In group 2, the rats (n = 41) were given pellets containing 10% of salted fish from 6 weeks of age. Rats in group 4 (n = 40), serving as controls, were only given ordinary pellets. Three rats had nasopharyngeal tumours, 2 from group 1 had a poorly differentiated carcinoma and a squamous cell carcinoma. One rat from group 2 had a squamous cell carcinoma. Four rats had nasal tumours, one fibrosarcoma and one adenocarcinoma were found in rats from group 1. One rhabdomyosarcoma was found in group 2, and one soft tissue sarcoma was found in a rat in group 3. No nasal or nasopharyngeal tumours appeared in the control group. The difference in the occurrence of malignant nasal and nasopharyngeal tumours among the four experimental groups was statistically significant (one tailed p for trend = 0.041). The frequency of tumours appearing in other organs such as the breast, kidney, lung, liver and brain was not significantly different between the salted fish treated groups and the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

From pericytes to perivascular tumours: correlation between pathology, stem cell biology, and tissue engineering.

PubMed

Mravic, Marco; Asatrian, Greg; Soo, Chia; Lugassy, Claire; Barnhill, Raymond L; Dry, Sarah M; Peault, Bruno; James, Aaron W

2014-09-01

Pericytes were once thought only to aid in angiogenesis and blood pressure control. Gradually, the known functions of pericytes and other perivascular stem cells (PSC) have broadly increased. The following review article will summarize the known functions and importance of pericytes across disciplines of pathology, stem cell biology, and tissue engineering. A literature review was performed for studies examining the importance of pericytes in pathology, stem cell biology, and tissue engineering. The importance of pericytes most prominently includes the identification of the perivascular identity of mesenchymal stem cells (or MSC). Now, pericytes and other PSC are known to display surface markers and multilineage differentiation potential of MSC. Accordingly, interest in the purification and use of PSC for mesenchymal tissue formation and regeneration has increased. Significant demonstration of in vivo efficacy in bone and muscle regeneration has been made in laboratory animals. Contemporaneously with the uncovering of an MSC identity for pericytes, investigators in tumour biology have found biologically relevant roles for pericytes in tumor formation, lymphovascular invasion, and perivascular tumor spread. As well, the contribution of pericytes to perivascular tumors has been examined (and debated), including glomus tumour, myopericytoma and solitary fibrous tumour/hemangiopericytoma. In addition, an expanding recognition of pericyte mimicry and perivascular tumour invasion has occurred, encompassing common malignancies of the brain and skin. In summary, pericytes have a wide range of roles in health and disease. Pericytes are being increasingly studied for their role in tumour formation, growth and invasion. Likewise, the application of pericytes/PSC for mesenchymal tissue engineering is an expanding field of interest.

Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma

PubMed Central

KOBARI, YUKI; KONDO, TSUNENORI; TAKAGI, TOSHIO; OMAE, KENJI; NAKAZAWA, HAYAKAZU; TANABE, KAZUNARI

2017-01-01

Background/Aim: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma. Patients and Methods: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment. Results: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3. Conclusion: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting. PMID:28652455

Giant gastrointestinal stromal tumour of rare sarcomatoid epithelioid subtype: Case study and literature review

PubMed Central

Lech, Gustaw; Korcz, Wojciech; Kowalczyk, Emilia; Guzel, Tomasz; Radoch, Marcin; Krasnodębski, Ireneusz Wojciech

2015-01-01

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, but they represent less than 3% of all gastrointestinal tract malignancies. This is a detailed case study of a 52-year-old male patient treated for very uncommon histological subtype of gastric GIST with atypical clinical presentation, asymptomatic progress and late diagnosis. The resected tumour, giant in diameters, was confirmed to represent the most rare histopathologic subtype of GISTs - sarcomatoid epithelioid GIST. We report this case and review the literature with a special focus on pathomorphological evaluation, biological aggressiveness and prognostic factors. To our knowledge this is the first report of giant GIST of very uncommon sarcomatoid epithelioid subtype. It is concluded that clinicians should pay attention to the fact that initial diagnosis may be delayed due to mildly asymptomatic and non-specific clinical presentation. Asymptomatic tumours diagnosed at a late stage, which is often the case, can be large on presentation. Prognosis for patients diagnosed with GIST depend on tumour size, mitotic rate, histopathologic subtype and tumour location. That is why early diagnosis and R0 resection, which is usually feasible and safe even in giant gastric sarcomatoid epithelioid subtype of GISTs, are the key factors for further treatment and good prognosis. PMID:25805949

c-erbB-2 in astrocytomas: infrequent overexpression by immunohistochemistry and absence of gene amplification by fluorescence in situ hybridization.

PubMed Central

Haapasalo, H.; Hyytinen, E.; Sallinen, P.; Helin, H.; Kallioniemi, O. P.; Isola, J.

1996-01-01

Recent studies suggest that aberrations of c-erbB-2 may be involved in astrocytic brain tumours. We screened immunohistochemically c-erbB2 protein (p185) expression in 94 astrocytic grade 1-4 neoplasms of the brain. The amplification of the c-erbB-2 oncogene was investigated in protein overexpression cases by dual colour fluorescence in situ hybridisation (FISH). p185 overexpression was correlated with p53 and epidermal growth factor receptor (EGFR) expression, as well as with clinicopathological features. Only two anaplastic (grade 3) astrocytomas and one glioblastoma (grade 4) showed overexpression of p185 protein by immunohistochemistry (monoclonal MAb1 antibody TA250), whereas none of the grade 1-2 astrocytomas was positive. Interestingly, the expression of p185 was confined solely to the cytoplasm of neoplastic astrocytic cells and not to the cell membranes as found in malignancies with amplification of the c-erbB-2 oncogene. Two of the three overexpression cases were also positive by EGFR. No amplification of the c-erbB-2 gene was observed by FISH in the three tumours with immunohistochemical p185 overexpression or seven weakly positive/negative tumours. In conclusion, our results suggest that p185 overexpression is infrequent in astrocytomas, that it is of no important diagnostic or prognostic value and that c-erbB-2 oncogene amplification is not seen in the few cases in which there is overexpression. Images Figure 1 Figure 2 PMID:8605096

The recurrent architecture of tumour initiation, progression and drug sensitivity.

PubMed

Califano, Andrea; Alvarez, Mariano J

2017-02-01

Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.

Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-¹⁰Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model.

PubMed

Roda, E; Nion, S; Bernocchi, G; Coccini, T

2014-10-02

Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood-brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-(10)Boronophenyl)alanine, L-(10)BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-(10)BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-(10)BPA toxicity at 80 µg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-(10)BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39 ± 0.01 × 10(-3)cm min(-1)), corroborating the scarce probability that L-(10)BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds. Copyright © 2014 Elsevier B.V. All rights reserved.

Novel population of small tumour-initiating stem cells in the ovaries of women with borderline ovarian cancer

PubMed Central

Virant-Klun, Irma; Stimpfel, Martin

2016-01-01

Small stem cells with diameters of up to 5 μm previously isolated from adult human ovaries indicated pluripotency and germinal lineage, especially primordial germ cells, and developed into primitive oocyte-like cells in vitro. Here, we show that a comparable population of small stem cells can be found in the ovarian tissue of women with borderline ovarian cancer, which, in contrast to small stem cells in “healthy” ovaries, formed spontaneous tumour-like structures and expressed some markers related to pluripotency and germinal lineage. The gene expression profile of these small putative cancer stem cells differed from similar cells sorted from “healthy” ovaries by 132 upregulated and 97 downregulated genes, including some important forkhead box and homeobox genes related to transcription regulation, developmental processes, embryogenesis, and ovarian cancer. These putative cancer stem cells are suggested to be a novel population of ovarian tumour-initiating cells in humans. PMID:27703207

Successful management of metastatic transmissible venereal tumour to skin of mammary region.

PubMed

Varughese, E E; Singla, V K; Ratnakaran, U; Gandotra, V K

2012-12-01

A Dalmatian female presented with a history of vaginal bleeding and was diagnosed as having transmissible venereal tumour (TVT) after cytological examination of the vaginal growth revealed typical TVT cells. A cytology of the aspirate from multiple nodules in the skin near the abdominal and inguinal pair of mammary glands revealed similar cells suggestive of metastasis to skin of mammary region. Chemotherapy was initiated with weekly injections of vincristine sulphate (0.025 mg/kg BW, IV, SID) and haematological examination was performed pre- and post-treatment to assess the prognosis of the patient and side effects of the drug. The major side effects observed during the course of the treatment were high body temperature, mild neutropaenia and significant decrease in packed cell volume, haemoglobin, total leucocyte and erythrocyte count. Four weekly injections of vincristine were administered, and 4 weeks from initiation of treatment, the tumour and nodules were gone, suggesting complete recovery. © 2012 Blackwell Verlag GmbH.

Hyaluronan and hyaluronectin in the extracellular matrix of human brain tumour stroma.

PubMed

Delpech, B; Maingonnat, C; Girard, N; Chauzy, C; Maunoury, R; Olivier, A; Tayot, J; Creissard, P

1993-01-01

Hyaluronan (HA) and the hyaluronan-binding glycoprotein hyaluronectin (HN) were measured in 23 gliomas and 8 meningiomas and their location was revisited in 35 tumours. A clear-cut difference was found in the HN/HA ratio values of glioblastomas (below 0.5) and that of astrocytomas (above 0.5 P < 0.001). Besides their location in the intercellular part of gliomas, HA and HN displayed a perivascular location in 1/3 astrocytomas, 17/24 glioblastomas, and 3/7 meningiomas, suggesting they could be produced also by the vascular stroma of tumours and that they would characterise the neoangiogenesis. All cultivated glioma cells tested produced HA in vitro, whereas only 1/11 cell lines produced HN, at a low level. The results obtained suggest that glioma HA and HN are produced by both cancer cells and vascular stroma cells, which contribute to the edification of the extracellular matrix. In meningiomas only the stroma would be responsible for HA and HN production.

An Intraoperative β- Detecting Probe for Radio-Guided Surgery in Tumour Resection

NASA Astrophysics Data System (ADS)

Russomando, Andrea; Bellini, Fabio; Bocci, Valerio; Collamati, Francesco; De Lucia, Erika; Faccini, Riccardo; Marafini, Michela; Mattei, Ilaria; Chiodi, Giacomo; Patera, Vincenzo; Recchia, Luigi; Sarti, Alessio; Sciubba, Adalberto; Camillocci, Elena Solfaroli; Paramatti, Riccardo; Voena, Cecilia; Donnarumma, Raffaella; Mancini-Terracciano, Carlo; Morganti, Silvio

2016-10-01

The development of the β- based radio-guided surgery aims to extend the technique to those tumours where surgery is the only possible treatment and the assessment of the resection would most profit from the low background around the lesion, as for brain tumours. To validate the technique, prototypes of the intraoperative β- probe have been developed. This paper discusses the design details of one of the prototypes and its tests performed in laboratory. In such tests particular care has to be taken to reproduce the surgical field conditions. The tests showed that the prototype under study has 70% efficiency on electrons with an energy threshold at 540 keV, a point-like resolution of 2.8±0.1 mm, and a sensitivity to photons lower than 1%. The tests also demonstrated, with an innovative technique to produce specific phantoms, that 0.5 ml residuals can be safely identified in 1 s with tumor-non-tumor ratio equal to 10.

Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.

PubMed

Li, Ningning; Zhang, Ying; Sidlauskas, Kastytis; Ellis, Matthew; Evans, Ian; Frankel, Paul; Lau, Joanne; El-Hassan, Tedani; Guglielmi, Loredana; Broni, Jessica; Richard-Loendt, Angela; Brandner, Sebastian

2018-05-03

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

Kinetics of depopulation, repopulation and host cell infiltration in the rhabdomyosarcoma R1H after 14 MeV neutron irradiation.

PubMed

Brammer, I; Zywietz, F; Beck-Bornholdt, H P; Jung, H

1992-05-01

The kinetics of depopulation and repopulation of the solid transplantable rhabdomyosarcoma R1H in the rat was studied following irradiation with 5 Gy of 14 MeV neutrons. Several parameters were sequentially measured over a time period of 4 weeks after irradiation: the tumour volume was assessed by in situ caliper measurements; the numerical density of tumour cells was obtained by morphometry; the clonogenic fraction of tumour cells was derived from in vitro colony assay; and the numerical ratio of host to tumour cells was determined by flow cytometry. From these primary parameters the number of clonogenic tumour cells, non-clonogenic tumour cells, and nucleated host cells per tumour, as well as their variation with time, were derived. The results were compared with two sets of data obtained previously for the same tumour exposed to 15 Gy of 200 kVp X-rays. Survival of tumour cells was reduced to 5.5 +/- 0.5% by 5 Gy neutrons and to 4.5 +/- 0.5% by 15 Gy X-rays, i.e. an RBE of close to 3. There was a lag period before the onset of repopulation (4.9 +/- 0.4 days and 4.9 +/- 0.5 days, respectively), followed by a high initial rate of repopulation corresponding to a doubling time of 2.0 +/- 0.2 days for neutrons and 2.1 +/- 0.2 days for X-rays. The rate of depopulation was significantly different for the two treatment modalities; the halving time for the number of non-clonogenic tumour cells was 11 +/- 4 days for neutrons and 2.8 +/- 0.5 days for X-rays.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of the CT Compatible Stereotaxic Craniotomy with MRI Scans of the Patients for Removing Cranial Lesions Located Eloquent Areas and Deep Sites of Brain.

PubMed

Gulsen, Salih

2015-03-15

The first goal in neurosurgery is to protect neural function as long as it is possible. Moreover, while protecting the neural function, a neurosurgeon should extract the maximum amount of tumoral tissue from the tumour region of the brain. So neurosurgery and technological advancement go hand in hand to realize this goal. Using of CT compatible stereotaxy for removing a cranial tumour is to be commended as a cornerstone of these technological advancements. Following CT compatible stereotaxic system applications in neurosurgery, different techniques have taken place in neurosurgical practice. These techniques are magnetic resonance imaging (MRI), MRI compatible stereotaxis, frameless stereotaxy, volumetric stereotaxy, functional MRI, diffusion tensor (DT) imaging techniques (tractography of the white matter), intraoperative MRI and neuronavigation systems. However, to use all of this equipment having these technologies would be impossible because of economic reasons. However, when we correlated this technique with MRI scans of the patients with CT compatible stereotaxy scans, it is possible to provide gross total resection and protect and improve patients' neural functions.

Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer

PubMed Central

Jin, Xin; Valiente, Manuel; Er, Ekrem Emrah; Lopez-Soto, Alejandro; Jacob, Leni; Patwa, Ruzeen; Shah, Hardik; Xu, Ke; Cross, Justin R.; Massagué, Joan

2016-01-01

SUMMARY Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. Breast and lung cancer cells express protocadherin 7 (PCDH7) to favor the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells employ these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines IFNα and TNFα. As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, which support tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle for the applicability of this therapeutic strategy to treat established brain metastasis. PMID:27225120

Schwanomma From Cervical Sympathetic Chain Ganglion - A Rare Presentation.

PubMed

Asma, A Affee; Kannah, E

2015-10-01

Schwanommas arising from cervical sympathetic chain are tumours that are rare in occurrence. These lesions are usually difficult to differentiate from a vagal schwanomma and a carotid body tumour during the initial workup. In this report, a rarely seen huge cervical sympathetic chain schwanomma case with partial Horner's syndrome is being presented in detail, which to our known knowledge, is one of the few cases reported in literature.

Frequency of serum tumour marker monitoring in patients with non-seminomatous germ cell tumours.

PubMed Central

Seckl, M. J.; Rustin, G. J.; Bagshawe, K. D.

1990-01-01

In patients relapsing on surveillance following orchidectomy for stage 1 non-seminomatous germ cell tumours, it is essential that treatment is initiated before they develop advanced disease with a poor prognosis. Patients who start chemotherapy with levels of human chorionic gonadotrophin (HCG) greater than 1,000 i.u. l-1 and/or alpha-fetoprotein (AFP) level greater than 500 ku l-1 have been shown to have a worse prognosis than patients with lower marker levels. We studied 64 patients between 1968 and 1987 with rising serial tumour markers. The potential time in which markers could rise to poor prognostic levels was calculated assuming an exponential rate of increase. Adverse levels were predicted in one patient (1.6%) within 7 days, in two patients (3.1%) within 14 days, in eight patients (12.5%) within 4 weeks and in 16 patients (25%) within 6 weeks. This suggests that, initially, weekly marker estimations should be performed on stage 1 surveillance patients. The extra cost to a specialist follow-up laboratory of weekly as opposed to the usual monthly marker measurements will be less than 33,600 pounds for every 400 patients on surveillance. One extra patient is likely to be cured for this sum. PMID:1695522

Role of chemotherapy prior to orchiectomy in metastatic testicular cancer-is testis really a sanctuary site?

PubMed

Reddy, B Vinusha; Sivakanth, A; Naveen Babu, G; Swamyvelu, Krishnamurthy; Basavana Goud, Yg; Madhusudhana, Ba; Challa, Vasu Reddy

2014-01-01

A germ-cell tumour (GCT) of the testis is a chemosensitive tumour with high cure rates even in advanced disease. Radical inguinal orchiectomy is the initial procedure used to diagnose it which helps to risk-stratify these patients. However, in patients with life-threatening metastases, primary chemotherapy was attempted in a few studies, followed by delayed orchiectomy. The aim of this review is to study the histopathological findings of delayed orchiectomy and the retroperitoneal lymph node dissection (RPLND) specimens, to assess difference and concordance in response rates in histological types of GCTs in pathological specimens. Overall, 352 patients received initial chemotherapy followed by orchiectomy, and 235 of them had undergone RPLND. Delayed orchiectomy specimens had viable tumour in 74 (21%) patients, scarring/necrosis in 171 patients (48.5%), and teratoma in 107 (30.3%) patients. RPLND specimens had residual disease in 36 (15.3%) patients, scarring/necrosis in 100 patients (42.5%), and teratoma in 99 patients (42.3%). Patients with seminoma who underwent delayed orchiectomy had complete disappearance of tumour in 81.3% of cases, and in non-seminomatous GCT, it was 43.4%. These results raise the question of the existence of a blood-testis barrier in patients with advanced GCT and argue against the testis as a sanctuary site.

Cannabinoids and brain injury: therapeutic implications.

PubMed

Mechoulam, Raphael; Panikashvili, David; Shohami, Esther

2002-02-01

Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.

Chemoembolization in the treatment of metastatic ileocolic carcinoid.

PubMed

Diculescu, Mircea; Atanasiu, Călina; Arbănaş, Tudor; Croitoru, Adina; Mihalcea, Adela; Becheanu, Gabriel; Costinean, Stefan; Gheorghe, Liana; Capşa, Răzvan

2002-06-01

Carcinoid tumours are enigmatic, slow growing malignancies, which occur most frequently (74%) in the gastrointestinal tract. Symptoms of the carcinoid syndrome (flushing and diarrhoea) are infrequent, occurring in approximately 10% of the patients with small bowel carcinoid. A 45-year-old patient with multiple liver metastases, diagnosed in 1994 with nonHodgkin's lymphoma after undergoing surgery for a distal ileal tumour, was referred to us by the Department of Haematology. At that moment the issue of a differential diagnosis with a carcinoid tumour arose, due to the long evolution and lack of evidence to support the initial diagnosis. The carcinoid syndrome was in fact present (the patient experiencing flush after small amounts of alcohol and emotions) and also we identified elevated values of 5HIAA. Reevaluation of the histologic sections of the ileal tumour as well as an ultrasound guided fine needle aspiration of an intrahepatic lesion confirmed the diagnosis of "carcinoid tumour". This conclusion lead to new therapeutic options for this patient. One of the main therapeutic options used in treating multiple liver metastases from a carcinoid tumour is chemoembolization and this case offered an excellent opportunity to present this therapy.

Multivariate modelling of prostate cancer combining magnetic resonance derived T2, diffusion, dynamic contrast-enhanced and spectroscopic parameters.

PubMed

Riches, S F; Payne, G S; Morgan, V A; Dearnaley, D; Morgan, S; Partridge, M; Livni, N; Ogden, C; deSouza, N M

2015-05-01

The objectives are determine the optimal combination of MR parameters for discriminating tumour within the prostate using linear discriminant analysis (LDA) and to compare model accuracy with that of an experienced radiologist. Multiparameter MRIs in 24 patients before prostatectomy were acquired. Tumour outlines from whole-mount histology, T2-defined peripheral zone (PZ), and central gland (CG) were superimposed onto slice-matched parametric maps. T2, Apparent Diffusion Coefficient, initial area under the gadolinium curve, vascular parameters (K(trans),Kep,Ve), and (choline+polyamines+creatine)/citrate were compared between tumour and non-tumour tissues. Receiver operating characteristic (ROC) curves determined sensitivity and specificity at spectroscopic voxel resolution and per lesion, and LDA determined the optimal multiparametric model for identifying tumours. Accuracy was compared with an expert observer. Tumours were significantly different from PZ and CG for all parameters (all p < 0.001). Area under the ROC curve for discriminating tumour from non-tumour was significantly greater (p < 0.001) for the multiparametric model than for individual parameters; at 90 % specificity, sensitivity was 41 % (MRSI voxel resolution) and 59 % per lesion. At this specificity, an expert observer achieved 28 % and 49 % sensitivity, respectively. The model was more accurate when parameters from all techniques were included and performed better than an expert observer evaluating these data. • The combined model increases diagnostic accuracy in prostate cancer compared with individual parameters • The optimal combined model includes parameters from diffusion, spectroscopy, perfusion, and anatominal MRI • The computed model improves tumour detection compared to an expert viewing parametric maps.

Re-Operative Pancreaticoduodenectomy: Challenges and Outcomes.

PubMed

Bhandare, Manish S; Mehta, Nikhil; Chaudhari, Vikram; Kumar, Naveena An; Pai, Esha; Goel, Mahesh; Shrikhande, Shailesh V

2018-05-23

Tata Memorial Centre (TMC) is a high-volume centre for pancreatic tumour resections. We found a continually increasing referral of pancreatic tumours for re-evaluation for surgery, after an initial unsuccessful attempt at resection. To evaluate reasons of initial in-operability, the feasibility of re-operative pancreatico-duodenectomy (R-PD) and short- and long-term outcomes after R-PD. Data was collected from a prospective database of GI and hepato-pancreato-biliary service, TMC, Mumbai from January 2008 to December 2016. Forty patients with periampullary/pancreatic head tumours were referred to us after exploration. Thirty were planned for re-exploration, of whom 25 patients underwent successful R-PD, either upfront (n = 12) or after neo-adjuvant therapy (n = 13). Twenty were adenocarcinomas, 5 had other histologies. Majority of the patients were deemed inoperable in view of suspected vascular involvement at the time of initial surgery (68%). R0 resection was achieved in 90% of adenocarcinoma cases (n = 18). Postoperative major morbidity was 20% and mortality was 4% (n = 1). The estimated 1-, 2- and 5-year survival for those with adenocarcinoma was 83, 71.2, and 29.9% respectively. R-PD is safe and should be performed in experienced centres and can achieve long-term outcomes, comparable to conventional PD. The most common reason for denying resection at initial surgery was suspected or perceived vascular involvement. © 2018 S. Karger AG, Basel.

Functional Brain Imaging

PubMed Central

2006-01-01

Executive Summary Objective The objective of this analysis is to review a spectrum of functional brain imaging technologies to identify whether there are any imaging modalities that are more effective than others for various brain pathology conditions. This evidence-based analysis reviews magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) for the diagnosis or surgical management of the following conditions: Alzheimer’s disease (AD), brain tumours, epilepsy, multiple sclerosis (MS), and Parkinson’s disease (PD). Clinical Need: Target Population and Condition Alzheimer’s disease is a progressive, degenerative, neurologic condition characterized by cognitive impairment and memory loss. The Canadian Study on Health and Aging estimated that there will be 97,000 incident cases (about 60,000 women) of dementia (including AD) in Canada in 2006. In Ontario, there will be an estimated 950 new cases and 580 deaths due to brain cancer in 2006. Treatments for brain tumours include surgery and radiation therapy. However, one of the limitations of radiation therapy is that it damages tissue though necrosis and scarring. Computed tomography (CT) and magnetic resonance imaging (MRI) may not distinguish between radiation effects and resistant tissue, creating a potential role for functional brain imaging. Epilepsy is a chronic disorder that provokes repetitive seizures. In Ontario, the rate of epilepsy is estimated to be 5 cases per 1,000 people. Most people with epilepsy are effectively managed with drug therapy; but about 50% do not respond to drug therapy. Surgical resection of the seizure foci may be considered in these patients, and functional brain imaging may play a role in localizing the seizure foci. Multiple sclerosis is a progressive, inflammatory, demyelinating disease of the central nervous system (CNS). The cause of MS is unknown; however, it is thought to be due to a combination of etiologies, including genetic and environmental components. The prevalence of MS in Canada is 240 cases per 100,000 people. Parkinson’s disease is the most prevalent movement disorder; it affects an estimated 100,000 Canadians. Currently, the standard for measuring disease progression is through the use of scales, which are subjective measures of disease progression. Functional brain imaging may provide an objective measure of disease progression, differentiation between parkinsonian syndromes, and response to therapy. The Technology Being Reviewed Functional Brain Imaging Functional brain imaging technologies measure blood flow and metabolism. The results of these tests are often used in conjunction with structural imaging (e.g., MRI or CT). Positron emission tomography and MRS identify abnormalities in brain tissues. The former measures abnormalities through uptake of radiotracers in the brain, while the latter measures chemical shifts in metabolite ratios to identify abnormalities. The potential role of functional MRI (fMRI) is to identify the areas of the brain responsible for language, sensory and motor function (sensorimotor cortex), rather than identifying abnormalities in tissues. Magnetoencephalography measures magnetic fields of the electric currents in the brain, identifying aberrant activity. Magnetoencephalography may have the potential to localize seizure foci and to identify the sensorimotor cortex, visual cortex and auditory cortex. In terms of regulatory status, MEG and PET are licensed by Health Canada. Both MRS and fMRI use a MRI platform; thus, they do not have a separate licence from Health Canada. The radiotracers used in PET scanning are not licensed by Health Canada for general use but can be used through a Clinical Trials Application. Review Strategy The literature published up to September 2006 was searched in the following databases: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, and International Network of Agencies for Health Technology Assessment (INAHTA). The database search was supplemented with a search of relevant Web sites and a review of the bibliographies of selected papers. General inclusion criteria were applied to all conditions. Those criteria included the following: Full reports of systematic reviews, randomized controlled trials (RCTs), cohort-control studies, prospective cohort studies (PCS’), and retrospective studies. Sample sizes of at least 20 patients (≥ 10 with condition being reviewed). English-language studies. Human studies. Any age. Studying at least one of the following: fMRI, PET, MRS, or MEG. Functional brain imaging modality must be compared with a clearly defined reference standard. Must report at least one of the following outcomes: sensitivity, specificity, accuracy, positive predictive value (PPV), receiver operating characteristic curve, outcome measuring impact on diagnostic testing, treatment, patient health, or cost. Summary of Findings There is evidence to indicate that PET can accurately diagnose AD; however, at this time, there is no evidence to suggest that a diagnosis of AD with PET alters the clinical outcomes of patients. The addition of MRS or O-(2-18F-Fluoroethyl)-L-Tyrosine (FET)-PET to gadolinium (Gd)-enhanced MRI for distinguishing malignant from benign tumours during primary diagnosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients to distinguish malignant from benign tumours is unclear, because patients with a suspected brain tumour will likely undergo a biopsy despite additional imaging results. The addition of MRS, FET-PET, or MRI T2 to Gd-enhanced MRI for the differentiation of recurrence from radiation necrosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients with a suspected recurrence is in the monitoring of patients. Based on the evidence available, it is unclear if one of the imaging modalities (MRS, FET-PET, or MRI T2) offers significantly improved specificity over another. There may be a role for fMRI in the identification of surgical candidates for tumour resection; however, this requires further research. Based on the studies available, it is unclear if MEG has similar accuracy in localizing seizure foci to intracranial electroencephalogram (ICEEG). More high-quality research is needed to establish whether there is a difference in accuracy between MEG and ICEEG. The results of the studies comparing PET to noninvasive electroencephalogram (EEG) did not demonstrate that PET was more accurate at localizing seizure foci; however, there may be some specific conditions, such as tuberous sclerosis, where PET may be more accurate than noninvasive EEG. There may be some clinical utility for MEG or fMRI in presurgical functional mapping; however, this needs further investigation involving comparisons with other modalities. The clinical utility of MRS has yet to be established for patients with epilepsy. Positron emission tomography has high sensitivity and specificity in the diagnosis of PD and the differential diagnosis of parkinsonian syndromes; however, it is unclear at this time if the addition of PET in the diagnosis of these conditions contributes to the treatment and clinical outcomes of patients. There is limited clinical utility of functional brain imaging in the management of patients with MS at this time. Diagnosis of MS is established through clinical history, evoked potentials, and MRI. Magnetic resonance imaging can identify the multifocal white lesions and other structural characteristics of MS. PMID:23074493

Functional brain imaging: an evidence-based analysis.

PubMed

2006-01-01

The objective of this analysis is to review a spectrum of functional brain imaging technologies to identify whether there are any imaging modalities that are more effective than others for various brain pathology conditions. This evidence-based analysis reviews magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) for the diagnosis or surgical management of the following conditions: Alzheimer's disease (AD), brain tumours, epilepsy, multiple sclerosis (MS), and Parkinson's disease (PD). TARGET POPULATION AND CONDITION Alzheimer's disease is a progressive, degenerative, neurologic condition characterized by cognitive impairment and memory loss. The Canadian Study on Health and Aging estimated that there will be 97,000 incident cases (about 60,000 women) of dementia (including AD) in Canada in 2006. In Ontario, there will be an estimated 950 new cases and 580 deaths due to brain cancer in 2006. Treatments for brain tumours include surgery and radiation therapy. However, one of the limitations of radiation therapy is that it damages tissue though necrosis and scarring. Computed tomography (CT) and magnetic resonance imaging (MRI) may not distinguish between radiation effects and resistant tissue, creating a potential role for functional brain imaging. Epilepsy is a chronic disorder that provokes repetitive seizures. In Ontario, the rate of epilepsy is estimated to be 5 cases per 1,000 people. Most people with epilepsy are effectively managed with drug therapy; but about 50% do not respond to drug therapy. Surgical resection of the seizure foci may be considered in these patients, and functional brain imaging may play a role in localizing the seizure foci. Multiple sclerosis is a progressive, inflammatory, demyelinating disease of the central nervous system (CNS). The cause of MS is unknown; however, it is thought to be due to a combination of etiologies, including genetic and environmental components. The prevalence of MS in Canada is 240 cases per 100,000 people. Parkinson's disease is the most prevalent movement disorder; it affects an estimated 100,000 Canadians. Currently, the standard for measuring disease progression is through the use of scales, which are subjective measures of disease progression. Functional brain imaging may provide an objective measure of disease progression, differentiation between parkinsonian syndromes, and response to therapy. FUNCTIONAL BRAIN IMAGING: Functional brain imaging technologies measure blood flow and metabolism. The results of these tests are often used in conjunction with structural imaging (e.g., MRI or CT). Positron emission tomography and MRS identify abnormalities in brain tissues. The former measures abnormalities through uptake of radiotracers in the brain, while the latter measures chemical shifts in metabolite ratios to identify abnormalities. The potential role of functional MRI (fMRI) is to identify the areas of the brain responsible for language, sensory and motor function (sensorimotor cortex), rather than identifying abnormalities in tissues. Magnetoencephalography measures magnetic fields of the electric currents in the brain, identifying aberrant activity. Magnetoencephalography may have the potential to localize seizure foci and to identify the sensorimotor cortex, visual cortex and auditory cortex. In terms of regulatory status, MEG and PET are licensed by Health Canada. Both MRS and fMRI use a MRI platform; thus, they do not have a separate licence from Health Canada. The radiotracers used in PET scanning are not licensed by Health Canada for general use but can be used through a Clinical Trials Application. The literature published up to September 2006 was searched in the following databases: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, and International Network of Agencies for Health Technology Assessment (INAHTA). The database search was supplemented with a search of relevant Web sites and a review of the bibliographies of selected papers. General inclusion criteria were applied to all conditions. Those criteria included the following: Full reports of systematic reviews, randomized controlled trials (RCTs), cohort-control studies, prospective cohort studies (PCS'), and retrospective studies.Sample sizes of at least 20 patients (≥ 10 with condition being reviewed).English-language studies.Human studies.Any age.STUDYING AT LEAST ONE OF THE FOLLOWING: fMRI, PET, MRS, or MEG.Functional brain imaging modality must be compared with a clearly defined reference standard.MUST REPORT AT LEAST ONE OF THE FOLLOWING OUTCOMES: sensitivity, specificity, accuracy, positive predictive value (PPV), receiver operating characteristic curve, outcome measuring impact on diagnostic testing, treatment, patient health, or cost. There is evidence to indicate that PET can accurately diagnose AD; however, at this time, there is no evidence to suggest that a diagnosis of AD with PET alters the clinical outcomes of patients. The addition of MRS or O-(2-(18)F-Fluoroethyl)-L-Tyrosine (FET)-PET to gadolinium (Gd)-enhanced MRI for distinguishing malignant from benign tumours during primary diagnosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients to distinguish malignant from benign tumours is unclear, because patients with a suspected brain tumour will likely undergo a biopsy despite additional imaging results. The addition of MRS, FET-PET, or MRI T2 to Gd-enhanced MRI for the differentiation of recurrence from radiation necrosis may provide a higher specificity than Gd-enhanced MRI alone. The clinical utility of additional imaging in patients with a suspected recurrence is in the monitoring of patients. Based on the evidence available, it is unclear if one of the imaging modalities (MRS, FET-PET, or MRI T2) offers significantly improved specificity over another. There may be a role for fMRI in the identification of surgical candidates for tumour resection; however, this requires further research. Based on the studies available, it is unclear if MEG has similar accuracy in localizing seizure foci to intracranial electroencephalogram (ICEEG). More high-quality research is needed to establish whether there is a difference in accuracy between MEG and ICEEG. The results of the studies comparing PET to noninvasive electroencephalogram (EEG) did not demonstrate that PET was more accurate at localizing seizure foci; however, there may be some specific conditions, such as tuberous sclerosis, where PET may be more accurate than noninvasive EEG. There may be some clinical utility for MEG or fMRI in presurgical functional mapping; however, this needs further investigation involving comparisons with other modalities. The clinical utility of MRS has yet to be established for patients with epilepsy. Positron emission tomography has high sensitivity and specificity in the diagnosis of PD and the differential diagnosis of parkinsonian syndromes; however, it is unclear at this time if the addition of PET in the diagnosis of these conditions contributes to the treatment and clinical outcomes of patients. There is limited clinical utility of functional brain imaging in the management of patients with MS at this time. Diagnosis of MS is established through clinical history, evoked potentials, and MRI. Magnetic resonance imaging can identify the multifocal white lesions and other structural characteristics of MS.

Evaluation of photodynamic treatment efficiency on glioblastoma cells received from malignant lesions: initial studies

NASA Astrophysics Data System (ADS)

Borisova, Ekaterina; Kyurkchiev, Dobroslav; Tumangelova-Yuzeir, Kalina; Angelov, Ivan; Genova-Hristova, Tsanislava; Semyachkina-Glushkovskaya, Oxana; Minkin, Krassimir

2018-04-01

Photodynamic therapy is well-established and extensively used method in treatment of different cancer types. This research reveals its potential in the treatment of cultivated human glioblastoma cells with adherent morphology. As the blood-brain barrier (BBB) permeability of the drugs is a significant problem that could not be solved easily for large biomolecules, we search for an appropriate low-molecular weight photosensitizer that could be applied for photodynamic treatment of glioblastoma cells. We used delta-aminolevulinic acid (5-ALA), which could pass BBB and plays the role of precursor of a protoporphyrin IX (PpIX) - photosensitizer, that is accumulated selectively in the tumour cells and could be a proper tool in PDT of glioblastoma. However, differences from patient to patient and between the cell activities could also lead to different effectiveness of the PDT treatment of the tumour areas. Therefore in our study we investigated not only the effect of using different fluence rates and light doses, but aims to establish more efficient values for further clinical applications for each sub-type of the GBM lesions. For the needs of PDT application an illumination device was developed in Laboratory of Biophotonics, BAS based on light-emitting diode (LED) matrix light sources for therapeutic application emitting at 635 nm. The device is optimized for PDT in combination with aminolevulinic acid/protoporphyrin IX applied as a photosensitizer drug. By the means of FACSCalibur flow cytometer (Becton Dickinson, USA) and Cell Quest Software was made evaluation of PDT effect on used human glioblastoma cells. Treatment of glioblastoma tumours continues to be a very serious issue and there is growing need in development of new concepts, methods and cancer-fighting strategies. PDT may contribute in accomplishing better results in cancer treatment and can be applied as well in combination with other techniques.

New Zealand adolescents' cellphone and cordless phone user-habits: are they at increased risk of brain tumours already? A cross-sectional study.

PubMed

Redmayne, Mary

2013-01-10

Cellphone and cordless phone use is very prevalent among early adolescents, but the extent and types of use is not well documented. This paper explores how, and to what extent, New Zealand adolescents are typically using and exposed to active cellphones and cordless phones, and considers implications of this in relation to brain tumour risk, with reference to current research findings. This cross-sectional study recruited 373 Year 7 and 8 school students with a mean age of 12.3 years (range 10.3-13.7 years) from the Wellington region of New Zealand. Participants completed a questionnaire and measured their normal body-to-phone texting distances. Main exposure-metrics included self-reported time spent with an active cellphone close to the body, estimated time and number of calls on both phone types, estimated and actual extent of SMS text-messaging, cellphone functions used and people texted. Statistical analyses used Pearson Chi2 tests and Pearson's correlation coefficient (r). Analyses were undertaken using SPSS version 19.0. Both cellphones and cordless phones were used by approximately 90% of students. A third of participants had already used a cordless phone for ≥ 7 years. In 4 years from the survey to mid-2013, the cordless phone use of 6% of participants would equal that of the highest Interphone decile (≥ 1640 hours), at the surveyed rate of use. High cellphone use was related to cellphone location at night, being woken regularly, and being tired at school. More than a third of parents thought cellphones carried a moderate-to-high health risk for their child. While cellphones were very popular for entertainment and social interaction via texting, cordless phones were most popular for calls. If their use continued at the reported rate, many would be at increased risk of specific brain tumours by their mid-teens, based on findings of the Interphone and Hardell-group studies.

New Zealand adolescents’ cellphone and cordless phone user-habits: are they at increased risk of brain tumours already? A cross-sectional study

PubMed Central

2013-01-01

Background Cellphone and cordless phone use is very prevalent among early adolescents, but the extent and types of use is not well documented. This paper explores how, and to what extent, New Zealand adolescents are typically using and exposed to active cellphones and cordless phones, and considers implications of this in relation to brain tumour risk, with reference to current research findings. Methods This cross-sectional study recruited 373 Year 7 and 8 school students with a mean age of 12.3 years (range 10.3-13.7 years) from the Wellington region of New Zealand. Participants completed a questionnaire and measured their normal body-to-phone texting distances. Main exposure-metrics included self-reported time spent with an active cellphone close to the body, estimated time and number of calls on both phone types, estimated and actual extent of SMS text-messaging, cellphone functions used and people texted. Statistical analyses used Pearson Chi2 tests and Pearson’s correlation coefficient (r). Analyses were undertaken using SPSS version 19.0. Results Both cellphones and cordless phones were used by approximately 90% of students. A third of participants had already used a cordless phone for ≥ 7 years. In 4 years from the survey to mid-2013, the cordless phone use of 6% of participants would equal that of the highest Interphone decile (≥ 1640 hours), at the surveyed rate of use. High cellphone use was related to cellphone location at night, being woken regularly, and being tired at school. More than a third of parents thought cellphones carried a moderate-to-high health risk for their child. Conclusions While cellphones were very popular for entertainment and social interaction via texting, cordless phones were most popular for calls. If their use continued at the reported rate, many would be at increased risk of specific brain tumours by their mid-teens, based on findings of the Interphone and Hardell-group studies. PMID:23302218

MO-F-CAMPUS-T-03: Continuous Dose Delivery with Gamma Knife Perfexion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghobadi,; Li, W; Chung, C

2015-06-15

Purpose: We propose continuous dose delivery techniques for stereotactic treatments delivered by Gamma Knife Perfexion using inverse treatment planning system that can be applied to various tumour sites in the brain. We test the accuracy of the plans on Perfexion’s planning system (GammaPlan) to ensure the obtained plans are viable. This approach introduces continuous dose delivery for Perefxion, as opposed to the currently employed step-and-shoot approaches, for different tumour sites. Additionally, this is the first realization of automated inverse planning on GammaPlan. Methods: The inverse planning approach is divided into two steps of identifying a quality path inside the target,more » and finding the best collimator composition for the path. To find a path, we select strategic regions inside the target volume and find a path that visits each region exactly once. This path is then passed to a mathematical model which finds the best combination of collimators and their durations. The mathematical model minimizes the dose spillage to the surrounding tissues while ensuring the prescribed dose is delivered to the target(s). Organs-at-risk and their corresponding allowable doses can also be added to the model to protect adjacent organs. Results: We test this approach on various tumour sizes and sites. The quality of the obtained treatment plans are comparable or better than forward plans and inverse plans that use step- and-shoot technique. The conformity indices in the obtained continuous dose delivery plans are similar to those of forward plans while the beam-on time is improved on average (see Table 1 in supporting document). Conclusion: We employ inverse planning for continuous dose delivery in Perfexion for brain tumours. The quality of the obtained plans is similar to forward and inverse plans that use conventional step-and-shoot technique. We tested the inverse plans on GammaPlan to verify clinical relevance. This research was partially supported by Elekta, Sweden (vendor of Gamma Knife Perfexion)« less

MO-F-CAMPUS-T-05: Correct Or Not to Correct for Rotational Patient Set-Up Errors in Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Briscoe, M; Ploquin, N; Voroney, JP

2015-06-15

Purpose: To quantify the effect of patient rotation in stereotactic radiation therapy and establish a threshold where rotational patient set-up errors have a significant impact on target coverage. Methods: To simulate rotational patient set-up errors, a Matlab code was created to rotate the patient dose distribution around the treatment isocentre, located centrally in the lesion, while keeping the structure contours in the original locations on the CT and MRI. Rotations of 1°, 3°, and 5° for each of the pitch, roll, and yaw, as well as simultaneous rotations of 1°, 3°, and 5° around all three axes were applied tomore » two types of brain lesions: brain metastasis and acoustic neuroma. In order to analyze multiple tumour shapes, these plans included small spherical (metastasis), elliptical (acoustic neuroma), and large irregular (metastasis) tumour structures. Dose-volume histograms and planning target volumes were compared between the planned patient positions and those with simulated rotational set-up errors. The RTOG conformity index for patient rotation was also investigated. Results: Examining the tumour volumes that received 80% of the prescription dose in the planned and rotated patient positions showed decreases in prescription dose coverage of up to 2.3%. Conformity indices for treatments with simulated rotational errors showed decreases of up to 3% compared to the original plan. For irregular lesions, degradation of 1% of the target coverage can be seen for rotations as low as 3°. Conclusions: This data shows that for elliptical or spherical targets, rotational patient set-up errors less than 3° around any or all axes do not have a significant impact on the dose delivered to the target volume or the conformity index of the plan. However the same rotational errors would have an impact on plans for irregular tumours.« less

Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms

PubMed Central

Cruceru, Maria Linda; Neagu, Monica; Demoulin, Jean-Baptiste; Constantinescu, Stefan N

2013-01-01

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called ‘leukaemia of the brain’, given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation. PMID:23998913

Cancer stem cells (CSCs), cervical CSCs and targeted therapies

PubMed Central

Huang, Ruixia; Rofstad, Einar K.

2017-01-01

Accumulating evidence has shown that cancer stem cells (CSCs) have a tumour-initiating capacity and play crucial roles in tumour metastasis, relapse and chemo/radio-resistance. As tumour propagation initiators, CSCs are considered to be promising targets for obtaining a better therapeutic outcome. Cervical carcinoma is the most common gynaecological malignancy and has a high cancer mortality rate among females. As a result, the investigation of cervical cancer stem cells (CCSCs) is of great value. However, the numbers of cancer cells and corresponding CSCs in malignancy are dynamically balanced, and CSCs may reside in the CSC niche, about which little is known to date. Therefore, due to their complicated molecular phenotypes and biological behaviours, it remains challenging to obtain “purified” CSCs and continuously culture CSCs for further in vitro studies without the cells losing their stem properties. At present, CSC-related markers and functional assays are used to purify, identify and therapeutically target CSCs both in vitro and in vivo. Nevertheless, CSC-related markers are not universal to all tumour types, although some markers may be valid in multiple tumour types. Additionally, functional identifications based on CSC-specific properties are usually limited in in vivo studies. Furthermore, an optimal method for identifying potential CCSCs in CCSC studies has not been previously published, and these techniques are currently of great importance. This article updates our knowledge on CSCs and CCSCs, reviews potential stem cell markers and functional assays for identifying CCSCs, and describes the potential of targeting CCSCs in the treatment of cervical carcinoma. PMID:27343550

Lung cancer perfusion: can we measure pulmonary and bronchial circulation simultaneously?

PubMed

Yuan, Xiaodong; Zhang, Jing; Ao, Guokun; Quan, Changbin; Tian, Yuan; Li, Hong

2012-08-01

To describe a new CT perfusion technique for assessing the dual blood supply in lung cancer and present the initial results. This study was approved by the institutional review board. A CT protocol was developed, and a dual-input CT perfusion (DI-CTP) analysis model was applied and evaluated regarding the blood flow fractions in lung tumours. The pulmonary trunk and the descending aorta were selected as the input arteries for the pulmonary circulation and the bronchial circulation respectively. Pulmonary flow (PF), bronchial flow (BF), and a perfusion index (PI, = PF/ (PF + BF)) were calculated using the maximum slope method. After written informed consent was obtained, 13 consecutive subjects with primary lung cancer underwent DI-CTP. Perfusion results are as follows: PF, 13.45 ± 10.97 ml/min/100 ml; BF, 48.67 ± 28.87 ml/min/100 ml; PI, 21 % ± 11 %. BF is significantly larger than PF, P < 0.001. There is a negative correlation between the tumour volume and perfusion index (r = 0.671, P = 0.012). The dual-input CT perfusion analysis method can be applied successfully to lung tumours. Initial results demonstrate a dual blood supply in primary lung cancer, in which the systemic circulation is dominant, and that the proportion of the two circulation systems is moderately dependent on tumour size. A new CT perfusion technique can assess lung cancer's dual blood supply. A dual blood supply was confirmed with dominant bronchial circulation in lung cancer. The proportion of the two circulations is moderately dependent on tumour size. This new technique may benefit the management of lung cancer.

Global Gene Expression Analysis of Canine Osteosarcoma Stem Cells Reveals a Novel Role for COX-2 in Tumour Initiation

PubMed Central

Pang, Lisa Y.; Gatenby, Emma L.; Kamida, Ayako; Whitelaw, Bruce A.; Hupp, Ted R.; Argyle, David J.

2014-01-01

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation. PMID:24416158

Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation.

PubMed

Pang, Lisa Y; Gatenby, Emma L; Kamida, Ayako; Whitelaw, Bruce A; Hupp, Ted R; Argyle, David J

2014-01-01

Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation.

Difficulties in prenatal diagnosis of tumour in the fetal sacrococcygeal area

PubMed Central

Krekora, Michał; Blitek, Marek; Kęsiak, Marcin; Piaseczna-Piotrowska, Anna; Łukaszek, Stanisław; Krasomski, Grzegorz; Słodki, Maciej; Szaflik, Krzysztof; Respondek-Liberska, Maria

2016-01-01

Prenatal ultrasound at the 20th week of gestation revealed a 3-cm tumour in the sacrococcygeal area. Initially, a sacrococcygeal teratoma was suspected on the basis of fetal ultrasonography, which revealed normal heart anatomy and an increasing tumour mass. The diagnosis was then changed to fetus in fetu or teratoma. Prenatal magnetic resonance imaging at the 34th week of pregnancy confirmed the ultrasound diagnosis. No other anomalies were found. Elective caesarean section was performed at term. The care team included a paediatric surgeon, obstetricians, neonatologists, midwives, and an anesthesiologist. A female newborn was delivered in good condition. The tumour was resected in the operating room and mature teratoma was established by histopathological evaluation. Surprisingly, agenesis of the right forearm was revealed which had not been detected prenatally, despite many examinations (both in our hospital and earlier at a primary care obstetrician office). PMID:27482281

The Cancer Genome Atlas Pan-Cancer Analysis Project

PubMed Central

Weinstein, John N.; Collisson, Eric A.; Mills, Gordon B.; Shaw, Kenna M.; Ozenberger, Brad A.; Ellrott, Kyle; Shmulevich, Ilya; Sander, Chris; Stuart, Joshua M.

2014-01-01

Cancer can take hundreds of different forms depending on the location, cell of origin and spectrum of genomic alterations that promote oncogenesis and affect therapeutic response. Although many genomic events with direct phenotypic impact have been identified, much of the complex molecular landscape remains incompletely charted for most cancer lineages. For that reason, The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumours to discover molecular aberrations at the DNA, RNA, protein, and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences, and emergent themes across tumour lineages. The Pan-Cancer initiative compares the first twelve tumour types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumour types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. PMID:24071849

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

PubMed

Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D; Huang, Min-Nung; Sanchez-Perez, Luis; Nair, Smita K; Congdon, Kendra L; Reap, Elizabeth A; Archer, Gary E; Desjardins, Annick; Friedman, Allan H; Friedman, Henry S; Herndon, James E; Coan, April; McLendon, Roger E; Reardon, David A; Vredenburgh, James J; Bigner, Darell D; Sampson, John H

2015-03-19

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Cancer and the metastatic substrate

PubMed Central

Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

2016-01-01

Seventy percent of cancer patients have detectable metastases when they receive a diagnosis and 90% of cancer deaths result from metastases. These two facts emphasise the urgency for research to study the mechanisms and processes that enable metastasis. We need to develop a greater understanding of the cellular and molecular mechanisms that cause metastasis and also we need to do more. We must also consider the micro- and macro-environmental factors that influence this disease. Studying this environmental context has led us to update the ‘seed and soil’ hypothesis which dates back to the 19th century. This theory describes cancerous cells as seeds and the substrate as the soil in target organs though this may seem antiquated. Nonetheless, the tissue specificity that researchers have recently observed in metastatic colonisation supports the validity of the seed and soil theory. We now know that the metastatic potential of a tumour cell depends on multiple, reciprocal interactions between the primary tumour and distant sites. These interactions determine tumour progression. Studies of metastasis have allowed us to develop treatments that focus on therapeutic effectiveness. These new treatments account for the frequent metastasis of some tumours to target organs such as bones, lungs, brain, and liver. The purpose of this review is first to describe interactions between the cellular and molecular entities and the target organ tumour environment that enables metastasis. A second aim is to describe the complex mechanisms that mediate these interactions. PMID:28105072

Cystic meningiomas.

PubMed

Borovich, B; Guilburd, J N; Doron, Y; Soustiel, J F; Zaaroor, M; Braun, J; Gruszkiewicz, J; Feinsod, M

1988-01-01

Four cases of cystic meningiomas were found among 194 meningiomas diagnosed by computed tomography (CT) and operated on during a 7 year period, an incidence of 2%. The cysts were in all cases peritumoral. The cyst's wall was the brain itself, and the ependymal ventricular wall was part of their medial boundary. They contained xanthochromic fluid with a high protein content. Three meningiomas were parasagittal and one was adjacent to the pteryon and the external part of the sphenoid ridge. The mural nodules were in 2 cases apparent single nodes although in one it was part of multiple distant and regional growths, in another the tumour was built by the aggregation of 2 nodes, the remaining case was an "en plaque" meningioma. All were definitely attached to the dura. Histological pattern was different in every case. Those parasagittal were: one pure meningotheliomatous, one mixed meningotheliomatous with pseudo psammomatous and lipoblastic sections and one highly vascular angioblastic; the pteryonal case was psammomatous and microcystic. CT diagnosis is difficult because glial, metastatic and other tumours may look cystic and resemble cystic meningiomas. Nevertheless in 3 cases the correct diagnosis was suspected preoperatively because the solid portion of the tumour showed intense and homogeneous contrast enhancement with a sharp edge and was located adjacent to the dura. On the other hand in the remaining case, the parasagittal solid tumour was not readily apparent on CT (the "en plaque", case), and the tentative preoperative diagnosis was of an epidermoid tumour.(ABSTRACT TRUNCATED AT 250 WORDS)

Beyond anaemia management: evolving role of erythropoietin therapy in neurological disorders, multiple myeloma and tumour hypoxia models.

PubMed

Boogaerts, Marc; Mittelman, Moshe; Vaupel, Peter

2005-01-01

Recombinant human erythropoietin (epoetin) has become the standard of care in the treatment of anaemia resulting from cancer and its treatment, and chronic kidney disease. The discovery that erythropoietin and its receptor are located in regions outside the erythropoietic system has led to interest in the potential role of epoetin in other tissues, such as the central nervous system. Animal studies have shown that systemically applied epoetin can cross the blood-brain barrier, where it reduces tissue injury associated with stroke, blunt trauma and experimental autoimmune encephalomyelitis. Pilot studies in humans have shown that epoetin treatment given within 8 h of stroke reduces infarct size and results in a significantly better outcome when compared with placebo treatment. Studies also suggest that epoetin has the potential to improve cognitive impairment associated with adjuvant chemotherapy in patients with cancer. Anaemia is a major factor causing tumour hypoxia, a condition that can promote changes within neoplastic cells that further tumour survival and malignant progression and also reduces the effectiveness of several anticancer therapies including radiotherapy and oxygen-dependent cytotoxic agents. Use of epoetin to prevent or correct anaemia has the potential to reduce tumour hypoxia and improve treatment outcome. Several therapeutic studies in anaemic animals with experimental tumours have shown a beneficial effect of epoetin on delaying tumour growth. Furthermore, clinical observations in patients with multiple myeloma and animal studies have suggested that epoetin has an antimyeloma effect, mediated via the immune system through activation of CD8+ T cells. Therefore, the role of epoetin may go well beyond that of increasing haemoglobin levels in anaemic patients, although additional studies are required to confirm these promising results. Copyright 2005 S. Karger AG, Basel.

Schwanomma From Cervical Sympathetic Chain Ganglion – A Rare Presentation

PubMed Central

Asma, A. Affee

2015-01-01

Schwanommas arising from cervical sympathetic chain are tumours that are rare in occurrence. These lesions are usually difficult to differentiate from a vagal schwanomma and a carotid body tumour during the initial workup. In this report, a rarely seen huge cervical sympathetic chain schwanomma case with partial Horner’s syndrome is being presented in detail, which to our known knowledge, is one of the few cases reported in literature. PMID:26557566