Brain and Spinal Cord Tumours
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Childhood Brain Tumours
Pituitary Tumours
Primary CNS Lymphoma
Acoustic Neuroma
Neuro-oncology (specialty)

Information Patients and the Public (15 links)

Information for Health Professionals / Researchers (24 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Shamisa A, Bance M, Nag S, et al.
Glioblastoma multiforme occurring in a patient treated with gamma knife surgery: case report and review of the literature.
J Neurosurg. 2013; 119 Suppl:816-21 [PubMed] Related Publications
Stereotactic radiosurgery is being increasingly advocated as the primary modality for treatment of vestibular schwannomas (VS). This modality has been shown to arrest tumor growth, with few associated short-term morbidities, and with possibly better hearing and facial nerve preservation rates than microsurgery. Radiation-induced oncogenesis has long been recognized, although stereotactic radiosurgery de novo induction of a secondary tumor has never been clearly described. The authors report on a patient with a VS who did not have neurofibromatosis Type 2 and who underwent gamma knife surgery (GKS). This patient required microsurgical removal of the VS within 8 months because of development of a tumor cyst with associated brainstem compression and progressive hydrocephalus. The operation resulted in clinical stabilization and freedom from tumor recurrence. Seven and a half years after undergoing GKS, the patient presented with symptoms of raised intracranial pressure. Magnetic resonance imaging demonstrated a new ring-enhancing lesion in the inferior temporal lobe adjacent to the area of radiosurgery, which on craniotomy was confirmed to be a glioblastoma multiforme (GBM). Despite additional conventional external-beam radiation to the temporal lobe, the GBM has progressed. Whereas this first reported case of a GBM within the scatter field of GKS does not conclusively prove a direct causal link, it does fulfill all of Cahan's criteria for radiation-induced neoplasia, and demands increased vigilance for the potential long-term complications of stereotactic radiosurgery, and reporting of any similar cases.

Related: Acoustic Neuroma

Oddone E, Scaburri A, Bai E, et al.
Occupational brain cancer risks in Umbria (Italy), with a particular focus on steel foundry workers.
G Ital Med Lav Ergon. 2014 Apr-Jun; 36(2):111-7 [PubMed] Related Publications
OBJECTIVES: As a part of the Occupational Cancer Monitoring (OCCAM) project, a routine analysis based on Umbria region cancer registry (RTUP) database in 2002-2008 was performed. Among other results, the incidental finding of brain cancer increased risk in steel foundry workers in Terni province (Italy), lead us to deepen the analysis, focusing on this specific industrial sector.
METHODS: A monitoring study, based on Umbria Regional Cancer Registry data, was recently carried out. Brain cancer cases and controls identified within this preliminary study were selected. Therefore, we considered all incident cases (in Umbria region 2002-2008) of brain cancer occurred among workers occupied for at least one year in private companies since 1974 and controls randomly sampled from the same population. Afterwards, taking in to account results from steel foundry in Terni province, we further deepened our analysis, focusing on this productive sector. Odds ratios (ORs) and corresponding 90% confidence intervals (CIs) were calculated using multiple logistic regression models, adjusted by age at diagnosis or sampling, sex and province of residence, when appropriate.
RESULTS: Statistical analyses were carried out on 14913 subjects, 56 cases and 14857 controls. Significantly increased ORs were observed for garment, mechanical manufacturing and chemical industries. Moreover, the risk estimates were strongly correlated with exposures in iron and steel foundries and a cluster of 14 cases in the same foundry in Terni was observed (OR 9.59, 90% CI 2.76-33.34).
CONCLUSIONS: Results of this explorative study showed increased ORs of brain cancer in some productive branches, involving possible exposures to chemical compounds and/or solvents. Moreover, our results pointed out a significantly increased risk in Terni foundry workers, determining an interesting brain cancer cluster (14 cases). Further studies on this industrial sector are needed with improved definitions of tasks and exposures.

Pater K, Püsküllüoglu M, Zygulska AL
Oncological emergencies: increased intracranial pressure in solid tumours' metastatic brain disease.
Przegl Lek. 2014; 71(2):91-4 [PubMed] Related Publications
Increased intracranial pressure due to metastatic brain disease is one of the oncological emergencies. It may cause herniation or insufficient brain blood flow, thus it is a life-threatening condition. This article focuses on diagnostic and treatment options, which should be introduced immediately. The prognosis remains poor.

Related: Monoclonal Antibodies

Williams DS
Glioblastoma multiforme.
J Insur Med. 2014; 44(1):62-4 [PubMed] Related Publications
Glioblastoma Multiforme is the most common and most aggressive malignant primary brain tumor in humans.

Goschzik T, Gessi M, Denkhaus D, Pietsch T
PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region.
J Neuropathol Exp Neurol. 2014; 73(8):747-51 [PubMed] Related Publications
Papillary tumors of the pineal region (PTPR) are recognized as a distinct entity in the World Health Organization classification of CNS tumors. Papillary tumors of the pineal region frequently show loss of chromosome 10, but no studies have investigated possible target genes on this chromosome. Chromosome 10 harbors the PTEN (phosphatase and tensin homolog) gene, the inactivation of which, by mutation or epigenetic silencing, has been observed in different brain tumors, including high-grade gliomas. In this study, we investigated copy number changes by molecular inversion probe (MIP) analysis and the mutational status of PTEN in 13 PTPR by direct sequencing. MIP analysis of 5 PTPR showed chromosome 10 loss in all cases. In addition, there were losses of chromosomes 3, 14, 22, and X, and gains of whole chromosomes 8, 9, and 12 in more than 1 case. One case had a homozygous PTEN deletion; and 2 point mutations in exon 7 of PTEN (G251D and Q261stop) were found. Immunohistochemistry revealed decrease or loss of the PTEN protein and increased expression of p-Akt and p-S6. These results indicated that PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway may play a role in the biology of PTPR. This evidence may lead to the possible use of PI3K/Akt/mTOR inhibitors in therapy for patients with PTPR.

Related: MUC1 gene PTEN Signal Transduction

Han W, Xia Q, Yin B, Peng XZ
Ribotrap analysis of proteins associated with FHL3 3'untranslated region in glioma cells.
Chin Med Sci J. 2014; 29(2):78-84 [PubMed] Related Publications
OBJECTIVE: To screen the proteins associated with four-and-a-half LIM domains 3 (FHL3) 3' untranslated region (3'UTR) in glioma cells.
METHODS: Western blot was adopted to detect the regulatory effect of poly(C)-binding protein 2 (PCBP2) on FHL3. Biotin pull-down and sliver staining were employed to screen and verify the candidate binding proteins of FHL3 3'UTR. Then liquid chromatography-tandem mass spectrometry (LC-MS/MS) and molecule annotation system were used to identify and analyze the candidate binding proteins. Immuno- precipitation was conducted to study the interaction between PCBP2 and polypyrimidine tract-binding protein 1 (PTBP1), a binding protein identified by LC-MS/MS.
RESULTS: PCBP2 could bind to FHL3 mRNA 3'UTR-A and inhibited the expression of FHL3 in T98G glioms cells. 22 candidate binding proteins were identified. Among them, there were 11 RNA binding proteins, including PCBP2. PTBP1 associated with FHL3 mRNA 3'UTR and interacted with PCBP2 protein.
CONCLUSIONS: PCBP2 and PTBP1 can both associate with FHL3 mRNA 3'UTR through forming a protein complex.

Rafee S, Elamin YY, Cronin K, et al.
A rare case of nasopharyngeal carcinoma with widespread CNS metastases.
Ir Med J. 2014; 107(6):180-1 [PubMed] Related Publications
Nasopharyngeal cancer is unique among head and neck cancers. Despite definitive treatment, there is a high rate of recurrence, most commonly in the bone, lung or liver. Brain metastases and particularly, leptomeningeal carcinomatosis are extremely rare. We present a case of recurrent nasopharyngeal carcinoma with brain metastases and leptomeningeal carcinomatosis in the absence of local recurrence and systemic metastases.

Related: Nasopharyngeal Cancer

Nowak A, Dziedzic T, Czernicki T, et al.
Surgical treatment of parasagittal and falcine meningiomas invading the superior sagittal sinus.
Neurol Neurochir Pol. 2014; 48(3):174-80 [PubMed] Related Publications
OBJECTIVE: We present our experience with surgery of parasagittal and falcine meningiomas invading the superior sagittal sinus with special consideration of the surgical complications and the incidence of tumour recurrence.
MATERIALS AND METHODS: The analysis included 37 patients with parasagittal and falcine meningiomas invading the superior sagittal sinus. In 13 cases, the sinus was ligated and resected with tumour. In 14 cases, the sinus was entered with the goal of tumour resection and the sinus was reconstructed, while in 10 patients the sinus was not entered and the remaining residual tumour was observed for growth.
RESULTS: Out of 13 patients after radical resection of the tumour and invaded part of sinus, 9 revealed haemodynamic complications: venous infarction (4), significant brain oedema (3) and hypoperfusion syndrome (2). 2 out of 14 patients after resection of the tumour from the lumen of the superior sagittal sinus with subsequent sinus repair developed venous infarction after surgery. Among 27 patients after radical tumour excision the remote follow-up revealed recurrence in 2 patients. There were no significant haemodynamic complications in none of 10 cases, in which the residual tumour was left after surgery in the superior sagittal sinus. In this group, 3 cases were subjected to early post-operative radiotherapy and local recurrence was observed in 4 patients.
CONCLUSIONS: The aggressive surgical treatment of meningiomas infiltrating the superior sagittal sinus is associated with a high surgical risk. The incidence of recurrence of these tumours increases significantly in the case of non-radical excision of the tumour.

De Vos FY, Middelburg TA, Seynaeve C, de Jonge MJ
Ecthyma gangrenosum caused by Pseudomonas aeruginosa in a patient with astrocytoma treated with chemotherapy.
Kansenshogaku Zasshi. 2014; 88(3 Suppl 9-10):37-9 [PubMed] Related Publications
Ecthyma gangrenosum, presenting as embolic lesions caused by Pseudomonas aeruginosa infection, has distinct pathognomonic features and a high mortality rate in patients with bacteremia, but when recognized early is easily treated. In this case report we describe this disseminated infection in an adult patient treated with chemotherapy for an astrocytoma.

Tan WQ, Chen G, Jia B, Ye M
Artemisinin inhibits neuroblastoma proliferation through activation of AHP-activated protein kinase (AMPK) signaling.
Pharmazie. 2014; 69(6):468-72 [PubMed] Related Publications
Recent population studies suggest that the use of artemisinin is associated with reduced incidence and improved prognosis of certain cancers. In the current study, we assessed the effect of artemisinin on neuroblastoma cells using SHSY5Y cells. We found that artemisinin inhibited growth and modulated expression of cell-cycle regulators in these cells. Treatment with artemisinin was also associated with activation of AMP kinase and inhibition of mTOR/p70S6K/pS6 signaling in SHSY5Y cells. In addition, inhibition of AMPK signaling reversed impact on the anti-proliferative roles of artemisinin. Taken together, these results provide evidence for a mechanism that may contribute to the antineoplastic effects of artemisinin suggested by recent population studies and justify further work to explore its potential roles in neuroblastoma prevention and treatment.

Related: Neuroblastoma

Xu S, Wei J, Wang F, et al.
Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma.
J Natl Cancer Inst. 2014; 106(8) [PubMed] Related Publications
BACKGROUND: The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.
METHODS: An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided.
RESULTS: miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303).
CONCLUSIONS: These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.

Related: Apoptosis Signal Transduction TGFB1

Gerber NU, von Hoff K, Resch A, et al.
Treatment of children with central nervous system primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric trial HIT 2000 using hyperfractionated radiation therapy followed by maintenance chemotherapy.
Int J Radiat Oncol Biol Phys. 2014; 89(4):863-71 [PubMed] Related Publications
PURPOSE: The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4.
METHODS AND MATERIALS: After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine).
RESULTS: Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error [SE]) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively).
CONCLUSIONS: Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

Related: Childhood Brain Tumours Childhood Brain Tumors

Dockstader C, Wang F, Bouffet E, Mabbott DJ
Gamma deficits as a neural signature of cognitive impairment in children treated for brain tumors.
J Neurosci. 2014; 34(26):8813-24 [PubMed] Related Publications
Cognitive impairment is consistently reported in children treated for brain tumors, particularly in the categories of processing speed, memory, and attention. Although tumor site, hydrocephalus, chemotherapy, and cranial radiation therapy (CRT) are all associated with poorer function, CRT predicts the greatest deficits. There is a particularly high correlation between CRT and slowed information-processing speed. Cortical gamma-band oscillations have been associated with processing behaviorally relevant information; however, their role in the maintenance of cognition in individuals with processing deficits is unclear. We examined gamma oscillations using magnetoencephalography (MEG) in children undergoing CRT to test whether gamma characteristics can be a signature of cognitive impairment in this population. We collected resting-state data as well as data from baseline and active periods during two visual-motor reaction time tasks of varying cognitive loads from 18 healthy children and 20 patients. We found that only high-gamma oscillations (60-100 Hz), and not low-gamma oscillations (30-59 Hz), showed significant group differences in absolute power levels. Overall, compared with healthy children, patients showed the following: (1) lower total high-gamma (60-100 Hz) power during the resting state, as well as during task-related baseline and performance measures; (2) no change in gamma reactivity to increases in cognitive load; and (3) slower processing speeds both inside and outside MEG. Our findings show that high-gamma oscillations are disrupted in children after treatment for a brain tumor. The temporal dynamic of the high-gamma response during information processing may index cognitive impairment in humans with neurological injury.

Related: Childhood Brain Tumours Childhood Brain Tumors

Bumrungrachpukdee P, Pruphetkaew N, Phukaoloun M, Pheunpathom N
Recurrence of intracranial meningioma after surgery: analysis of influencing factors and outcome.
J Med Assoc Thai. 2014; 97(4):399-406 [PubMed] Related Publications
OBJECTIVE: To analyze the recurrent rate, timing, and influential factors of recurrence, including clinical outcome in patients with intracranial meningioma who underwent surgery.
MATERIAL AND METHOD: The medical records of surgically treated intracranial meningioma patients with histological confirmation were reviewed. The diagnosis of recurrence was based on clinical condition and imaging study during follow-up. The recurrent rate, timing of recurrence, factors that influence the recurrence and clinical outcome were analyzed Clinical outcome was measured by the Glasgow outcome scale.
RESULTS: One hundred eighty one patients were recruited. Mean tumor diameter was 4.9 cm (1.2-9 cm). Mean follow-up was 32.3 months. Median recurrent time was 21.6 months and overall recurrent rate was 21.5% with 5-year recurrence-free survival rate of 65%. Factors associated with tumor recurrence were headache at presentation (p = 0.002), Simpson grade III (p = 0.012), Simpson grade IV (p < 0.001), Simpson grade V (p = 0.004), WHO grade II (p = 0.004) and WHO grade III (p < 0.001). Mortality rate in recurrent group was 12.8% compared with 3.5% in non-recurrent group (p = 0.039). The favorable outcome was higher in non-recurrent group 91.5% compared with 76.9% in recurrent group(p = 0.02483).
CONCLUSION: The risk factors of recurrence were headache at presentation, extent of resection, and histological grading. The extent of resection identified by Simpson grading effect the recurrent rate as stated previously in the literature. The higher histological grade was associated with higher recurrent rate. The wide range of timing of tumor recurrence needs both clinical evaluation and imaging study in short- and long-term follow-up especially in high-risk group. Recurrent meningioma increased rate of morbidity and mortality.

Wongsirisuwan M, Karnchanapandh K
Comparative outcomes of keyhole supraorbital approach (KSA) and endonasal endoscopic transsphenoidal approach (EETA) in pituitary surgery.
J Med Assoc Thai. 2014; 97(4):386-92 [PubMed] Related Publications
BACKGROUND: Currently, minimal invasive surgery (the endonasal endoscopic transsphenoidal approach-EETA or keyhole supraorbital approach-KSA) is widely accepted as the best choice for pituitary tumor removal. To the best of the authors' knowledge, there is no study comparing the relative safety of these methods.
OBJECTIVE: To evaluate safety and compare the complications resulting from pituitary surgery using EETA and KSA.
MATERIAL AND METHOD: The retrospective review was performed between January 2003 and September 2013. One hundred thirty patients with pituitary adenomas were operated by using either EETA or KSA. The KSA was used on 92 cases, and the EETA was utilized on the other 38. Postoperative complications were analyzed using statistical methodologies to show statistical significance. The study was approved by the ethical committee of Rajavithi Hospital.
RESULTS: After statistical analysis, KSA provided better outcome in term of "headache improvement" than EETA. For complications, EETA had higher incidences of unimproved vision and reoperation rate than KSA. The other major finding of the present study was that in the early year of the operations, there was higher incidence of complications. This could be associated with the level of skills of the surgeons.
CONCLUSION: KSA had better outcome in term of operative time, length of hospital stay, estimated blood loss, and headache improvement than EETA. For complications, EETA had higher incidence of unimproved vision and reoperation rate than KSA.

Related: Pituitary Tumors

Suwaid MA, Ismail A
Magnetic resonance imaging of multiple spinal extra dural arachnoid cysts: a case report.
Niger Postgrad Med J. 2014; 21(1):78-80 [PubMed] Related Publications
Extradural arachnoid cysts develop from protrusions of arachnoid herniating through a dural defect. Solitary lesions are more common than multiple lesions. This report is an uncommon multiple spinal extradural arachnoid cysts, illustrating the value of magnetic resonance imaging in the diagnosis. A 42-year-old man presented with low back pain radiating into the left leg with associated paraesthesia. Magnetic resonance images showed two well defined expansile lobulated collections. These lesions expanded the spinal canal, appearing as both hyperintense and hypointense on T1 and T2 sequences respectively. The lesions were resected and the dorsal communicating channel was closed. He had remarkable pain reduction thereafter.

Lemercier P, Paz Maya S, Patrie JT, et al.
Gradient of apparent diffusion coefficient values in peritumoral edema helps in differentiation of glioblastoma from solitary metastatic lesions.
AJR Am J Roentgenol. 2014; 203(1):163-9 [PubMed] Related Publications
OBJECTIVE: Glioblastoma and solitary metastatic lesions can be difficult to differentiate with conventional MRI. The use of diffusion-weighted MRI to better characterize peritumoral edema has been explored for this purpose, but the results have been conflicting. The purpose of this study was to test the hypothesis that the gradient of apparent diffusion coefficient (ADC) values in peritumoral edema--that is, the difference in ADC values from the region closest to the enhancing tumor and the one closest to the normal-appearing white matter--may be a marker for differentiating glioblastoma from a metastatic lesion.
MATERIALS AND METHODS: Forty patients, 20 with glioblastoma and 20 with a solitary metastatic lesion, underwent diffusion-weighted brain MRI before surgical resection. The ADC values were retrospectively collected in the peritumoral edema in three positions: near, an intermediate distance from, and far from the core enhancing tumor (G1, G2, and G3). The ADC gradient in the peritumoral edema was calculated as the subtractions ADCG3 - ADCG1, ADCG3 - ADCG2, and ADCG2 - ADCG1. The ADC values in the enhancing tumor, peritumoral edema, ipsilateral normal-appearing white matter, contralateral healthy white matter, and CSF were also collected.
RESULTS: A gradient of ADC values was found in the peritumoral edema of glioblastoma. The ADC values increased from the region close to the enhancing tumor (1.36 ± 0.24 × 10(-3) mm(2)/s) to the area near the normal-appearing white matter (1.57 ± 0.34 × 10(-3) mm(2)/s). In metastatic lesions, however, those values were nearly homogeneous (p = 0.04).
CONCLUSION: The ADC gradient in peritumoral edema appears to be a promising tool for differentiating glioblastoma from a metastatic lesion.

Woditschka S, Evans L, Duchnowska R, et al.
DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer.
J Natl Cancer Inst. 2014; 106(7) [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood.
METHODS: Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group).
RESULTS: Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression.
CONCLUSIONS: BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain.

Related: Breast Cancer BARD1

Badoual M, Gerin C, Deroulers C, et al.
Oedema-based model for diffuse low-grade gliomas: application to clinical cases under radiotherapy.
Cell Prolif. 2014; 47(4):369-80 [PubMed] Related Publications
OBJECTIVES: Diffuse low-grade gliomas are characterized by slow growth. Despite appropriate treatment, they change inexorably into more aggressive forms, jeopardizing the patient's life. Optimizing treatments, for example with the use of mathematical modelling, could help to prevent tumour regrowth and anaplastic transformation. Here, we present a model of the effect of radiotherapy on such tumours. Our objective is to explain observed delay of tumour regrowth following radiotherapy and to predict its duration.
MATERIALS AND METHODS: We have used a migration-proliferation model complemented by an equation describing appearance and draining of oedema. The model has been applied to clinical data of tumour radius over time, for a population of 28 patients.
RESULTS: We were able to show that draining of oedema accounts for regrowth delay after radiotherapy and have been able to fit the clinical data in a robust way. The model predicts strong correlation between high proliferation coefficient and low progression-free gain of lifetime, due to radiotherapy among the patients, in agreement with clinical studies. We argue that, with reasonable assumptions, it is possible to predict (precision ~20%) regrowth delay after radiotherapy and the gain of lifetime due to radiotherapy.
CONCLUSIONS: Our oedema-based model provides an early estimation of individual duration of tumour response to radiotherapy and thus, opens the door to the possibility of personalized medicine.

Cuddapah VA, Robel S, Watkins S, Sontheimer H
A neurocentric perspective on glioma invasion.
Nat Rev Neurosci. 2014; 15(7):455-65 [PubMed] Related Publications
Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood-brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease.

Mack F, Schäfer N, Kebir S, et al.
Carmustine (BCNU) plus Teniposide (VM26) in recurrent malignant glioma.
Oncology. 2014; 86(5-6):369-72 [PubMed] Related Publications
BACKGROUND: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking.
METHODS: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m(2), day 1/42) and VM26 (45-60 mg/m(2), days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity.
RESULTS: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed.
CONCLUSION: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM.

Related: Carmustine Teniposide

Roci E, Cakani B, Brace G, et al.
Platinum-based chemotherapy in recurrent high-grade glioma patients: retrospective study.
Med Arch. 2014; 68(2):140-3 [PubMed] Related Publications
INTRODUCTION: To investigate the efficacy of platinum-based chemotherapy in patients with recurrent high-grade glioma (HGG) who had received previous alkylating line of chemotherapy.
MATERIAL AND METHODS: Case notes of patients who had received chemotherapy with carboplatin or cysplatin for recurrent HGG between June 2006 and July 2012 were reviewed. Baseline characteristics and outcomes after treatment were recorded.
RESULTS: Forty-eight patients received carboplatin/cysplatin as second line chemotherapy for recurrent HGG (grade III n = 6; grade IV n = 42). The median number of cycles completed was 4. Fifteen patients (28%) had at least minor response, 22 (49%) had stable disease and 11 (23%) had progressive disease. Six month progression-free survival was 30% (52% in patients with grade III glioma and 18% in patients with grade IV glioma). The median time to disease progression from the first treatment with platinum drug was 3.2 months. The median survival was 8 months (10 months for patients with grade III glioma and 7 months for patients with grade IV glioma). Among patients with either stable disease or a partial response, the median survival was 12 months compared with 3 months in patients with progressive disease. No survival or response rate differences were noted regarding the type of previous chemotherapy, nitrosoureas or temozolomide.
CONCLUSIONS: Single-agent carboplatin/cysplatin has modest activity in patients with recurrent HGG previously treated with one line of chemotherapy, nitrosoureas or temozolomide. Despite the improvement of median survival of patients achieving stable disease or a partial response to treatment, more effective regimens are required for this patient population.

Related: Carboplatin Cisplatin

Patel AP, Tirosh I, Trombetta JJ, et al.
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.
Science. 2014; 344(6190):1396-401 [PubMed] Article available free on PMC after 20/12/2014 Related Publications
Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.

Ohtakara K, Hoshi H
Preliminary clinical outcomes of image-guided 3-dimensional conformal radiotherapy for limited brain metastases instead of stereotactic irradiation referral.
Anticancer Res. 2014; 34(6):2997-3005 [PubMed] Related Publications
To determine the preliminary clinical outcomes of image-guided 3-dimensional conformal radiotherapy (IG-3DCRT) for limited but variably-sized brain metastases (BM). Sixty-two lesions in 24 patients were retrospectively evaluated; out of these patients 75% were ≥ 65 years of age, and 37.5% were categorized into recursive partitioning analysis (RPA) class 3. The median value for the maximum diameter of the lesions was 19 mm (range=4-72 mm). The median sole treatment dose was 36 Gy in 10 fractions. The median survival durations after IG-3DCRT were 12.0 months and 3.2 months for patients categorized into RPA classes ≤ 2 and 3, respectively. Local recurrences occurred in two lesions with a 6-month local control probability of 93.0%. Major toxicities included radiation necrosis in two patients. IG-3DCRT is feasible even for patients with limited BM who are categorized into RPA class 3, and confers clinical outcomes comparable to those of stereotactic radiosurgery, including excellent local control and minimal toxicity even for large tumors.

Related: Cancer Prevention and Risk Reduction

Lee D, Sun S, Ho AS, et al.
Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response.
Anticancer Res. 2014; 34(6):2957-66 [PubMed] Related Publications
BACKGROUND: Intratumoural hypoxia is associated with chemoresistance in glioblastoma multiforme (GBM), a highly malignant brain tumour. Adaptive response to endoplasmic reticulum stress induced by temozolomide is a major obstacle in recurrent GBM. We investigated whether hyperoxia resensitizes temozolomide-resistant GBM cells to temozolomide by abrogating the hypoxia-induced, unfolded protein response (UPR)-related protective mechanisms.
MATERIALS AND METHODS: We examined changes to key UPR modulators in temozolomide-sensitive and -resistant human GBM cells (D54 and U87) treated with/without temozolomide at different oxygen concentrations using western blotting, and cytotoxic benefits of overexpressing key chaperone, P4HB, in GBM cells (U87 and U251) under normoxia and hyperoxia.
RESULTS: Hyperoxia, alone or synergistically with temozolomide, activated the UPR in sensitive and resistant D54 and U87 cell lines. Hyperoxia also reduced survival benefit of U87 and U251 cells with P4HB overexpression through the UPR.
CONCLUSION: Hyperoxia enhanced GBM cell sensitivity to temozolomide, likely through UPR, highlighting an important treatment modality targeting chemosensitive and -resistant GBM.

Related: Apoptosis Dacarbazine Temozolomide

Stoczynska-Fidelus E, Och W, Rieske P, et al.
Spontaneous in vitro senescence of glioma cells confirmed by an antibody against IDH1R132H.
Anticancer Res. 2014; 34(6):2859-67 [PubMed] Related Publications
BACKGROUND: We have recently suggested that glioblastoma cells become spontaneously senescent in cell culture conditions. The antibody specific against IDH1(R132H) offers the perfect opportunity to verify this hypothesis.
MATERIALS AND METHODS: We analyzed the features of senescence in 8 glioma cell cultures showing the IDH1(R132H) mutation based on combination of immunocytochemistry, enzymo-cytochemistry, BrdU incorporation assay and real-time microscopic observation.
RESULTS: We report that glioma cells showing the IDH1(R132H) mutation become rapidly and spontaneously senescent in vitro. Senescence was observed in both classical and novel serum-free cell culture conditions. Importantly, the senescent IDH1(R132H)-positive cells showed the expression of stemness marker (SOX2).
CONCLUSION: In vitro senescence appeared to be the main reason of the difficulties in any kind culturing of glioma cells. 3D cell cultures prolonged the survival and in vitro proliferation of neoplastic IDH1(R132H)-positive cells, however, did not enhance the stabilization efficiency. Senescence of glioma cells is spontaneously triggered in vitro, which offers the opportunity of potential new therapeutic strategies based on this phenomenon.

Related: Monoclonal Antibodies IDH1 gene

Schwab B, Rudolph A, Jost E, Klinge U
Collaborative network of predictive markers complicates formation of prognostic groups in patients with advanced lung cancer.
Anticancer Res. 2014; 34(6):2745-54 [PubMed] Related Publications
BACKGROUND: Evaluation of cancer therapies is mainly based on prolonging remission status and effect of survival. Various serological, clinical or histological markers are used to estimate the patient's prognosis, and to tailor specific therapies for patients with poor prognosis. However, it is still a challenge to combine all this information into a comprehensive risk prediction.
PATIENTS AND METHODS: In 58 patients with advanced non small cell lung cancer we recorded 38 parameters (15 from clinic, 10 from histology, 13 from serology) to analyze their impact on survival. We both used univariate as well as multivariate approaches and decision tree analysis.
RESULTS: Univariate analysis showed that ECOG status, stage, and the presence of cerebral or bone metastasis had a significant impact on survival, as well as the serum markers CA15-3, TPA, Cyfra. In a multivariate approach only ECOG and stage had a significant impact on survival. Considering correlation coefficients of >0.3 as an indicator of a functional relationship, we found several relations among the clinical (9), histological (8) or the serological parameters (13). Survival was related to 9 parameters by significant direct and cross-relation coefficients. The use of already few variables with its different possible options led to many different patterns in the cohort, almost all being specific for individual patients, and thereby underlining their heterogeneity. Decision tree analysis revealed that by including either stage and kind of therapy or stage and expression of YB-1 allows to identify sub-groups with distinct prognosis.
CONCLUSION: Clinical, serological and histological markers, all provide prognostic information. Because they are all linked in a collaborative network, the formation of homogenous prognostic groups by use of single markers is limited. Alternative statistical approaches with focus on decision trees may allow use of various information to assess individual patients into distinct risk groups.

Related: Lung Cancer

Sharma P, Mukherjee A, Bal C, et al.
Somatostatin receptor-based PET/CT of intracranial tumors: a potential area of application for 68 Ga-DOTA peptides?
AJR Am J Roentgenol. 2013; 201(6):1340-7 [PubMed] Related Publications
OBJECTIVE: Similar to neuroendocrine tumors (NETs) at other sites, a wide array of intracranial tumors also express somatostatin receptors (SSTRs). This expression can be exploited for both imaging and therapy. The introduction of (68)Ga-labeled tetraazacyclododecanetetraacetic acid (DOTA)-peptide PET/CT has given new dimension to SSTR-based imaging because of its improved sensitivity and excellent spatial resolution.
CONCLUSION: However, in contrast to gastropancreatic and bronchopulmonary NETs, limited literature is available regarding the use of (68)Ga-DOTA-peptide PET/CT in intracranial tumors. Here, we briefly review the available literature and highlight the potential role that (68)Ga-DOTA-peptide PET/CT can play in the management of intracranial tumors.

Pollack IF, Jakacki RI, Butterfield LH, et al.
Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas.
J Clin Oncol. 2014; 32(19):2050-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Diffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG.
PATIENTS AND METHODS: GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging.
RESULTS: Twenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13Rα2 in 10, EphA2 in 11, and survivin in three.
CONCLUSION: GAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.

Related: Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood BIRC5

Yu PJ, Hyman KM, Cassiere HA, et al.
Metastatic meningioma extending into the left atrium through the pulmonary vein.
Ann Thorac Surg. 2014; 97(6):2173-5 [PubMed] Related Publications
Left atrial extension of pulmonary tumors through the pulmonary vein is most often associated with primary malignancies and is rarely associated with metastatic disease. We present the first, to our knowledge, reported case of a patient with a history of intracranial meningioma resections presenting with metastatic meningioma to the right lower lobe with extension into the left atrium through the pulmonary vein.

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