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Brain and Spinal Cord Tumours

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Childhood Brain Tumours
Pituitary Tumours
Primary CNS Lymphoma
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Neuro-oncology (specialty)

Information Patients and the Public (15 links)

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Latest Research Publications

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

Sun L, Joh DY, Al-Zaki A, et al.
Theranostic Application of Mixed Gold and Superparamagnetic Iron Oxide Nanoparticle Micelles in Glioblastoma Multiforme.
J Biomed Nanotechnol. 2016; 12(2):347-56 [PubMed] Related Publications
The treatment of glioblastoma multiforme, the most prevalent and lethal form of brain cancer in humans, has been limited in part by poor delivery of drugs through the blood-brain barrier and by unclear delineation of the extent of infiltrating tumor margins. Nanoparticles, which selectively accumulate in tumor tissue due to their leaky vasculature and the enhanced permeability and retention effect, have shown promise as both therapeutic and diagnostic agents for brain tumors. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been leveraged as T2-weighted MRI contrast agents for tumor detection and imaging; and gold nanoparticles (AuNP) have been demonstrated as radiosensitizers capable of propagating electron and free radical-induced radiation damage to tumor cells. In this study, we investigated the potential applications of novel gold and SPION-loaded micelles (GSMs) coated by polyethylene glycol-polycaprolactone (PEG-PCL) polymer. By quantifying gh2ax DNA damage foci in glioblastoma cell lines, we tested the radiosensitizing efficacy of these GSMs, and found that GSM administration in conjunction with radiation therapy (RT) led to ~2-fold increase in density of double-stranded DNA breaks. For imaging, we used GSMs as a contrast agent for both computed tomography (CT) and magnetic resonance imaging (MRI) studies of stereotactically implanted GBM tumors in a mouse model, and found that MRI but not CT was sufficiently sensitive to detect and delineate tumor borders after administration and accumulation of GSMs. These results suggest that with further development and testing, GSMs may potentially be integrated into both imaging and treatment of brain tumors, serving a theranostic purpose as both an MRI-based contrast agent and a radiosensitizer.

Kanakavelu N, Jebaseelan Samuel J
Determination of patient set-up error and optimal treatment margin for intensity modulated radiotherapy using image guidance system.
J BUON. 2016 Mar-Apr; 21(2):505-11 [PubMed] Related Publications
PURPOSE: The geometrical uncertainties in the patient positioning during intensity modulated radiotherapy (IMRT) are crucial as there is potential to underdose the tumor and overdose the nearby critical structures. Image guided techniques provide a solution to assess the patient set-up uncertainties and help determine the optimal planning target volume (PTV) margin to the clinical tumor volume (CTV).
METHODS: A retrospective study was conducted to evaluate patient set-up errors along the three translational directions at different treatment sites such as the brain, the head and neck (H&N) and the prostate. A total of 60 patients' set-up error data was analysed to evaluate the systematic and random errors and the optimal CTV-PTV margin.
RESULTS: For brain and H&N sites, more than 90, 80 and about 100% of the total image acquisitions were less than 3 mm in lateral, longitudinal and vertical directions respectively. For the prostate cases, the frequency of patient set-up error to be less than 3 mm were 79.7, 75.6 and 80% in lateral, longitudinal and vertical directions respectively. About 0.6% had more than 7 mm error in the lateral and longitudinal directions for the prostate site. CTV-PTV margin of 3.4, 3.4 and 1.9 mm for brain cases, 3.5, 3 and 1.8 mm for H&N cases and 5, 4.6 and 4.5 mm for the prostate cases in the lateral, longitudinal and vertical directions respectively were determined.
CONCLUSION: Image guidance is an effective method to evaluate the accuracy of IMRT treatment delivery. The optimal CTV-PTV margin can be determined to ensure adequate dose to CTV, specific to the site.

Esbah O, Demirci U, Dane F, et al.
Multicenter experience of adult medulloblastoma: A study of Anatolian Society of Medical Oncology (ASMO).
J BUON. 2016 Mar-Apr; 21(2):456-60 [PubMed] Related Publications
PURPOSE: Medulloblastoma (MB) is rarely seen in adults. For adjuvant therapy in adults the same therapy protocols used in pediatric cases are used. The present study retrospectively evaluated the data of MB patients who were treated in different Oncology Centers in Turkey.
METHODS: The data of 60 adult patients with MB from 8 Oncology Centers diagnosed between 2005 and 2012 were retrospectively analyzed.
RESULTS: The median patient age was 28.8 years (range 16-54). The administered chemotherapy included procarbazine+lomustin+vincristine (group A, N=31) and cyclophosphamide/ifosfamide+vincristine+cisplatin (group B, N=13). Median chemotherapy courses were 4 (range 1-8). Median progression free survival (PFS) was 76 months and median overall survival (OS) has not been reached in both groups. In young female patients and in those who received adjuvant chemotherapy, median PFS and OS were longer but without statistical significance. Mean PFS and OS were 65.9 months and 101.2 months in group A and 113.6 months and 141.6 months in group B, respectively.
CONCLUSION: Improved survival results were obtained in women, in patients aged below 25 years, in those who underwent gross total excision (GTE) and in those who received adjuvant therapy with cyclophosphamide/ifosphamide.

Akbar SN, Hermel DJ, Alday G
An Uncommon Complication of Esophageal Cancer.
Conn Med. 2016; 80(4):227-9 [PubMed] Related Publications
Esophageal cancer is one of the rarer solid tumors that metastasize to the central nervous system. We describe a case of a 57-year-old male, previously confirmed to have obstructive esophageal adenocarcinoma with local mediastinal and esophagogastric lymph node involvement undergoing chemotherapy, who presented with altered mental status, headache, nausea, 15-pound weight loss, and neck stiffness. Prior staging with an MRI of the brain and spine was unrevealing, but a lumbar puncture demonstrated adenocarcinomatous spread to the cerebrospinal fluid, consistent with leptomeningeal carcinomatosis.

Chen Q, Boire A, Jin X, et al.
Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.
Nature. 2016; 533(7604):493-8 [PubMed] Related Publications
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.

Wierzbicka-Tutka I, Sokołowski G, Bałdys-Waligórska A, et al.
PTTG and Ki-67 expression in pituitary adenomas.
Przegl Lek. 2016; 73(2):53-8 [PubMed] Related Publications
INTRODUCTION: The unpredictable biology of pituitary adenomas makes it a therapeutic challenge. Moreover ,histopathology of pituitary carcinomas and locally invasive adenomas are indistinguishable from benign tumors and a new marker which would enable to differentiate those lesions is vital. The aim of the study was to evaluate Ki-67 and PTTG (pituitary tumour--transforming gene) expression in pituitary adenomas and their applicationas markers of tumour aggressiveness.
MATERIAL AND METHODS: A retrospective analysis of 55 patients: 32 females(58%) and 23 males (42%), mean age 50 ± 16 years who underwent pituitary tumor surgery between 2003-2012. Ki-67 and PTTG indices were determined by immunohistochemical staining. Magnetic resonance imaging or computed tomography was performed beforehand and one year after surgery to figure a potential tumour progression, tumour size and correlation to adjacent tissues.
RESULTS: The expression of Ki-67and PTTG was revealed in cell nucleiin 88% and 85% of adenomas, respectively. The median Ki-67 and PTTG indices were 1.4 and 1.0, respectively(p = 0.006). In the group with macroadenoma as compared with the group with microadenoma, median Ki-67 index was higher (1.4% vs. 1.03%; p = 0.02). We did not find correlation between both Ki-67 and PTTG indices and tumour progression. Tumours with positive immunostaining towards FSH revealed lower Ki-67 and PTTG indices than the rest with a negative one (0.6% vs.1.84%, p = 0.0004 and 0.67% vs 1.23%,p = 0.047; respectively). However, PTTG index was higher in the group with acromegaly as compared to the group with clinically non-functioning pituitary adenoma (NFPA) (1.28% vs.0.35%; p = 0.02).
CONCLUSIONS: Positive nuclear expression of Ki-67 and PTTG was observed in the majority of pituitary adenomas. Only higher Ki-67 expression was related to the tumour invasiveness found on MRI/CT. Tumour progressionwas not related to both Ki-67 and PTTG expression.

Bavle AA, Lin FY, Parsons DW
Applications of Genomic Sequencing in Pediatric CNS Tumors.
Oncology (Williston Park). 2016; 30(5):411-23 [PubMed] Related Publications
Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers.

Baritchii A, Jurj A, Soritau O, et al.
Sensitizer drugs for the treatment of temozolomide-resistant glioblastoma.
J BUON. 2016 Jan-Feb; 21(1):199-207 [PubMed] Related Publications
PURPOSE: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Despite maximal cytoreductive surgery followed by chemoradiotherapy the prognosis is still poor. Although surgery and radiotherapy may have reached maximal effectiveness, chemotherapy has the potential to improve survival. The aim of this study was to evaluate in vitro the antitumor efficacy of tamoxifen (TAM), raloxifen (RAL), pyrimethamine (PYR) and alphanizomenon flos-aquae (AFA) in combination with temozolomide (TMZ) plus ionizing radiation against cultured glioblastoma stem-like cells and primary glioblastoma cells , as possible way to increase the treatment options in patients with therapy-refractory GBM.
METHODS: Stem-like tumor cells and glioblastoma cells isolated from two GBM biopsies were established by cell proliferation assays. TAM, RAL, PYR and AFA were added prior to TMZ and ionizing irradiation.
RESULTS: All tested drugs enhanced the cytotoxic effect of TMZ and sensitized cancer cells to radiotherapy as demonstrated by MTT assay and different staining reagents (TMRE, Hoechst dye and Annexin V) used for monitoring of several events in apoptosis.
CONCLUSION: The administration of certain selective estrogen receptor modulators (SERMs) (TAM and RAL), PYR and AFA before conventional postoperative chemo radiotherapy for glioblastoma might increase therapy efficiency compared to standard oncological treatment. These results need to be extended in vivo on laboratory animals in order to test the encouraging results obtained in vitro.

Fang BJ, Geng FY, Lu FQ, et al.
Expression and clinical significance of nestin in astrocytic tumors.
J BUON. 2016 Jan-Feb; 21(1):191-8 [PubMed] Related Publications
PURPOSE: This study aimed to investigate the expression and clinical significance of nestin in human astrocytic tumors.
METHODS: Indirect immunofluorescent staining and flow cytometry were used to quantitatively detect the nestin content in 35 specimens, including 3 normal brain tissues, 29 astrocytic tumor (AT) tissues, and 3 peritumoral tissues.
RESULTS: In normal brain tissues, nestin expression was extremely low. Nestin expression was significantly positively correlated with the histological grade of astrocytic tumors (p<0.05, rs=0.83). Nestin content in the peritumoral tissues was between the levels of nestin in tumor tissue and in normal brain tissue (p<0.01). Nestin expression was unrelated to the patient's gender, age, tumor location, size, etc. (p>0.05).
CONCLUSION: The application of flow cytometry in the determination of nestin content could improve the accuracy of early cancer diagnosis. This method would be helpful for developing a reference range that is closely related to the pathological grading of ATs through routine assessments of nestin in many patients. Additionally, through examining nestin levels in peritumoral tissues, the invasiveness of ATs can be clarified.

Li HG, Chen JX, Xiong JH, Zhu JW
Myricetin exhibits anti-glioma potential by inducing mitochondrial-mediated apoptosis, cell cycle arrest, inhibition of cell migration and ROS generation.
J BUON. 2016 Jan-Feb; 21(1):182-90 [PubMed] Related Publications
PURPOSE: To study the antiproliferative effects of myricetin in human glioma U251 cells together with assessing its effects on cell cycle, apoptosis, apoptosis-related proteins, reactive oxygen species (ROS) generation and cell migration.
METHODS: Cell viability of human glioma cells after myricetin treatment was assessed by MTT assay. Phase-contrast and confocal fluorescence microscopies were used to assess the morphological changes that occured in these cells following myricetin treatment. Flow cytometry using propidium iodide (PI) and Annexin-V FITC as probes was employed to evaluate the effects on cell cycle arrest and apoptosis induction, respectively. The effect of myricetin on intracellular ROS production was measured by flow cytometry with a fluorescent probe CM-DCFH2-DA.
RESULTS: Myricetin induced a dose-dependent as well as time-dependent growth inhibitory effect in U251 human glioma cells. Myricetin treatment resulted in U251 cells detachment from adjacent cells making clusters of cells floating in the medium. Detached cells had irregular shape and incapable to maintain their membranes intact. Apoptotic cell death was induced by myricetin treatment as witnessed by fluorescence microscopy. The percentage of early and late apoptotic cells increased from 0.41% and 8.2% to 23.1% and 10.2%, 25.2% and 19.4%, to finally 36.2% and 28.4% after treatment with 15 μM, 60 μM and 120 μM of myricetin, respectively. We also observed a dose-dependent increase in Bax and Bad levels and a dose-dependent decrease in Bcl-2 and Bcl-xl expression levels following myricetin treatment. Cell cycle arrest in G2/M phase of the cell cycle was also induced by the drug treatment. A concentration-dependent ROS generation was also witnessed and a 3-fold increase of ROS production was seen after 60 μM myricetin treatment.
CONCLUSION: Myricetin exerts anticancer effects in U251 human glioma cells by inducing mitochondrial-mediated apoptosis, G2/M phase cell cycle arrest, ROS generation and inhibition of cell migration.

Buckner JC, Shaw EG, Pugh SL, et al.
Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma.
N Engl J Med. 2016; 374(14):1344-55 [PubMed] Related Publications
BACKGROUND: Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results.
METHODS: We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy.
RESULTS: A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival.
CONCLUSIONS: In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.).

Marcu-Malina V, Garelick D, Peshes-Yeloz N, et al.
Peripheral blood-derived, γ9δ2 t cell-enriched cell lines from glioblastoma multiforme patients exert anti-tumoral effects in vitro.
J Biol Regul Homeost Agents. 2016 Jan-Mar; 30(1):17-30 [PubMed] Related Publications
The goal of this work was to assess the potential of T cells expressing Vγ9Vδ2+ T cell receptors (TCR, γ9δ2T cells) present in peripheral blood (PB) m ononuclear cells (MC, PBMC) of glioblastoma multiforme (GBM) patients to act as anti-tumoral agents. We found that γ9δ2T cell levels were decreased in patients' PB relative to a cohort of healthy donors (HD) (respectively 0.52±0.55%, n=16, vs 1.12±0.6%, n=14, p=0.008) but did not significantly correlate with postoperative survival (R=0.6, p=0.063). Importantly, however, the γ9δ2T cells could be expanded in vitro to consist 51±23% of the cultured lymphocytes (98% CD3+). This was achieved after 14 days of culture in medium containing the amino-bisphosphonate (ABP) Zoledronate (Zol) and interleukin (IL)-2, resulting in γ9δ2T cell-enriched lines (gdTCEL) similar to those of HD derived gdTCEL (54±19%). Moreover, gdTCEL from patients and HD mediated cytotoxicity to GBM-derived cell lines (GBMDCL), which was abrogated by immune-magnetic removal of the γ9δ2T cells. Furthermore, low level interferon (IFN) γ secretion was induced by gdTCEL briefly co-cultured with GBMDCL or autologous - tumor-derived cells, which was greatly amplified in the presence of Zol. Importantly, IFNγ secretion was inhibited by mevastatin but enhanced by cross-linking of butyrophilin 3A1 (CD277) on a CD277+ GBMDCL (U251MG) or by pretreatment of GBMDCL with temozolomide (TMZ). Taken together, these data suggest that γ9δ2T cells in PB of GBM patients can give rise to gdTCEL that mediate anti-tumoral activities.

Stojsavljević M, Tasić G, Nikolić I, et al.
Acta Clin Croat. 2015; 54(4):402-8 [PubMed] Related Publications
The verified presence of a glioblastoma multiforme (GBM) tumor in the motor area of the brain, in a patient lacking preoperative neurological deficit, offers no certainty that the tumor can be radically removed without the possibility of causing postoperative motor deficit. We present a series of 60 patients hospitalized at the Clinical Department of Neurosurgery, Clinical Center of Serbia in Belgrade between October 2011 and February 2015, harboring tumors located within and in the vicinity of the motor zone of the brain. By using Karnofsky's index (KI), the pre- and postoperative conditions of the patients were evaluated. Regarding electrical stimulation of the motor cortex, significantly lower values of the electrical current intensity, frequency, and pulse wave duration (p < 0.01) were needed for triggering motor response in case of GBM tumor compared to a slowly growing tumor (low-grade). Patients with low-grade gliomas (LGG) had statistically significantly higher KI values pre- and postoperatively than patients with GBM (p < 0.01). Using electrical stimulation of the cortex, a higher grade of resection of LGG could be achieved as compared with the group presenting with GBM (χ² = 5.281; df = 1; p < 0.05). Our findings and review of the results reported by other authors underline the necessity of routine application of electrical stimulation of the cerebral cortex in order to identify the primary motor field (M1).

Chow DS, Horenstein CI, Canoll P, et al.
Glioblastoma Induces Vascular Dysregulation in Nonenhancing Peritumoral Regions in Humans.
AJR Am J Roentgenol. 2016; 206(5):1073-81 [PubMed] Related Publications
OBJECTIVE: Glioblastoma is an invasive primary brain malignancy that typically infiltrates the surrounding tissue with malignant cells. It disrupts cerebral blood flow through a variety of biomechanical and biochemical mechanisms. Thus, neuroimaging focused on identifying regions of vascular dysregulation may reveal a marker of tumor spread. The purpose of this study was to use blood oxygenation level-dependent (BOLD) functional MRI (fMRI) to compare the temporal dynamics of the enhancing portion of a tumor with those of brain regions without apparent tumors.
MATERIALS AND METHODS: Patients with pathologically proven glioblastoma underwent preoperative resting-state BOLD fMRI, T1-weighted contrast-enhanced MRI, and FLAIR MRI. The contralesional control hemisphere, contrast-enhancing tumor, and peritu-moral edema were segmented by use of structural images and were used to extract the time series of these respective regions. The parameter estimates (beta values) for the two regressors and resulting z-statistic images were used as a metric to compare the similarity of the tumor dynamics to those of other brain regions.
RESULTS: The time course of the contrast-enhancing tumor was significantly different from that of the rest of the brain (p < 0.05). Similarly, the control signal intensity was significantly different from the tumor signal intensity (p < 0.05). Notably, the temporal dynamics in the peritumoral edema, which did not contain enhancing tumor, were most similar to the those of enhancing tumor than to those of control regions.
CONCLUSION: The findings show that the disruption in vascular regulation induced by a glioblastoma can be detected with BOLD fMRI and that the spatial distribution of these disruptions is localized to the immediate vicinity of the tumor and peritumoral edema.

Junaid M, Asheen A, Ur Rehman M, et al.
J Ayub Med Coll Abbottabad. 2015 Oct-Dec; 27(4):869-73 [PubMed] Related Publications
BACKGROUND: Tumours of the spinal cord, spinal meninges and cauda equina are relatively rare and their spectrum has not been studied extensively in Khyber Pakhtun Khawa province. We describe here the cases of spinal tumours treated in our setup over a period of two years.
METHODS: This Descriptive Case Series was carried out with of 80 patients operated in our centre from January 2013 to January 2015. The clinical presentation of these tumours as well as demographic findings was analysed. Patients who underwent surgery for their tumours were included in the study. Patients were selected for surgery depending on their radiological and clinical findings. Lesions that were suggestive of metastasis were biopsied and further care was shared between specialized departments depending on the primary source.
RESULTS: Male to female ratio was 1.5:1. Most of the spinal tumours were secondary tumours while meningiomas were the most common primary tumours. Most commonly patients belonged to young age group A (below 30 years.) 32.5%. Most common presentation was with paraparesis (27.5%) and paralysis (25%). A majority of patients regained good neurological function and did not show signs of recurrence at 1 year follow up.
CONCLUSION: Given the limited experience at our centre, we believe that a wide range of spinal tumours can be successfully treated provided that clinical end points are kept in mind and treatment is individualized. Frankel grading is useful to assess surgical outcome in the patients.

Czernicki T, Kunert P, Nowak A, et al.
Epidermoid cysts of the cerebellopontine angle: Clinical features and treatment outcomes.
Neurol Neurochir Pol. 2016; 50(2):75-82 [PubMed] Related Publications
OBJECTIVE: To report clinical characteristics, treatment outcomes and risk of recurrence in patients with surgically treated cerebellopontine angle epidermoids.
METHODS: In 1994-2013, we operated 17 patients, including 7 with tumor limited to the cerebellopontine angle, 7 with cerebellopontine angle tumor penetrating supratentorially, and 3 with cerebellopontine angle tumor extending along skull base to contralateral cerebellopontine angle. All patients were followed-up for the mean duration of 126 months.
RESULTS: On admission cranial nerve symptoms predominated. Total tumor removal was achieved in 5 patients, and incomplete removal (with small tumor remnants left on vessels, nerves, or brainstem) in 12 patients. Postoperatively, preoperative deficits worsened in 2 and new postoperative deficits occurred in 10 patients. The extent of tumor expansion had no effect on postoperative morbidity and risk of recurrence. During long-term follow-up, improvement or resolution of preoperative deficits was seen in 11 of 17 patients, and new postoperative deficits in 8 of 10 patients. Symptomatic recurrences after an average of more than 9 years were noted in 5 patients, 3 of whom were reoperated. Recurrences occurred in some younger patients and always in area of primary tumor. No effect of extent of tumor removal on risk of recurrence was found.
CONCLUSIONS: The extent of tumor removal had no effect on the risk of recurrence, and thus it may be acceptable to leave tumor capsule fragments adhering closely to nerves, vessels, or brainstem. During long-term follow-up, resolution or improvement of present preoperatively and new postoperative neurological deficits may be expected in most patients.

Matsumoto S, Koba Y, Kohno R, et al.
Secondary Neutron Doses to Pediatric Patients During Intracranial Proton Therapy: Monte Carlo Simulation of the Neutron Energy Spectrum and its Organ Doses.
Health Phys. 2016; 110(4):380-6 [PubMed] Related Publications
Proton therapy has the physical advantage of a Bragg peak that can provide a better dose distribution than conventional x-ray therapy. However, radiation exposure of normal tissues cannot be ignored because it is likely to increase the risk of secondary cancer. Evaluating secondary neutrons generated by the interaction of the proton beam with the treatment beam-line structure is necessary; thus, performing the optimization of radiation protection in proton therapy is required. In this research, the organ dose and energy spectrum were calculated from secondary neutrons using Monte Carlo simulations. The Monte Carlo code known as the Particle and Heavy Ion Transport code System (PHITS) was used to simulate the transport proton and its interaction with the treatment beam-line structure that modeled the double scattering body of the treatment nozzle at the National Cancer Center Hospital East. The doses of the organs in a hybrid computational phantom simulating a 5-y-old boy were calculated. In general, secondary neutron doses were found to decrease with increasing distance to the treatment field. Secondary neutron energy spectra were characterized by incident neutrons with three energy peaks: 1×10, 1, and 100 MeV. A block collimator and a patient collimator contributed significantly to organ doses. In particular, the secondary neutrons from the patient collimator were 30 times higher than those from the first scatter. These results suggested that proactive protection will be required in the design of the treatment beam-line structures and that organ doses from secondary neutrons may be able to be reduced.

Puls T
Incidental findings of a Vestibular Schwannoma on Brain MRI.
B-ENT. 2015; 11(4):309-12 [PubMed] Related Publications
Brain magnetic resonance imaging (MRI) is the gold standard for diagnosing a vestibular schwannoma (VS). The prevalence of VS ranges from 0.02-2.4%; the incidence is 20 per million per year. This case report describes two cases of VS identified on brain MRIs that were not related to the purpose of the MRI examination. A literature search was performed to find existing audiometric-based protocols for guiding MRI referrals. Asymmetric sensorineural hearing loss appeared to be the most important indication for excluding VS. However, no consensus was found on the significance of asymmetry or on the severity required to exclude VS. In light of the current absence of a reliable audiometric-based protocol for MRI referral, it seems reasonable to refer every patient with audiovestibular symptoms for a brain MRI, despite the view that the low number of incidental findings may not justify the additional cost.

Kaczmarska-Turek D, Bartnik P, Kacperczyk J, et al.
Toxic epidermal necrolysis in patient with malignant astrocytoma.
Pol Merkur Lekarski. 2016; 40(235):25-7 [PubMed] Related Publications
UNLABELLED: Toxic epidermal necrolysis (TEN) is a severe, life-threatening mucocutaneus adverse reaction, most commonly triggered by medication. Treatment in some aspects is still controversial.
CASE REPORT: Patient with malignant astrocytoma, treated with palliative radiotherapy, developed massive erythema with bullae. Patient suffered from tumor-related epilepsy, treated pharmacologically with carbamazepine. After dermatological consultation TEN was diagnosed. The bacterial growth tests from blood were Staphylococci positive. An antibiotic therapy was performed and carbamazepine was withdrawn. Cyclosporine was administered. After 2 weeks of treatment, skin changes vanished and patient's condition improved. TEN could not be omitted in diagnosis of extensive skin changes because the causative drug removal is crucial for survival and pharmacological treatment varies in similar conditions. TEN as a drug-related disease more likely occurs in severely ill patients.

Kong X, Guan J, Ma W, et al.
CD34 Over-Expression is Associated With Gliomas' Higher WHO Grade.
Medicine (Baltimore). 2016; 95(7):e2830 [PubMed] Related Publications
CD34 is a transmembrane phosphoglycoprotein that was first identified on hematopoietic stem and progenitor cells. CD34 is known as an optimum marker for microvascular density studies and it is positively stained in pathological and physiologic vessels. The use of CD34 for the prognosis, diagnosis, and treatment of neoplasms has been increasingly discussed. The implications and utilities of CD34 in WHO grades of gliomas and its prognosis have been reported rarely. Also, the WHO grades and prognosis researches remains unclear and controversial. A meta-analysis is the best choice for drawing a convincing conclusion. Several databases were searched. We carefully assess the relevant articles and standard mean differences (SMDs) with 95% confidence intervals (95% CIs) were estimated in terms of the relationship between CD34 expression levels with gliomas' WHO grades, patients' ages and gender. We used the Galbraith figure, the I test, and Cochran Q test to evaluate the heterogeneity of the included studies. A sensitivity analysis was conducted to assess the pooled results' stability. A Contour-enhanced funnel plot evaluation was made to assess potential publication bias. Ethics review and approval was not necessary because the meta-analysis did not involve any direct human trials or animal experiments. There were 12 eligible studies, including 684 patients who were considered in the present meta-analysis. All of them were conducted in China. CD34 overexpression in glioma tissues was associated closely, according to the pooled SMD, with higher WHO grade (III + IV) (SMD -1.503, 95% CI -1.685 to -1.321; P = 0.000). There were no significant associations between CD34 and age (SMD -0.223, 95% CI -0.602 to 0.156; P = 0.248) and CD34 and gender (SMD -0.059, 95% CI -0.439, 0.321; P = 0.761). No publication bias was detected according to Contour-enhanced funnel plot. Our results suggested that CD34 overexpression is associated with higher WHO grades of gliomas. CD34 may serve as a potential diagnostic and prognostic marker, or it could be a useful therapy target.

Kristensen LS, Michaelsen SR, Dyrbye H, et al.
Assessment of Quantitative and Allelic MGMT Methylation Patterns as a Prognostic Marker in Glioblastoma.
J Neuropathol Exp Neurol. 2016; 75(3):246-55 [PubMed] Related Publications
Methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is a predictive and prognostic marker in newly diagnosed glioblastoma patients treated with temozolomide but how MGMT methylation should be assessed to ensure optimal detection accuracy is debated. We developed a novel quantitative methylation-specific PCR (qMSP) MGMT assay capable of providing allelic methylation data and analyzed 151 glioblastomas from patients receiving standard of care treatment (Stupp protocol). The samples were also analyzed by immunohistochemistry (IHC), standard bisulfite pyrosequencing, and genotyped for the rs1690252 MGMT promoter single nucleotide polymorphism. Monoallelic methylation was observed more frequently than biallelic methylation, and some cases with monoallelic methylation expressed the MGMT protein whereas others did not. The presence of MGMT methylation was associated with better overall survival (p = 0.006; qMSP and p = 0.002; standard pyrosequencing), and the presence of the protein was associated with worse overall survival (p = 0.009). Combined analyses of qMSP and standard pyrosequencing or IHC identified additional patients who benefited from temozolomide treatment. Finally, low methylation levels were also associated with better overall survival (p = 0.061; qMSP and p = 0.02; standard pyrosequencing). These data support the use of both MGMT methylation and MGMT IHC but not allelic methylation data as prognostic markers in patients with temozolomide-treated glioblastoma.

Fritchie KJ, Jin L, Rubin BP, et al.
NAB2-STAT6 Gene Fusion in Meningeal Hemangiopericytoma and Solitary Fibrous Tumor.
J Neuropathol Exp Neurol. 2016; 75(3):263-71 [PubMed] Related Publications
Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are considered to be distinct entities in the WHO Classification of CNS Tumours (2007). They harbor NAB2-STAT6 fusions similar to their soft tissue counterparts, supporting the view that they are part of a tumor continuum. We examined 30 meningeal-based tumors originally diagnosed as either SFT or HPC. These showed a spectrum of morphologic features and were diagnosed as SFTs, malignant SFTs, HPCs, or tumors with "intermediate" features. All of the tumors showed nuclear expression of STAT6. SFTs consistently expressed diffuse CD34, while HPCs and intermediate tumors had heterogeneous staining. NAB2-STAT6 fusions were identified in 20 cases, including 7 with exon 4-exon 3, 9 with exon 6-exon 17, and 4 with exon 6-exon 18 fusions. NAB2 exon 4-STAT6 exon 3 fusion correlated with classic SFT morphology and older age and showed a trend toward less mitotic activity; there was also a trend toward more aggressive behavior in tumors lacking NAB2 exon 4-STAT6 exon 3. Thus, despite their clinical and morphologic differences, meningeal-based SFTs, HPCs, and tumors with intermediate features, similar to their soft tissue counterparts, form a histopathologic spectrum unified by STAT6 immunoexpression and NAB2-STAT6 fusion.

Chung SR, Choi YJ, Kim HS, et al.
Tumor Vascular Permeability Pattern Is Associated With Complete Response in Immunocompetent Patients With Newly Diagnosed Primary Central Nervous System Lymphoma: Retrospective Cohort Study.
Medicine (Baltimore). 2016; 95(6):e2624 [PubMed] Free Access to Full Article Related Publications
A dynamic contrast-enhanced MR imaging (DCE-MRI) could provide the information about tumor drug delivery efficacy. We investigated the potential utility of the permeability pattern of DCE-MRI for predicting tumor response to high dose-methotrexate treatment and progression-free survival (PFS) in patients with primary CNS lymphoma (PCNSL). Clinical and conventional imaging parameters were assessed as potential predictors of tumor response in 48 immunocompetent PCNSL patients in a preliminary study. Fifty additional immunocompetent patients (27 men and 23 women; mean age, 60.6 years) with PCNSL underwent DCE-MRI before starting first-line treatment with high dose-methotrexate. The DCE-MRI pattern was categorized as diffuse or nondiffuse. After 4 courses of high dose methotrexate, patients underwent follow-up brain MR imaging to identify their complete response (CR). Predictors of CR and PFS were analyzed using clinical parameters, conventional MRI, and DCE-MRI. CR was noted in 20 (74.1%) of 27 patients with diffuse DCE-MRI pattern and in 4 (17.4%) of 23 patients with nondiffuse DCE-MRI pattern. The diffuse DCE-MRI pattern showed a significantly higher association with CR than the nondiffuse pattern (P < 0.001). Multivariate Cox proportional hazards model revealed that the DCE-MRI pattern (hazard ratio = 0.70; P = 0.045), age (hazard ratio = 1.47; P = 0.041), and adjuvant autologous stem-cell transplantation (hazard ratio = 6.97; P = 0.003) tended to be associated with a PFS. The pretreatment diffuse DCE-MRI pattern can be used as a potential imaging biomarker for predicting CR and a longer PFS in patients with newly diagnosed PCNSLs.

Johnson MD, Avkshtol V, Baschnagel AM, et al.
Surgical Resection of Brain Metastases and the Risk of Leptomeningeal Recurrence in Patients Treated With Stereotactic Radiosurgery.
Int J Radiat Oncol Biol Phys. 2016; 94(3):537-43 [PubMed] Related Publications
PURPOSE: Recent prospective data have shown that patients with solitary or oligometastatic disease to the brain may be treated with upfront stereotactic radiosurgery (SRS) with deferral of whole-brain radiation therapy (WBRT). This has been extrapolated to the treatment of patients with resected lesions. The aim of this study was to assess the risk of leptomeningeal disease (LMD) in patients treated with SRS to the postsurgical resection cavity for brain metastases compared with patients treated with SRS to intact metastases.
METHODS AND MATERIALS: Four hundred sixty-five patients treated with SRS without upfront WBRT at a single institution were identified; 330 of these with at least 3 months' follow-up were included in this analysis. One hundred twelve patients had undergone surgical resection of at least 1 lesion before SRS compared with 218 treated for intact metastases. Time to LMD and overall survival (OS) time were estimated from date of radiosurgery, and LMD was analyzed by the use of cumulative incidence method with death as a competing risk. Univariate and multivariate analyses were performed with competing risk regression to determine whether various clinical factors predicted for LMD.
RESULTS: With a median follow-up time of 9.0 months, 39 patients (12%) experienced LMD at a median of 6.0 months after SRS. At 1 year, the cumulative incidence of LMD, with death as a competing risk, was 5.2% for the patients without surgical resection versus 16.9% for those treated with surgery (Gray test, P<.01). On multivariate analysis, prior surgical resection (P<.01) and breast cancer primary (P=.03) were significant predictors of LMD development. The median OS times for patients undergoing surgery compared with SRS alone were 12.9 and 10.6 months, respectively (log-rank P=.06).
CONCLUSIONS: In patients undergoing SRS with deferral of upfront WBRT for intracranial metastatic disease, prior surgical resection and breast cancer primary are associated with an increased risk for the development of LMD.

Gao F, Guo R, Hu XJ, et al.
Noninvasive Tumor Grading of Glioblastomas Before Surgery Using Arterial Spin Labeling. A Cohort Study.
Anal Quant Cytopathol Histpathol. 2015; 37(6):339-46 [PubMed] Related Publications
OBJECTIVE: To assess the clinical value of using arterial spin labeling (ASL) technique preoperatively for non-invasive tumor grading in glioblastoma (GBM) patients.
STUDY DESIGN: Forty-nine patients with GBMs were selected, including 21 patients with high-grade gliomas and 28 patients with low-grade gliomas. ASL perfusion imaging was performed with GE Signa Excite HD 3.0 T MR scanning system (GE Healthcare). Relative cerebral blood flow (rCBF) and relative tumor blood flow (rTBF) were quantified in all patients. Statistical analysis was performed with STATA version 12.0 software. Further, relevant human cohort studies published in Chinese and English languages were identified by database searches and screened. Data was extracted and meta-analysis was performed using Comprehensive Meta-analysis version 2.0 software.
RESULTS: The ratios of rTBF to rCBF in the contralateral white matter, contralateral gray matter, and contralateral hemisphere of high-grade gliomas were higher than low-grade gliomas (all p < 0.05). ASL results in the solid tumors revealed that rCBF was greater in high-grade gliomas. Such differences in rCBF were not significant (p > 0.05) when 2 and 5 cm distances from tumor margin were compared. Importantly, rCBF values showed statistical differences when the 2 cm distance was compared with the 5 cm distance from tumor margin (all p < 0.05). Finally, meta-analysis results supported the conclusion that rCBF and rTBF values were significantly higher in high-grade GBM as compared to low-grade GBM.
CONCLUSION: We present convincing data that ASL is highly effective in differentiating between high-grade and low-grade gliomas, and thus is a useful tool for preoperative evaluation of GBM.

Kim SH, Ezhilarasan R, Phillips E, et al.
Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner.
Cancer Cell. 2016; 29(2):201-13 [PubMed] Article available free on PMC after 08/02/2017 Related Publications
Activation of nuclear factor κB (NF-κB) induces mesenchymal (MES) transdifferentiation and radioresistance in glioma stem cells (GSCs), but molecular mechanisms for NF-κB activation in GSCs are currently unknown. Here, we report that mixed lineage kinase 4 (MLK4) is overexpressed in MES but not proneural (PN) GSCs. Silencing MLK4 suppresses self-renewal, motility, tumorigenesis, and radioresistance of MES GSCs via a loss of the MES signature. MLK4 binds and phosphorylates the NF-κB regulator IKKα, leading to activation of NF-κB signaling in GSCs. MLK4 expression is inversely correlated with patient prognosis in MES, but not PN high-grade gliomas. Collectively, our results uncover MLK4 as an upstream regulator of NF-κB signaling and a potential molecular target for the MES subtype of glioblastomas.

Ramaswamy V, Taylor MD
Fall of the Optical Wall: Freedom from the Tyranny of the Microscope Improves Glioma Risk Stratification.
Cancer Cell. 2016; 29(2):137-8 [PubMed] Related Publications
A recent study uses an integrated genomic approach to identify biologically defined subgroups of adult diffuse glioma. These results further lay the foundation for a pathological classification scheme for gliomas that incorporates both histology and molecular biomarkers, which appears far more robust than the current scheme, based solely on morphology.

Zhang CG, Huang JC, Liu T, Li XY
Anticancer effects of bishydroxycoumarin are mediated through apoptosis induction, cell migration inhibition and cell cycle arrest in human glioma cells.
J BUON. 2015 Nov-Dec; 20(6):1592-600 [PubMed] Related Publications
PURPOSE: To evaluate the cytotoxic and apoptotic effects of bishydroxycoumarin (BHC) against human glioma cells and to study their mode of action.
METHODS: Three cells were used in the experiments. MTT and LDH assays were used to assess the cytotoxic effects of BHC while an in vitro wound healing assay was used to study the effect of BHC on cell migration. Fluorescence microscopy and annexin V-FITC assay were used to study the cellular morphology and apoptotic effects while flow cytometry in combination with propidium iodide (PI) were used to study cell cycle arrest induced by BHC.
RESULTS: BHC induced substantial and dose-dependent cytotoxic effects against all three cell lines with U87MG cell line being most susceptible. BHC also inhibited cell migration and induced characteristic morphological changes including chromatin condensation, nuclear shrinkage which increased with increasing dose of BHC. The apoptotic cell population (both early and late apoptotic cells) increased with increasing dose of BHC which also induced substantial G0/G1 cell cycle growth arrest in U87MG cells.
CONCLUSION: This study provides help to elucidate the translational potential of the in vitro results to be used for further in vivo studies on human glioma using animal or human subjects. The mechanistic pathway studied in this report could be helpful in explaining the mode of action of these classes of natural products.

Kim MM, Camelo-Piragua S, Schipper M, et al.
Gemcitabine Plus Radiation Therapy for High-Grade Glioma: Long-Term Results of a Phase 1 Dose-Escalation Study.
Int J Radiat Oncol Biol Phys. 2016; 94(2):305-11 [PubMed] Article available free on PMC after 01/02/2017 Related Publications
PURPOSE: To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG).
PATIENTS AND METHODS: Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m(2) during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity.
RESULTS: Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m(2)/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen.
CONCLUSIONS: Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG.

Karunamuni R, Bartsch H, White NS, et al.
Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma.
Int J Radiat Oncol Biol Phys. 2016; 94(2):297-304 [PubMed] Article available free on PMC after 01/02/2017 Related Publications
PURPOSE: Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients.
METHODS AND MATERIALS: We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thickness between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling.
RESULTS: Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by -0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness.
CONCLUSIONS: We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.

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