Research and Clinical Trials News

Research and Clinical Trials News

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Metabolic molecule drives growth of aggressive brain cancer

  • Wednesday, 10 July 2013 20:36

COLUMBUS, Ohio – A study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has identified an abnormal metabolic pathway that drives cancer-cell growth in a particular glioblastoma subtype. The finding might lead to new therapies for a subset of patients with glioblastoma, the most common and lethal form of brain cancer.

The physician scientists sought to identify glioblastoma subtype-specific cancer stem cells. Genetic analyses have shown that high-grade gliomas can be divided into four subtypes: proneural, neural, classic and mesenchymal.

This study shows that the mesenchymal subtype is the most aggressive subtype, that it has the poorest Prognosis among affected patients, and that cancer stem cells isolated from the mesenchymal subtype have significantly higher levels of the enzyme ALDH1A3 compared with the proneural subtype.

The findings, published recently in the Proceedings of the National Academy of Sciences, show that high levels of the enzyme drive Tumor growth.

"Our study suggests that ALDH1A3 is a potentially functional biomarker for mesenchymal Glioma stem cells, and that inhibiting that enzyme might offer a promising therapeutic approach for high-grade gliomas that have a mesenchymal signature," says principal investigator Ichiro Nakano, MD, PhD, associate professor of neurosurgery at the OSUCCC – James. "This indicates that therapies for high-grade gliomas should be personalized, that is, based on the tumor subtype instead of applying one treatment to all patients," he says.

The National Cancer Institute estimates that 23,130 Americans will be diagnosed with brain and other nervous system tumors in 2013, and that 14,000 people will die of these malignancies. Glioblastoma accounts for about 15 percent of all brain tumors, is resistant to current therapies and has a survival as short as 15 months after diagnosis.

Little is known, however, about the metabolic pathways that drive the growth of individual glioblastoma subtypes – knowledge that is crucial for developing novel and effective targeted therapies that might improve treatment for these lethal tumors.

For this study, Nakano and his collaborators used cancer cells from 40 patients with high-grade gliomas, focusing on tumor cells with a stem-cell signature. The researchers then used microarray analysis and pre-clinical animal assays to identify two predominant glioblastoma subtypes, proneural and mesenchymal.

Key technical findings include:

  • Genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, were significantly up-regulated in mesenchymal glioma stem cells compared to proneural stem cells;
  • Mesenchymal glioma stem cells show significantly higher radiation resistance and high expression of DNA-repair genes;
  • Radiation induces transformation of proneural glioma stem cells into mesenchymal-like glioma stem cells that are highly resistant to radiation treatment; inhibiting the ALDH1 pathway reverses this resistance.
  • Inhibiting ALDH1A3-mediated pathways slows the growth of mesenchymal glioma stem cells and might provide a promising therapeutic approach for glioblastomas with a mesenchymal signature.

"Overall, our data suggest that a novel signaling mechanism underlies the transformation of proneural glioma stem cells to mesenchymal-like cells and their maintenance as stem-like cells," Nakano says. Currently, their discoveries are in provision patent application, led by the Technology Licensing Office at University of Pittsburgh.

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Funding from the American Cancer Society, the NIH/National Cancer Institute (CA135013, CA130966, CA158911, CA148629, CA047904); the NIH/National Institute of General Medical Sciences (GM087798, GM099213); NIH/National Institute of Neurological Disorders and Stroke (NS037704); NIH/National Institute of Environmental Health Sciences (ES019498); NIH/National Library of Medicine (LM009657); NIH/National Center for Research Resources (RR024153); the James S. McDonnell Foundation; the Zell Family Foundation; the Northwestern Brain Tumor Institute; the National Research Foundation of Korea; and the China Scholarship Council supported this research.

Other researchers involved in this study were Ping Mao, Kaushal Joshi, Sung-Hak Kim, Peipei Li and Luke Smith, The Ohio State University; Lucas Santana-Santos, Soumya Luthra, Uma R. Chandran, Panayiotis V. Benos, Jianfeng Li and Robert W. Sobol, the University of Pittsburgh; Maode Wang, Xi'an Jiaotong University, China; and Bo Hu and Shi-Yuan Cheng, Korea University, Republic of Korea.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S. News & World Report.

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Sugar makes cancer light-up in MRI scanners

  • Wednesday, 10 July 2013 20:31

IMAGE: UCL scientists have developed a new technique for detecting the uptake of sugar in tumors, using magnetic resonance imaging.

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A new technique for detecting Cancer by imaging the consumption of sugar with magnetic resonance imaging ( MRI) has been unveiled by UCL scientists. The breakthrough could provide a safer and simpler alternative to standard radioactive techniques and enable radiologists to image tumours in greater detail.

The new technique, called 'glucose chemical exchange saturation transfer' (glucoCEST), is based on the fact that tumours consume much more glucose (a type of sugar) than normal, healthy tissues in order to sustain their growth.

The researchers found that sensitising an MRI scanner to glucose uptake caused tumours to appear as bright images on MRI scans of mice.

Lead researcher Dr Simon Walker-Samuel, from the UCL Centre for Advanced Biomedical Imaging (CABI) said: "GlucoCEST uses radio waves to magnetically label glucose in the body. This can then be detected in tumours using conventional MRI techniques. The method uses an injection of normal sugar and could offer a cheap, safe alternative to existing methods for detecting tumours, which require the injection of radioactive material." Professor Mark Lythgoe, Director of CABI and a senior author on the study, said: "We can detect cancer using the same sugar content found in half a standard sized chocolate bar. Our research reveals a useful and cost-effective method for imaging cancers using MRI – a standard imaging technology available in many large hospitals."

IMAGE: Tumors use large quantities of glucose to sustain their growth. By injecting normal, unlabeled sugar, UCL scientists have developed a way to detect its accumulation in tumors using magnetic resonance...

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He continued: "In the future, patients could potentially be scanned in local hospitals, rather than being referred to specialist medical centres." The study is published in the journal Nature Medicine and trials are now underway to detect glucose in human cancers.

According to UCL's Professor Xavier Golay, another senior author on the study: "Our cross-disciplinary research could allow vulnerable patient groups such as pregnant women and young children to be scanned more regularly, without the risks associated with a dose of radiation." Dr Walker-Samuel added: "We have developed a new state-of-the-art imaging technique to visualise and map the location of tumours that will hopefully enable us to assess the efficacy of novel cancer therapies."

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The work was supported by public and charitable funding from the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Cancer Research UK, Engineering and Physical Sciences Research Council (EPSRC) and the British Heart Foundation (BHF).

IMAGE: Glucose uptake varies within tumors, as demonstrated using a new technique developed by scientists at UCL. 'Hot' regions at the edge of the Tumor show increased uptake compared with 'cold'...

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Notes for editors:

1. Members of the media who would like more information, or to interview the researchers quoted, please contact David Weston UCL Media Relations Office on tel: +44 (0)20 3108 3844, out of hours: +44 (0)7917 271 364, email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

2. High resolution images are available from UCL Media Relations. Please credit UCL if used.

3. The paper "Imaging glucose uptake and metabolism in tumors" is published online ahead of print in Nature Medicine, July 7th 2013.

4. The UCL Centre for Advanced Biomedical Imaging is a new multidisciplinary research centre for experimental imaging. The Centre is built around a number of groups at UCL and brings together imaging technologies across UCL with specific applications in the biomedical sciences. Dr Simon Walker-Samuel and Professor Mark Lythgoe are affiliated to UCL Division of Medicine. Professor Xavier Golay is affiliated to the UCL Institute of Neurology.

About UCL (University College London)

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender and the first to provide systematic teaching of law, architecture and medicine.

We are among the world's top universities, as reflected by our performance in a range of international rankings and tables. According to the Thomson Scientific Citation Index, UCL is the second most highly cited European university and the 15th most highly cited in the world.

UCL has nearly 27,000 students from 150 countries and more than 9,000 employees, of whom one third are from outside the UK. The university is based in Bloomsbury in the heart of London, but also has two international campuses – UCL Australia and UCL Qatar. Our annual income is more than £800 million.

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Suspicions confirmed: Brain tumors in children have a common cause

  • Wednesday, 10 July 2013 20:25

Brain Cancer is the primary cause of cancer mortality in children. Even in cases when the cancer is cured, young patients suffer from the stress of a treatment that can be harmful to the developing brain. In a search for new target structures that would create more gentle treatments, cancer researchers are systematically analyzing all alterations in the genetic material of these tumors. This is the mission of the PedBrain consortium, which was launched in 2010. Led by Professor Stefan Pfister from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), the PedBrain researchers have now published the results of the first 96 genome analyses of pilocytic astrocytomas.

Pilocytic astrocytomas are the most common childhood brain tumors. These tumors usually grow very slowly. However, they are often difficult to access by surgery and cannot be completely removed, which means that they can recur. The disease may thus become chronic and have debilitating effects for affected children.

In previous work, teams of researchers led by Professor Dr. Stefan Pfister and Dr. David Jones had already discovered characteristic mutations in a major proportion of pilocytic astrocytomas. All of the changes involved a key cellular signaling pathway known as the MAPK signaling cascade. MAPK is an abbreviation for "mitogen-activated protein kinase." This signaling pathway comprises a cascade of phosphate group additions (phosphorylation) from one protein to the next – a universal method used by cells to transfer messages to the nucleus. MAPK signaling regulates numerous basic biological processes such as embryonic development and differentiation and the growth and death of cells.

"A couple of years ago, we had already hypothesized that pilocytic astrocytomas generally arise from a defective activation of MAPK signaling," says David Jones, first author of the publication. "However, in about one fifth of the cases we had not initially discovered these mutations. In a whole-genome analysis of 96 tumors we have now discovered activating defects in three other genes involved in the MAPK signaling pathway that have not previously been described in astrocytoma."

"Aside from MAPK mutations, we do not find any other frequent mutations that could promote cancer growth in the tumors. This is a very clear indication that overactive MAPK signals are necessary for a pilocytic astrocytoma to develop," says study director Stefan Pfister. The disease thus is a prototype for rare cancers that are based on defects in a single biological signaling process.

In total, the genomes of pilocytic astrocytomas contain far fewer mutations than are found, for example, in medulloblastomas, a much more Malignant pediatric brain Tumor. This finding is in accordance with the more benign growth behavior of astrocytomas. The number of mutations increases with the age of the affected individuals.

About one half of pilocytic astrocytomas develop in the Cerebellum, the other 50 percent in various other brain regions. Cerebellar astrocytomas are genetically even more homogenous than other cases of the disease: In 48 out of 49 cases that were studied, the researchers found fusions between the BRAF gene, a central component of the MAPK signaling pathway, and various other fusion partners.

"The most important conclusion from our results," says study director Stefan Pfister, "is that targeted agents for all pilocytic astrocytomas are potentially available to block an overactive MAPK signaling cascade at various points. We might thus in the future be able to also help children whose tumors are difficult to access by surgery."

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International collaboration in tumor genome analysis

The International Cancer Genome Consortium (ICGC), a network of scientists from currently 15 countries, aims to obtain a comprehensive description of genomic and epigenomic changes in all significant types of cancer. Germany takes part with the PedBrain Tumor Project to analyze pediatric brain tumors (medulloblastoma, which in Germany affects approximately 100 children each year; and pilocytic astrocytoma, which is diagnosed in approximately 200 children each year). Within the PedBrain Tumor Project, 300 samples of each tumor type will be analyzed, along with the same number of samples of healthy tissue from the same patients, to identify changes that are cancer-specific.

The PedBrain Tumor network consists of researchers from seven institutes led by project coordinator Peter Lichter of DKFZ. Alongside the DKFZ, participating project partners in Heidelberg are: the National Center for Tumor Diseases (NCT), Heidelberg University and the University Hospital, and the European Molecular Biology Laboratory (EMBL). In addition, scientists from Düsseldorf University Hospital and the Max Planck Institute for Molecular Genetics in Berlin have taken on tasks in the network project.

The German Cancer Aid (Deutsche Krebshilfe) provided funds of eight million Euros for PedBrain Tumor. Since July 1, 2012, the project has received another seven million Euros from the Federal Ministry of Education and Research (BMBF).

David T.W. Jones. Barbara Hutter, Natalie Jäger, Andrey Korshunov, Marcel Kool, Hans-Jörg Warnatz, Thomas Zichner, Sally R. Lambert, Marina Ryzhova, Dong Anh Khuong Quang, Adam M. Fontebasso, Adrian M. Stütz, Sonja Hutter, Marc Zuckermann, Dominik Sturm, Jan Gronych, Bärbel Lasitschka, Sabine Schmidt, Huriye Şeker-Ci1, Hendrik Witt, Marc Sultan, Meryem Ralser, Paul A. Northcott, Volker Hovestadt, Sebastian Bender, Elke Pfaff, Sebastian Stark, Damien Faury, Jeremy Schwartzentruber, Jacek Majewski, Ursula D. Weber, Marc Zapatka, Benjamin Raeder, Matthias Schlesner, Catherine L. Worth, Cynthia C. Bartholomae, Christof von Kalle, Charles D. Imbusch, Sylwester Radomski, Chris Lawerenz, Peter van Sluis, Jan Koster, Richard Volckmann, Rogier Versteeg, Hans Lehrach, Camelia Monoranu, Beate Winkler, Andreas Unterberg, Christel Herold-Mende, Till Milde, Andreas E. Kulozik, Martin Ebinger, Martin U. Schuhmann, Yoon-Jae Cho, Scott L. Pomeroy, Andreas von Deimling, Olaf Witt, Michael D. Taylor, Stephan Wolf, Matthias A. Karajannis, Charles G. Eberhart, Wolfram Scheurlen, Martin Hasselblatt, Keith L. Ligon, Mark W. Kieran, Jan O. Korbel, Marie-Laure Yaspo, Benedikt Brors, Jörg Felsberg, Guido Reifenberger, V. Peter Collins, Nada Jabado, Roland Eils, Peter Lichter and Stefan M. Pfister on behalf of the ICGC PedBrain Tumor Project: Recurrent alterations in FGFR1 and NTRK2 represent novel therapeutic targets in childhood astrocytoma. Nature Genetics (2013) DOI:10.1038/ng.2682

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 2,500 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

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Using fat to fight brain cancer

  • Wednesday, 13 March 2013 07:31

Johns Hopkins researchers use a type of stem cells from human adipose tissue to chase migrating Cancer cells

In laboratory studies, Johns Hopkins researchers say they have found that stem cells from a patient's own fat may have the potential to deliver new treatments directly into the brain after the surgical removal of a glioblastoma, the most common and aggressive form of brain Tumor.

The investigators say so-called mesenchymal stem cells (MSCs) have an unexplained ability to seek out damaged cells, such as those involved in cancer, and may provide clinicians a new tool for accessing difficult-to-reach parts of the brain where cancer cells can hide and proliferate anew. The researchers say harvesting MSCs from fat is less invasive and less expensive than getting them from bone marrow, a more commonly studied method.

Results of the Johns Hopkins proof-of-principle study are described online in the journal PLOS ONE.

"The biggest challenge in brain cancer is the migration of cancer cells. Even when we remove the tumor, some of the cells have already slipped away and are causing damage somewhere else," says study leader Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery, oncology and neuroscience at the Johns Hopkins University School of Medicine. "Building off our findings, we may be able to find a way to arm a patient's own healthy cells with the treatment needed to chase down those cancer cells and destroy them. It's truly personalized medicine."

For their test-tube experiments, Quinones-Hinojosa and his colleagues bought human MSCs derived from both fat and bone marrow, and also isolated and grew their own stem cell lines from fat removed from two patients. Comparing the three cell lines, they discovered that all proliferated, migrated, stayed alive and kept their potential as stem cells equally well.

This was an important finding, Quinones-Hinojosa says, because it suggests that a patient's own fat cells might work as well as any to create cancer-fighting cells. The MSCs, with their ability to home in on cancer cells, might be able to act as a delivery mechanism, bringing drugs, nanoparticles or some other treatment directly to the cells. Quinones-Hinojosa cautions that while further studies are under way, it will be years before human trials of MSC delivery systems can begin.

Ideally, he says, if MSCs work, a patient with a glioblastoma would have some adipose tissue (fat) removed — from any number of locations in the body — a short time before surgery. The MSCs in the fat would be drawn out and manipulated in the lab to carry drugs or other treatments. Then, after surgeons removed the brain tumor, they could deposit these treatment-armed cells into the brain in the hopes that they would seek out and destroy the cancer cells.

Currently, standard treatments for glioblastoma are Chemotherapy, radiation and surgery, but even a combination of all three rarely leads to more than 18 months of survival after diagnosis. Glioblastoma tumor cells are particularly nimble, migrating across the entire brain and establishing new tumors. This migratory capability is thought to be a key reason for the low cure rate of this tumor type.

"Essentially these MSCs are like a 'smart' device that can track cancer cells," Quinones-Hinojosa says.

Quinones-Hinojosa says it's unclear why MSCs are attracted to glioblastoma cells, but they appear to have a natural affinity for sites of damage in the body, such as a wound. MSCs, whether derived from bone marrow or fat, have been studied in animal models to treat trauma, Parkinson's disease, ALS and other diseases.

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This research was supported by the National Institutes of Health's National Institute of Neurological Disorders and Stroke (R01-NS070024), the Maryland Stem Cell Research Fund and the Howard Hughes Medical Institute.

Other Johns Hopkins researchers involved in the study include Courtney Pendleton, M.D.; Qian Li, Ph.D.; David A Chesler, M.D., Ph.D.; Kristy Yuan, M.D.; and Hugo Guerrero-Cazares, M.D., Ph.D.

For more information:

http://www.hopkinsmedicine.org/neurology_neurosurgery/experts/profiles/team_member_profile/36A35BDE9B71CB08318C8F419FD7ACB4/Alfredo_Quinones-Hinojosa

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Low T3 syndrome predicts unfavorable outcomes in surgical patients with brain tumor

  • Tuesday, 12 March 2013 20:05

Charlottesville, VA (March 12, 2013). In a study of 90 patients undergoing surgery for brain Tumor, researchers in Lithuania (Lithuanian University of Health Sciences) and the United States (University of North Carolina at Chapel Hill and Brigham & Women's Hospital, Harvard University) have discovered that the finding of low T3 (triiodothyronine) syndrome is predictive of unfavorable clinical outcomes and depressive symptoms. Details of this study are furnished in the article "Low triiodothyronine syndrome as a predictor of poor outcomes in patients undergoing brain tumor surgery: a pilot study. Clinical article," by Adomas Bunevicius, M.D., Ph.D., and colleagues, published today online, ahead of print, in the Journal of Neurosurgery.

Low T3 syndrome is a term used to describe the finding of low blood serum concentrations of T3, which can be accompanied by abnormal T4 (thyroxine) to T3 conversion and high concentrations of reverse T3 (rT3) without any obvious sign of thyroid disease. Previous reports have shown that the finding of low levels of T3 in critically ill patients and patients undergoing surgery for some disorders is widespread and associated with unfavorable clinical outcomes. To see if this was true for patients undergoing brain tumor surgery, Dr. Bunevicius and colleagues performed perioperative thyroid function tests. (Surgery is the most common treatment for brain tumors.) The researchers also examined whether there was an association between low T3 syndrome and symptoms of anxiety and depression, which in patients harboring brain tumors are common complications and are associated with poor prognoses.

The researchers evaluated thyroid function profiles in 90 patients (median age 55 years, 71% women) on the morning of brain surgery and again on the following morning. If patients were found to have a free T3 level of 3.1 picomoles per liter (pmol/L) or less, they were given a diagnosis of low T3 syndrome. The Hospital Anxiety and Depression Scale was used pre- and postoperatively to identify cases of anxiety and depression. The Glasgow Outcome Scale was used at the time of hospital discharge to determine clinical outcomes.

The researchers identified a high prevalence of low T3 syndrome in this patient cohort: 38% of patients before brain tumor surgery and 54% of patients after surgery. In a comparison of preoperative and postoperative thyroid hormone profiles, the researchers found significant decreases in the concentrations of free T3 and thyroid-stimulating hormone (TSH) as well as in the T4 to T3 conversion; they also found significant increases in the concentration of free T4 (all p < 0.001). Perioperative low T3 syndrome was associated with a five-fold increased risk of unfavorable outcome at the time of hospital discharge, compared to patients with normal T3 concentrations. A significantly increased risk of unfavorable outcome was associated with preoperative and postoperative low T3 syndrome in a univariate binary regression analysis as well as in a multivariate binary regression analysis in which adjustments were made for patient age and sex, preoperative impairments in function, histological type of brain tumor, and previous treatment for brain tumor.

There were significant improvements in postoperative scores for symptoms of depression and anxiety, when compared with scores obtained preoperatively. The researchers found a four-fold increased risk of preoperative symptoms of depression in patients with preoperative low T3 syndrome. The association between these two factors was verified in a univariate regression analysis and in a multivariate regression analysis in which adjustments were made for sociodemographic and clinical factors.

The researchers note: "this is the first study to examine perioperative thyroid axis function in patients undergoing brain tumor surgery." The primary finding of the study is that low T3 syndrome is a clear biomarker for unfavorable clinical outcomes in this patient group. Diagnosis and preoperative management of low T3 syndrome should therefore be a consideration in patients undergoing surgery for brain tumor. Adds Dr. Adomas Bunevicius, the first author, "Thyroid hormone concentrations can easily be investigated in routine clinical settings. The tests are inexpensive and readily available worldwide. Thyroid hormone concentrations can be potentially relevant for risk stratification in patients undergoing surgery for brain tumors."

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Bunevicius A, Deltuva V, Tamasauskas S, Tamasauskas A, Laws ER Jr., Bunevicius R. Low triiodothyronine syndrome as a predictor of poor outcomes in patients undergoing brain tumor surgery: a pilot study. Clinical article. Journal of Neurosurgery, published online, ahead of print, March 12, 2013; DOI: 10.3171/2013.1.JNS121696.

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