Research and Clinical Trials News

Research and Clinical Trials News

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Palisade’s NeuralTools replaces dangerous contrast dye for brain tumour scans

  • Thursday, 24 January 2013 13:43

24 January 2013, London, UK - Doctors at the Biswas X-Ray and Scan Centre use NeuralTools from Palisade to determine the pathological changes in brain tumours. The neural network tool can be deployed instead of injecting contrast dye intravenous gadolinium, which is highly toxic despite it being widely used in MRIs to enhance or discriminate brain tumours.

Gadolinium is a paramagnetic substance that has small local magnetic fields that cause a shortening of the relaxation times of the surrounding atoms ultimately improving tissue discrimination in MRI. This can give a higher or lower signal between two tissues enabling them to be better differentiated. 

However, gadolinium can cause complications for patients, and has been linked to the development of nephrogenic system fibrosis, a serious condition of the joints, skin and internal organs. Dr Biswas, a member of the Indian Radiological Association and founder of the Biswas X-Ray and Scan Centre located in Asansol, eastern India, wanted to create the enhancement to the Brain Tumour enabled by gadolinium, but without using the substance.

With neural networks analysis able to intelligently predict outcomes based on multiple pieces of input data, Palisade’s NeuralTools was the software of choice for Dr Biswas for this research. As a sophisticated neural networks tool that works directly in Microsoft Excel, NeuralTools could create accurate new predictions based on patterns in known data that were easily accessible, and simple to read.

Historical magnetic values of tissue, both brain and tumour pre and post-gadolinium injection, were used as data inputs and a neural network was designed. This predicts the signal and grey shade values of unknown tissues in four application areas: function fitting, pattern recognition, clustering and time series analysis. 

The mathematical analysis of the predicted values from the NeuralTools analysis enabled Dr Biswas to create an MRI-like image of brain lesions without the dangers of using gadolinium contrast dye.

Dr Biswas explains, “The result of this study means contrast enhancement like simulation of brain tumours can be done accurately.  Using NeuralTools, and specifically its Live Prediction feature, we have been able to stop using gadolinium, whilst the discrimination of various brain tumours pathology can still be made.”

He added, “We are delighted with NeuralTools; part of this study would simply have been impossible without it.  The live prediction function is also extremely useful, and something that has been key to the study – it provides us with very accurate data very quickly.  NeuralTools will continue to be a key element of the work we are doing here.”

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Forecasting brain tumors like a storm

  • Thursday, 24 January 2013 02:07

New method is first to predict brain Cancer outcome and quickly show if therapy is effective

CHICAGO --- The critical question shortly after a brain cancer patient starts treatment: how well is it working? But there hasn't been a good way to gauge that.

Now Northwestern Medicine researchers have developed a new method -- similar to forecasting storms with computer models -- to predict an individual patient's brain Tumor growth. This growth forecast will enable physicians to rapidly identify how well the tumor is responding to a particular therapy. The approach allows a quick pivot to a new therapy in a critical time window if the current one isn't effective.

The study is based on 33 patients with glioblastoma, the most common and aggressive form of brain cancer. The paper will be published Jan. 23 in the journal PLOS ONE.

"When a hurricane is approaching, weather models tell us where it's going," said senior author Kristin Swanson, professor and vice chair of research for neurological surgery at Northwestern University Feinberg School of Medicine. "Our brain tumor model does the same thing. We know how much and where the tumor will grow. Then we can know how much the treatment deflected that growth and directly relate that to impact on patient survival."

Swanson also is a member of the Northwestern Brain Tumor Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Maxwell Neal, lead author, is a post-doctoral researcher in bioengineering at the University of Washington.

The method will advance brain tumor treatment, Swanson said, by helping distinguish effective treatments from ineffective ones and enabling clinicians to optimize treatment plans on a patient-by-patient basis.

Muddy Zone Right After Treatment

"There is this muddy zone right after the first round of treatments when it's hard for the clinician to know whether to change therapy because she doesn't have the metrics that correlate to outcome," Swanson said. "The doctor can't yet gauge how much it helped."

If the doctor determines the treatment isn't effective, she can try a different type of treatment or help the patient enroll in a clinical trial with a new drug being tested. The information also is helpful to the patient.

"The patient wants to know the therapy is doing something for them," Swanson said. "On the flip side, if the therapy isn't helping, then it may not be worth the side affects he is enduring."

Not All Brain Tumors are the Same

Brain cancer patients are in great need of an approach to find optimal personalized treatments.

Brain tumors vary in their growth rate, shape and density but existing methods for measuring a treatment's impact ignore this variation. The methods (and thus physicians) cannot distinguish between a patient with a fast-growing tumor that responds well to treatment and a patient with a slow-growing tumor that responds poorly.

By using a personalized, patient-specific approach that accounts for tumor features such as 3-dimensional shape, density and growth rate, the new Northwestern method can make this distinction.

Is it Working? How the Model Forecasts Growth and Measures Effectiveness

To measure a treatment's effectiveness, the scientists performing the study created a unique computer model of each patient's tumor and predicted how it would grow in the absence of treatment, explained Neal.

The prediction model was based on the MRI scans that the patient received on the day of diagnosis and on the day of surgery. The difference between these two scans enabled researchers to estimate how fast the tumor was growing along with the density of tumor cells throughout the brain.

Researchers then scored the effectiveness of the patient's treatment by comparing the size of the patient's tumor after treatment to the model-predicted size if untreated.

"The study demonstrated that higher-scoring patients survived significantly longer than lower-scoring patients and their tumors took significantly longer to recur," Neal said. "The score can guide clinicians in determining the effectiveness of the therapy."

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Northwestern researchers hope to make the computer model an iPad app or offer it on a website where a clinician can simply enter a patients' MRI data to calculate the response score.

The research was supported by the National Cancer Institute of the National Institutes of Health, grants R01 CA164371, R01 NS 060752, U54 CA143970. In addition, the research was funded by the McDonnell Foundation, the Brain Tumor Funders Collaborative, the University of Washington Academic Pathology Fund, and the James D. Murray Endowed Chair.

NORTHWESTERN NEWS: www.northwestern.edu/newscenter/

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Oxygen-free energy designed to fuel brain development spurs on growth of cancer

  • Wednesday, 23 January 2013 10:44

The metabolic process which fuels the growth of many cancers has its origins in normal brain growth finds a new study published in BioMed Central's open access journal Cancer & Metabolism. Using knock-out mice the study shows that interfering with Hexokinase-2 (Hk2), an enzyme integral to glucose metabolism, reduces the aggressiveness of medulloblastoma, the most common Malignant brain Tumor in children, and allows long term survival of mice.

Most cells only convert glucose to lactate in the absence of oxygen, for example, during a short burst of intensive exercise (anaerobic glycolysis). However rapidly dividing cells, including many cancer cells, convert glucose to lactate even in the presence of oxygen (aerobic glycolysis).

Researchers from the University of North Carolina have found that Hk2 switches on aerobic glycolysis in progenitor cells of the brain and in medulloblastoma. In the absence of Hk2, brain development was disordered. Additionally they found that deleting the Hk2 gene in mice genetically Prone to develop medulloblastoma reduced the aggressiveness of the tumors, allowing long-term survival of the mice.

Dr. Timothy Gershon, who led this study, explained, "As long ago as 1924 Otto Warburg hypothesized that cancers use glycolysis to provide energy for growth even in the presence of oxygen. We found that glycolysis in the presence of oxygen is a developmental process that is co-opted in cancer to support malignant growth. We can now think about targeting this process in patients".

Open access publisher BioMed Central is proud to announce the launch of the Cancer & Metabolism . Professor Chi van Dang, co-Editor-in-Chief, commented that "It has become self-evident that metabolism and bioenergetics are regulated by cancer genes. Cancer & Metabolism is launched uniquely to fulfil the needs of a burgeoning field." Professor Michael Pollak, co-Editor-in-Chief, added that "The scope of Cancer & Metabolism will allow for an interdisciplinary readership including cancer biologists, endocrinologists, oncologists, clinical trialists and population scientists."

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Media contact

Dr Hilary Glover
Scientific Press Officer, BioMed Central
Tel: +44 (0) 20 3192 2370
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Notes

1. Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma Timothy R Gershon, Andrew Crowther, Andrey Tikunov, Idoia Garcia, Ryan Annis, Hong Yuan, C Ryan Miller, Jeffrey Macdonald, James M Olson and Mohanish Deshmukh Cancer & Metabolism 2013 1:1 doi:10.1186/2049-3002-1-2

Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central's open access policy.

Article citation and URL available on request on the day of publication.

2. Cancer & Metabolism publishes studies on all aspects of the relationship between cancer and metabolism, including molecular biology and genetics of cancer metabolism; whole-body metabolism, including diabetes and obesity, in relation to cancer; metabolomics in relation to cancer; metabolism-based imaging; and preclinical and clinical studies of metabolism-related cancer therapies.

3. BioMed Central (http://www.biomedcentral.com/) is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector. @BioMedCentral

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Genomic sequencing identifies mutant 'drivers' of common brain tumor

  • Wednesday, 23 January 2013 10:34

Study pinpoints targets for potential drug treatment of meningiomas

IMAGE: Rameen Beroukhim, M.D., Ph.D., and his colleagues at Dana-Farber Cancer Institute and Broad Institute scientists report that large-scale genomic sequencing has revealed two DNA mutations that appear to drive about...

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BOSTON—Large-scale genomic sequencing has revealed two DNA mutations that appear to drive about 15 percent of brain tumors known as meningiomas, a finding that could lead to the first effective drug treatments for the tumors, report scientists from Dana-Farber Cancer Institute and the Broad Institute.

Surgery and radiation currently are the only treatments for meningiomas – slow-growing, often benign tumors that develop in the membranes surrounding the brain. Meningiomas can grow dangerously large, however, causing seizures and limb weakness, and occasionally are fatal. In some instances, the tumors grow aggressively or their locations make surgery and radiation a challenge to carry out, and Chemotherapy has proven ineffective as an alternative.

The researchers report in the journal Nature Genetics that they have identified two mutations, SMO and AKT1, in the genomes of 15 percent of a group of meningiomas removed during surgery. The findings are being published on the journal's web site in advance of appearing in a print edition.

"The wonderful thing about those mutations is that there are already drugs in the clinic to target cancers with those mutations," said Rameen Beroukhim, MD, PhD, a medical oncologist and cancer biologist at Dana-Farber and the Broad Institute.

"Clinically, there is no medical treatment for meningioma that is known to be effective," said Beroukhim, senior author of the paper along with William C. Hahn, MD, PhD, director of the Center for Cancer Genome Discovery at Dana-Farber, and Ian F. Dunn, MD, a neurosurgeon at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC).

Beroukhim said that surgery can effectively treat many meningiomas, but the locations of some tumors make surgery a difficult or impossible option. For other patients, there are not curative treatments, so the discovery of the mutations in some meningiomas "is potentially the first path to an effective medical treatment," Beroukhim noted.

Meningiomas are diagnosed in about 18,000 patients annually in the United States. They account for about one-third of primary brain tumors (those that originate in the brain) and are twice as common in women. They are generally slow-growing, and many patients don't require treatment unless the Tumor expands and presses on vital structures. But a significant number recur following treatment, and many become Malignant.

Beroukhim said that little has been uncovered about the genetic makeup of meningiomas. In the current study, the scientists sequenced either the entire genome or just the protein-coding regions (exomes) in samples of 17 meningiomas. Genes that were found to be altered in those tumors were then sequenced in two additional groups of tumors.

Compared to most types of tumors, the researchers found, the meningiomas had fewer numbers of genetic changes or damage. In some of the tumors they found mutations in two genes that have roles in known cancer-causing signaling pathways. One, SMO, found in three tumors, is a member of the Hedgehog pathway. The second, AKT1, was discovered in five tumors and is a part of the PI3K-AKT-mTOR pathways that is implicated in breast, colorectal and lung cancers. A sixth tumor had a previously unknown mutation in the mTOR pathway.

Together, these mutant gene pathways appeared to be key drivers of 15 percent of the meningiomas studied. Experimental drugs that inhibit those abnormal pathways are in clinical trials and have shown promising activity, the researchers said, suggesting "that patients with these meningiomas may benefit from such targeted therapies already in development or use."

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Co-first authors of the report are Priscilla Brastianos, MD, of Dana-Farber and Peleg Horowitz, MD, PhD, of Brigham and Women's Hospital. Other authors are at the Broad, Harvard Medical School, Brigham and Women's, and Massachusetts General Hospital.

The research was supported by the Brain Science Foundation, the Pediatric Low-Grade Astrocytoma Foundation, and other foundations, the National Institutes of Health (K08 CA122833, K08 NS064168 and K12 CA090354-11), and the U.S. Department of Defense (W81XWH-12-1-0136.)

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Boston Children's Hospital as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

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Mayo Clinic Researchers Identify Enzyme Involved in Deadly Brain Tumors

  • Friday, 18 January 2013 14:36
  • Last Updated ( Friday, 18 January 2013 14:43 )

Enzyme possible key to developing tissue regeneration therapy

ROCHESTER, Minn. — One of the most common types of brain tumors in adults, Glioblastoma Multiforme, is one of the most devastating. Even with recent advances in surgery, radiation and Chemotherapy, the aggressive and invasive tumors become resistant to treatment, and Median survival of patients is only about 15 months. In a study published in Neuro-Oncology, researchers at Mayo Clinic identify an important association between the naturally occurring enzyme Kallikrein 6, also known as KLK6, and the Malignant tumors.

"Our study of Kallikrein 6 showed that higher levels of this enzyme in the Tumor are negatively associated with patient survival, and that the enzyme functions by promoting the survival of tumor cells," says senior author Isobel Scarisbrick, Ph.D., of Mayo Clinic's Department of Physical Medicine and Rehabilitation.

The findings introduce a new avenue for potential treatment of deadly glioblastomas: targeting the function of KLK6. The tumor cells became more susceptible to treatment when researchers blocked the receptors where the KLK6 enzyme can dock and initiate the survival signal.

Researchers looked at 60 samples of grade IV astrocytomas — also known at this stage as glioblastomas — as well as less aggressive grade III astrocytomas. They found the highest levels of KLK6 were present in the most severe grade IV tumors. Looking at the tumor samples, researchers found higher levels of KLK6 associated with shorter patient survival. Those with the highest levels lived 276 days, and those with lower levels lived 408 days.

"This suggests that the level of KLK6 in the tumor provides a prognosticator of patient survival," Dr. Scarisbrick says.

The group also investigated the mechanism of the enzyme to determine whether it plays a significant role in tumor growth. Researchers also found glioblastoma cells treated in a petri dish with KLK6 become resistant to radiation and chemotherapy treatment.

"Our results show that KLK6 functions like a hormone, activating a signaling cascade within the cell that promotes tumor cell survival," Dr. Scarisbrick says. "The higher the level of the enzyme, the more resistant the tumors are to conventional therapies."

The study is the latest step in Dr. Scarisbrick's investigations of KLK6 in nervous system cells known as astrocytes. Glioblastomas arise from astrocytes that have grown out of control. Her lab has shown that KLK6 also plays a role in the perseverance of inflammatory immune cells that occur in multiple sclerosis and in aberrant survival of T-lymphocyte leukemia cell lines.

"Our findings in Glioma affirm KLK6 as part of a fundamental physiological mechanism that's relevant to multiple diseases and have important implications for understanding principles of tissue regeneration," she says. "Targeting KLK6 signaling may be a key to the development of treatments for pathologies in which it is necessary to intervene to regulate cell survival and tissue regeneration in a therapeutic fashion. Ultimately, we might be able to harness the power of KLK6 for the repair of damaged organs."

The study was funded by a National Institutes of Health Brain Tumor SPORE grant, an NIH Mayo Neuro-oncology Training Grant and a grant from the National Institute of Neurological Diseases and Stroke. Other authors include Kristen Drucker, Ph.D., Alex Paulsen, Caterina Giannini, M.D., Ph.D., Paul Decker, Joon Uhm, M.D., Brian O'Neill, M.D., and Robert Jenkins, M.D., Ph.D., all of Mayo Clinic; and Sachiko Blaber and Michael Blaber, Ph.D., of Florida State University.

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About Mayo Clinic

Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit MayoClinic.com or MayoClinic.org/news.

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