Can Zika Be Used To Fight Glioblastoma Brain Tumors?

MedicalResearch.com Interview with:

Milan G. Chheda, MD Assistant Professor  Department of Medicine  Oncology Division  Molecular Oncology  Department of Neurology Washington University School of Medicine in St. Louis

Dr. Chheda

Milan G. Chheda, MD
Assistant Professor
Department of Medicine
Oncology Division
Molecular Oncology
Department of Neurology
Washington University School of Medicine in St. Louis

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Glioblastoma is an extremely aggressive brain tumor. Most patients die in less than two years. A longstanding challenge has been killing tumor cells that are inherently resistant to our current therapies (radiation and chemotherapy). These cells, called cancer stem cells, are extremely hardy. A longstanding dream of oncologists has been to devise a way to find them and kill them. The public health epidemic in 2015 made Zhe Zhu, post-doctoral fellow in Jeremy Rich’s lab, wonder whether Zika virus could work on cancer stem cells, that share properties with stem cells in fetal brain. Zika virus doesn’t cause significant problems in adults.

We took a lesson from nature and tested Zika virus.

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Targeting CD44s May Make Glioblastoma More Sensitive To Clinical Treatment

MedicalResearch.com Interview with:

Chonghui Cheng, M.D., Ph.D. Associate Professor Department of Molecular & Human Genetics Lester & Sue Smith Breast Center Baylor College of Medicine Houston, TX77030

Dr. Cheng

Chonghui Cheng, M.D., Ph.D.
Associate Professor
Department of Molecular & Human Genetics
Lester & Sue Smith Breast Center
Baylor College of Medicine
Houston, TX77030

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Understanding the mechanisms that give cancer cells the ability to survive and grow opens the possibility of developing improved treatments to control or cure disease. In the case of glioblastoma multiforme, the deadliest type of brain cancer, abnormal EGFR signaling is frequently observed.

Treatment with the EGFR inhibitor erlotinib attempts to kill cancer cells. However, the clinical benefit of treatment with this and other EGFR inhibitors has been limited by the development of drug resistance.

Scientists at Baylor College of Medicine discovered that the molecule CD44s seems to give cancer cells a survival advantage. Eliminating this advantage by reducing the amount of CD44s resulted in cancer cells being more sensitive to the deadly effects of the drug erlotinib.

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Stereotactic Radiation Therapy Achieves Superior Results in Some Brain Tumors

MedicalResearch.com Interview with:

Professor Rakesh Jalali, MD Professor of Radiation Oncology President, Indian Society of Neuro-Oncology Tata Memorial Parel, Mumbai India

Dr. Jalali

Professor Rakesh Jalali, MD
Professor of Radiation Oncology
President, Indian Society of Neuro-Oncology
Tata Memorial
Parel, Mumbai India 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Randomized controlled trials to test the efficacy of radiotherapy techniques are challenging to perform. High-precision conformal techniques such as stereotactic radiosurgery/radiotherapy, intensity modulated radiotherapy (IMRT) and particle therapy, etc have been incorporated into routine clinical practice including for brain tumors without always being supported by level-1 evidence.

We therefore conducted a prospective, randomized, controlled trial of stereotactic conformal radiotherapy compared to conventional radiotherapy in young patients with residual/progressive bening and low grade brain tumors requiring radiotherapy for optimal disease control.

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Targeted Radiosurgery Beats Whole Brain Radiation For Brain Tumor Survival

MedicalResearch.com Interview with:

N. Scott Litofsky, M.D. Chief of the Division of Neurological Surgery University of Missouri School of Medicine

Dr. N. Scott Litofsky,

N. Scott Litofsky, M.D.
Chief of the Division of Neurological Surgery
University of Missouri School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Radiosurgery is being used more often for treatment of brain metastases to avoid potential side effects of whole-brain radiation, such as cognition and mobility impairment. After surgical resection of a brain metastases, some radiation treatment is generally needed to control brain disease. Few studies have directly compared efficacy of tumor control between surgery followed by whole-brain radiation and surgery followed by radiosurgery.

Our objective was to compare outcomes in two groups of patients – one whose brain metastasis was treated with surgery followed by whole-brain radiation and one whose surgery was followed by radiosurgery to the post-operative tumor bed.

We found that tumor control was similar for both groups, with survival actually better in the radiosurgery group. The complications of treatment were similar.

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Mibefradil Dihydrochoride with Hypofractionated Radiation for Recurrent Glioblastoma

MedicalResearch.com Interview with:

Nataniel Lester-Coll, MD Chief Resident in Radiation Oncology at Yale New Haven, Connecticut

Dr. Nataniel Lester-Coll

Nataniel Lester-Coll, MD
Chief Resident in Radiation Oncology at Yale
New Haven, Connecticut 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Mibefradil diydrochloride was identified using a high-throughput compound screen for DNA double stranded break repair inhibitors. Mibefradil was found to radiosensitize GBM tumor cells in vitro and in vivo. Based on these findings, we sought to determine the maximum tolerated dose of mibefradil and radiation therapy in a Phase I recurrent GBM study. Eligible patients with recurrent  Glioblastoma Multiforme received Mibefradil over a 17 day period, with hypofractionated radiation (600 cGy x 5 fractions). There are 18 patients currently enrolled who have completed treatment. Thus far, there is no clear evidence of radionecrosis. A final dose level of 200 mg/day was reached as the maximum tolerated dose. The drug was very well tolerated at this dose. We saw intriguing evidence of enhanced local control in selected cases. Patients enrolled in a translational substudy who received Mibefradil prior to surgery were found to have adequate levels of Mibefradil in resected brain tumor tissue.

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Computer Bests Neuroradiologists in Distinguishing Tumor Recurrence From Radiation Necrosis

MedicalResearch.com Interview with:

Dr. Pallavi Tiwari PhD Assistant Professor biomedical engineering Case Western Reserve University

Dr. Pallavi Tiwari

Dr. Pallavi Tiwari PhD
Assistant Professor biomedical engineering
Case Western Reserve University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: One of the biggest challenges in neuro-oncology currently is distinguishing radionecrosis, a side-effect of aggressive radiation, from tumor recurrence on imaging. Surgical intervention is the only means of definitive diagnosis, but suffers from considerable morbidity and mortality. The treatments for radionecrosis and cancer recurrence are very different. Early identification of the two conditions can help speed prognosis, therapy, and improve patient outcomes.

The purpose of this feasibility study was to evaluate the role of machine learning algorithms along with computer extracted texture features, also known as radiomic features, in distinguishing radionecrosis and tumor recurrence on routine MRI scans (T1w, T2w, FLAIR). The radiomic algorithms were trained on 43 studies from our local collaborating institution – University Hospitals Case Medical Center, and tested on 15 studies at a collaborating institution, University of Texas Southwest Medical Center. We further compared the performance of the radiomic techniques with two expert readers.

Our results demonstrated that radiomic features can identify subtle differences in quantitative measurements of tumor heterogeneity on routine MRIs, that are not visually appreciable to human readers. Of the 15 test studies, the radiomics algorithm could identify 12 of 15 correctly, while expert 1 could identify 7 of 15, and expert 2, 8 of 15.

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Insurance Status Affects Glioblastoma Survival

MedicalResearch.com Interview with:

Wuyang Yang, M.D., M.S. Research Fellow Department of Neurosurgery Johns Hopkins Hospital Baltimore, MD 21287

Dr. Wuyang Yang

Wuyang Yang, M.D., M.S.
Research Fellow
Department of Neurosurgery
Johns Hopkins Hospital
Baltimore, MD 21287

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The treatment for glioblastoma (GBM) patients involves a combined approach of surgery, radiation therapy and chemotherapy. Despite advancement in the therapeutic approaches for GBM, differing socioeconomic status result in disparities in health-care access, and may superimpose a significant impact on survival of glioblastoma patients. Insurance status is an indirect indicator of overall socioeconomic status of a patient, and has been shown to correlate with survival of patients with malignant tumor in other parts of the body. We conducted the first study to determine a relationship between different types of insurance and survival of GBM patients.

In our study of 13,665 cases of GBM patients, we found that non-Medicaid insured patients have a significant survival benefit over uninsured and even Medicaid insured patients. This is the first time a study describes this relationship in glioblastoma patients, and also the first to compare and quantify the likelihood of poor prognosis between different insurance categories. A difference in insurance coverage was also uncovered, and patients with insurance were more likely to be older, female, white, and married. In addition, we found that younger, female, married patients with smaller tumor size survive longer than other patients, which confirmed findings in existing literature.

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Optune as Standard Treatment Option for Newly Diagnosed Glioblastoma

Novocure is the developer of Optune, which uses Tumor Treating Fields to treat cancer. Tumor Treating Fields, or TTFields, are low intensity, alternating electric fields within the intermediate frequency range. TTFields disrupt cell division through physical interactions with key molecules during mitosis. This non-invasive treatment targets solid tumors.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The National Comprehensive Cancer Network (NCCN) has recommended Optune as a standard treatment option for newly diagnosed glioblastoma (GBM) in its Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers. NCCN panel members designated Optune together with temozolomide as a category 2A treatment for newly diagnosed GBM for patients with good performance status, indicating uniform consensus among panel members to add Optune to the guidelines for newly diagnosed GBM. Optune has been included in the NCCN Guidelines as a category 2B treatment option for recurrent GBM since 2015. The recommendation follows the publication of Novocure’s EF-14 phase 3 pivotal trial data in The Journal of the American Medical Association (JAMA) in December, 2015. The EF-14 phase 3 pivotal trial demonstrated that adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival in newly diagnosed GBM.
Glioblastoma, also called glioblastoma multiforme, or GBM, is a type of primary brain cancer. Approximately 12,500 GBM tumors, or tumors that may transform into GBM, are diagnosed in the U.S. each year. GBM is the most common type of primary brain cancer in adults. It is more likely to appear in older adults and to affect men than women. GBM is one of the deadliest forms of cancer, with patients typically not surviving beyond 15 months after diagnosis.

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Soluble Aspirin May Be Able To Cross Blood-Brain Barrier To Attack Glioblastomas

MedicalResearch.com Interview with:

Dr Kieran Breen PhD Director of Research, Brain Tumour Research University of Portsmouth, UK

Dr. Kieran Breen

Dr Kieran Breen PhD
Director of Research, Brain Tumour Research
University of Portsmouth, UK

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There is evidence that aspirin (acetyl salicylic acid) can be toxic to brain tumour cells. However, its existing preparations cannot readily enter the brain because the drug is a suspension rather than being completely soluble. Furthermore, there can be significant side effects associated with the existing form of the drug including gastric bleeding. The object of this research was to develop a new formulation of aspirin which is truly soluble. When combined with two other compounds, the drug enters the brain and can therefore target the tumour cells. This study also showed that aspirin can kill tumour cells without causing any damage to the normal nerve cells. Continue reading

Meningioma Risk Lower In Patients With High Blood Sugar and Diabetes

MedicalResearch.com Interview with:

Dr. Judith Schwartzbaum PhD Associate professor of epidemiology Ohio State's Comprehensive Cancer Center

Dr. Judith Schwartzbaum

Dr. Judith Schwartzbaum PhD
Associate professor of epidemiology
Ohio State’s Comprehensive Cancer Center

MedicalResearch.com: What is the background for this study?

Response: Meningioma is a slow-growing brain tumor that is associated with obesity. To further understand this risk we examined records of blood sugar levels within approximately 15 years before tumor diagnosis comparing blood sugar levels of people who developed meningioma to those in people who did not.

MedicalResearch.com:What are the main findings?

Response: To our surprise we found that risk of this tumor was lower in people with high levels of blood sugar and diabetes.

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Neuroblastoma: Adding Novel Monoclonal Antibody To Chemotherapy Shrunk More Tumors

MedicalResearch.com Interview with:

Wayne L. Furman, MD Department of Oncology Jude Children's Research Hospital Memphis, TN 38105-3678

Dr. Wayne Furman

Wayne L. Furman, MD
Department of Oncology
Jude Children’s Research Hospital
Memphis, TN 38105-3678

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Furman: Despite improvement in 2-yr EFS from 46% to 66% with the inclusion of dinutuximab, a monoclonal antibody that recognizes a glycoprotein on neuroblasts called ‘GD2’ (disialoganglioside), more than one-third of children with high-risk neuroblastoma still are not cured. Therefore novel therapeutic approaches are needed for this subset of patients. The clinical evaluation of various anti-GD 2 monoclonal antibodies in children with neuroblastoma has been exclusively focused on treatment of patients after recovery from consolidation, in a state of ‘minimal residual disease’. This is because traditionally chemotherapy has been thought to be too immunosuppressive to combine with monoclonal antibodies. However recent studies suggest, even in the setting of “bulky” solid tumors, the combination of chemotherapy with monoclonal antibodies can enhance the effectiveness of the antibodies. First, chemotherapy can increase the efficacy of antibodies by depleting cells of the immune system that suppress immune function. Also chemotherapy-induced tumor cell death can trigger tumor antigen release, uptake by antigen processing cells and an enhanced antitumor immune response. There is also data that anti-GD2 monoclonal antibodies can suppress tumor cell growth independent of immune system involvement. Furthermore anti-GD2 monoclonal antibodies and chemotherapy have non-overlapping toxicities. All of these reasons were good reasons to evaluate the addition of a novel anti-GD2 monoclonal antibody, called hu14.18K322A, to chemotherapy, outside the setting of minimal residual disease, in children with newly diagnosed children with high-risk neuroblastoma.

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Dog Genome Can Be Used To Identify Human Brain Tumor Genes

MedicalResearch.com Interview with:

Katarina Truvé PhD Swedish University of Agricultural Sciences and  Kerstin Lindblad-Toh Uppsala University

Dr. Katarina Truvé

Katarina Truvé PhD
Swedish University of Agricultural Sciences and
Kerstin Lindblad-Toh
Uppsala University

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Truvé: Gliomas are malignant brain tumors that are rarely curable. These tumors occur with similar frequencies in both dogs and humans. Gliomas in dogs are strikingly similar at the biological and imaging level to human tumor counterparts. Some dog breeds such as Boxer and Bulldog are at considerably higher risk of developing glioma. Since these breeds at high risk are recently related, they are most likely carrying shared genetic risk factors. Our goal was therefore to use the dog genome to locate genes that may be involved in the development of glioma in both dogs and humans. We found a strongly associated locus and identified three candidate genes, DENR, P2RX7 and CAMKK2 in the genomic region. We have shown that CAMKK2 is lower expressed in glioma tumors than normal tissue in both dogs and human, and it has been reported that the associated canine mutation in P2RX7 results in a decrease in receptor function.

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Anti-Hypertension Drug Prazosin May Inhibit Glioblastoma Brain Tumor Cells

MedicalResearch.com Interview with:

Hervé Chneiweiss MD PhD Bâtiment A3 pièce 336 Case courrier 2 Plasticité Gliale et Tumeurs cérébrales Neuroscience Paris Seine (directeur) Inserm/Université Pierre et Marie Curie

Dr. Herve Chneiweiss

Hervé Chneiweiss MD PhD
Bâtiment A3 pièce 336 Case courrier 2 Plasticité Gliale et Tumeurs cérébrales Neuroscience Paris Seine (directeur) Inserm/Université Pierre et Marie Curie

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Chneiweiss: Treatments available for glioblastoma — malignant brain tumors — have little effect. An international collaboration[1] led by the Laboratoire Neurosciences Paris-Seine (CNRS/ INSERM/UPMC)[2] tested active ingredients from existing medications and eventually identified one compound of interest, prazosin, on these tumors.

We chose to study the most common malignant tumors that develop from brain cells, glioblastomas, which represent the fourth most frequent cause of cancer deaths among adults and the second in children. This is due to the inefficacy of current treatments. Indeed, a glioblastoma can resist treatment and reawaken from a very small number of tumor cells called glioblastoma-initiating cells (GIC). It is these cells — whose characteristics and properties resemble those of stem cells — that were targeted in the study.

Rather than trying to discover new compounds, the team opted for repositioning existing drugs. In other words, we tested a collection of substances used for so long to treat other conditions that their patents have now fallen into the public domain[3]. This method makes it possible to develop new active ingredients cheaply and very rapidly. Twelve hundred compounds were thus tested on normal human neural stem cells and on glioblastoma-initiating cells from different aggressive tumors. Twelve of these compounds showed a toxic effect on GIC — and none on the normal neural stem cells. The most effective was prazosin. Tested in mice carrying glioblastoma-initiating cells, prazosin significantly reduced the size of tumors and prolonged survival of the mice by more than 50%.

[1] Including scientists from the Laboratoire d’Innovation Thérapeutique (CNRS/Université de Strasbourg), the Stanford University Institute for Stem Cell Biology and Regenerative Medicine (USA) and the Instituto Estadual do Cérebro Paulo Niemeyer in Rio de Janeiro (Brazil).

[2] This laboratory forms part of the Institut de Biologie Paris-Seine.

[3] Pharmaceutical compounds are protected by a patent for 20 years after their discovery. Because of the length of the clinical trials that are necessary before a drug can be put on the market, the duration of their patent protection does not normally exceed 10-15 years after a Marketing Authorization (MA) is granted.

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Dual Treatment Strategies Can Slow Glioblastoma Tumor Growth

MedicalResearch.com Interview with:

Rakesh K. Jain, Ph.D. A.W.Cook Professor of Radiation Oncology (Tumor Biology) Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA 02114

Dr. Rakesh Jain

Rakesh K. Jain, Ph.D.
A.W.Cook Professor of Radiation Oncology (Tumor Biology)
Director, E.L. Steele Laboratory
Department of Radiation Oncology
Harvard Medical School and
Massachusetts General Hospital
Boston, MA    02114

MedicalResearch.com: What is glioblastoma and why is it difficult to treat?

Dr. Jain: Glioblastoma (GBM) is the most common malignant tumor of the brain, and remains highly lethal. The standard treatment consists of surgical removal followed by chemo-radiation and anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) antibody. Unfortunately, glioblastoma cells invade the brain far from the original tumor mass. Hence, even with the best surgical techniques it is not possible to remove all tumor cells, as they are embedded in vital parts of the brain at the time of the surgery. As a result, even after multimodal therapies, most  glioblastoma patients succumb to their disease within 2 years. New approaches are desperately needed.

MedicalResearch.com: What is anti-angiogenic therapy and why is it used for glioblastoma?

Dr. Jain: One key feature ofglioblastomas is their highly abnormal, leaky and ineffective vasculature. This leads to brain swelling around the tumor and poor tumor blood perfusion, which in turn can render the tumors more aggressive. These vascular abnormalities are due to the uncontrolled overproduction in GBMs of angiogenic factors such as VEGF. Anti-angiogenic therapies using anti-VEGF agents can transiently “normalize” the GBM vasculature structure and function and reduce brain swelling, increase blood perfusion, and impact morbidity and survival. Unfortunately, even when this therapy is added to the standard therapy with surgery and chemo-radiation, GBM patients typically do not survive on average more than 1.5 years.

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Single Gene Rearrangement Uses Three Paths To Cause Rare Brain Tumor

MedicalResearch.com Interview with:

Dr. Adam C. Resnick, Ph.D Assistant Professor of Neurosurgery Faculty, Abramson Cancer Center Director of Children's Brain Tumor Tissue Consortium Division of Neurosurgery Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery Children's Hospital of Philadelphia

Dr. Adam Resnick

Dr. Adam C. Resnick, Ph.D
Assistant Professor of Neurosurgery
Faculty, Abramson Cancer Center
Director of Children’s Brain Tumor Tissue Consortium
Division of Neurosurgery
Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery
Children’s Hospital of Philadelphia

 

Payal Jain, PhD Candidate Division of Neurosurgery, Children's Hospital of Philadelphia Department of Neurosurgery Cell and Molecular Biology Graduate Group Gene Therapy and Vaccines Program Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Payal Jain

Payal Jain, PhD Candidate
Division of Neurosurgery, Children’s Hospital of Philadelphia
Department of Neurosurgery
Cell and Molecular Biology Graduate Group
Gene Therapy and Vaccines Program
Perelman School of Medicine
University of Pennsylvania Philadelphia, Pennsylvania

 

Medical Research: What is the background for this study? What are the main findings?

Response: This study originates from our long-standing interest in studying pediatric low-grade gliomas (PLGGs), which are the most commonly diagnosed brain tumor in children. While several PLGGs have been found to harbor mutations/gene fusions driving the mitogen-associated protein kinase (MAPK) pathway leading to clinical trials testing MAPK inhibitors, these tumors remain poorly categorized and not enough is known about specific genetic mutations driving different tumor sub-types and the potential for specific targeted therapeutics.

Our current study encompasses analysis of the largest combined genomic dataset of pediatric low-grade gliomas samples.  In doing this we, identified the MYB-QKI gene fusion, a non-MAPK related event, as the common genetic event driving a rare PLGG sub-type, called angiocentric gliomas. We have reported a novel tri-partite mechanism by which MYB-QKI mediates its oncogenic effect, this being the first report of a single gene rearrangement utilizing three different paths to cause cancer.

  • First, this gene rearrangement activates MYB, which is a proto-oncogene that is normally not expressed in the developed brain.
  • Second, we found that the rearrangement leads to translocation of QKI-related enhancers close to MYB’s promoters, thereby driving MYB-QKI expression in these tumors. Furthermore, MYB-QKI can also regulate its expression in a positive feedback loop.
  • Third, the tumor suppressor activities of QKI are disrupted in MYB-QKI. Such collaboration of genetic and epigenetic dysregulation in a single genetic rearrangement has previously not been reported.

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Rosacea Linked To Slight Increased Risk of Glioma

Alexander Egeberg, MD PhD National Allergy Research Centre, Departments of Dermato-Allergology and Cardiology Herlev and Gentofte University Hospital, University of Copenhagen Hellerup, Denmark

Dr. Alexander Egeberg

MedicalResearch.com Interview with:
Alexander Egeberg, MD PhD
National Allergy Research Centre, Departments of Dermato-Allergology and Cardiology
Herlev and Gentofte University Hospital
University of Copenhagen
Hellerup, Denmark  

Medical Research: What is the background for this study? What are the main findings?
Dr. Egeberg: There appears to be an overlap in the pathogenesis of rosacea and glioma, focused around matrix metalloproteinases.

Rosacea may be associated with an increased risk of glioma, however, it is important to note that the absolute risk is still low. Whether this is a causal link is not known.

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TTF for Glioblastoma-Alternating Electrical Fields Plus Chemo Extends Survival

Roger Stupp, MD Professor & Chairman Department of Oncology & Cancer Center University of Zurich & University Hospital Zurich (USZ) Zürich / Switzerland

Dr. Roger Stupp

MedicalResearch.com Interview with:
Roger Stupp, MD
Professor & Chairman
Department of Oncology & Cancer Center
University of Zurich & University Hospital Zurich (USZ)
Zürich / Switzerland

Medical Research: What is the background for this study?

Dr. Stupp: Tumor Treating Fields are an entirely novel modality in cancer treatment. Over 10 years ago researchers demonstrated that alternating electrical fields will block cell growth, interfere with organelle assembly, in particular perturb the spindle apparatus and cell division, all leading to mitotic arrest and ultimately apoptosis. This was shown in vitro, but importantly also in vivo animal models including not only mice and rats, but also hamsters and rabbits with deep seated solid tumours. So the question was whether we can demonstrate such an effect also in the clinic.

Glioblastoma are locally invasive and aggressive tumours in the brain. They usually do not metastasise however they grow diffusely within the CNS and despite the best possible surgery, radiation and chemotherapy virtually always recur. We thus applied alternating electrical fields therapy, so called Tumor Treating Fields to the scalp of patients with newly diagnosed glioblastoma. After the end of standard chemoradiotherapy (TMZ/RT), patients were randomized to receive either standard maintenance TMZ-chemotherapy alone or in combination with TTFields. Almost 700 patients were randomized, here we report on a preplanned interim analysis looking at the first 315 patients included once they were followed for at least 18 months. The data on the first 315 patients are mature and allowed the IDMC to conclude that the trial should be stopped and the results made available.

Medical Research: What are the main findings?

Dr. Stupp: The study demonstrated a consistent prolongation of both progression-free and also of overall survival for patients who have been treated with TTFields in addition to standard therapy. The median progression-free survival and overall survival were prolonged by 3 months, translating to an absolute increase in overall survival at 2 years of 14%, from 29% to 43%. Or a hazard ratio of 0.74 for overall survival and of 0.62 for progression-free survival.

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Genetic Signatures May Lead To Precision Treatments For Childhood Brain Tumors

Roger Packer MD Senior Vice President Center for Neuroscience & Behavioral Health Children's National Medical Center Washington, D.C.

Medicalresearch.com Interview with:
Roger Packer MD
Senior Vice President
Center for Neuroscience & Behavioral Health
Children’s National Medical Center
Washington, D.C.

 

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Packer: The background is that medulloblastoma is the most common childhood malignant brain tumor. It carries with it a variable prognosis. For some subsets of patients, with current available treatment which includes surgery, radiation and chemotherapy, we see survival rates as high as 90% (and often cures) 5 years following diagnosis and treatment. However, for some subsets of patients, survival rates are much poorer, in those with higher risk characteristics as low as 40% at 5 years. Current treatment also carries with it a significant risk for long term sequelae, including intellectual loss secondary to radiation therapy and persistent, at times devastating neurologic complications such as unsteadiness.

To try to improve our understanding and ultimately our therapy for medulloblastoma, an international working group has shared patient specimens and patient information to attempt to determine what the molecular predictors of outcome are for children with medulloblastoma and if such molecular genetic findings can be used to develop better, safer therapies. Children’s National is part of this international collective of institutions, which published this and other studies.

The main findings of this study are that complex, integrated genetic analysis of tumor specimens can be used to better understand and set the scene for better treatment of medulloblastoma.  Medulloblastoma can be broken into relatively distinct, molecular subtypes each with its own prognosis and potential therapy. A major finding of this study was that within a given tumor, different areas showed the same molecular genetic pattern. The importance of this is that since the tumors are relatively the same in different areas, molecularly-targeted therapies have an excellent chance of working on the entire tumor, resulting in better tumor control and safer treatments.

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Chemotherapy and Radiation For Brain Cancer Lead To Brain Shrinkage

Jorg Dietrich, MBA MMSc MD PhD Director, Cancer & Neurotoxicity Clinic and Brain Repair Research Program Massachusetts General Hospital Cancer Center Assistant Professor of Neurology Harvard Medical SchoolMedicalResearch.com Interview with:
Jorg Dietrich, MBA MMSc MD PhD 
Director, Cancer & Neurotoxicity Clinic and Brain Repair Research Program
Massachusetts General Hospital Cancer Center
Assistant Professor of Neurology
Harvard Medical School

Medical Research: What is the background for this study? What are the main findings?

Dr. Dietrich: Understanding the adverse effects associated with cancer therapy is an important issue in oncology. Specifically, management of acute and delayed neurotoxicity of chemotherapy and radiation in brain cancer patients has been challenging. There is an unmet clinical need to better characterize the effects of standard cancer therapy on the normal brain and to identify patients at risk of developing neurotoxicity. In this regard, identifying novel biomarkers of neurotoxicity is essential to develop strategies to protect the brain and promote repair of treatment-induced damage.

In this study, we demonstrate that standard chemotherapy and radiation in patients treated for glioblastoma is associated with progressive brain volume loss and damage to gray matter – the area of the brain that contains most neurons.

A cohort of 14 patients underwent sequential magnetic resonance imaging studies prior to, during and following standard chemoradiation to characterize the pattern of structural changes that occur as a consequence of treatment.

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Recurrent Glioblastoma: Treatment with Cytomegalovirus Immunotherapy

MedicalResearch.com Interview with:
Dr Andrea Schuessler
QIMR Berghofer Medical Research Institute
Herston, Queensland 4006

MedicalResearch.com: What are the main findings of the study?

Dr . Schuessler: Recurrent glioblastoma is a very aggressive brain cancer and most patients do not survive much longer than 6 months. Our study has assessed a novel immunotherapy and treated 10 patients with late stage cancer. The treatment did not have any serious side effects and most of the patients have survived much longer than the expected 6 months. Importantly, four of the 10 patients have not shown signs of disease progression during the study period with one of them still being cancer free four years after the treatment.
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Glioblastoma: Avastin Did Not Improve Survival or Symptoms

Minesh P. Mehta, M.B., Ch.B. F.A.S.T.R.O. Professor of Radiation Oncology, University of Maryland School of Medicine Radiation oncologist, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Chair, RTOG brain tumor committeeMedicalResearch.com Interview with:
Minesh P. Mehta, M.B., Ch.B. F.A.S.T.R.O.
Professor of Radiation Oncology,
University of Maryland School of Medicine
Radiation oncologist, University of Maryland Marlene and Stewart Greenebaum Cancer Center

MedicalResearch.com: What are the main findings of the study?

Dr. Mehta: RTOG 0825 was a clinical trial evaluating whether the addition of a novel drug that inhibits tumor vascular growth, bevacizumab, to the standard of care for glioblastoma, an aggressive brain tumor, would prolong survival. Patients were allocated randomly to one of two different treatment regimens – the standard of care, which includes radiotherapy and a drug known as temozolomide, or another regimen of radiation, temozolomide and bevacizumab. The trial design was double-blinded, and therefore, on one arm patients received the bevacizumab, whereas on the other arm they received a placebo. The survival on both arms was equivalent, and therefore it was fairly concluded that bevacizumab failed to prolong survival when given initially as part of treatment for glioblastoma.

Freedom from progression, referred to as progression-free survival was also measured on this trial, and although bevacizumab appeared to lengthen progression-free survival, this level of benefit did not meet the pre-defined goals, and is therefore regarded as statistically not demonstrating an improvement.

Additional endpoints included outcomes reported by the patient, including the burden of symptoms, and the impact of these on the quality of life, as well as effects on the brain, known as neurocognitive changes. Bevacizumab did not improve these endpoints either.

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Scientists map genetic mutations in the second-most common form of brain cancer, oligodendroglioma

Johns Hopkins Kimmel Cancer Center scientists have completed a comprehensive map of genetic mutations occurring in the second-most common form of brain cancer, oligodendroglioma. The findings, reported in the Aug. 4 issue of Science, also appear to reveal the biological cause of the tumors, they say.

To create the map, the scientists sequenced protein-coding genes in seven oligodendroglioma tissue samples, and focused attention on recurring mutations in two genes not previously associated with these tumors – CIC and FUBP1. The investigators say that CIC and FUBP1 are known to regulate cell-signaling processes, and CIC mutations have been rarely linked to sarcoma, breast and prostate cancers.

More mutations in the two genes were found in an additional 27 oligodendroglioma samples. In all, two-thirds of the samples studied had CIC and FUBP1 mutations.

“Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor,” says Nickolas Papadopoulos, Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

In brain cancer, the Hopkins investigators say CIC and FUBP1 mutations may be the “missing link” in what scientists describe as a “two-hit” theory of cancer development. The theory is based on the fact that each cell in the human body has two copies of 23 chromosomes containing thousands of protein-producing genes. If a gene on one chromosome is damaged or deleted, the other copy makes up for the loss of protein. But if the second copy fails as well, the cell cannot make the proper protein and may become cancerous.

In oligodendrogliomas, the “first hit” has long been known to occur in regions of chromosome 1 and 19, which fuse together resulting in a loss of many genes on both chromosomes. Up to 70 percent of oligodendroglioma patients have these DNA fusions, and most of them respond better to chemotherapy and radiation than those who lack the deletions in the chromosomes. For more than a decade, researchers have been looking for evidence of a “second hit” in specific mutated genes that allow oligodendrogliomas to develop.

In the current study, the Johns Hopkins investigators found mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19, suggesting that these mutations represent the second hit needed to create cancer.

“Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer,” says Kenneth Kinzler, Ph.D., professor and co-director of the Ludwig Center at Johns Hopkins. “Knowing the genetic roadmap of a cancer is the key to attacking it.”

Oligodendrogliomas account for up to 20 percent of brain cancers and more commonly occur in younger people aged 30 to 45. The cancer forms most often in the frontal lobe of the brain in cells that coat neurons. Median survival of 10 years is considered far better than other brain cancers. Oligodendrogliomas are treated initially with surgery, followed by chemotherapy and radiation.

The research team says its next step will be to test whether patients with CIC and FUBP1 mutations have the same favorable prognosis as those who have the chromosome 1 and 19 fusion, says Chetan Bettegowda, M.D., Ph.D., chief resident in the Department of Neurosurgery at Johns Hopkins.

“We can focus now on when these mutations develop during tumor formation, whether they can guide prognosis, and how they might form targets for therapy,” says Bettegowda.

Bettegowda says the gene map uncovered mutations in other genes, such as PIK3CA, which have been well-studied in cancer. It is possible, he says, that oligodendroglioma patients with mutations in PIK3CA or other genes could be enrolled in current clinical trials using experimental therapies that target these mutations.

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Funding for the research was provided by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, state funding from Sao Paulo (FAPESP), the National Cancer Institute and National Institutes of Health.

Contributors to the research include Nishant Agrawal, Yuchen Jiao, Mark Sausen, Laura D. Wood, Ralph H. Hruban, Fausto J. Rodriguez, Daniel P. Cahill, Gregory Riggins, Victor Velculescu and Bert Vogelstein of Johns Hopkins; Roger McLendon, Darell Bigner and Hai Yan of Duke University; and Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie of the University of Sao Paulo, Brazil.