Archive for the ‘Neurosurgery’ Category

One-two punch for brain tumors? New clinical trial opens

The experimental approach, based on U-M research, delivers two different genes directly into the brains of patients following the operation to remove the bulk of their tumors.

The idea: trigger immune activity within the brain itself to kill remaining tumor cells — the ones neurosurgeons can’t take out, which make this type of tumor so dangerous.

It’s the first time this gene therapy approach is being tried in humans, after more than a decade of research in experimental models.

One of the genes is designed to kill tumor cells directly, and is turned on when the patient takes a certain drug. The other gene spurs the body’s own immune system to attack remaining cancer cells. Both are delivered into brain cells via a harmless virus.

The Phase I clinical trial has already enrolled two patients who have tolerated the gene delivery without complications. All patients in the study must have a presumptive diagnosis of WHO grade 3 or 4 malignant primary glioma, such as glioblastoma multiforme; patients must not have been treated yet by any therapy. They must also meet other criteria for inclusion in the trial.

More patients will be able to enroll at a pace of about one every three weeks, through a careful selection process. In addition to surgery and gene therapy at U-M, each will receive standard chemotherapy and radiation therapy as well as follow-up assessments for up to two years.

“We’re very pleased to see our years of research lead to a clinical trial, because based on our prior work we believe this combination of cell-killing and immune-stimulating approaches holds important promise,” says principal investigator Pedro Lowenstein, M.D., Ph.D., the U-M Medical School Department of Neurosurgery professor who has co-led the basic research effort to develop and test the strategy.

Co-leader Maria Castro, Ph.D., notes that the patients who agree to take part in the Phase I trial will be the first in the world to help establish the safety of the approach in humans. “Without them, and without our partners on the U-M Neurosurgery team, and donors to the Phase One Foundation that support our work, we wouldn’t be able to take this important step in testing this novel therapeutic approach.”

For more about the trial, visit http://umhealth.me/gliomatrial or call 1-800-865-1125.

source : http://www.sciencedaily.com/releases/2014/09/140902143230.htm

Finding keys to glioblastoma therapeutic resistance

“There is a growing interest to guide cancer therapy by sequencing the DNA of the cancer cell,” said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, UC San Diego Division of Neurosurgery and the principal investigator of the study. “Our study demonstrates that the sensitivity of glioblastoma to a drug is influenced not only by the content of its DNA sequences, but also by how the DNA sequences are organized and interpreted by the cell.”

The team of scientists, led by Chen, used a method called comparative gene signature analysis to study the genetic profiles of tumor specimens collected from approximately 900 glioblastoma patients. The method allows investigators to discriminate whether specific cellular processes are “turned on” or “turned off” in glioblastomas. “Our study showed that not all glioblastomas are the same. We were able to classify glioblastomas based on the type of cellular processes that the cancer cells used to drive tumor growth,” said Jie Li, PhD, senior postdoctoral researcher in the Center for Theoretical and Applied Neuro-Oncology at UC San Diego and co-first author of the paper.

One of these cellular processes involves Epidermal Growth Factor Receptor (EGFR). The study revealed that EGFR signaling is suppressed in a subset of glioblastomas. Importantly, this suppression is not the result of altered DNA sequences or mutations. Instead, EGFR is turned off as a result of how the DNA encoding the EGFR gene is organized in the cancer cell. This form of regulation is termed “epigenetic.” Because EGFR is turned off in these glioblastomas, they become insensitive to drugs designed to inhibit EGFR signaling.

“Our research suggests that the selection of appropriate therapies for our brain tumor patients will require a meaningful synthesis of genetic and epigenetic information derived from the cancer cell,” said co-first author Zachary J. Taich.

The paper’s abstract can be found at: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2350

source : http://www.sciencedaily.com/releases/2014/08/140825185321.htm

Imaging system guides brain tumor removal to improve patient outcomes

The imaging system is known as desorption electrospray ionization mass spectrometry (DESI MS). The technique was developed by R. Graham Cooks, Ph.D., at Purdue University, and the brain study was done with collaborators at Harvard Medical School and Dana Farber Cancer Institute, and is described in the June 30 issue of the Proceedings of the National Academies of Science. DESI MS promises to be a significant improvement over the current method of distinguishing brain tumor tissue from healthy tissue, which relies on an extremely lengthy and difficult procedure for surgeons and patients.

The current protocol uses frozen section pathology, which involves removing suspected tumor tissue and having it analyzed by pathologists. They use a freezing and staining method that takes about 20 minutes and is too slow to be repeated multiple times during surgery. This method, developed more than 150 years ago, is both inefficient and lacks precision. It can result in incomplete tumor removal and regrowth, as well as inadvertent damage to healthy tissue, which can cause significant deficits in functioning for patients.

The new technique solves some of the problems of the current method. Researchers use the ability of mass spectrometry to identify metabolites that are present in brain tumors, but not in healthy tissue. As surgery progresses, tissue samples are removed and sprayed with a charged liquid that splashes onto the surface of the tissue, lifting off droplets; the droplets are then sucked into a mass spectrometer, where the mass and charge of the metabolites are measured. Brain gliomas produce large amounts of a tumor metabolite, 2-hydroxyglutarate (2-HG), which is captured in the droplets. This very rapid, objective method allows for clear delineation of tumor versus non-tumor tissue, so surgeons can remove all, and only, tumor tissue.

The DESI MS system was first tested on glioma specimens from 35 patients. Twenty one of the 35 samples contained high levels of 2-HG, a product of the mutant form of a gene known as IDH, which is associated with tumor formation. The results clearly demonstrated that DESI MS can detect 2-HG in tumor tissue with very high sensitivity and specificity.

The researchers went on to test the system in an operating room. The group installed a complete DESI MS system in the Advanced Multimodality Image Guided Operating (AMIGO) suite at Brigham and Women’s Hospital that is a part of the National Center for Image-Guided Therapy. The AMIGO surgical suite is an operating room with built-in imaging devices such as MRI, so the surgeon can use it to map the tumor pre-operatively. Tissue sections from tumors from two patients were examined using DESI MS. In both cases, the post-operative analysis confirmed that intraoperative DESI MS had accurately detected the presence of 2-HG in each tumor.

The researchers chose detection of 2-HG to test the DESI MS system because about 80% of gliomas and glioblastomas are associated with mutations in the IDH gene, which results in high levels of 2-HG. The approach described here could be applicable to the resection of all 2-HG-producing tumors.

Gliomas are tumors of brain glial cells and account for the majority of malignant brain tumors in adults. Gliomas make up approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. These experiments provide proof-of-concept of the accuracy and practicality of the DESI MS system, and suggest that the system can be used with this common 2-HG-producing tumor, as well as other tumors in which a metabolic marker of malignancy is produced.

The DESI MS system was shown to be extremely accurate and was easily adapted for use in the clinical setting. It does not have the limitations of MRI, which cannot provide information about the type of tumor, and requires that surgery be halted for an hour or longer for scanning and interpretation of results. Moreover, each operating room that contains an MRI machine costs more than $10 million. In contrast, DESI MS platforms could be set up in any operating room at a very small fraction of the cost. The DESI MS system promises to be a powerful new tool for both research and clinical applications with the potential to transform surgical care of patients with brain tumors and other solid tumors.

source : http://www.sciencedaily.com/releases/2014/08/140812163419.htm