Same Day Procedure May Transform Treatment Approach to Retinoblastoma

Expanded results of a study conducted on children with eye cancer (retinoblastoma) shows that chemotherapy delivered through endovascular (through the vessel) means not only successfully cures the cancer in a majority of cases, but achieves this cure with preserved vision. Study outcomes were presented this week at the Society of NeuroInterventional Surgery (SNIS) 6th Annual Meeting in Boca Raton, FL by lead author Pierre Gobin, Professor of Radiology in Neurosurgery and Neurology at the Weill Cornell Medical Center at New York Presbyterian Hospital in New York City.

“This is an exciting development in the neurointerventional community, as results prove that chemotherapy delivered through endovascular techniques is a powerful tool in addressing the most severe forms of retinoblastoma,” says Gobin, who says that the study is the product of teamwork between New York Presbyterian Hospital and the Eye Cancer Center of Memorial Sloan Kettering Cancer Center, New York City, with support from David Abramson, M.D., Brian Marr, M.D., Ira Dunkel, M.D. And Scott Brodie, M.D.

Retinoblastoma, the seventh most common pediatric cancer, is a malignant eye tumor in children that arises in cells in the developing retina. Typically, this cancer is associated with a late diagnosis as one of the only symptoms, a white pupil replacing the normal black, presents when the tumor occupies over one-third of the eye. Conventional therapy for this cancer includes laser treatment, as well as techniques that utilize extreme cold to freeze and destroy abnormal cells or deliver radioactive substances in timed intervals to kill the tumor. If these treatments fail, physicians resort to intravenous chemotherapy or radiation therapy. Despite this wide array of treatment options, however, a late diagnosis often requires the removal of the eye.

According to Gobin, the study was initiated in 2006 to determine if chemotherapy delivered through endovascular methods (through a catheter inserted in the groin and threaded up through the vessels to the site of the tumor), otherwise known as chemosurgery, would produce better outcomes for retinoblastoma patients, including preserving the eye and vision as well as avoiding intravenous chemotherapy, which is administered over the course of six months to a year and can be frequently associated with port infections and sickness for the duration of that time. Since the study was initiated, 49 children, ranging in age from 1 month to 10 years, have been treated with this technique. Of this number, all suffered from advanced retinoblastoma and were candidates for removal of the eye. Additionally, half of the patients had already failed prior conventional treatments, including intravenous chemotherapy or radiation therapy; nine patients had already had an eye removed.

Study participants were chosen following an eye examination under anesthesia, allowing physicians to confirm the diagnosis and determine the extent of the disease. For those who qualified, chemosurgery was performed soon thereafter, and was repeated every three to four weeks, up to six times.

To date, 144 chemosurgeries have been performed, which equates to a mean of three per patient. Results indicate that physicians were able to technically perform the procedure successfully in almost every case. Short-term follow-up, occurring after six or more months of stability after the last treatment, showed that of 27 eyes, 21 are cured (77 percent) and 13 are cured with preserved vision (48 percent). Six eyes could not be saved. Overall, of the population of eyes that were treated, 50 percent of patients would have lost an eye on conventional treatment; of those who kept an eye, a majority would not have experienced useful vision. With chemosurgery, only ten percent of patients lost an eye.

In general, patients tolerated the procedure well with minimal side effects that resolved once

addressed. In only four out of 46 eyes treated did severe complications occur which eventually led to blindness. All four eyes had received previous extensive treatment consisting of intravenous chemotherapy and radiation therapy.

Due to the overwhelming success observed with chemosurgery, Gobin says this treatment option has considerably reduced the number of conventional treatments, including the toxic intravenous chemotherapy, and most significantly, the number of eye losses. “The results really do have the potential to change the entire treatment approach to advanced retinoblastoma. In our center, chemosurgery is now the first line of treatment for this potentially devastating condition.”

Retinoblastoma occurs in approximately 350 – 400 children each year. Approximately 80 percent of patients are diagnosed under 3 years of age.

Source: Society of NeuroInterventional Surgery


Scientists Track Impact of DNA Damage in the Developing Brain

  • Author: Health Informer
  • Filed under: Health News
  • Date: Jul 28,2009

St. Jude technique yields clues about brain cells targeted by faulty single-strand DNA repair and offers new hints about the roots of neurological disease

Switching off a key DNA repair system in the developing nervous system is linked to smaller brain size as well as problems in brain structures vital to movement, memory and emotion, according to new research led by St. Jude Children’s Research Hospital scientists.

The work, published in the August issue of the journal Nature Neuroscience, also provides the first evidence that cells known as cerebellar interneurons are targeted for DNA damage and are a likely source of neurological problems in humans. The cerebellum coordinates movement and balance. The cerebellar interneurons fine tune motor control.

“These data will be important for understanding the role the DNA damage response plays in preventing neurological disease,” the investigators wrote.

The study also marks the first time researchers have switched off a pathway for repairing damaged single DNA strands in an organ system, in this case the mouse brain and nervous system. While the results suggest certain brain cells are particularly vulnerable, investigators report that with time DNA damage accumulates throughout the nervous system. Some mice in the study eventually develop seizures and difficulty walking.

Peter J. McKinnon, Ph.D., a member of St. Jude Genetics and Tumor Cell Biology, said the work provides a new model for understanding how single-strand DNA damage affects the nervous system and offers a new focus for tracking the origins of neurological disease.

The research also reflects growing scientific interest in damage to single strands of DNA. “A variety of human disease syndromes result from problems in the DNA-repair system,” explained McKinnon, the paper’s senior author.

DNA is the double-stranded molecule found in nearly every cell. In organisms both simple and complex, it serves as the biochemical blueprint for assembling and sustaining life. Diseases like cancer have long been associated with unrepaired damage to both strands of DNA. Single-strand DNA damage is far more common, but was generally considered less catastrophic to the cell.

But the last decade brought evidence linking single-strand DNA damage with human diseases, including ataxia with oculomotor apraxia (AOA1) and spinocerebellar ataxia with axonal neuropathy (SCAN1). Both disorders are inherited and are characterized by progressive difficulty with walking and other movement. AOA1 is among the most common form of certain inherited movement disorders in Japan and Portugal. McKinnon said those reports sparked new interest in single-strand DNA repair.

This study focused on Xrcc1, a protein long recognized as the master regulator of a pathway essential for single-strand DNA repair in the nervous system. The brain is thought to be particularly susceptible to such damage because neurons consume large amounts of oxygen, which can result in excessive production of free radicals and leave them vulnerable to single-strand DNA damage. Because brain cells do not divide, they cannot use the backup repair systems found in other tissues.

Investigators developed a way to switch off Xrcc1 production in the mouse brain and nervous system as development began. The system meant Xrcc1 still worked normally in the rest of the body.

The strategy used mice developed to make a particular enzyme, known as cre recombinase, in just the nervous system. St. Jude researchers then developed a mouse that carried an Xrcc1 gene outfitted with biochemical tags targeting the gene for inactivation by the enzyme. The result was a mouse whose nervous system lacked Xrcc1 and so was unable to efficiently repair the single-strand DNA damage.

The shutdown triggered a dramatic decline of interneurons throughout the cerebellum. In a subgroup of those cells, the damage triggered apoptosis, or programmed cell death. But the findings suggested the greatest loss occurred as the immature cerebellar interneurons, or progenitor cells, were poised to complete differentiation. In those cells, McKinnon said, loss of Xrcc1 activated the p53 pathway and blocked the cells from completing the cell cycle. “The cells appear to undergo permanent arrest,” said McKinnon, noting it is one of the few in vivo examples of the p53 pathway leading to cell cycle arrest rather than apoptosis.

In the hippocampus, which plays a role in memory and emotion, investigators reported abnormal gene expression and neuronal function. Some neurons were eventually replaced by scar tissue in a process known as gliosis. Overall changes in the hippocampus mimicked those found in the brains of adults with the seizure disorder known as temporal lobe epilepsy. In this study, the loss of Xrcc1 also resulted in seizures in mice.

The other authors of this paper were Youngsoo Lee, Sachin Katyal, Yang Li and Helen R. Russell, all of St. Jude; and Sherif F. El-Khamisy and Keith W. Caldecott of the University of Sussex, Brighton, UK.

The work was supported in part by the National Institutes of Health and ALSAC.

Source: St. Jude Children’s Research Hospital


Dr. Rezaian has created a method of minimally invasive laser back surgery to treat herniated discs in the spine. Anyone who has experienced the pain involved with a herniated spinal disc knows that it can be excruciating.

Since cartilage discs separate the spinal vertebrae and provide cushioning for the impact involved in daily movement, a herniated disc results in extreme pain that can cause immobility. Herniated discs also tend to push into the nerves surrounding the spine, resulting in pain that spreads throughout the arms and legs. Without spinal surgery, a herniated disc can rupture and cause irreversible paralysis.

Traditional spinal surgery for herniated discs has proven to be an inadequate solution for the ailment. Not only does the traditional back surgery involve deep incisions, risky general anesthesia and a very invasive procedure, it is only effective in relieving back pain for about 70% of the people who undergo surgery. The biggest concern is that, for many, pain after spine surgery can be even worse than the pain before the procedure.

Knowing that there was to be a better way to treat herniated discs, Los Angeles orthopaedic and spinal surgeon Dr. Rezaian, of the California Orthopaedic Medical Clinic, worked for years to help perfect a laser back surgery technique. His laser surgery technique, known as Universal Endoscopic Laser Discectomy (UED), is 98% effective in relieving patients of their back pain. Even more impressive than the success rate, however, is the rapid recovery time and minimally invasive nature of the laser back surgery. Unlike traditional back surgery to remove herniated discs, laser surgery does not leave any scars and allows patients to recover in an abbreviated time frame. Instead of spending weeks or months out of commission, patients are able to return to work quickly without excruciating back pain or lifelong scarring.

The laser back surgery procedure has been successfully performed on people of all ages, from 13 year old teenagers to senior citizens at the ripe age of 93. Since laser back surgery only requires local anesthesia, it is an all-around safer procedure and can be performed on people whose health may not permit undergoing general anesthesia.

For more information  http://www.laserbacksurgery.com/


A breakthrough in transgenic animal production enables development of new human disease models

Scientists from The Medical College of Wisconsin in Milwaukee, Sangamo Biosciences, Inc., Sigma-Aldrich Corporation, Open Monoclonal Technology, Inc. and INSERM announced the creation of the first genetically modified mammals developed using zinc finger nuclease (ZFN) technology.

In a paper published in the July 24, 2009 issue of Science, researchers describe the novel application of ZFNs to generate rats with permanent, heritable gene mutations, paving the way for the development of novel genetically modified animal models of human disease. ZFN technology will make the generation of such animals faster and will create new opportunities in species other than mice.

“Until now, rat geneticists lacked a viable technique for ‘knocking out,’ or mutating, specific genes to understand their function,” said Howard Jacob, Ph.D. Director of the Human and Molecular Genetics Center at the Medical College of Wisconsin. “This study demonstrates that ZFN technology bypasses the current need to conduct cumbersome experiments involving nuclear transfer (cloning) or embryonic stem cells and allows rapid creation of new animal models.”

In the study published in Science titled “Knockout Rats via Embryo Microinjection of Zinc Finger Nucleases,” (Geurts, et al.) scientists used ZFNs to knock out an inserted reporter gene and two native rat genes without causing measurable effects on other genes. Importantly, offspring of the ZFN-mutated rats also carried the modifications, demonstrating the genetic changes were permanent and heritable. Together, these results demonstrate the ability to deliver engineered ZFNs into early-stage embryos and rapidly generate heritable, knockout mutations in a whole organism.

Rats are physiologically more similar to humans than are mice for many traits and are ideal subjects for modeling human diseases. Extensive genetic characterization has revealed that approximately 90 percent of the rat’s 25,000-30,000 estimated genes are analogous to those in humans and mice, and their larger size makes them a superior model for drug-evaluation studies using serial sampling. Generating rats with knockout mutations has been a major challenge, but the new technique will increase the rat’s usefulness in research pertaining to physiology, endocrinology, neurology, metabolism, parasitology, growth and development and cancer. Along with his colleagues, Dr. Jacob’s team hopes to use knockout rats to gain a better understanding of disease processes related to hypertension, heart disease, kidney failure and cancer.

ZFNs are engineered proteins that induce double strand breaks at specific sites in an organism’s DNA. Such double-strand breaks stimulate the cell’s natural DNA-repair pathways and can result in site-specific changes in the DNA sequence. Previously, ZFNs were used to knock out specific genes in fruit flies, worms, cultured human cells and zebrafish embryos and are now in human clinical trials for the treatment of HIV/AIDS. This is the first example of successful gene editing in mammalian embryos using this technology.

“Our ZFN technology is widely applicable across species,” stated Philip Gregory, D.Phil., Sangamo’s vice president of research. “Used in conjunction with standard laboratory techniques, ZFNs provide a powerful solution to the challenge of making gene knockouts in cells and in whole organisms. We believe that this technology will become the method of choice for genome engineering in cells, plants and transgenic animals.”

In the first commercial application of this technique, OMT, a private biotechnology company developing a new rat-based human antibody platform, used Sangamo’s ZFNs to knock out the gene encoding rat immunoglobulin M (IgM), an important gene for rat antibody production. Inactivation of rat IgM expression is the first step in generating rats that exclusively express human antibodies encoded by transgenic human immunoglobulin genes. “Creating a knockout rat was the biggest challenge OMT faced,” said Dr. Roland Buelow, CEO of OMT and a senior author of the paper. “Inactivation of endogenous rat antibody expression is essential for human antibody expression in genetically engineered animals. To solve this problem, we used ZFN technology in an application that has the potential to revolutionize genetic engineering of animals.”

“We have invested our time and resources to develop the CompoZr platform because we see enormous potential in a technology that can precisely manipulate the genome of living organisms,” said Dr. David Smoller, President of Sigma-Aldrich’s Research Biotech business unit. “We are proud to be part of the public-private collaboration developing the proof-of-concept for this technique, which we believe will become the standard for the creation of genetically engineered research animals.”

Sigma-Aldrich, the sole source of commercial zinc finger nucleases for the research community, markets Sangamo’s ZFN technology through its CompoZr(TM) line of products and services. To get more information, please visit http://www.compozrzfn.com/.

Source: Sigma-Aldrich


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