New results from a prospective clinical trial conducted in France show that children with low-risk retinoblastoma do not need postoperative (adjuvant) chemotherapy to prevent disease recurrence or metastasis; the results also suggest that certain patients with intermediate-risk disease can receive less aggressive adjuvant treatment, or perhaps forego it altogether. Avoiding chemotherapy spares patients from treatment side effects and long-term health risks, such as cardiovascular disease and development of a second cancer.

Retinoblastoma accounts for 3 percent of all cancers diagnosed in children under the age of 15. An estimated 300 cases of retinoblastoma will be diagnosed in the United States this year, most before the age of five years. About two-thirds of children with retinoblastoma have unilateral disease. In developed countries, this type of disease is typically detected around two years of age. More than 95 percent of such patients are cured by surgical removal of the affected eyeball, with eyesight preserved in the other eye. However, some patients remain at risk of disease spreading and recurrence.

To estimate the risk of disease recurrence and metastasis, doctors examine the surgically removed eye under a microscope and classify the tumor as either low-, intermediate- or high-risk. All patients whose tumors are considered high-risk receive intensive postoperative chemotherapy and radiation therapy. There is no consensus, however, on the need for adjuvant therapy and the optimal treatment approach for patients in the other two risk categories. Therefore, protocols for adjuvant chemotherapy use in these patient groups have varied widely.

“Our study confirms that it is not necessary to give adjuvant treatment to many children with unilateral retinoblastoma,” said lead study author Isabelle Aerts, MD, a pediatric oncologist at Institut Curie in Paris, France. “I think that our results will help establish the standard of care for such patients, reducing variations in postoperative chemotherapy protocols.”

In the study, 123 patients with unilateral, non-hereditary retinoblastoma were assigned to one of three risk groups according to previously established criteria. The median age at the time of eye removal surgery was 23 months. The 70 patients with low-risk disease received no postoperative chemotherapy; the 52 patients with intermediate-risk disease received four courses of adjuvant chemotherapy (etoposide, carboplatin, vincristine, cyclophosphamide), and the only patient with high-risk disease received six courses of high-dose adjuvant therapy (etoposide, carboplatin, thiotepa, vincristine and cyclophosphamide).

At a median follow-up period of 71 months, all patients were alive. None of the patients experienced disease worsening, relapse, distant metastasis or secondary cancers. The adjuvant chemotherapy was safe overall. These data confirm that the specific regimens administered in this study, which are already being used around the world, are very effective and safe.

The excellent outcomes observed in this study confirm it is safe for patients with low-risk disease to go without adjuvant therapy and suggest that it may be safe to reduce the intensity of or even eliminate adjuvant chemotherapy in some patients with intermediate-risk disease, specifically those with a risk feature known as isolated choroidal invasion—spreading of tumor cells to the layer of blood vessels and connective tissue at the back of the eye. However, more research is needed to establish clinical criteria for identifying such patients. As all patients were alive at the end of the follow-up period, it is not clear whether adjuvant treatment played a vital role, or if surgery would have been sufficient.

Dr. Aerts and her research team have recently launched a new study to confirm these results and also determine if treatment could be reduced in some patients in the intermediate-risk category. In this ongoing study, patients with intermediate-risk disease and isolated choroidal invasion are being treated with only two cycles of adjuvant chemotherapy.

An international group of investigators has identified seven new genetic regions associated with age-related macular degeneration. The findings, reported online March 3 in Nature Genetics, could point to new biological pathways and therapeutic targets for AMD. 

The AMD Gene Consortium, a network of 18 research groups supported by the National Eye Institute, also confirmed 12 genetic loci identified in previous studies. The study represents the most comprehensive genome-wide analysis of genetic variations associated with AMD. 

The consortium’s efforts have now explained up to 65 percent of the genetics of AMD, said Jonathan Haines, PhD, director of the Vanderbilt Center for Human Genetics Research. 

In addition to genetic causes, which may account for about half of all cases of AMD, risk factors include age, smoking, high blood pressure, obesity and diet. “We’re getting closer and closer to understanding the full list of risk factors for AMD,” said Dr. Haines, one of the lead authors of the study and principal investigator of the coordinating center for the consortium. 

Dr. Haines and others discovered the first genetic risk factor for AMD in 2005—Complement Factor H, which is involved in inflammatory signaling pathways. Since then, researchers have identified a number of other genetic loci associated with AMD, but the studies usually involved small numbers of individuals. 

“It was very clear that if we wanted to make real progress in understanding the genetics of AMD, we needed to pull all of these various datasets together—which is what the AMD Gene Consortium has done,” Dr. Haines said. 

A strength of the AMD Gene Consortium, Dr. Haines noted, is the participation of groups from all over the world. The consortium combined existing genome-wide association scans and performed additional genotyping studies. The researchers examined genetic data from more than 17,000 patients with advanced AMD and more than 60,000 people without AMD. 

The loci they identified include genes involved in immune system signaling, lipid metabolism, remodeling of the matrix that surrounds cells and blood vessel development. The researchers are continuing to study the genetic regions, Dr. Haines said. 

“This paper is a global population look at genetic loci, and now we’re drilling down to the details and discovering rare variants in genes that may suggest how they participate in causing AMD,” Dr. Haines said. 

The hope, he said, is that a full understanding of genetic and environmental risk factors will allow the computation of an AMD risk score. Several companies already offer tests that generate risk scores, but they are based on older information. 

“If we can identify the people who are at greatly increased risk for AMD, perhaps we can begin to do clinical trials to test treatments that may prevent the disease,” Dr. Haines said. 

The largest ever genome-wide association study on myopia has identified 20 new genetic associations for the condition. The study, which was specific to individuals of European ancestry, also replicated two known associations. The study included an analysis of genetic data and survey responses from more than 50,000 customers of 23andMe, a personal genetics company, and demonstrates that the genetic basis of myopia is complex and affected by multiple genes. 

In the United States, an estimated 30 to 40 percent of the adult population is myopic.

The study, “Genome-Wide Analysis Points to Roles for Extracellular Matrix Remodeling, the Visual Cycle, and Neuronal Development in Myopia” was published on February 28, 2013 in PLOS Genetics. 

Although environmental factors (such as level of education, outdoor exposure, reading and near work) are implicated in the development of myopia, it is well-established that genetics plays a substantial role as well. The identification of these 20 novel genetic associations shows that several new genetic pathways play a role in the development of human myopia, including extracellular remodeling, the visual cycle, eye and body growth, retinal neuron development and general neuronal development or signaling.

“This study highlights the potential importance of early neuronal development in the progression of myopia and opens the door for additional research into the complex interactions that underlie vision development,” said Nicholas Eriksson, PhD, author and 23andMe principal scientist. Based on the findings of this study, the company has launched a new research survey designed to provide insights that may expand understanding of the genetics of eyesight more broadly. 

A Johns Hopkins University team has found that there is a kind of turf war going on in the retina, where intrinsically photosensitive retinal ganglion cells (ipRGCs) are jockeying for the best position to receive information from rod and cone cells about light levels. By studying these specialized cells in mice, the researchers found that the cells actually kill each other to seize more space and find the best position to do their job.

The work could have implications for several conditions, including autism and some psychiatric disorders, where neural circuits influence our behavior. “In a nutshell, death in our retina plays a vital role in assembling the retinal circuits that influence crucial physiological functions such as circadian rhythms and sleep-wake cycles,” said Samer Hattar, PhD, an associate professor of biology in the Krieger School of Arts and Sciences. “Once we have a greater understanding of the circuit formation underlying all of our neuronal abilities, this could be applied to any neurological function.”

Dr. Hattar and his team determined that without this cell death, circadian blindness overcame the mice, who could no longer distinguish day from night. The mice were genetically modified to prevent cell death by removing the Bax protein, an essential factor for cell death to occur. The team discovered that if cell death is prevented, ipRGCs distribution is highly affected, leading the surplus cells to bunch up and form ineffectual clumps incapable of receiving light information from rods and cones for the alignment of circadian rhythms. To detect this, the researchers used wheel running activity measurements in mice that lacked the Bax protein as well as the melanopsin protein, which allows ipRGCs to respond only through rods and cones and compared this to animals where only the Bax gene was deleted.

The authors said that when death is prevented, the ability of rods and cones to signal light to our internal clocks is highly impaired. This shows that cell death plays an essential role in setting the circuitry that allows the retinal rods and cones to influence our circadian rhythms and sleep.  REVIEW