Contact: Leonard N. Karp
215-575-3720
lkarp@philadelphiamedicine.com
August 24, 2007
For immediate release:
In this month’s edition:
- Pooling International Data About Childhood Tumors Helps Researchers Gauge How Aggressive Treatment Must Be; Runaway Neuroblastoma Tumors Respond to New Molecular Methods
- Brain Implant Being Studied at Jefferson Could Predict and Stop Epilepsy Seizures Before They Even Begin
- Western Diet Linked To Increased Risk of Breast Cancer in Postmenopausal Asian Women
Editors note: Research, new techniques and improved facilities by Philadelphia International Medicine hospitals and physicians may lead to new ways to treat some of our most challenging diseases. Below are just some examples from our hospitals.
Pooling International Data About Childhood Tumors Helps Researchers Gauge How Aggressive Treatment Must Be; Runaway Neuroblastoma Tumors Respond to New Molecular Methods
Philadelphia – Sorting types of cancer into higher- and lower-risk groups is not merely a matter of scientific interest, but a matter of life and death. Undertreating a highly aggressive cancer could lead to the preventable death of a child, whereas overtreating a less aggressive form may subject a child to unnecessary side effects and complications. With some children, what is left undone may be just as important as what is done to treat their tumors.
Yet some cancers behave in ways that defy easy categorization. A case in point is neuroblastoma, a solid tumor of the peripheral nervous system that accounts for 10 percent of all childhood cancers and 15 percent of cancer deaths in children. These tumors occur almost exclusively in children, usually arising in the abdomen or chest.
Unfortunately, Hunter Tuccio had a very aggressive form of neuroblastoma. In September 1997, two months short of his second birthday, the active toddler abruptly lost his characteristic energy and appetite. "In less than a week, he deteriorated to the point that he couldn’t move his eyeballs," said his mother, Susan Tuccio. His pediatrician, in Ridgefield, Ct., had him admitted to the local hospital where ultrasound detected a tumor in Hunter’s abdomen, on his adrenal gland.
The diagnosis was neuroblastoma. "After you find out your child has cancer, your world is never the same," said Ms. Tuccio. A search for answers led her to The Children’s Hospital of Philadelphia, where pediatric oncologists have been world leaders in caring for children with neuroblastoma and studying this disease in the laboratory.
Hunter’s neuroblastoma was classified as stage 4: the cancer had spread beyond the primary tumor. Even worse, the tumor cells contained multiple copies of a particular gene, labeled MYCN, which is a cancer-causing "oncogene." Often compared to an accelerator pedal, MYCN can cause cancer cells to multiply in a runaway fashion. When MYCN is amplified -- which means that cells have 200 copies rather than the normal two copies of the defective gene -- the prognosis is grave. In fact, at the time of Hunter’s diagnosis, only about 20 percent of children with this high-risk type of neuroblastoma were surviving with the conventional treatment of chemotherapy, radiation and surgery.
"MYCN amplification is the most important factor predicting a patient’s likelihood of survival from neuroblastoma," says Garrett Brodeur, MD, chief of Oncology at The Children’s Hospital of Philadelphia, whose research has helped oncologists worldwide establish better standards for diagnosing and treating children with neuroblastoma. "If we use only the child’s age and disease stage as criteria for assigning risk, some patients will be undertreated and some will be overtreated."
Hunter underwent intensive treatments at Children’s Hospital, under pediatric oncologist Stephan Grupp, MD, PhD, director of Stem Cell Biology. The regimen required a succession of high-dose chemotherapy drugs, surgery to remove the primary tumor, local and full-body radiation, and two stem cell transplants, six weeks apart.
The stem cells used are those that develop into blood cells, including crucial immune system cells. They were removed from Hunter’s blood, then frozen and stored while the boy received intensive doses of chemotherapy and radiation to kill tumor cells. Because those high-dose treatments also killed healthy blood cells, his stem cells were thawed and transplanted back into Hunter to help make blood cells again, after being purged to eradicate any lurking cancer cells.
Such transplants formerly were done with stem cells taken from the bone marrow of neuroblastoma patients. However, stem cells found in peripheral blood provide better results. "Peripheral blood stem cells regenerate faster than bone marrow stem cells," says Dr. Grupp. "By doing tandem transplants, six weeks apart, we can use higher doses and a greater variety of treatments to kill the tumor cells. This isn’t possible with bone marrow."
Hunter’s tumor shrank after a second round of chemotherapy and his nurses nicknamed him "the Bull," in recognition of his big size and hearty personality. Because he had not tolerated sedation drugs well, his mother coached Tuccio as he remained still for 30 minutes during his full-body radiation treatment. Three years after finishing his treatments, Hunter is an active, growing 5-year-old, preparing for kindergarten in the fall.
"We don’t say a child is cured three years after neuroblastoma treatment, but after three years, the likelihood of a relapse is low," said Dr. Grupp, who added that Hunter participated in a clinical trial that helped raise the bar for treating high-risk neuroblastoma. The tandem treatment protocol achieved survival rates (after three years) of 60 percent, three times the survival rate before stem cell transplants. (Journal of Clinical Oncology, July 2000, vol. 18, pp. 2567-2575).
Based on these results, the Children’s Cancer Group, a multicenter national cooperative group of pediatric oncology centers, will conduct a larger study of the tandem transplant protocol for high-risk neuroblastoma, with Dr. Grupp as the principal investigator.
While Dr. Grupp works to refine treatments, Dr. Brodeur’s team continues to define more accurate risk groupings. He chaired the medical committees that devised the International Neuroblastoma Staging System published in 1988 and 1993, as well as the International Neuroblastoma Risk Groups published in 1997. Working with pediatric oncologists from the U.S., Europe and Japan, Dr. Brodeur helped establish diagnostic standards that have been adopted by numerous other medical groups worldwide.
"Having international criteria with common definitions allows us to compare data from studies performed around the world," said Dr. Brodeur, who noted that the numbers of children in any one center’s study are too small from which to draw sound scientific conclusions. "Having uniform standards makes it possible to pool data from more than one center and to evaluate the effectiveness of different treatments. What is unique about the consensus we have reached for neuroblastoma is that it goes beyond conventional clinical staging to incorporate molecular characteristics of the cancers, yielding more accurate risk groupings and guiding better treatments."
Dr. Brodeur’s team also continues to explore the molecular mechanisms of neuroblastoma. While important, the MYCN oncogene is not the whole story. For instance, specific genes, called Trk genes, govern production of cell receptors for nerve growth factors. Those nerve growth factors, in turn, affect whether neuroblastoma cells continue to grow, mature into nondividing cells, or die.
By using drugs called Trk inhibitors to block the Trk receptor pathways, it may be possible to trigger tumor cells to undergo apoptosis -- the process of cellular suicide. Trk inhibitors may also weaken the resistance of neuroblastoma cells to chemotherapy, and could be used in combination with conventional anticancer drugs.
Dr. Brodeur and his colleagues found that a Trk inhibitor, designated CEP-751, significantly slowed neuroblastoma tumor growth in mice, with minimal side effects. (Medical Pediatric Oncology. 2001, vol. 36, pp. 181-184). It is not yet ready for human trials. However, by targeting specific signaling pathways known to be important in this cancer, this approach may produce effective treatment with fewer of the toxic side effects seen with many chemotherapy drugs.
"We may have reached almost as far as we can in killing cells with conventional chemotherapy and radiation," says Dr. Brodeur. "The next steps will involve manipulating molecular pathways to prevent tumor growth or to make tumors more susceptible to cancer drugs. We may also induce them to differentiate into benign tumors, or to trigger the cell death pathway. Such approaches are likely to be more effective and less toxic than current approaches. In my opinion, these newer approaches represent the future of cancer treatment."
Brain Implant Being Studied at Jefferson Could Predict
and Stop Epilepsy Seizures Before They Even Begin
An implanted stimulator being studied at Thomas Jefferson University Hospital may be able to predict and prevent seizures before they start in people with uncontrolled epilepsy.
Researchers at the Jefferson Comprehensive Epilepsy Center are enrolling patients in a study of the Responsive Neurostimulator System (RNS) made by Neuropace to determine if it is effective in stemming seizures. The system contains a computer chip that detects seizures and then delivers electric current to the brain to stop them.
"If it works as well as we hope, this device will be an exciting leap forward in the field," said Michael Sperling, MD, director of the Jefferson Comprehensive Epilepsy Center and the Baldwin Keyes Professor of Neurology, Jefferson Medical College of Thomas Jefferson University. "This is the first closed-loop system being used in humans designed to stop seizures."
Earlier devices, such as a vagal nerve stimulator, gave out intermittent electrical stimulation to stop seizures, but never directly to the brain, explained Christopher Skidmore, MD, principal investigator of the study at Jefferson. The RNS only delivers an electrical current when a seizure is detected and stimulation is needed.
More than two million people in the U.S. have epilepsy, the third most common neurological disorder in the country. Approximately 30 to 40 percent of people with epilepsy have seizures that cannot be controlled with medications, leaving many unable to work or drive.
Uncontrolled seizures related to epilepsy are generally treated with antiepileptic medications. However, many individuals treated with medication alone continue to experience seizures or medication side effects. Uncontrolled epilepsy can severely diminish quality of life and is often associated with increased rates of injury, depression and death. Some people with severe epilepsy may be candidates for epilepsy surgery to remove the part of the brain that triggers the seizures, but this is not always feasible.
The RNS system is an implantable device designed to detect abnormal electrical activity in the brain and deliver small amounts of electrical stimulation in response. It is placed by a surgeon within the skull and beneath the scalp. The device is then connected to two wires containing electrodes that are placed within the brain or resting on the brain surface in the area of the seizure focus. By continuously monitoring brain electrical activity, after identifying the "signature" of a seizure’s onset, the device delivers brief electrical stimulations with the intention of suppressing the seizure before any symptoms occur.
An early study of the RNS system in 65 adults with medically uncontrolled epilepsy indicated that the device was safe.
As this is a controlled study, all study participants will receive the implant but only half of them will have the device activated in the initial phase. The others will have the device activated 16 weeks after surgery once the controlled phase is complete, said Dr. Sperling.
"Patients who have the device activated one month after surgery will be monitored weekly at the epilepsy center to tweak the chip’s programming for optimal performance," Dr. Skidmore said.
Patients will also receive a device that is able to scan the chip for information about seizures just by holding a wand over the scalp, he said. The information can then be downloaded by the patient onto a computer and sent via telephone to epilepsy researchers to review.
Participants in the RNS study must be from 18 to 70 years of age and meet the following requirements:
- have disabling (significant enough to impair functional abilities or day-to-day life activities) motor simple partial seizures, complex partial seizures and/or secondarily generalized seizures;
- failed treatment with a minimum of two antiepileptic medications; and
- experienced an average of three or more disabling seizures every 28 days for three consecutive periods prior to enrollment and have no more than two regions that induce seizures in the brain.
Western Diet Linked To Increased Risk of Breast Cancer in Postmenopausal Asian Women
Postmenopausal Asian women who eat a "meat-sweet" or Western diet are at greater risk of developing breast cancer than those who eat a "vegetable-soy" diet, according to a new study. The findings mark the first time an association between a Western diet and breast cancer has been identified in Asian women.
The study, published in the July issue of Cancer Epidemiology, Biomarkers & Prevention, involved women in the Shanghai Breast Cancer Study. Eligible cases included all women 25 to 64 years of age with a new diagnosis of breast cancer from August 1996 to March 1998. Controls were selected from the Shanghai Resident Registry of permanent residents in urban Shanghai.
"The issue (of diet) is of particular relevance to women in Asia, for whom breast cancer rates are traditionally low but increasing steadily in recent years," explained Marilyn Tseng, PhD, an associate member in the population science division at Fox Chase Cancer Center.
The transition in breast cancer risk has been attributed to environmental factors, possibly the incorporation of Western dietary pattern foods into traditional dietary habits as a part of broader, societal socioeconomic changes. However, the association of dietary patterns with breast cancer risk has not been studied previously in Asian women.
Through in-person interviews with the Shanghai study participants and residents of Shanghai, researchers established the existence of two primary dietary patterns—the "meat-sweet" diet and a "vegetable-soy" diet. The "meat-sweet" diet includes various meats—primarily pork but also poultry, organ meats, beef and lamb and with saltwater fish, shrimp and other shellfish as well as candy, dessert, bread and milk. The "vegetable-soy" pattern is associated with different vegetables, soy-based products, and freshwater fish.
Of 1,602 eligible breast cancer cases identified during the study period, in-person interviews were completed for 1,459 (91.1 percent). In-person interviews were completed for 1,556 (90.3 person) of the 1,724 eligible controls.
The "meat-sweet" pattern was significantly associated with increased risk of breast cancer among overweight postmenopausal women. Specifically, high intake of the "meat-sweet" pattern was associated with a greater than twofold increased risk of estrogen-receptor-positive (ER+) breast cancer among these women. The results showed no overall association of breast cancer risk with the "vegetable-soy" pattern.
"Our study suggests the possibility that the "meat-sweet" pattern increased breast cancer risk by increasing obesity, Dr. Tseng said. "Low consumption of a Western dietary pattern plus successful weight control may protect against breast cancer in a traditionally low-risk Asian population that is poised to more broadly adopt foods characteristic of Western societies."
Grants from the National Institutes of Health, the American Cancer Society, and the Commonwealth of Pennsylvania supported this research.
Tseng’s co-authors include Xiaohui Cui at Fox Chase, a graduate student from the department of epidemiology of the Harvard School of Public Health; Yu-Tang Gao, MD, from the Shanghai Cancer Institute; and Qi Dai, MD, PhD, Xiao-Ou Shu, MD, MPH, PhD, and Wei Zheng, MD, PhD, MPH, from the School of Medicine and the Vanderbilt-Ingram Cancer Center at Vanderbilt University.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation’s first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach.