PHILADELPHIA INTERNATIONAL MEDICINE NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
In this month’s issue:
1. Jefferson study used DNA therapy to shrink tumors
2. Children's Hospital program successfully shrinks bone tumors, saving limbs
3. Mannequin helps physicians gain CME credits at Crozer
Philadelphia - Philadelphia International Medicine hospitals, when combined conduct more than $400 million annually in medical research, provide the latest medical care available to international patients. Below are some examples of how PIM hospitals are considered leaders in health care in the United States.
Researchers at Jefferson Medical College have used DNA therapy known as antisense to treat patients with usually fatal brain tumors. The majority of patients treated to date have had partial responses, and one has even recovered well enough to take up golf again. While most have relapsed since their initial treatment, the doctors hope the therapy will eventually be further developed and help provide patients a better quality of life.
David W. Andrews, MD, associate professor of neurosurgery; Renato Baserga, MD, distinguished professor of microbiology and immunology and deputy director of Jefferson's Kimmel Cancer Center; Robert Aiken, MD, associate professor of neurology, all at Jefferson Medical College of Thomas Jefferson University in Philadelphia and their colleagues treated 12 patients who had either glioblastoma or anaplastic astrocytoma, both deadly brain cancers, and who had failed prior therapy. In a Phase I trial, which is designed only to answer questions of drug safety, eight patients (three were treated twice) unexpectedly improved, meaning some of their tumors shrank in size, including two patients whose tumors temporarily "disappeared."
The therapy entails using antisense against the type-1 insulin-like growth factor receptor, or IGF-1R, causing a biologically programmed death of tumor cells by a process called apoptosis and at the same time stirring the immune system to action. IGF-1R plays a role in the proliferation of cells, sending a signal for growth, differentiation, proliferation, and protection against apoptosis.
"The observation is quite remarkable and very unexpected," says Dr. Baserga, who has pioneered much of the basic science known about IGF-1R's role in cancer development and as a potential anticancer drug target for pharmaceutical companies. "It's a one-two punch. We knew that targeting the IGF receptor induces apoptosis, but unexpectedly, it also induced a host immune response that strengthens the killing of tumor cells."
The study results appear April 15 in the Journal of Clinical Oncology.
"This treatment has the potential to eventually be used for other cancers," Dr. Andrews says. But not yet. Despite the promising results, the work, for now, is on hold. The Food and Drug Administration has required more preclinical data. In addition, the scientists are frustrated by the lack of available antisense, which must be produced according to strict FDA standards.
In the study, Dr. Andrews removed each patient's tumor, made a suspension of tumor cells, and then treated them outside the body with antisense to IGF-1R. He then implanted the treated cells, now encapsulated in special "diffusion" chambers, in the patient's abdomen for 24 hours, allowing the antisense to kill tumor cells through apoptosis.
Antisense therapy is designed to target and turn off the mutated genes that cause cancer. Antisense DNA drugs work by binding to RNA messages from disease genes so that the genetic code in the RNA cannot be read. In contrast to the shotgun approach of chemotherapy, which kills both normal and cancerous cells, antisense exclusively attacks cancer cells. When the gene translation mechanism is turned off, cells can no longer make the protein products that cause disease.
Children's Hospital program successfully shrinks bone tumors, saving limbs
Limb-sparing procedures are a growing option for children with malignant tumors of the extremities because of several advances including magnetic resonance imaging (MRIs) that improve the surgeon's ability to visualize and access tumors preoperatively. Removing only the tumor while sparing the limb is also easier with improved chemotherapy regimens. The drugs shrink tumors so more tissue, bone and muscle can be spared and better mobility can be restored.
In the case of a 10-year old boy, a pelvic tumor was situated dangerously close to his hip joint, spinal cord and bladder. It took 13 weeks of chemotherapy before his doctor, John P. Dormans, MD, chief of the hospital's Division of Orthopedic surgery, could remove the tumor. In a pioneering operation called an interval hemipelvectomy with "A-frame" free vascular fibula reconstruction, Dr. Dormans and his musculoskeletal team (composed of team members from orthopedic surgery and plastic surgery), removed the boy's tumor as well as a surrounding cuff of normal pelvic tissue. His pelvis was rebuilt using the fibula bone from his leg -- one of two bones in the lower leg -- and the blood vessels attached to it.
After healing his rebuilt pelvis and reconstruction, the boy was able to resume activities. In fact, today, he not only frequents the slopes, but the swimming pool and golf links. A slight limp is all that hints of the tumor that was eating away his pelvis and threatening his life years ago.
He is a shining example of how treatment technology has beaten limb -- and life -- threatening cancer in children. Today, 85 percent of the 880 kids diagnosed annually with bone (osteosarcoma and Ewing's Sarcoma) and soft tissue cancer are cured-and up to 90 percent without limb loss. "A little more than two decades ago, 85 percent of children and teens lost their lives. Limb removal was the standard treatment," Dr. Dormans says.
Studies have shown that there is no survival disadvantage for patients treated with limb-sparing surgery compared to those treated with amputation as long as surgery involves removing the entire tumor with wide margins (a cuff of normal tissue surrounding the entire tumor).
As tumor removal procedures evolve, there are more customized limb-sparing options. "Kids with bone cancer are like snowflakes," says Dr. Dormans. "Each tumor is different and requires a different approach."
There are 206 bones in the body that may involve cancer, and deciding which option is best depends upon the location of the tumor, the size of the tumor and whether it has spread to other areas of the body, such as other bones and the lungs.
Depending on these factors, once the cancerous bone or soft tissue tumor is removed, replacement options may involve one of the following:
In each case, soft tissue and muscle are transferred to cover and close the site and restore motor power. Chemotherapy often follows surgery. Physical therapy helps retrain muscles and nerves. While all this rehabilitation and healing is going on, the extremity appears normal with barely a trace of what occurred inside.
"Many kids opt to have an endoprothesis because it's invisible and function and movement are good, but limb-sparing is not always the best option for every child," says Dr. Dormans. For one thing, growth in young children -- particularly the growth of the legs -- presents a major challenge. While an expandable endoprothesis can be lengthened in small increments to allow for the growth of the child, the healthy leg may grow at a faster pace in very young children. This can result in a significant difference in leg lengths.
One way to remedy this problem is to halt the growth plates in the healthy leg. A child's activity level is another consideration. "Kids who wish to partake in high impact sports such as running or contact sports such as football learn that an endoprothesis cannot bear the brunt of these activities," says Dr. Dormans. For this reason, some kids with difficult tumors in difficult sites choose other reconstructive options.
For very young children with cancer above the knee, one alternative is rotationplasty. This procedure removes the diseased bone and replaces the knee joint with the ankle joint. "By moving up the ankle and reattaching it to where the knee joint was, we can preserve more mobility," says Dr. Dormans. The patient is fitted with an artificial prothesis to replace the missing lower leg while retaining full knee mobility.
To help kids make the best decision, doctors at Children's Hospital musculoskeletal tumor program encourage them to meet other young people who have had various surgical options including limb-sparing surgery.
Research papers available:
Himelstein, Bruce B., M.D., and Dormans, John P., M.D., "Malignant Bone Tumors of Childhood," Common Orthopedic Problems, 1, Pediatric Clinics of North America, 1996, vol. 1; 43, number 4. Rougraff BT, et. al. "Limb Salvage Compared with Amputation for Osteosarcoma of the Distal End of the Femur: A long-term oncological, functional, and quality-of-life study," Journal of Bone Joint Surgery, 1994; 76A; 649-656.
Dormans, John P., M.D., "Limb-salvage Surgery vs. Amputation for Children with Extremity Sarcoma," Chapter 25, pp. 289-303 in The Child with a Limb Deficiency, Herring, JA. & Birch, JG, editors, The American Academy of Orthopaedic Surgeons, 1998.
Mannequin helps physicians gain CME credits at Crozer
Continuing education is of utmost importance to Crozer-Chester Medical Center physicians and staff who consistently strive to provide excellence in clinical services to the people of our community. CME courses from Crozer-Keystone Health System and other PIM-member hospitals are available to international physicians by calling PIM at 215-735-3575 and asking for Lucia Rosenberg (e-mail: lrosenberg@philadelphiamedicine.com).
As an example, offered for the first time in a hospital setting in the Philadelphia region, 43 medical center anesthesiologists, certified registered nurse anesthetists, student nurse anesthetists (SNA), paramedics, and other medical disciplines tested their medical expertise recently during learning sessions with "Stan," a human simulator that mimics human responses rather than a real patient, as their patient.
Interactive, hands-on learning sessions were conducted in Crozer's Recovery Room, under the direction of Hal Doerr, MD, director of simulation for Baylor Medical Center in Houston. Developed at the University of Florida in Gainesville, other mannequins similar to "Stan" are used to train physicians, residents and nurses.
Interactive, hands-on learning sessions were conducted in Crozer's Recovery Room, under the direction of Hal Doerr, MD, director of simulation for Baylor Medical Center in Houston. Developed at the University of Florida in Gainesville, other mannequins similar to "Stan" are used to train physicians, residents and nurses.
Olesh Babiak, MD, chairman of Crozer's Department of Anesthesia, explained, " The simulator sessions were invaluable. After each scenario, a debriefing session highlighted any glitches, and provided a streamlined approach to dealing with elements that might have occurred during a particular crisis.
Babiak continued, "I learned a great deal not only from participating but also from observing other colleagues in action as well as from sharing ideas with them and Dr. Doerr. The anesthesia simulator will one day be broadly used in training beyond the Operating Room, and will complement, not replace our conventional methods of training healthcare providers."
"Stan" is a life-size mannequin and can accurately mirror an anesthetized male or female patient who requires immediate medical intervention. He is one of 110 human simulators-some small children, and others with the capability of mimicking "pregnant" women with fetuses-that each cost approximately $176,000 to produce. These state-of-the-art mannequins are constantly being refined to present a variety of crisis scenarios that might occur. They can be programmed to be young or old, healthy, injured or very ill.
Physicians and other healthcare professionals observe physical signs such as muscles stiffening, chest rising, change in pulse rates, urinary output, heart and breathing sounds. They can also study hemo-dynamic data that is displayed on the physiological monitors to assess vital signs and existing conditions.
Doerr uses a laptop computer to offer 600 different symptoms that is not only able to infuse "Stan" with life but also with potentially life-threatening symptoms. Because specific medications cause a patient's pupils to dilate and pulse to beat irregularly, clinicians must identify the identical disease-related symptoms in 'Stan', and react appropriately.
"Stan" reacts to intravenous drugs, CPR, defibrillation, intubation, ventilation, catheterization, and a host of other procedures.
A data recorder provides the user with a continuous, time-based record of the "patient's" physiology, and interventions by the hands-on exercise participants.
Doerr explained, "It's all about crisis management. As a medical team each member must do his or her particular part to keep the patient alive, and provide appropriate treatment."
Philadelphia International Medicine is an organization that provides medical and patient support services to international patients. It also provides continuing medical education and health care training and education to international physicians, administrators and other practitioners. As the international department of several Philadelphia-area hospitals, international patients gain access to physicians and hospitals rated among the best in the world through one telephone call to PIM. You can reach PIM by calling 1-215-735-3575; fax, 1-215-790-1267; or e-mail, physicians@philadelphiamedicine.com. You can find out more about PIM through its Website at www.philadelphiamedicine.com.
- 30 -