PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
March 26, 2004

In this month's edition:

1. Failure of DNA Repair Mechanism Precedes Final Stage of Deadly Leukemia, New Penn Study Shows
2. New Advancements In Treatment of Vocal Cord Paralysis at Thomas Jefferson University Hospital Help Patients Speak Up
3. Children's Hospital Study Focuses on Circulation Abnormality That Can Target Pregnant Women Carrying Twins

Failure of DNA Repair Mechanism Precedes Final Stage of Deadly Leukemia, New Penn Study Shows

Philadelphia - Medical researchers at the Abramson Cancer Center of the University of Pennsylvania, a member of Philadelphia International Medicine, have discovered that the last stage of chronic myelogenous leukemia (CML), a deadly blood cancer, is preceded by the unique blocking action of a blood cell's normal cycle of DNA production and repair.

The researchers linked the blocking action to a known oncogene, BCR/ABL, and suspect it to be the cause of blast crisis, the second and final stage of CML disease when the body no longer makes enough healthy white blood cells to fight off infection or prevent bleeding. Their findings appear in the March 23rd edition of the journal Cancer Cell.

"The BCR/ABL oncogene is known to play a direct role in the first, non-deadly stage of CML, where over-production of white cells occurs - and can be treated for a limited time by medication," said lead author Martin Carroll, MD, an Assistant Professor of Medicine at Penn's School of Medicine. "Now we know that BCR/ABL also disrupts the cell's ability to repair itself, blocking a protein called ATR that regulates normal DNA synthesis. This leads to an accumulation of genetic mutations, or mistakes - which immediately precedes the final, incurable stage of CML."

It can take up to a year for a patient to transition from the first phase of CML to blast crisis. In this deadly, blast crisis phase of CML, new white blood cells fail to mature into fully-functioning cells - and, instead, become myeloblasts in a state of arrested differentiation.

In order to block ATR and DNA repair, cancer researchers also found that the concentration of BCR/ABL moves into the nucleus of the cell - where DNA is produced - from its original concentration in the cell's cytoplasm. Further research is planned to determine if this movement of BCR/ABL is a trigger or effect of blast crisis.

Researchers were able to determine the workings of BCR/ABL by comparing the amounts of damaged to un-damaged DNA in a cell line when the oncogene was turned "on" and "off." DNA damage was linked to the protein ATR and measured using comet assays.

"If blocking DNA repair proves to be the cause of blast crisis, then we may be able to prevent CML from progressing to its final stage by interrupting the action of cancer gene BCR/ABL," said Carroll. "Ultimately, this could lead to a long-term treatment for the disease that may also be applied to other progressive cancers."

Funding for the study was provided through grants from Penn's School of Medicine and the National Cancer Institute (NCI). Started in January 1999, the study will continue through 2004 to determine the causal nature, if any, between BCR/ABL and blast crisis.

CML is a fatal blood cancer that primarily affects people over age 40. There are approximately 5,000 new cases each year in the United States, and nearly 2,000 people die from the disease. During the first stage of the illness, people live for three to five years after diagnosis. On average, people live for only three months to one year after entering the final, second stage of the disease.

New Advancements In Treatment of Vocal Cord Paralysis at Thomas Jefferson University Hospital Help Patients Speak Up

People with chronic hoarseness and breathy voices often learn to live with their impediment, accepting it as an unfortunate characteristic that they feel can never change. In some cases, this voice change is due to vocal cord paralysis, a condition that can be a sign of other serious medical conditions that can lead to other health problems and affect quality of life.

Yet modern treatments offer an almost certain improvement of the condition and are surprisingly less traumatic than one might imagine. At Thomas Jefferson University Hospital, a founder of Philadelphia International Medicine, two procedures are being offered by otolaryngologists to patients with vocal cord paralysis. With both, a significant voice improvement is achieved within weeks - and in some cases right after the procedure. The procedures -- thyroplasty and vocal cord injection -- have demonstrated a high rate of success and are associated with a low level of discomfort, a one-day hospital stay and a short post-surgery recovery period.

The surgeries can be beneficial to very ill patients - especially patients suffering from severe lung cancer, cervical spine fractures, and stroke - who may have lost some or all of their ability to speak because of resulting vocal cord paralysis. Stripped of their ability to communicate with their physicians and family at a time of critical illness, the surgery can restore their ability to speak. This results in a significant, immediate improvement in their quality of life.

Vocal cord paralysis affects the vocal cords, folds of mucous membranes positioned within the larynx. "When the vocal folds are in normal position, they are in a V pattern," explained Joseph R. Spiegel, MD, associate professor of otolaryngology-head and neck surgery, Jefferson Medical College of Thomas Jefferson University." The folds open into an open V for breathing and then close and come together for speaking.

"The voice is a function of air that blows up through the vocal folds. For the voice to work and sound the right way, the folds must be able to close together like two reeds on a reed instrument in order to vibrate and create the proper sounds. "When a vocal cord is paralyzed, it cannot come into the middle to touch the other vocal cord," said Spiegel. "There is a leak between them in which the air that is blowing up is not being used to make the vocal cords vibrate."

With paralysis, the voice becomes weak and hoarse. Whether the vocal cord is partially or completely paralyzed, the person may suffer from anything from a mildly hoarse voice to almost no voice at all.

"Some people with vocal cord paralysis complain that they get short of breath when they try to talk simply because so much air is escaping through the vocal cords that they can only get a few words out before they have to take a breath," said Spiegel. "It can be exhausting."

One of the first procedures offered at Thomas Jefferson University Hospital is thyroplasty -- a viable surgical option for many. With thyroplasty, local anesthesia is used and a small cut is made in the neck along one of the natural neck wrinkles.

Surgery is conducted through the incision, and a material is wedged into and implanted next to the vocal cord to move the paralyzed vocal cord to a position that allows the folds to come closer together. Because the patient is awake, he or she can speak upon request so that the surgeons can test the placement of the implant. The implant is malleable and can be adjusted by the surgeon if need be.

"The immediate voice correction with thyroplasty is quite remarkable," said Maurits S. Boon, MD, clinical instructor in otolaryngology-head and neck surgery. "It's something that can be appreciated the day of surgery." This is not to say that the final voice product will occur that day. Healing and swelling after surgery affect the voice for a few weeks.

The second option offered is the vocal cord injection procedure that involves injections of material placed in the vocal fold to move the folds closer together to create a more normal voice. In injection cases, surgeons must decide carefully on the amount of substance introduced. "We purposefully insert more substance than we want to be there permanently because we know some of it is going to be absorbed," explained Spiegel. "In these cases, the patient is usually under general anesthesia and we cannot interact to hear the voice changes, we have to gauge how we think it's going to be three to six weeks afterward."

Although most patients undergo the procedures to restore or improve the ability to speak, it is sometimes recommended for health reasons, said Boon. "Vocal cord paralysis can affect the way people swallow. So, what is swallowed may go down the wrong pipe, if you will." Indeed, the vocal folds are a final barrier that keeps unwanted material, such as food and drink, from going into the windpipe.

"If the vocal folds cannot close completely, people lose that final barrier," said Spiegel. "This is not always a problem, but if people have additional problems, such as when they have had a stroke or weakness of other muscles in their throat, then the addition of vocal cord paralysis can be a real concern."

Thyroplasty and injection surgery have been successful for patients, but the success rate must be weighed against the goals that are expected. Said Boon, "We look at goals on different levels. Some patients have the goal of basic speech communications and conversational speech because they are unable to have conversational speech prior to the procedure. In these cases, the procedure is almost entirely successful."

Boon added, "As we have become more experienced with the procedure, we have been using both the thyroplasty and the injection procedure to try to improve the voices of people who have had more minor losses and weaknesses due to scarring and other problems."

In such patients, surgery might be used to restore a high pitch that the patient couldn't achieve before, or restore the ability to "raise" the voice, which may be vital to a classroom teacher or other professional. "In these cases, these procedures are slightly less successful in terms of fine goals. About three-quarters of these cases are successful," said Spiegel.

Vocal cord paralysis can be the result of a variety of causes and can affect individuals of all ages. Children can be born with vocal cord paralysis. The most common symptom in very young children is stridor, a sound produced by turbulent flow of air through a narrowed segment of the respiratory tract. Other symptoms of vocal cord paralysis in children include obstruction, a weak cry, difficulty speaking, and aspiration.

Children make up only a small percentage of patients seen for evaluation of vocal cord paralysis. "Most commonly, the vocal cord paralysis patients we see are in the older age groups because the most common causes we see are stroke, lung cancer, and paralysis caused by surgery for heart problems and thyroid problems," said Spiegel. "Most patients are 50 and older. Still, because of trauma and other problems, we do see and routinely treat younger people."

Patients who come to otolaryngologists with vocal cord paralysis must undergo a complete evaluation to determine the cause of the problem, said Boon. "We cannot assume we know the cause unless we have an extremely good story. For example, if someone were stabbed in the neck on the left side and suddenly has a left side vocal cord paralysis, we don't have to look a lot further into what caused it. But if somebody comes in with a change in their voice and is found to have a vocal cord paralysis, we have to do all the necessary studies."

These studies include imaging patients using computed axial tomography (CAT scan) and magnetic resonance imaging (MRI). Because the vocal folds primarily receive nervous control from a nerve called a recurrent laryngeal nerve that has a relatively long course, the studies are needed to ensure that there is not a malignancy affecting the nerve. Additionally, blood tests may be called for to rule out infectious or inflammatory causes of vocal cord paralysis.

After either procedure, patients are observed for up to 24 hours to rule out breathing problems. Few restrictions are placed on recovering patients. Patients are instructed to "take it easy" for a few days, but they generally eat normally and return to their normal daily lives very quickly.

The list of patients who would not qualify for thyroplasty or implant surgery is limited. Many patients who are relatively sick cannot tolerate general anesthesia because of heart, lung, or other problems, but can undergo thyroplasty with local anesthesia.

In such cases as lung cancer and stroke, surgeons may "push the limits" a bit and undertake the procedure in patients who are tenuous. "Verbal communication is so vital to their existence, and we respect that," said Spiegel. "We often do not realize how valuable our voice is until something goes wrong. Fortunately, modern medicine offers viable, successful treatments."

Children's Hospital Study Focuses on Circulation Abnormality That Can Target Pregnant Women Carrying Twins

Researchers at The Children's Hospital of Philadelphia, a founder of Philadelphia International Medicine, are beginning a study to compare two treatments for a serious condition that may occur in pregnant women carrying twins. Twin-twin transfusion syndrome (TTTS), abnormal circulation between the twins and the placenta they share, may cause one twin to be much smaller than the other, and surrounded by much less amniotic fluid. The imbalance in circulation may kill one or both fetuses, or damage the health of twins who survive.

Physicians usually diagnose TTTS using prenatal ultrasound, augmented by other tests such as fetal magnetic resonance imaging and amniocentesis. Although TTTS occurs in only 200 to 1800 pregnancies annually in the U.S., the condition has a disproportionately high impact. In approximately 17 percent of cases in which a twin dies before, during or shortly after birth, the cause is TTTS. Estimates of the frequency of TTTS vary widely because of differing criteria for diagnosing the syndrome.

Timothy M. Crombleholme, MD, a pediatric and fetal surgeon at the Center for Fetal Diagnosis and Treatment at Children's Hospital, is the principal investigator of the national, multicenter clinical trial, which is comparing two treatments for TTTS. The current standard treatment is amnioreduction, in which excess amniotic fluid surrounding one fetus is drained through a needle inserted into the mother's abdomen. Another treatment, laser photocoagulation, uses heat from a laser, inserted through a flexible tube, or fetoscope, to seal off the blood vessels connecting the two fetuses. The goal of the laser treatment is to separate the communicating circulation between the twins which causes the syndrome.

Without prenatal treatment for TTTS, both twins usually die. Even with treatment, survival of both twins is not guaranteed, and survivors are nearly always born prematurely, sometimes with health complications, including brain injury and heart conditions related to the abnormal pre-birth circulation.
Both treatments aim to obtain a more normal balance of amniotic fluid between the twins, although only the laser treatment addresses the underlying anatomical defect. However, the two treatments have not previously been directly compared in a clinical trial.

This study will evaluate which treatment, laser photocoagulation or amnioreduction, results in better survival rates and better cardiac, neurological and developmental outcomes. In addition to studying health outcomes immediately after birth, the researchers also will assess the twins' neurodevelopment at age 18 to 22 months.

Twelve medical centers throughout the United States will participate in the TTTS trial, sponsored by the National Institutes of Health. While all 12 centers perform amnioreduction, only two, The Children's Hospital of Philadelphia and the University of California, San Francisco, also perform fetoscopic laser coagulation. Those two institutions also are the only centers in the world offering comprehensive treatments in fetal surgery.

Enrollment for the multicenter TTTS study began in March 2002 and is scheduled to continue through March 2005. Throughout the country, researchers expect to recruit a total of 150 patients for the trial, of which approximately half will be recruited by The Children's Hospital of Philadelphia.

Because of the requirements of randomized studies, each mother who enrolls in the trial will be randomly assigned to either amnioreduction treatment or laser treatment. Participating centers will not perform the laser treatment outside of the clinical trial.

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 .