Biomarkers warn of a “silent killer”

High or low levels of certain proteins can signal the likelihood of ovarian cancer.

Epithelial ovarian cancer ranks as the most lethal of gynecological malignancies. It is only 10 percent as common as breast cancer, but its mortality rate is three times as high. The reason is simple: routine mammography and breast examinations can catch breast cancer early, but no such screening exists for ovarian cancer in its early stages. With few early symptoms, the disease passes under the medical radar until it has reached later stages of malignancy, and therapeutic options are often limited.

Now a group headed by Gil Mor, M.D., Ph.D., associate professor of obstetrics, gynecology and reproductive sciences, has found a way to detect the “silent killer” in its earliest stages, according to a report in May in the Proceedings of the National Academy of Sciences. The researchers at Yale, George Washington University and the Nevada Cancer Institute devised a still-unapproved screening test that measures levels of four cancer-related proteins—leptin, prolactin, osteopontin and insulin-like growth factor II (IGF-II)—in blood samples. These biomarkers are proteins that change in response to several different forms of cancer, perhaps as part of the immune response. “Our strategy is unique in that we are using a combination of proteins representative of how the total system reacts to cancer, rather than focusing on one protein,” said Mor. Previous studies had identified each of the four proteins as possible biomarkers, but Mor’s team found that individually none of the proteins served as a reliable indicator of cancer.

The researchers began with 169 proteins linked to epithelial ovarian cancer. They then narrowed the list to 35 proteins that were either far more or far less prevalent in women with advanced cancer than in healthy women. They further refined the biomarker pool to the four proteins, two of which are consistently overproduced (prolactin and osteopontin) and consistently underproduced (leptin and IGF-II) in women with cancer.

To put these findings to clinical use, women need only have blood drawn. Levels outside of the normal range of two or more of the biomarkers predict cancer. Follow-up analyses, such as ultrasound, can verify the diagnosis.

In a preliminary study of more than 200 women, the screen accurately detected ovarian cancer in 95 percent of cases. The specificity of the test—those correctly diagnosed as disease-free—also stood at 95 percent, but Mor stressed that the test is not ready for screening the general population. “Because this disease is relatively rare, a specificity of 95 percent means that 5,000 out of every 100,000 women tested by this method would give a false-positive result. That’s not acceptable,” he said. To increase the screen’s specificity to an acceptable 99.6 percent, Mor’s team is looking at adding three more proteins to the biomarker pool.

—Kara Nyberg

With the Canary Database, animals become sentinels for environmental hazards

Before the effects of mercury poisoning showed up in the children of Minamata, Japan, in the 1950s, cats were getting sick with a neurological ailment dubbed “dancing cat disease.” In Africa, human outbreaks of the lethal Ebola virus follow the dying off of animals including apes and deer. And epidemiologists are keeping a watchful eye on avian flu, which has jumped from chickens to humans in Asia and Europe.

Since 2002 an interdisciplinary group of researchers at Yale has been creating a database that makes the connections between diseases in animals and diseases in humans. With funding from the National Library of Medicine, the Canary Database hopes to harness this information so that animals can serve as sentinels of impending human disease.

“If you have an animal that is sick from an environmental hazard, should human health professionals be concerned?” asked Peter M. Rabinowitz, M.D., M.P.H. ’95, fw ’98, associate professor of medicine and principal investigator of the database. The question is not hypothetical. It was a veterinarian at the Bronx Zoo who in 1999 reported the occurrence of dead crows to public health authorities, who did not initially recognize that the birds were signaling the emergence of West Nile virus in this hemisphere. “That is a good example,” Rabinowitz said, “of the communication barrier and world-view barrier we are trying to bridge.”

In order to overcome gaps between experts in animal health and those in human health, the Canary Database makes animal sentinel studies from a variety of biomedical databases easily accessible. Researchers can search the database for a wide variety of environmental hazards, both toxic and infectious; learn how these hazards have been studied in animal populations; and discover whether there is evidence linking the animal disease event to human health risk.

The database takes its name from the proverbial canary used by coal miners to warn of the presence of carbon monoxide. A collaboration of the Yale Occupational and Environmental Medicine program, the Yale Center for Medical Informatics and the U.S. Geological Survey National Wildlife Health Center, the database culls from veterinary literature papers on animal disease that might have relevance to humans. Five curators, including veterinarians and physicians around the country, review and curate the papers, adding information about epidemiological methods and linkages to human health outcomes.

The information they collect could be used to help public health practitioners detect impending disease outbreaks or terror attacks involving chemical or biological weapons. “We want to be a continuing resource,” Rabinowitz said.

—John Curtis

et cetera

Alcohol lowers cancer risk

The incidence of non-Hodgkin’s lymphoma (NHL) is rising throughout the world—in industrialized nations it ranks as the sixth most common cancer among men and the eighth most common among women. Although studies have suggested that alcohol consumption may lower the risk of NHL, results have been inconsistent.

In July a team at the Department of Epidemiology and Public Health reported in the journal Lancet Oncology that alcohol consumption does indeed lower the risk of nhl. Unlike prior studies, this one pooled data from nine studies covering more than 15,000 people in the United States, the United Kingdom, Sweden and Italy. “This study with a large sample size allows us sufficient statistical power to analyze the data by type of alcohol consumed and disease subtype,” said principal investigator Tongzhang Zheng, Sc.D., professor of epidemiology.

Further studies are needed to explore the link between alcohol consumption and the lower risk of NHL.

—J.C.

Music and sedatives

For decades, doctors and nurses in the operating room have turned to music to soothe the nerves of anxious patients. Several studies have found that patients who listen to music are less anxious before surgery and need less anesthesia.

But Zeev N. Kain, M.D., HS ’92, FW ’93, professor of anesthesiology, pediatrics and child psychiatry, wondered whether music did more than simply drown out the racket in the operating room. With colleagues at Yale and the American University of Beirut in Lebanon, he designed a study in which patients who had received spinal anesthesia—but were awake—could control the dosage of a sedative. They listened through headphones to either music of their choice or white noise generated by a relaxation device. As reported in May in the journal Anesthesia and Analgesia, patients who listened to music used significantly less sedative.

“Doctors and patients should both note that music can be used to supplement sedation in the operating room,” Kain said.

—Peter Farley


			Originally published in Yale Medicine, Autumn 2005. Copyright © 2005 Yale University School of Medicine. All rights reserved.