The number of new cases of melanoma increases at a rate of 4.3 percent a year, making it one of the fastest growing cancers in the United States. Caught early, melanoma is treatable. When the cancer spreads, it usually is fatal.
In the Jan. 24 issue of Oncogene, Dr. Paul B. Fisher, professor of clinical pathology, director of neuro-oncology research, and the Michael and Stella Chernow Urological Cancer Research Scientist, and members of his laboratory report how a certain cancer growth suppressing protein, called MDA-7, selectively kills both early stage and metastatic or advanced melanoma cells in cell culture experiments. The finding, he says, provides further evidence to support the use someday of MDA-7 as a systemic treatment for melanoma. Dr. Fisher first identified the mda-7 gene in 1995.
In the paper, Dr. Fisher shows how mda-7 kills early stage and metastatic melanoma cells by spurring them to undergo programmed cell death. He expressed the gene in metastatic melanoma cells with a replication-deficient adenovirus vector, Ad.mda-7. He found that mda-7 increased the ratio of cells in culture unable to divide, arresting the cells in their cell cycle at the G2/M phase. The cells transduced with the gene also displayed changes in the ratio of proteins that promote apoptosis, such as BAX and BAK, vs. proteins that protect cells from apoptosis, such as BCL-2 and BCL-XL.
Dr. Fisher also showed that high levels of MDA-7, due to infection with Ad.mda-7, do not harm healthy cells, a good characteristic for a potential therapeutic. Infected normal melanocytes and melanoma cells express and secrete the protein at high levels because of a secretory signal peptide sequence present in the gene. However, secretion by normal melanocytes is not detected, presumably because of its low level and the low sensitivity of the assay measuring secreted protein.
Dr. Fisher envisions that dermatologists could some day give patients with early stage melanoma the mda-7 gene as a form of gene therapy, and the secreted protein product, which is believed to induce its effect by interacting with receptors on the surface of cancer cells, could act systemically to destroy metastatic cells. The gene or its encoded product also may prove effective as a treatment for patients with metastatic disease. Proper dosing has yet to be determined. But studies are under way to test the safety of mda-7 in patients with other cancers.
The other authors on the paper are P&S associate research scientists Dr. Irina V. Lebedeva and Dr. Zao-zhung Su; Yonmee Chang, a New York University student volunteer; Dr. Shinichi Kitada, associate scientist at the Burnham Institute in La Jolla, Calif.; and Dr. John C. Reed, president and scientific director of the Burnham Institute.
Borderline personality disorder typically appears at a young age and is characterized by highly impulsive behavior, mood swings, an inability to control anger, and attempts at self-mutilation or suicide when real or imagined abandonment by other people is feared.
To determine the prevalence of the borderline personality disorder, the investigators, led by Dr. Raz Gross, postdoctoral research fellow in the psychiatric epidemiology training program, and Dr. Myrna Weissman, professor of epidemiology (in psychiatry) in the School of Public Health, analyzed data from a health survey of 218 patients who visited a general medicine group practice. Patients with the disorder were evaluated to determine the specific features of their disorder, the presence of other psychiatric disorders, the use of treatment, and how well the patient functioned in day-to-day activities and relationships.
The interviews revealed that 6 percent of the patients had borderline personality disorder, with similar symptoms as those in a mental health setting. But primary care physicians in the practice failed to identify the mental health problems in 43 percent of the patients, who were diagnosed by Dr. Gross and colleagues.
"Physicians need to identify these patients better and refer them to psychiatrists for treatment," Dr. Gross says. New mood stabilizers, originally given to manic-depressives, are effective in reducing the intensity of the patient's impulsive and reckless behaviors, which are particularly dangerous because they play a key role in self-mutilation and suicide attempts.
The researchers say recognizing borderline personality disorder in patients may alleviate some of the trouble they cause with their doctors. The patients often swing between idealizing and hating their physician and fail to follow treatment directions or to return for follow-up visits. By following guidelines for dealing with borderline personality patients in primary care, the physician may develop a better rapport with the patient, improving medical care.
The study appeared in the Jan. 14 issue of the Archives of Internal Medicine and was supported by Eli Lilly, Pharmacia-Upjohn, and the National Institute of Mental Health.
Harlem adult residents say they suffer more from oral health problems than other medical complaints, such as asthma, diabetes, and hypertension, according to a study by researchers at Columbia's School of Dental and Oral Surgery and Mailman School of Public Health.
The study, led by Dr. Georgina Zabos, assistant professor of clinical dentistry and health policy and management, found that 30 percent of the 695 Harlem residents surveyed indicate they suffer from problems with their teeth and gumsthe No. 1 complaint among 50 common health conditions listed in the questionnaire. The results are published in the January issue of the American Journal of Public Health.
"The results of this study are surprising, given that adults in Harlem suffer from higher rates of cancer, cardiovascular disease, and HIV/AIDS," Dr. Zabos says. "Very little is known about the prevalence or impact of oral diseases in the population. Clearly, further study is warranted."
The Harlem Health Promotion Center, a joint project of Harlem Hospital Center, the Mailman School of Public Health, and the Centers for Disease Control and Prevention, conducted the Harlem Household Survey between 1992 and 1994 to better understand and address the health problems of adult residents of Harlem.
Trained community residents interviewed 695 adults between the ages of 18 and 65 using a structured questionnaire. Participants indicated if they had experienced any of 50 common symptoms or health conditions on the list in the past 12 months. For each condition identified, participants were asked if they had obtained medical treatment.
More respondents30 percentreported oral health problems than other health concerns. Twenty-seven percent cited hypertension as a complaint during the study time period. Diabetes ranked lowest, with 7 percent indicating the disorder as a problem. While diabetes and hypertension ranked lower than oral health problems, they are nonetheless high for adults of this age group.
Of those who reported suffering from dental problems, one third did not receive care. The researchers suggest the high rates of unemployment, lower household income, and lack of health insurance prevalent in this population may have prevented residents from affording dental care. Those with public insurance, such as Medicaid, were only slightly more likely to obtain care than participants without insurance, even though Medicaid provides comprehensive dental benefits to adults. The authors feel it is likely that access to care is limited for residents with public insurance because most private practitioners do not accept Medicaid. Institutions providing treatment for the insured and uninsured are overburdened with too many patients, resulting in long waiting lists for services.
"Regardless of insurance status, lack of available and accessible care is the largest part of the problem for Harlem residents," says Dr. Zabos, who has maintained a clinical practice in Harlem for the past eight years. "Even though the study was conducted almost a decade ago, conditions have not changed."
Women who are HIV-1 positive are at an increased risk of human papillomavirus (HPV)-induced genital warts, preinvasive lesions, and invasive cancers of the vulvar and perianal region, according to a study led by P&S. As a result of the findings, the authors recommend that gynecological examination of affected women should include examination of the vulva and perianal region to identify HPV-associated lesions, which can lead to the development of invasive cancer cells.
In the prospective population study, led by Dr. Tom Wright, associate professor of pathology, 925 women with and without HIV had a gynecological examination twice yearly with an average follow-up of around three years. Examination included colposcopy (inspection of vaginal and cervical cells), testing for HPV, and identification of intraepithelial cancer cells and vulvovaginal and perianal condylomata acuminata, or genital warts.
At the initial examination, women with HIV infection presented with more vulvovaginal and perianal condylomata acuminata or intraepithelial neoplasia than uninfected women (6 percent vs. 1 percent). During subsequent follow-up, HIV-1-positive women were 16 times more likely to develop vulvovaginal or perianal lesions than HIV-1-negative women. Other risk factors identified for lesions included HPV infection, lower CD4 lymphocyte count, and a history of frequent drug injection.
"Our findings are important for clinicians who provide care for HIV-1-positive women," Dr. Wright says. "The unexpectedly large number of cases of high-grade vulvar and perianal intraepithelial neoplasia recorded in this study suggests that HIV-1-positive women are at increased risk of invasive vulvar and perianal carcinoma. As a result, we recommend that during gynecological examination, HIV-1-positive women should have a thorough inspection of the vulva and perianal region. Women with any degree of abnormality, except for typical, exophytic genital warts, should be referred for colposcopy and biopsy so that pre-invasive or invasive disease can be ruled out."
The results were published in the Jan. 12 issue of Lancet.
In the mid-1990s, U.S. HIV treatment guidelines recommended giving patients anti-HIV drugs as early as possible in what was called the "hit hard and hit early" approach. The drugs have had substantial impact on the lives of people infected with HIV, but they can be difficult to take, their use can cause serious side effects, and the virus can develop resistance to the medications. This has led to interest in identifying alternative ways to use these drugs in the long term.
A new multi-center study, sponsored by the National Institute of Allergies and Infectious Diseases, will enroll 6,000 HIV-infected individuals who will be monitored for an average of seven years to determine whether continuous use of anti-HIV drugs or intermittent use is the best approach to treating HIV-infected people. Dr. Wafaa El-Sadr, P&S professor of clinical medicine and professor of clinical epidemiology at the Mailman School of Public Health, is a principal investigator and co-chair of the study.
In the first year, study investigators will enroll 1,000 HIV-infected people and randomly assign them to a strategy of continuous use of anti-HIV drugs (viral suppression) or to a strategy of intermittent use of anti-HIV drugs (drug conservation) only when the risk of HIV complications rises. The viral suppression strategy (in which drugs are used to suppress HIV levels to low or undetectable levels) is recommended in guidelines employed by many physicians in the United States. Study participants following the drug conservation strategy will not take antiviral drugs until their CD4 T-cell count drops below 250 per cubic millimeter; they will take the drugs only until their CD4 T-cell counts rebound above 350. The long-term feasibility of the study will be evaluated after the first year. Based on a favorable outcome, an additional 5,000 people will be enrolled over the next three years.
This trial differs from previous AIDS treatment trials because of its duration and study design. The trial is the first to follow people for such a long period of time. It also will measure direct clinical events, such as progression to full-blown AIDS or death, rather than indirect markers of disease progression, such as CD4 T-cell count or viral load. It also will examine the effect of the treatment strategies on the development of heart disease, on changes in body composition and appearance, and on behaviors, such as adherence and HIV transmission risk behaviors.
More information about the trial, called the "Strategies for Management of Anti-Retroviral Therapies," or the SMART study, is available at http://www.clinicaltrials.gov; use the search term "smart."