CCR Grand Rounds February 15: Dr. Elias A. Zerhouni, Director, NIH; "The Future of Medical Imaging" February 22: Dr. Andrew P. Feinberg, King Fahd Professor of Medicine, Molecular Biology & Genetics, and Oncology, Johns Hopkins University School of Medicine; "Epigenetic Mechanisms in Human Disease" CCR Grand Rounds are held 8:30 to 9:30 a.m. at the NIH campus in Bethesda, Md., in the Clinical Center's Lipsett Amphitheater.

Obese and overweight men have lower levels of the blood protein prostate-specific antigen (PSA) that "could mask biologically consequential prostate carcinoma" when those men are given PSA tests for prostate cancer, according to a population study that will be published in the March issue of Cancer, and appearing now in the "early view" section of the journal's Web site (http://www3.interscience.wiley.com/cgi-bin/jhome/28741).

The study was conducted by Dr. Jacques Baillargeon and colleagues at the San Antonio Center of Biomarkers of Risk for Prostate Cancer, one of the NCI EDRN clinical and epidemiological centers.

Between 2001 and 2004, 2,779 men without prostate cancer were evaluated, comparing their blood serum PSA level with their body mass index (BMI), a standard measure for weight and obesity. PSA levels are already known to vary with an individual's race/ethnicity and age, but once these factors were controlled for, researchers also found a strict inverse relationship between weight and PSA levels. Thinner and fitter men had higher PSA levels than individuals with higher BMI scores.

According to the researchers, PSA levels appear to be suppressed by about one-third in men whose BMI scores are greater than 40. This tendency could lessen the value of the PSA screening test for overweight and obese men, producing false-negative results and delaying diagnosis of prostate cancer, the study concludes.

The PSA test is currently an FDA-approved, Medicare-reimbursed method of screening for prostate cancer among men over 50. Prostate cancer is the most common cancer in men, after skin cancer. Approximately 232,090 men in the United States will be diagnosed with the disease in 2005, and about 30,350 men will die from it.

Dramatic Rise in Esophageal Adenocarcinoma Appears
to be Real

Between 1975 and 2001, the number of cases of esophageal adenocarcinoma rose faster than for any other major cancer type in the United States, increasing more than six-fold from 3.8 to 23.3 cases per million people in that time period. Researchers from the VA Outcomes Group and the Center for the Evaluative Clinical Sciences at Dartmouth Medical School set out to determine whether the cause could be traced to overdiagnosis or reclassification. Their results are published in the January 19 Journal of the National Cancer Institute.

The research team looked at data from the SEER 9 program, which collects information on newly diagnosed cancer in Connecticut, Hawaii, Iowa, New Mexico, and Utah, as well as the cities of Atlanta, Detroit, San Francisco, and Seattle - in all, representing about 10 percent of the U.S. population. They found that the anatomic distribution of esophageal cancers has shifted over time toward the lower third of the esophagus, near the site of adenocarcinomas, while the incidence of adenocarcinoma in the upper portion of the stomach, near the opening of the esophagus, remained steady, thus refuting the possibility that disease reclassification is causing the trend.

They also identified a steep rise in the mortality from esophageal adenocarcinoma, while the proportion of disease diagnosed at early stage versus late stage has remained steady, thereby clearing overdiagnosis as a cause of the trend. "Our results strongly indicate…a true increase in disease burden," the authors write. "To explain a rise of this magnitude, however, the prevalence of a strong risk factor must also rise dramatically…Such a risk factor has not yet been identified and defining it should be a priority."

Online Gene Viewing Tool Available

Scientists at NCI's Core Genotyping Facility (CGF) are making available a Web-based tool, Genewindow, to facilitate some of the primary genetic research tasks facing scientists. Genewindow is an interactive genome browser designed to view and catalog the millions of known single-nucleotide polymorphisms (SNPs) found in all known human genes. The tool integrates schematic maps of genes with publicly available annotations from researchers.

The browser (http://genewindow.nci.nih.gov) is available at no charge and may be useful to universities, cancer centers, biotechnology companies, and laboratories worldwide.

Genewindow was developed to help automate and manage CGF's complicated work flow, which in 2004 delivered over 4 million genotypes in response to requests by NCI researchers. Typically, a researcher requires a local "map" when looking for a gene that might be associated with a particular trait, condition, or disorder. Analyzing the regions on a gene entails finding and mapping a particular region on a chromosome, then looking for SNPs that might vary from one individual to another.

CGF scientists designed Genewindow to be an intuitive, user-friendly reference tool that even non-geneticists can use to conduct gene studies. Genewindow has become "the primary tool for pre- and post-genetic bioinformatics and analytical work at the CGF," say the authors of an article published in the February issue of Nature Genetics. CGF plans other enhancements, and will release the source code so that other labs may use and adapt it to analyze their own data, even for species other than humans.

Localized Radiation Boosts Survival in Breast Cancer Patients

Patients with high-risk breast cancer who underwent a radical mastectomy and received adjuvant chemotherapy were more likely to survive if they also had localized radiation treatment, according to results of a 20-year follow-up study reported in the January 19 Journal of the National Cancer Institute.

The original trial in British Columbia, Canada included 318 premenopausal women with lymph node-positive breast cancer who had mastectomies and chemotherapy during the period of 1979-1986. They were randomly assigned to receive either no radiation treatment - the general standard of care - or locoregional radiation therapy (radiation to the lymph nodes and chest wall).

Dr. Joseph Ragaz and his colleagues from the McGill University Health Center first analyzed the patients' data at the 15-year mark and found that radiation therapy was associated with improved breast cancer survival but not with overall survival improvement. However, at the second follow-up 5 years later, the researchers discovered a 32-percent reduction in breast cancer mortality and a 27-percent reduction in overall mortality compared with chemotherapy alone.

The researchers believe the radiation therapy improves survival because it destroys microscopic cancer cells that chemotherapy cannot eradicate. "Our results, and those from other groups, confirm that in situations where residual disease remains, adjuvant chemotherapy alone in high-risk breast cancer patients is suboptimal and that the addition of locoregional radiation therapy is important to achieve the highest cure rate," they concluded.

Large International Study Confirms Dangers of Secondhand Smoke

A new study involving nonsmokers and former smokers in 10 European countries is the latest to warn that exposure to secondhand tobacco smoke is a risk factor for lung cancer and other respiratory diseases, particularly among ex-smokers.

At the start of the prospective study, which appeared February 1st on the British Medical Journal Web site, the researchers interviewed more than 120,000 nonsmokers and former smokers - men and women aged 35-74 - about their lifetime exposures to cigarette smoke. Seven years later, 97 people had developed lung cancer, 20 had developed upper respiratory cancers, and 14 had died from chronic obstructive pulmonary disease or emphysema.

The researchers found an association between exposure to environmental tobacco smoke and risk of lung cancer. The risk was higher among former smokers (who had stopped for at least 10 years) than among people who never smoked. The researchers suggest that former smokers may be more susceptible due to previously acquired genetic mutations.

The study also found that children who were exposed to environmental tobacco smoke at infancy were up to three times more likely to develop lung cancer as adults, compared with children who were not.

Although elevated risks for lung cancer among people exposed to secondhand smoke have been found before, this study's strengths include its large size and the ability to rule out other risk factors.

Dr. Paolo Vineis, of Imperial College London, is first author of the study, which was directed by Dr. Elio Riboli, of the International Agency for Research on Cancer. The study was part of the large, multicenter cohort European Prospective Investigation into Cancer and Nutrition study.