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RESEARCH BRIEFSCombination Therapy Shown Better for Early Prostate CancerResearchers at Brigham and Women's Hospital and the Dana–Farber Cancer Institute have found that combined radiation therapy and androgen suppression therapy is a more effective treatment for localized early-stage prostate cancer than radiation therapy alone. Anthony D'Amico, HMS associate professor of radiation oncology, Philip Kantoff, HMS associate professor of medicine, and their colleagues report in the Sept. 13 JAMA that intermediate- and high-risk patients treated with radiation and androgen suppression had a significant reduction in risk of an increase in prostate-specific antigen (PSA) within five years compared to men treated only with radiation. In the retrospective cohort study, 1,586 men with localized prostate cancer were organized into one of three risk groups based on tumor size and levels of PSA. Based on physician preferences, patients received radiation and six months of androgen suppression therapy or radiation therapy alone. Treatment outcome was assessed by PSA failure, defined by three consecutive rising PSA values obtained at least three months apart. No significant difference in risk was found between treatment groups for patients in the low-risk category, but intermediate- and high-risk patients had a fivefold and 2.5-fold reduction in risk of PSA failure, respectively, if they received the combined therapy. Previous studies have shown that patients with advanced cancer benefit from combination treatment, but there have been no data to guide doctors' treatment choices for patients with clinically localized disease. Because serious side effects are associated with androgen suppression therapy (including anemia, decreased bone density, mood swings, and impotence), the relative benefits and risks of combination therapy need to be determined, the authors say. This study offers statistical insight into the complicated decision. They warn, however, that prospective, randomized trials are necessary for conclusive evidence of the benefits of combined treatment over radiation alone. Third Gene Found for Disorder of Brain DevelopmentBack in the 1970s, Harvard researchers Richard Sidman and Verne Caviness found that mice with mutations in the reelin gene (RELN) developed cerebellar hypoplasia, abnormal cerebral cortical neuronal migration, and abnormal axonal connectivity. Scientists at Beth Israel Deaconess Medical Center and Massachusetts General Hospital have now revealed lissencephaly as a disease caused by mutations in the human homologue. Patients with lissencephaly, or "smooth brain," have impaired neuronal migration in the brain, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Affected children show a cerebral palsy–like syndrome characterized by severe clumsiness and an inability to walk, severe mental retardation, and seizures. To date, two lissencephaly genes have been identified, but they do not account for all known cases. Now Christopher Walsh, HMS professor of neurology at BID, and his colleagues report in the September Nature Genetics that they have identified another lissencephaly gene, RELN. By studying the pedigrees of two affected families, the researchers found that an autosomal recessive form of the disease maps to chromosome 7q22. In each case, the mutation occurred in the RELN gene. The study looked at families of a British couple who are half-first cousins (their fathers are half-brothers) and a Saudi Arabian couple who are first cousins. Multiple affected and unaffected children were genetically tested and compared. Although the mutations identified in the two families were different, both disrupted splicing of the RELN cDNA, resulting in low or undetectable amounts of reelin protein. Normally, the reelin protein binds to low-density lipoprotein superfamily receptors. It is thought to act on migrating cortical neurons, but since some lissencephaly patients also display abnormal neuromuscular connectivity and congenital lymphedema, it may also play a role outside the brain. Method Trims Time and Money to Make SNP MapsNow that the human genome is sequenced, a major focus of research is to find and catalog the common genetic differences that exist in the population and test them directly for links to disease. The overwhelming majority of human DNA sequence variation is attributable to single nucleotide polymorphisms (SNPs, pronounced "snips"), which are discovered by sampling several copies of a chromosomal locus in a population and comparing them for sequence differences. The two methods routinely used to detect these variations, locus-specific PCR amplification and the whole-genome shotgun approach, have their limitations. PCR is restricted to regions of known sequence, and whole-genome shotgun requires multiple coverage of the genome before SNPs are discovered. A new technique, developed by researchers from HMS, MIT, and the Whitehead Institute/MIT Center for Genome Research, avoids these obstacles. The method is described in the Sept. 28 Nature. David Altshuler, HMS instructor in medicine at Massachusetts General Hospital, and his colleagues have come up with a way to analyze "reduced representations" of the genome, each containing a manageable number of genetic loci. Called reduced representation shotgun sequencing, this automated and efficient method for making a SNP map samples specific subsets of the genome from several individuals and compares the resulting sequences. The technique is being used by the SNP Consortium, a public–private partnership to make a genomewide SNP map. This map currently has more than 300,000 SNPs in the public domain and is predicted to have more than 750,000 by the end of this year. According to Altshuler, "This should enable linkage-disequilibrium haplotype-based association studies of any region of the genome, dramatically enhancing the power of genetic analysis of common diseases." Altshuler and his colleagues are also working on the proper methodology for performing SNP association tests, because many published reports have been irreproducible. Altshuler; Joel Hirschhorn, HMS instructor in pediatrics at Children's Hospital; Eric Lander of the Whitehead; and others recently reported results from extensive genetic analyses of large sample sizes with appropriate controls. As reported in the September Nature Genetics, they found that of 16 published associations to Type II diabetes, only one could be confirmed. "The lack of replication of the others points to the need for larger samples, controls for population differences, and stronger statistical evidence prior to claiming an association," said Altshuler. —This and brief above by Tracy Hampton Some Early HIV Patients May Be Able to Stop Their TherapyA research team from Massachusetts General Hospital has shown that most HIV-infected individuals who begin antiviral therapy during the earliest stage of infection eventually can stop taking drugs and keep the virus under control with their immune system alone. In the study reported in the Sept. 28 Nature, a group of eight such patients took part in closely supervised interruptions of their drug treatment. Five are still off treatment after 8 to 11 months, maintaining low viral levels. "This is the first time that anyone has shown that the immune system can successfully be manipulated to keep HIV under control," said senior author Bruce Walker, director of the Partners AIDS Research Center at MGH and HMS professor of medicine. "We want to deliver two messages with this report: that diagnosing HIV infection and beginning antiviral treatment as early as possible can make a fundamental difference in the way the immune system handles the virus and that HIV treatment strategies based on the immune system—including vaccines—appear to have great potential." But he stressed that people taking the anti-HIV drug cocktail HAART (highly active antiretroviral therapy) should continue taking the drugs. Lead author Eric Rosenberg, HMS instructor in medicine at MGH, said, "While we're confident that someday we will be able to apply these findings to treatment of chronic HIV infection, there's a lot more we need to learn about augmenting the immune system's response against HIV." Several key parameters remain to be addressed: how long antiviral therapy should continue before discontinuation, how long the viral suppression might continue, and whether any factors might predict who will be successful with this treatment strategy. And studies in people who first start HAART six months or more after infection still have to be done. |
