CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: A prospective study in 399 individual consenting patients
The use of an apoptosis assay can significantly predict the differences in late toxicity between individuals with solid tumors, and may be used as a rapid screen for genetically hypersensitive patients, according to data presented by researchers from the Cornerstone University, Grand Rapids, MI. The apoptotic assay evaluates cell death induced by radiation in blood lymphocytes.
"We believe that this is the first rapid assay of intrinsic radiosensitivity that has been confirmed prospectively and can be used to prospectively eliminate from trials all patients likely to display severe (≥ grade 3) late effects, which has been a recurring concern in the clinic when developing new protocols," according to Nigel Crompton, Ph.D., professor of biology at Cornerstone University, and one of the study investigators.
Researchers tested 399 patients, who were treated by curative [50 Gy (gray) or more] radiation therapy, using a rapid (48 hours) apoptosis (cell death) assay, where fresh blood samples were irradiated with 8-Gy X rays. Median CD4 and CD8 T-lymphocyte apoptosis was 12 percent and 20 percent, respectively. While no correlation was found between early toxicity and T-lymphocyte apoptosis, the rapid assay significantly predicted the clinically critical grade 2 and 3 late toxicities.
The majority of the patients in the study had breast (149), head and neck (75) or prostate (36) cancers. The median follow-up period for all treated patients was 29 months.
Correlation of prostate cancer gene expression profiles with outcome following radical prostatectomy: Can we improve upon exiting prognostic models?
Gene expression data can be used to generate accurate outcome prediction models for prostate cancer. A new testing method based on gene expression and clinical variables performs significantly better than the best available clinical models, according to researchers at Memorial Sloan-Kettering Cancer Center. By using differentially expressed genes between recurrent and non-recurrent primary prostate tumors, researchers may be better able to create a more robust classifier.
Scientists analyzed the prostate tumors from patients with and without disease recurrence after radical prostatectomies were performed. They then used a stepwise logistic regression model to predict outcome using differentially expressed genes, which was evaluated by a leave-one-out cross-validation approach. The performance of the gene-based model and the combined clinical and gene expression model were compared to the classification accuracy of the Kattan nomogram.
"The Kattan nomogram was developed as a tool to help patients and their physicians decide among the major treatment choices for prostate cancer," according to William Gerald, M.D., Ph.D., lead investigator of the study. A combination of disease factors including stage of the cancer, prostate specific antigen (PSA) level, and biopsy pathology have been incorporated into the nomograms.
The classification accuracy of the model that combined gene expression data and clinical variables was superior to the Kattan nomogram alone. Expression profiles of recurrent and non-recurrent samples revealed a set of 153 differentially expressed genes. A logistic regression model based only on the expression of five to nine differentially-expressed genes accurately classified 59 of 79 tumor samples as recurrent and non-recurrent (75 percent classification accuracy) based on the results of the leave-one-out cross validation. The classification accuracy was not significantly better than the Kattan nomogram (accuracy 72 percent). However, the model combining the nomogram predicted probability and gene expression data and accurately classified 87 percent of samples.
P53 polymorphism is a major determinant of treatment outcome in head and neck cancer via its opposing effects on the properties of wild-type and mutant proteins
Head and neck cancer patients with a specific mutation of the p53 tumor suppressor gene may experience a worse clinical outcome despite treatment. Functional differences exist between the two polymorphic forms (existence of a gene in several allelic forms) of p53 in both the wild type (a gene that predominates in a natural population of organisms in contrast to that of natural or laboratory mutant forms) and mutant proteins. Wild-type p53 had significantly greater apoptosis-inducing activity following DNA damage induced by chemotherapy, according to researchers at the Ludwig Institute of Cancer Research, Imperial College School of Medicine, London, UK and at the Santa Croce Hospital in Cuneo, Italy. Conversely, cells expressing certain mutant 72R proteins are more resistant to anti-cancer agents such as cisplatin and adriamycin.
A common polymorphism in a section of DNA in the p53 gene encodes either arginine or proline at codon 72 (a specific sequence of three consecutive nucleotides that is part of the genetic code and that specifies a particular amino acid in a protein or starts or stops protein synthesis). In some human cancers - such as carcinomas of the head and neck and breast - mutation is detected more commonly in the R allele (any of the alternative forms of a gene that may occur at a given position). "The greater ability of 72R wild-type p53 to drive cells into apoptosis, together with "gain of function" selectively present in specific 72R mutant proteins may explain the preferential selection of 72R mutants in human cancer," according to Tim Crook, Ludwig Institute of Cancer Research, Imperial College School of Medicine, London, UK.
The study was conducted on the DNA of 70 patients with inoperable head and neck cancer who had been treated with chemo-radiation. Progression-free survival (PFS) of patients was significantly longer for cases without mutation (two-year PFS of 82 percent versus 46 percent with mutations), as well as for the cases with mutation of the 72P allele (two-year PFS of 83 percent versus 38 percent). Survival was significantly longer in cases lacking p53 mutation (two-year survival of 82 percent versus 62 percent), as well as for the cases with mutation of the 72P allele (two-year survival of 100 percent versus 53 percent). For p53 mutations shown to affect sensitivity to platinum, PFS and survival were significantly longer for cases expressing the 72P rather than 72R form of such mutations.
Founded in 1907, the American Association for Cancer Research (AACR) is a professional society of more than 20,000 laboratory and clinical scientists engaged in cancer research in the United States and more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals (Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention). AACR's annual meeting attracts more than 12,000 participants who share new and significant discoveries in the cancer field, and the AACR's specialty meetings throughout the year focus on all the important areas of basic, translational and clinical cancer research.
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