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Biomedical subjects

Mark Redston

Publications and source records attributed to Mark Redston.

8 recordsLinked to original sources
PubMed2003

Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.

BACKGROUND: Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. METHODS: Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. RESULTS: Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability. CONCLUSIONS: Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.

Analysis of Variance↗
PubMed2003

Heterozygosity for the BLM(Ash) mutation and cancer risk.

Bloom syndrome is an autosomal recessive disorder whose characteristics include an increased risk for many types of cancers. In contrast to the homozygous mutations of Bloom syndrome, heterozygous carriers of BLM mutations may be at increased risk for developing colorectal cancer. We have screened 2,333 Jewish individuals, including 497 individuals with colorectal cancer, 125 with adenomatous polyps, 767 with noncolorectal cancers and 944 controls for the truncating BLM(Ash) founder mutation. The BLM(Ash) mutation was carried by 0.80% of individuals with colorectal neoplasia, 0.87% of those with any type of cancer and 0.85% of controls. In addition to case-control data, we found no evidence to support a significant relationship between increased cancer risk and heterozygous BLM(Ash) mutations with respect to age of cancer diagnosis, tumor multiplicity or family cancer history.

Aged↗
PubMed2002

Mutation profiling of mismatch repair-deficient colorectal cncers using an in silico genome scan to identify coding microsatellites.

Human colorectal, endometrial, and gastric cancers with defective DNA mismatch repair (MMR) have microsatellite instability, a unique molecular alteration characterized by widespread frameshift mutations of repetitive DNA sequences. We developed "Kangaroo," a bioinformatics program for searches in nucleotide and protein sequence databases, and performed an in silico genome scan for DNA coding microsatellites that may have novel mutations in MMR-deficient cancers. Examination of 29 previously untested coding polyadenines revealed widespread mutations in MMR-deficient colorectal cancers, with the highest frequencies in ERCC5, CASP8AP2, p72, RAD50, CDC25, RECQL1, CBF2, RACK7, GRK4, and DNAPK (range, 10-33%). This algorithm allows comprehensive mutation profiling of MMR-deficient cancers, an important step in understanding the pathogenesis of these neoplasms.

Algorithms↗
PubMed2002

Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors.

PURPOSE: To compare microsatellite instability (MSI) testing with immunohistochemical (IHC) detection of hMLH1 and hMSH2 in colorectal cancer. PATIENTS AND METHODS: Colorectal cancers from 1,144 patients were assessed for DNA mismatch repair deficiency by two methods: MSI testing and IHC detection of hMLH1 and hMSH2 gene products. High-frequency MSI (MSI-H) was defined as more than 30% instability of at least five markers; low-level MSI (MSI-L) was defined as 1% to 29% of loci unstable. RESULTS: Of 1,144 tumors tested, 818 showed intact expression of hMLH1 and hMSH2. Of these, 680 were microsatellite stable (MSS), 27 were MSI-H, and 111 were MSI-L. In all, 228 tumors showed absence of hMLH1 expression and 98 showed absence of hMSH2 expression: all were MSI-H. CONCLUSION: IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.

Aged↗
PubMed2002

Multi-detector row helical CT in preoperative assessment of small (< or = 1.5 cm) liver metastases: is thinner collimation better?

PURPOSE: To determine the value of collimations less than 5 mm in detecting hepatic metastases 1.5 cm or smaller by using multi-detector row helical computed tomography (CT). MATERIALS AND METHODS: Thirty-one patients underwent contrast material-enhanced multi-detector row helical CT before hepatic resection in this prospective study. Images were reconstructed at collimations of 5.00, 3.75, and 2.50 mm with 50% overlap and reviewed independently by three radiologists. Each lesion was characterized as metastatic, benign, or equivocal and graded for conspicuity. Criterion standards were pathologic assessment of the resected liver and follow-up of the nonresected liver. Only lesions 1.5 cm or smaller were analyzed. RESULTS: There were a total of 88 liver lesions 1.5 cm or smaller, and 25 of these were metastases. Pooled sensitivity for all lesions improved with thinner collimation (66% [58 of 88 lesions], 69% [61 of 88], and 82% [72 of 88] at collimations of 5.00, 3.75, and 2.50 mm, respectively), and this was statistically significant (P =.01). However, no significant difference was noted between collimations in the pooled sensitivity for metastatic lesions (80% [20 of 25 lesions] at all collimations) (P >.99). No statistical difference was noted in the conspicuity of lesions at different collimations (P =.18). CONCLUSION: Image reconstruction with multi-detector row helical CT at collimations less than 5 mm may not improve sensitivity in the detection of hepatic metastases 1.5 cm or smaller.

Adult↗
PubMed2002

Prolonged gastrointestinal transit in a patient with a glucagon-like peptide (GLP)-1- and -2-producing neuroendocrine tumor.

Neuroendocrine tumors overexpressing the proglucagon- derived peptides have been associated with severe constipation. The relationship between two of the intestinal proglucagon-derived peptides, glucagon-like peptide (GLP)-1 and -2, and delayed gastrointestinal transit, was characterized in a patient with a neuroendocrine proglucagon-derived peptide tumor. A 60-yr-old female presented with intractable constipation and intermittent vomiting. Gastric, oral-ileal and colonic transit times, and plasma hormone levels were determined before tumor resection. Expression of the proglucagon-derived peptides by the tumor was determined by immunohistochemistry, Northern blot analysis, HPLC, and RIA. Oral-cecal transit was more than 3 h, and a barium follow-through study showed dilated and thickened folds with most of the barium concentrated in the ileum at 24 h; residual barium was identified in the colon at 14 d post ingestion. Circulating levels of GLP-1 and -2 were 300- to 400-fold elevated compared with levels in normal human subjects. Normal bowel function was restored by tumor resection. Consistent with the elevated plasma hormone levels, the tumor was found to express the proglucagon gene, and immunoreactive GLP-1 and -2 were detected by both immunohistochemistry and RIA. Overexpression of glucagon-like peptide-1 and -2 is associated with markedly prolonged gastrointestinal transit in humans. These findings are consistent with a role for these peptides in the regulation of gastrointestinal motility.

Female↗