Loss of heterozygosity at 18q21 is indicative of recurrence and therefore poor prognosis in a subset of colorectal cancers.
(17/13490)
Adjuvant therapies are increasingly used in colorectal cancers for the prevention of recurrence. These therapies have side-effects and should, thus, be used only if really beneficial. However, the development of recurrence cannot be predicted reliably at the moment of diagnosis, and targeting of adjuvant therapies is thus based only on the primary stage of the cancer. Loss of heterozygosity (LOH) in the long arm of chromosome 18 is suggested to be related to poor survival and possibly to the development of metastases. We studied the value of LOH at 18q21 as a marker of colorectal cancer prognosis, association with clinicopathological variables, tumour recurrence and survival of the patients. Of the 255 patients studied, 195 were informative as regards LOH status when analysed in primary colorectal cancer specimens using the polymerase chain reaction (PCR) and fragment analysis. LOH at 18q21 was significantly associated with the development of recurrence (P = 0.01) and indicated poor survival in patients of Dukes' classes B and C, in which most recurrences (82%) occurred. An increased rate of tumour recurrence is the reason for poor survival among patients with LOH at 18q21 in primary cancer. These patients are a possible target group for recurrence-preventing adjuvant therapies. (+info)
Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood.
(18/13490)
BACKGROUND: In 1993, a randomized controlled trial in Minnesota showed, after 13 years of follow-up, that annual fecal occult blood testing was effective in reducing colorectal cancer mortality by at least 33%. Biennial screening (i.e., every 2 years) resulted in only a 6% mortality reduction. Two European trials (in England and in Denmark) subsequently showed statistically significant 15% and 18% mortality reductions with biennial screening. Herein, we provide updated results-through 18 years of follow-up--from the Minnesota trial that address the apparent inconsistent findings among the trials regarding biennial screening. METHODS: From 1976 through 1977, a total of 46551 study subjects, aged 50-80 years, were recruited and randomly assigned to an annual screen, a biennial screen, or a control group. A screen consisted of six guaiac-impregnated fecal occult blood tests (Hemoccult) prepared in pairs from each of three consecutive fecal samples. Participants with at least one of the six tests that were positive were invited for a diagnostic examination that included colonoscopy. All participants were followed annually to ascertain incident colorectal cancers and deaths. RESULTS: The numbers of deaths from all causes were similar among the three study groups. Cumulative 18-year colorectal cancer mortality was 33% lower in the annual group than in the control group (rate ratio, 0.67; 95% confidence interval [CI] = 0.51-0.83). The biennial group had a 21% lower colorectal cancer mortality rate than the control group (rate ratio, 0.79; 95% CI = 0.62-0.97). A marked reduction was also noted in the incidence of Dukes' stage D cancers in both screened groups in comparison with the control group. CONCLUSION: The results from this study, together with the other two published randomized trials of fecal occult blood screening, are consistent in demonstrating a substantial, statistically significant reduction in colorectal cancer mortality from biennial screening. (+info)
G-protein gamma 7 is down-regulated in cancers and associated with p 27kip1-induced growth arrest.
(19/13490)
We previously identified and cloned human G protein gamma 7 (G-gamma 7) gene, which is down-regulated in pancreatic cancer. We examined G-gamma 7 expression in other gastrointestinal tract cancers. In 24 of 30 patients with gastrointestinal tract cancer, Northern blot assay and immunohistochemical staining revealed significantly lower G-gamma 7 expression in tumors than in normal tissues from the same patients. Semiquantitative reverse transcription PCRs also showed lower G-gamma 7 expression in tumors than in corresponding normal tissues in 69 of 90 patients. To examine the biological role of G-gamma 7 in cancer, the G-gamma 7 cDNA was transfected into a human esophageal carcinoma cell line, KYSE150, that lacks G-gamma 7 expression. G-gamma 7 expression suppressed cell growth and tritiated-thymidine uptake when cells were confluent G-gamma 7 expression also suppressed tumorigenicity in BALB/c nude mice until 3 weeks after transplantation. G-gamma 7 expression increased the Go/G1 population and decreased the S phase population when cells were at high density. We confirmed that this change was associated with p27K1P1 expression. These findings suggest that human G-gamma 7 is associated with p27kip1-induced growth arrest and may be a therapeutic target in cancers. (+info)
Nonpolarized secretion of human meprin alpha in colorectal cancer generates an increased proteolytic potential in the stroma.
(20/13490)
Epithelial cells of the normal human colonic mucosa secrete an astacin-type metalloprotease, meprin a (E. C. 3.4.24.18, N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase), into the intestinal lumen. We found that Caco-2 cells, a colon carcinoma cell line, expressed endogenous meprin alpha, which was secreted at both the basolateral and apical plasma membrane. The expression of meprin alpha in colorectal cancer was confirmed using Northern blot analysis. On tissue sections, a diversity of carcinoma cells with varying immunoreactivity for meprin alpha was observed. Western blots of a series of 11 paired samples of carcinomas and normal control colon tissue revealed that meprin alpha protein accumulated at significant levels in 6 carcinomas at Union International Contre le Cancer tumor stages I-IV. In contrast, the protease was never detected in normal control tissue samples. Meprin alpha zymogen was activated in the tumor tissue, as shown by a 3-fold increase in enzymatic activity. In conclusion, we describe a cancer-specific sorting of meprin alpha, leading to a redistribution with consecutively increased proteolytic activity in the tumor stroma. Because the protease is known to cleave extracellular matrix components in vitro, meprin a may contribute to tumor progression by facilitating migration, intravasation, and metastasis of carcinoma cells. (+info)
Additional value of whole-body positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose in recurrent colorectal cancer.
(21/13490)
PURPOSE: To assess the additional value of the whole-body [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan as a staging modality complementing conventional diagnostic methods (CDM) in patients suspected of having recurrent colorectal adenocarcinoma. PATIENTS AND METHODS: In 103 patients, the discordances between FDG-PET and CDM results were identified and related to the final diagnosis obtained by histopathology or clinical follow-up (> 1 year). All FDG-PET studies were reviewed with full knowledge of the CDM findings. RESULTS: In a region-based analysis, discordances between CDM and FDG-PET findings were found in 40 of 412 regions (10%). In these, FDG-PET had additional diagnostic value in 14 of 16 locoregional, six of seven hepatic, seven of eight abdominal, and eight of nine extra-abdominal regions. In a patient-based analysis, CDM categorized a subgroup of 60 patients as having resectable recurrent disease limited to the liver (n = 37) or locoregional region (n = 23). In 13 of these patients, there were discordant FDG-PET findings, detecting additional tumor sites in nine patients and excluding disease in three patients and yielding an additional diagnostic value in 20% of the patients. A second subgroup consisted of 13 patients with inconclusive CDM findings (n = 5) or with elevated plasma carcinoembryonic antigen levels and an otherwise negative conventional work-up (n = 8). In these patients, FDG-PET results were correct in eight of nine discordances, yielding a positive additional diagnostic value in 62% of the patients. CONCLUSION: Whole-body FDG-PET can have a clear impact on the therapeutic management in the follow-up of patients with colorectal cancer. (+info)
Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.
(22/13490)
PURPOSE: To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. RESULTS: The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION: Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted. (+info)
Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.
(23/13490)
PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity. (+info)
Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer.
(24/13490)
Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers. (+info)