Intravenous ghrelin accelerates postoperative gastric emptying and time to first bowel movement in humans.

BACKGROUND: Ghrelin has been shown to stimulate gastric emptying in healthy humans and patients with delayed gastric emptying. The aim of this study is to assess the effect of ghrelin on gastric emptying on day 2 after open colorectal surgery. METHODS: Twenty-four patients (mean age 69.2 ± 1.4, BMI 25.8 ± 0.8 kg m(-2) ) were randomized to saline or ghrelin infusion (15 pmol kg(-1)  min(-1) ) during 3 h before and on day 2 after open colorectal surgery. Of these, 20 were assessed both before and after surgery. At start of infusion, a liquid meal (480 kcal, 200 mL) was administered together with 1.5 g acetaminophen. Plasma was obtained at regular intervals together with visual analogue scales for hunger, satiety and nausea. Acetaminophen was analyzed as a marker of gastric emptying. Plasma glucose, insulin, acyl-ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinoptrophic peptide (GIP), pancreatic polypeptide and peptide YY (PYY) were analyzed. KEY RESULTS: Gastric emptying was faster during ghrelin infusion compared to saline before and after surgery (P < 0.02). In addition, plasma glucose was increased (P < 0.05). With ghrelin infusion, plasma insulin was unchanged except for lower values postoperatively (P < 0.05). Ghrelin did not alter plasma concentrations of gut peptides. After surgery, ghrelin shortened the time to first bowel movement compared to saline (2.1 ± 0.3 vs 3.5 ± 0.4 days, P = 0.02). CONCLUSIONS & INFERENCES: A 3-h ghrelin infusion increased the gastric emptying rate and hastened the time to first bowel movement after surgery. Ghrelin/ghrelin receptor agonists have a therapeutic potential in postoperative ileus; Karolinska Clinical Trial Registry nr CT20110084.

Randomized clinical trial of fluid restriction in colorectal surgery.

BACKGROUND: Perioperative fluid therapy can influence postoperative hospital stay and complications after elective colorectal surgery. This trial was designed to examine whether an extremely restricted perioperative fluid protocol would reduce hospital stay beyond the existing fast-track hospital time of 7 days after surgery. METHODS: Patients were randomized to restricted or standard perioperative intravenous fluid regimens in a single-centre trial. Randomization was stratified for colonic, rectal, open and laparoscopic surgery. Patients were all treated within a fast-track protocol (careful preoperative preparation, optimal analgesia, early oral nutrition and early mobilization). The primary endpoint was length of postoperative hospital stay. The secondary endpoint was complications within 30 days. RESULTS: Seventy-nine patients were randomized to restricted and 82 to standard fluid therapy. Patients in the restricted group received a median of 3050 ml fluid on the day of surgery compared with 5775 ml in the standard group (P < 0·001). There was no difference between groups in primary hospital stay (median 6·0 days in both groups; P = 0·194) or stay including readmission (median 6·0 days in both groups; P = 0·158). The proportion of patients with complications was significantly lower in the restricted group (31 of 79 versus 47 of 82; P = 0·027). Vasopressors were more often required in the restricted group (97 versus 80 per cent; P < 0·001). CONCLUSION: Restricted perioperative intravenous fluid administration does not reduce length of stay in a fast-track protocol.

COLOR II. A randomized clinical trial comparing laparoscopic and open surgery for rectal cancer.

INTRODUCTION: Laparoscopic resection of rectal cancer has been proven efficacious but morbidity and oncological outcome need to be investigated in a randomized clinical trial. TRIAL DESIGN: Non-inferiority randomized clinical trial. METHODS: The COLOR II trial is an ongoing international randomized clinical trial. Currently 27 hospitals from Europe, South Korea and Canada are including patients. The primary endpoint is loco-regional recurrence rate three years post-operatively. Secondary endpoints cover quality of life, overall and disease free survival, post-operative morbidity and health economy analysis. RESULTS: By July 2008, 27 hospitals from the Netherlands, Belgium, Germany, Sweden, Spain, Denmark, South Korea and Canada had included 739 patients. The intra-operative conversion rate in the laparoscopic group was 17%. Distribution of age, location of the tumor and radiotherapy were equal in both treatment groups. Most tumors are located in the mid-rectum (41%). CONCLUSION: Laparoscopic surgery in the treatment of rectal cancer is feasible. The results and safety of laparoscopic surgery in the treatment of rectal cancer remain unknown, but are subject of interim analysis within the COLOR II trial. Completion of inclusion is expected by the end of 2009. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT00297791 (www.clinicaltrials.gov).

The role of combined allelic imbalance and mutations of p53 in tumor progression and survival following surgery for colorectal carcinoma.

The role of p53 mutations in disease progression and survival of colorectal cancer is unclear, since numerous studies have reported different conclusions. However, few reports, if any, have evaluated disease progression and survival in relationship to 'functional' and 'non-functional' p53 status defined by genetic and molecular indications. Malignant colorectal tumors, from 72 unselected patients who underwent primary and potentially curative elective tumor resections, were either classified as p53 functional (p53+/+, p53+/-) or non-functional (p53-/-) based on DNA sequence analysis of all p53 exons, including determination of allelic imbalance of p53 (LOH), according to four DNA markers; 2 within the coding gene and two markers in the immediate flanking regions of p53. Tumor frequency of microsatellite instability was also analyzed according to Dukes' A-D stages. Dukes' staging predicted survival as expected, while the conceptual p53 status, functional p53 vs non-functional p53, did not clear-cut predict disease specific survival. p53 mutations alone or allelic imbalance inside the reading frame of the gene were unpredictive of survival, while allelic imbalance downstream of p53 predicted reduced survival (p < 0.05). The present study demonstrates that base mutations in combination with allelic imbalance within the reading frame of p53 do not predict survival or progression of colorectal cancer, while allelic imbalance upstream coding parts of the gene predicted disease-specific survival in univariate analysis. Thus, structural alterations within the gene seem less important than alterations in regions with potential control elements.

Serum anti-p53 in relation to mutations across the entire translated p53 gene in colorectal carcinomas.

Previous reports have claimed that antibodies to mutated p53 protein indicate poor outcome in malignant disease. The mechanism behind this highly specific process is unclear, although it has been claimed that certain DNA alterations are prone to induction of immune response, since wild-type p53 is almost never immunogenic. The aim of the present analysis was to evaluate whether the presence of anti-p53 was statistically significantly related to any certain DNA alterations in the entirely expressed p53 gene in primary tumors of colorectal cancer. P53 serum antibodies were determined by an enzyme linked immunosorbant assay (ELISA). P53 antibodies were detected in serum of 24 of 88 patients (27%). Twenty-two of 24 (92%) sero-positive patients had mutations in their p53 gene while only 22 of 64 (34%) sero-negative patients had p53 mutations (p<0.01). Mutations were mainly missense with a trend to significantly higher frequency of deletions in sero-negative patients compared to sero-positive subjects (8/25, 32% and 2/22, 9% respectively, p<0.08). Mutations in sero-positive patients were mainly located in exon 5 and 7 and within conserved regions (17 of 22 mutations). In sero-negative patients missense mutations were usually located in exon 5, 7 and 8 being also most frequently located within conserved regions. Most of the p53 deletions in sero-negative patients were however located outside conserved regions (seven of eight deletions). There was no statistical difference between sero-positive and negative patients concerning the spectrum of mutations along the expressed gene. Our study demonstrates that p53 antibodies are usually related to p53 gene mutations but a mutational event is not sufficient to elicit self-immunization. Cellular protein binding to p53 or individual differences of major histocompatibility complex based presentation of p53 protein sequences by immune cells is therefore the most likely explanation between sero-negative and sero-positive patients.

Enzymatic mutation detection in the P53 gene.

BACKGROUND: The enzymatic mutation detection (EMD) assay uses the bacteriophage resolvase T4 endonuclease VII, which cleaves preformed heteroduplex molecules at mismatch sites, forming two shorter fragments that can be resolved by gel electrophoresis. The method can be used to detect single and multiple base changes, as well as insertions and deletions. METHODS: The sensitivity, specificity, and positional accuracy of mutation detection by EMD with the PASSPORT(TM) Mutation Scanning Kit were assessed in a blind fashion for three analytical platforms (radioactive detection and automated laser sequencers ALFexpress and ABI PRISM 377). PCR products of 703 bp covering codons 188-393 of the P53 gene were prepared from colorectal tumor samples and analyzed by EMD; the results were compared to data from cDNA sequencing. A 1362-bp PCR product prepared from IL4r gene was used to test detection of multiple base changes in long PCR products. RESULTS: The sensitivity for detection of mutations using EMD exceeded 90%, and the specificity exceeded 80% on all analysis platforms. The method localized 90% of mutations to within two codons and four codons for automated laser sequencers and detection by radioactivity, respectively. The method detected at least five mismatches in heteroduplexes >1 kb. CONCLUSIONS: The EMD system facilitates efficient detection of genetic variation in fragments exceeding 1 kb irrespective of location and type. The technology is particularly well suited to the detection of mutations in genes frequently mutated at unpredictable locations.

Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival.

Intratumoral thymidylate synthase (TS) expression and M(r) 53,000 phosphoprotein (p53) overexpression were studied immunohistochemically in sections from stored paraffin-embedded primary colorectal cancers in 70 patients who had undergone surgery during the years 1987-1990. These cancers were classified according to Dukes' stage A-D, using monoclonal antibodies TS 106 and DO-7. In patients with Dukes' stage A-C tumors, univariate analyses showed that there was a significant correlation (P = 0.048) between disease-free survival and TS expression and between TS expression and time to death with colorectal cancer (P = 0.038). In patients with Dukes' stage A-D tumors, overall survival was correlated to TS expression (P = 0.015), Dukes' stage (P < 0.001), and level of tumor differentiation (P = 0.044) but not to p53 overexpression. Patients with low intratumoral TS expression survived significantly longer than patients with high expression. Cox multivariate analysis showed that Dukes' stage (P < 0.001) and TS expression (P = 0.043) could independently serve as prognostic factors for time to death with colorectal cancer in patients with Dukes' stage A-D tumors.

Missense mutations in hMLH1 associated with colorectal cancer.

One of the most prevalent hereditary syndromes associated with colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC). The inherited gene defects in HNPCC have been shown to reside in DNA mismatch repair genes, mostly hMSH2 or hMLH1. Most HNPCC patients are heterozygous with regard to the relevant mismatch repair gene; they have one normal and one mutated allele, and mismatch repair in normal somatic cells is functional. Cancer predisposition in HNPCC is believed to be associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair. This gives rise to DNA microsatellite instability (MSI), an increased somatic mutation rate, and eventually, to the accumulation of mutations in genes involved in colorectal carcinogenesis. In support of this theory, colorectal tumors in HNPCC patients and in mice deficient for hMSH2 or hMLH1 show MSI. Here, we describe two missense mutations in hMLH1 exon 16 associated with colorectal cancer. Interestingly, the tumors do not show MSI. This raises some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations and these will be missed if an MSI test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggests that the mechanism involved in carcinogenesis could be different from that generally hypothesized.

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor.

Hereditary non-polyposis colorectal cancer (HNPCC) is linked to an inherited defect in the DNA mismatch repair system. DNA from HNPCC tumours shows microsatellite instability (MSI). It has been reported that HNPCC patients have a better prognosis than patients with sporadic colorectal cancer. We examined whether the presence of MSI in a series of unselected colorectal tumours carries prognostic information. In a series of 181 unselected colorectal tumours, 22 tumours (12%) showed MSI. Survival analysis at 5-10 years follow-up showed no statistically significant difference in prognosis between MSI-positive and -negative tumours. Our results suggest that the MSI phenotype as such is not an independent prognostic factor.

Colorectal cancer with and without microsatellite instability involves different genes.

There is evidence supporting a multistep genetic model for colorectal tumorigenesis. In familial adenomatosis polyposis (FAP), the inherited defect is a mutation in the APC gene. The vast majority of all sporadic colorectal cancers also show mutations in the APC gene, and the tumorigenesis in sporadic colorectal cancer and FAP is assumed to involve the same genes. Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes and, as a result of defective mismatch repair, microsatellite instability (MSI) is frequently seen. Tumorigenesis in HNPCC was first thought to involve mutations in the same genes as in FAP and sporadic colorectal cancer. Recently, however, an alternative pathway to development of colorectal cancer has been suggested in colorectal tumors with MSI, compared to those tumors without the MSI phenotype. We used a consecutive series of 191 sporadic colorectal cancers to find out if there were any differences between the two groups of tumors regarding the prevalence of mutations in the APC, KRAS, TP53, and TGFbetaR2 genes. As expected, 86% (19/22) of MSI-positive tumors showed a mutation in TGFbetaR2, while only one of 164 (0.6%) MSI-negative tumors did. A highly statistically significant negative association was found between MSI and alterations in APC and TP53. The MSI-positive tumors were screened for mutations in exon 3 of beta-catenin, which has been suggested to substitute for the APC mutation in the genesis of colorectal cancer, without finding mutations in any of the 22 MSI-positive tumors. The number of mutations found in KRAS was lower in MSI-positive than in MSI-negative tumors but the difference was not statistically significant. Our results strongly support the idea that carcinogenesis in MSI-positive and MSI-negative colorectal cancer develops through different pathways.

Prognostic value of p53 genetic changes in colorectal cancer.

PURPOSE: To explore whether there is a linkage between different mutations in the p53 gene in primary colorectal cancer and the risk of death from colorectal cancer in a large group of patients with long follow-up. We also compared a complementary DNA-based sequencing method and an immunohistochemical (IHC) method for detecting p53 protein overexpression in colorectal cancer. MATERIALS AND METHODS: The entire coding region of the p53 gene was sequenced in 191 frozen tumor samples collected from January 1988 to November 1992. RNA was extracted and synthesized to cDNA. p53 was amplified by the polymerase chain reaction, and the DO-7 monoclonal antibody was used in the IHC assessments. RESULTS: Mutations were detected in 99 samples (52%) from 189 patients. There was a significant relationship between the p53 mutational status and the cancer-specific survival time, with shorter survival time for patients who had p53 mutations than for those who did not (P = .01, log-rank test). Mutations outside the evolutionarily conserved regions were associated with the worst prognosis. Multivariate analysis showed that the presence of p53 mutations was an independent prognostic factor (relative hazard, 1.7, P = .03). There was no significant relationship between overexpression of p53 protein, as determined by IHC analysis, and cancer-specific survival. CONCLUSION: Mutational analyses of the p53 gene, using cDNA sequencing in colorectal cancer, provide useful prognostic information. In addition, cDNA sequencing gives better prognostic information than IHC assessment of p53 protein overexpression.

Mutation analyses of KRAS exon 1 comparing three different techniques: temporal temperature gradient electrophoresis, constant denaturant capillary electrophoresis and allele specific polymerase chain reaction.

Mutations in the KRAS gene is a key event in the carcinogenesis of many human cancers and may serve as a diagnostic marker and a target for therapeutic intervention. In this study we have applied three different techniques for mutation detection of KRAS exon 1 mutations: Allele specific polymerase chain reaction (AS-PCR), temporal temperature gradient electrophoresis (TTGE) and constant denaturant capillary electrophoresis (CDCE). Samples from 191 sporadic colon carcinomas were analyzed. AS-PCR were performed with oligonucleotides specific for know mutations in codon 12 and 13 of the KRAS gene. In TTGE analyses, linear ramping of the temperature were performed during electrophoresis in a constant denaturant gel. CDCE analyses were performed using fluorescin labeled PCR-products. Separation was achieved under constant denaturing conditions using high temperature in a gel-filled capillary followed by laser detection. A mutated KRAS gene was found in 42/191 (22.0%) of the samples using AS-PCR, in 62/191 (32.5%) using TTGE and in 66/191 (34.6%) of the samples using CDCE. In the TTGE and CDCE analyses the sequence of the mutant were determined by comparing the electrophoretic pattern to that of known mutations or by mixing the sample with known mutations prior to reanalysis. In a titration experiment mixing mutant and wild-type alleles prior to PCR, the sensitivity for mutation detection was shown to be 10(-2) for TTGE and under optimized conditions 10(-3) for CDCE.

Ki-ras mutations and prognosis in colorectal cancer.

A total of 191 colorectal adenocarcinomas, obtained from consecutive patients with a median follow-up of 6 years, were studied in order to evaluate the possible association of Ki-ras mutations with tumour stage, tumour differentiation and survival time. Resected full-cross tumour samples were screened for Ki-ras mutations in codons 12 and 13 using temporal temperature gradient gel electrophoresis (TTGE). Ki-ras mutations were detected in 62 (32%) of the samples. The most frequent mutation, observed in 21 samples, was from GGT to GAT changing glycine to aspartic acid in codon 12. The study did not show any association between Ki-ras mutations and Dukes' stage or tumour differentiation. Patients with Ki-ras mutations had a marginally shorter survival time (median 50 months) compared with patients without (median 59 months), but the difference was not statistically significant. The results indicate that Ki-ras gene mutations have no relevant prognostic importance in this cohort of colorectal cancer patients.

Increased serum p53 antibody levels indicate poor prognosis in patients with colorectal cancer.

Serum p53 antibody levels were analysed using an enzyme-linked immunosorbent assay in serum samples obtained before surgery from 184 consecutive patients with primary colorectal cancer. Possible associations with tumour stage and tumour differentiation and the relation to patient survival time after a median follow-up of 6 years were studied. Analysis of serum p53 antibodies in the entire material demonstrated prognostic value in univariate analysis (P = 0.02); a finding that did not remain (P = 0.07) when the Dukes' stage was included in a multivariate analysis model. When the survival analysis was restricted to the potentially cured patients in Dukes' stages A-C, the serum p53 antibody levels retained independent prognostic value (P = 0.03). No clear association with tumour differentiation was found. We conclude that analysis of serum p53 antibodies may be of value for the identification of patients with different prognoses. This may be of relevance for selection of patients for adjuvant treatment.

[Iatrogen perforation of the rectum after colon radiography]. / Iatrogen perforasjon av rectum ved røntgen colon.

Perforation of the rectum following barium enema is relatively rare, occurring in 1 of 3,000 procedures. Colorectal perforation is a serious condition and early diagnosis is of paramount importance in order to avoid any delay in treating the patient. Direct suture of the perforation, lavage, presacral drainage and stomia are the preferred methods of primary surgical treatment.

Trends in colorectal cancer incidence in Sweden 1959-93 by gender, localization, time period, and birth cohort.

OBJECTIVES: This study examined invasive colorectal cancer incidence-rates in Sweden from 1959 through 1993 (n = 134,643 cases). METHODS: Age-standardized rates were calculated using the Swedish population in 1970 as a reference. RESULTS: In right-sided colon cancer (ascending and transverse colon including right and left flexures), male age-standardized rates rose from 8.0 to 15.0 (1.8 percent annually, 95 percent confidence interval [CI] = 1.3-2.4) and female rates increased from 9.1 to 14.4 (1.5 percent annually, CI = 1.0-2.0). For left-sided colon cancer (descending and sigmoid colon), the rates have been stable recently. For rectal cancer, the rates among men rose from 18.8 to 23.0 and among women from 10.7 to 14.7. For both men and women, the relative risk (RR) of right-sided colon cancer had been increasing in successive generations, until leveling-off in those born after 1930. The RR of left-sided colon cancer had been almost constant for cohorts born before 1930 but steadily decreasing in later-born cohorts. The RR of rectal cancer was slightly increasing in successive cohorts. CONCLUSIONS: Changes in lifestyle or carcinogenic exposures during early life probably explain Swedish colorectal cancer incidence-trends better than improved diagnostic activities.

Randomized trial of a biofragmentable bowel anastomosis ring in high-risk colonic resection.

BACKGROUND: Biofragmentable anastomosis ring (BAR) has been proven to be a safe anastomotic device in elective surgery. The use of this anastomotic ring in high-risk patients has not been established. METHODS: During a 5-year period (1990-1995), 100 high-risk patients undergoing colonic resection and suitable for a primary anastomosis were allocated randomly to a standard suture technique or to anastomosis performed with a BAR. High risk was defined as large bowel obstruction, complicated diverticular disease, Crohn's disease, local cancer recurrence, previously irradiated colon, and trauma to the colon or rectum. The patients were equally distributed to the two groups regarding sex, age, emergency surgery and concomitant diseases. RESULTS: In three patients allotted to the BAR group, the device could not be used. There were three (6 per cent) postoperative deaths in each group; none was related to anastomotic problems. Three anastomotic dehiscences were diagnosed, two (4 per cent) in the BAR group and one (2 per cent) in the suture group. Postoperative complications and postoperative recovery were similar. CONCLUSION: This study shows that the BAR anastomosis probably is as safe as the standard band-sewn anastomosis in high-risk colorectal surgery. As the cost of a BAR anastomosis is substantially higher than that for a hand-sewn anastomosis, the latter technique is still the preferred method in the authors' unit.

Stromal tenascin distribution as a prognostic marker in colorectal cancer.

A total of 169 colorectal adenocarcinomas, obtained from patients with a median follow-up of 6.5 years, were studied with immunohistochemical staining on cryosections using a monoclonal anti-tenascin antibody to evaluate the possible association between the staining patterns and tumour stage, tumour differentiation and survival. We found two different staining patterns in the tumour stroma--a diffuse stromal fibrillar staining in 92 out of 169 (54%) tumours and a subglandular staining in the remaining 77 tumours. When the entire group of patients (P < 0.01) and the group of potentially cured patients (P < 0.03) were analysed univariately, it was found that diffuse stromal fibrillar staining was associated with a shorter survival time than subglandular staining. In a multivariate analysis, the Dukes' stage and age were independent prognostic factors, whereas the tenascin expression did not retain a clear independent relationship to survival (P = 0.06). Hence, it appears that the tumour expression of tenascin may be a potential prognostic marker in colorectal cancer, in so far as a diffuse stromal fibrillar staining pattern seems to indicate an increased risk of poor outcome. However, after adjustment for age and Dukes' stage, the additional prognostic value of tenascin remains to be established in further analyses.

Limited clinical significance of the serum tumour marker Ca 72-4 in colorectal cancer.

BACKGROUND: We explored the potential value of CA 72-4 in the staging and prognostic prediction of colorectal cancer, as compared to six previously investigated serum tumour markers - CEA, CA 19-9, CA 50, CA 242, TPA, and TPS. MATERIALS AND METHODS: CA 72-4 was analysed using an immunoradiometric assay in serum samples obtained, prior to surgery, from 196 consecutive patients resected between Jan. 1987 and Nov. 1992. RESULTS: CA 72-4 levels increased with progressive tumour stages; a high level correlated with poor prognosis. However, the information obtained from CA 72-4 did not improve the ease of staging, as compared with other tumour markers. Various combinations of CA 72-4 with the other tumour markers did not add any substantial information to the staging process either. The value of the CA 72-4 in prognostic prediction, as shown in the univariate analysis, was limited in the multivariate tumour marker analyses. CONCLUSIONS: CA 72-4 does not improve the staging and prognostic prediction of colorectal cancer, when compared with other serum tumour markers used.

Immunohistological p53 staining is of limited value in the staging and prognostic prediction of colorectal cancer.

PURPOSE: To compare immunohistochemical staining using different anti-p53 antibodies, and to evaluate the possible clinical implications of the overexpression of p53 in a series of patients resected for colorectal cancer with a long follow-up. METHODS: Tumor biopsy samples were collected from 294 surgical colorectal cancer specimens, obtained from two series of patients with a median follow-up of 4.5 years. The samples stained with four commercially available anti-p53 antibodies, (mouse monoclonal antibodies 421, 1801, and DO-7; and rabbit polyclonal antibody CM1), were evaluated and compared with cryosections from a subset of 20 biopsies from tumors in various stages and grades, obtained from patients with different outcomes. RESULTS: DO-7 gave a homogeneous nuclear staining, which, when further investigated, turned out to be identical in the formalin-fixed paraffin-embedded and in the frozen specimens. Therefore, DO-7 was found to be suitable for the further analysis of archival or frozen sections from the sample. p53 overexpression was shown in 162 (55%) cases, with a significantly higher proportion having DNA aneuploidy (p<0.01) in left-sided colonic and rectal tumors (p<0.01). p53 staining was not associated with tumor stage, tumor grade, or survival. CONCLUSIONS: A significantly higher proportion of p53 overexpressing tumors are DNA aneuploid, indicating that mutations in the TP53 gene constitute a sign of genetic instability, which might be of importance in malignant transformation. However, we could not find any indication that TP53 mutations, as reflected in the overexpression of p53, constitute a prerequisite for tumor progression in colorectal cancer.