Management of colorectal cancer in patients with inflammatory bowel disease.

BACKGROUND: This study evaluated the clinicopathological features and survival rates of patients with inflammatory bowel disease who developed colorectal cancer (CRC). METHODS: A retrospective review was performed on a prospectively maintained institutional database (1981-2011) to identify patients with inflammatory bowel disease who developed CRC. Clinicopathological parameters, management and outcomes were analysed. RESULTS: A total of 2,843 patients with inflammatory bowel disease were identified. One thousand six hundred and forty-two had ulcerative colitis (UC) and 1,201 had Crohn's disease (CD). Following exclusion criteria, there were 29 patients with biopsy-proven colorectal carcinoma, 22 of whom had UC and 7 had CD. Twenty-six patients had a preoperative diagnosis of malignancy/dysplasia; 16 of these were diagnosed at surveillance endoscopy. Nodal/distant metastasis was identified at presentation in 47 and 71 % of the UC and CD group, respectively. Operative morbidity for UC and CD was 33 and 17 %, respectively. Despite the less favourable operative outcomes following surgery management of UC-related CRC, overall 5-year survival was significantly better in the UC group compared to the CD group (41 vs. 29 %; p = 0.04) reflecting the difference in stage at presentation between the two groups. CONCLUSIONS: Patients who undergo surgery for UC-related CRC have less favourable short-term outcomes but present at a less advanced stage and have a more favourable long-term prognosis than similar patients with CRC and CD.

Bradykinin regulates human colonic ion transport in vitro.

BACKGROUND AND PURPOSE: Kinins are acknowledged as important regulators of intestinal function during inflammation; however, their effects on human intestinal ion transport have not been reported. Here, we used muscle-stripped human colonic tissue and cultured T(84)-cell monolayers to study bradykinin (BK) actions on human intestinal ion transport. EXPERIMENTAL APPROACH: Ion transport was measured as changes in short-circuit current (I(sc)) across colonic epithelia mounted in Ussing chambers. KEY RESULTS: In intact tissue, there was a distinct polarity to BK-elicited I(sc) responses. Whereas basolateral BK stimulated sustained responses (EC(50)=0.5+/-0.1 microM), those to apical BK were more rapid and transient (EC(50)=4.1+/-1.2 nM). In T(84) cells, responses to both apical and basolateral BK were similar to those seen upon apical addition to intact tissues. Cross-desensitization between apical and basolateral domains was not observed. BK-induced responses were largely due to Cl(-) secretion as shown by their sensitivity to bumetanide and removal of Cl(-) from the bathing solution. Studies using selective agonists and antagonists indicate responses to BK are mediated by B(2) receptors. Finally, responses to basolateral BK in intact tissues were inhibited by tetrodotoxin (1 microM), atropine (1 microM), capsaicin (100 microM) and piroxicam (10 microM). BK-stimulated prostaglandin (PG)E(2) release from colonic tissue. CONCLUSIONS: BK stimulates human colonic Cl(-) secretion by activation of apical and basolateral B(2) receptors. Responses to apical BK reflect a direct action on epithelial cells, whereas those to basolateral BK are amplified by stimulation of enteric nerves and PG synthesis.

Infliximab therapy in Crohn's disease: a pragmatic approach?

BACKGROUND: Infliximab is recognized as an effective therapy in unresponsive luminal and fistulating Crohn's disease. The use of maintenance or 'on demand' therapy thereafter is controversial. AIM: To assess the need for maintenance infliximab therapy in a clinical setting where immunomodulatory agents are widely used and where episodic therapy is used in preference to maintenance therapy. METHODS: Ninety-three patients with Crohn's disease receiving infliximab; 72 with unresponsive luminal disease and 21 with fistulous disease. Data collected included disease site and duration, surgical and smoking history, initial response rates, duration of response maintenance and concomitant medications. RESULTS: Fifty-six of 72 (78%) patients with luminal disease and 11 of 21 (52%) with fistulous disease achieved an initial response. Ten of 67 responders required conversion to maintenance infliximab infusions, while 31 remain in remission. Patients with luminal disease and those who had not taken previous surgery had higher response rates to infliximab. Younger patients and those with small bowel disease had higher relapse rates following initial response. Three patients developed allergic reactions to infliximab and one patient died of progressive pulmonary disease 6 weeks after their first infusion. CONCLUSIONS: Many patients with Crohn's disease can be maintained successfully with an episodic infliximab regimen.

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

AIMS: To standardize the pathological analysis of total mesorectal excision specimens of rectal cancer following neoadjuvant chemoradiotherapy for locally advanced disease (T3/T4), including tumour regression. METHODS AND RESULTS: Standardized dissection and reporting was used for 60 patients who underwent total mesorectal excision following long-course chemoradiotherapy. Tumour regression was scored by two pathologists (K.S., D.G.) using both an established 5-point tumour regression grade (TRG), and a novel 3-point grade. Both scores were evaluated for interobserver variability. A complete or near-complete pathological response (3-point TRG 1) was found in 10 patients (17%). Using the 5-point TRG, there was good agreement between both pathologists (kappa = 0.64). Using the 3-point grade, agreement was excellent (kappa = 0.84). No disease recurrence has been reported in patients with a complete, or near complete pathological response (3-point TRG 1), after a mean follow-up of 22 months. CONCLUSION: Tumour regression grade is a useful method of scoring tumour response to chemoradiotherapy in rectal cancer. TRG 1 and 2 can be regarded as a complete pathological response (ypT0). A modified 3-point grade has the advantage of better reproducibility, with similar prognostic significance.

Expression of Cathepsin B and L antigen and activity is associated with early colorectal cancer progression.

Cathepsin B and Cathepsin L are cysteine proteases important in the process of invasion and metastasis. The aim of our study was to assay antigen and activity levels of these enzymes and to correlate these with established clinical and pathological prognostic parameters including patient survival. 99 patients undergoing operations for colorectal cancer were included in this study. We quantitated cathepsin B and L levels in matched normal mucosa and cancer samples using an enzyme-linked immunosorbent assay (ELISA) and specific activity assays and expressed the results as tumour/normal ratios. Significant correlations were found between tumour/normal cathepsin B and L antigen and activity ratios. Cathepsin B and L tumour/normal activity ratios were greater than 1 in early stage disease and there were gradual reductions in cathepsin B (P = 0.02) and L (P = 0.03) activity ratios with advancing tumour stage. Survival of patients with potentially curative disease was inversely related to both cathepsin B (P = 0.007) and L (P = 0.001) activity ratio, in addition to cathepsin L antigen ratio (P = 0.008). Our findings suggest that cysteine proteases play an important role in colorectal cancer progression.

Peritoneal involvement in stage II colon cancer.

A pathologist (K.S.) reviewed histologic slides for peritoneal involvement by tumor cells for 118 patients with stage II colon cancer. Patients were followed up for a median of 6 years. Tumor cells were found free in the peritoneal space in 16 cases (13.6%). The presence of cancer cells free in the peritoneal space was associated with lymphovascular invasion (P = .001) and neural invasion (P < .001). The overall 5-year survival was 80% in the patient population, but was 39% and 86% for those with and without tumor cells free in the peritoneal space, respectively (P < .0001). Multivariate analysis confirmed that free tumor cells within the peritoneal space (P < .0001) and lymphovascular invasion (P = .007) were related independently to outcome. Peritoneal involvement with tumor cells free in the peritoneal space in stage II colon cancer is a powerful indicator of outcome; patients have a survival similar to that for patients with stage III disease.

Percutaneous endoscopic gastrostomy: 5 years of clinical experience on 238 patients.

Since Percutaneous Endoscopic Gastrostomy (PEG) feeding was introduced, 20 years ago it has been increasingly utilised in medical practice. The aim of this study was to assess the current indications and complications associated with PEG feeding. This study was a retrospective review of hospital charts dealing with PEG placement over a period of five years. The indications for insertion were, central nervous disease 76% (n = 156), other benign disease 14% (n = 28) and malignancy 10% (n = 21). Cerebrovascular accidents (CVA) alone accounted for 47% (n = 97). Ninety seven (50%) patients had minor complications, which included 43 (22%) wound infections. There were 6 (3%) major complications, including peritonitis, perforation and aspiration pneumonia. There were four deaths (2%) related to PEG placement, of whom three developed aspiration pneumonia and one peritonitis. The overall 30 day mortality rate was 16%. There was a 75% increase in the use of PEG placement over the five year period. PEG placements were associated with a 53% morbidity and a 2% procedure related mortality. There was a 16% 30 day mortality following PEG placement suggesting that the selection criteria for PEG placement may need to be refined further.

Tissue cytokine and chemokine expression in inflammatory bowel disease.

OBJECTIVE AND DESIGN: This study aimed to determine if mucosal expression of the chemokines IL-8, RANTES and MCP-1 and the pro-inflammatory cytokines TNFalpha and IL-6 are elevated in patients with inflammatory bowel disease. MATERIALS AND SUBJECTS: Intestinal mucosa samples were obtained at the time of surgical resection, n = 16 from each of the following groups: normal/control, CD and UC. METHODS: An homogenate was prepared of each tissue sample and cytokines measured by ELISA. RESULTS: IL-8 was significantly increased in both disease groups compared to controls Similarly, RANTES levels were also significantly increased. MCP-1 levels were increased in both disease groups, this increase was statistically significant in the UC group only. TNFalpha and IL-6 were significantly increased in the CD group only. CONCLUSIONS: Chemokines, together with key cytokines that promote their release are elevated in mucosal tissues from patients with IBD. It is likely that these chemokines play an important role in the perpetuation of tissue destructive inflammatory processes.

Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Human colonic anti-secretory activity of the potent NK(1) antagonist, SR140333: assessment of potential anti-diarrhoeal activity in food allergy and inflammatory bowel disease.

1. This in vitro study was designed to determine the potential use of the NK(1) antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimuli on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated. 2. Submucosal and sensory nerve fibre stimulation using electrical field stimulation (1 ms/7 Hz/7 V) and capsaicin (50 microM) respectively, mast cell activation by anti-IgE (1/250 dilution) and granulocyte stimulation using fMLP (50 microM) each released SP and evoked a secretory response. 3. SP and the NK(1) selective agonist, Sar-SP (0.1 - 1000 nM) stimulated an increase in colonic secretion which was antagonized by SR140333 (pD'(2)=6.7 and 7.25 versus SP and Sar-SP respectively). 4. SR140333, at a concentration that blocked NK(1)-mediated secretion (500 nM), also reduced the secretory response to both alphaIgE and capsaicin. This suggests a pathophysiologic role for NK(1) receptors. 5. Capsaicin evoked SP release was increased in tissue taken from Crohn's disease but not ulcerative colitis patients. The response to SP was however reduced by 70 and 89% respectively. 6. Mast cells and sensory afferents contribute to allergic diarrhoea. Since SR140333 reduced the secretory response to mast cell and afferent stimulation this compound may be particularly useful in reducing the symptoms of food allergy.

Flow cytometric analysis of Clostridium difficile adherence to human intestinal epithelial cells.

Clostridium difficile is the most common cause of diarrhoea in hospitalised patients. Bacterial adherence to gut epithelial cells is a likely prerequisite to infection and toxin production. A novel flow cytometric method was developed for detecting adherence of C. difficile to human colonic and small intestinal epithelial cells (EC) and human intestinal cell lines. Small intestinal and colonic EC were isolated from biopsy specimens with mucolytic and chelating agents. Adherence of fluorochrome-labelled C. difficile to EC was measured by flow cytometry and was calculated as increase in median fluorescent intensity (deltaMFI). Cells with bacteria attached could be distinguished easily from cells alone or cells with unlabelled bacteria attached. Toxin-positive C. difficile adhered to colonic and small intestinal EC (deltaMFI mean 21.2 SD 16.7, n = 33 and 16.5 SD 20.7, n = 19 respectively). The toxin-negative strain also adhered to both epithelial cell types (deltaMFI 26.1 SD 32.5, n = 17 and 18.3 SD 31.3, n = 16). Adherence of toxin-positive C. difficile to the intestinal cell lines Caco-2 (deltaMFI 9.4 SD 4.4, n = 14) and HT29 (deltaMFI 8.1 SD 3.1, n = 12) was quantifiable, although at a significantly lower level than with primary colonic epithelial cells. Adherence of the toxin-negative strain was slightly lower, deltaMFI 6.5 SD 1.8, n = 9 with Caco-2 cells and deltaMFI 6.0 SD 2.0, n = 10 with HT29 cells. Adherence of C. difficile to epithelial cell lines was blocked with C. difficile antiserum, confirming specificity of adherence. In conclusion, flow cytometry is a useful approach to quantifying adherence of C. difficile to human colonic and small intestinal epithelial cells. Binding of toxin-negative as well as toxin-positive bacteria was detectable by this approach. Analysis of C. difficile adherence to target cells may have important implications for the understanding of the pathogenesis of C. difficile-related disease.

Replication error phenotype, clinicopathological variables, and patient outcome in Dukes' B stage II (T3,N0,M0) colorectal cancer.

AIMS: To examine the relation between the replication error (RER) phenotype and other genetic events, clinical features, and long term survival in patients with Dukes' B stage II (T3,N0,M0) colorectal cancer. METHODS: RER phenotype was investigated in 159 patients by PCR amplification of microsatellite marker loci on chromosomes 5q, 17p, 17q, and 18q from tumour DNA extracted from archival tissue. Data on activating c-Ki-ras mutations were available from a previous study. Immunohistochemical detection of p53 and c-erbB-2 expression was performed on paraffin wax embedded tissue. RESULTS: Of 159 colorectal cancers studied, 22 (14%) were RER+ while 137 (86%) were RER- for two or more loci. RER+ tumours were more commonly located in the right colon, tended to be larger than RER- tumours, and were more often poorly differentiated than RER- cancers. No significant associations were seen between RER status and the presence of a mutant c-Ki-ras gene, or between RER status and p53, c-erbB-2, or c-myc gene expression. Univariate survival analysis showed that outcome was similar in RER+ and RER- cases. Multivariate survival analysis showed that the relative risk of death for patients with RER+ cancers was 0.95 that of patients with RER- cancers. CONCLUSIONS: The results suggest that, while the RER phenotype may be associated with some differences in tumour pathology (site, size, differentiation), it is not associated with the genetic alterations studied or with significant differences in long term survival.

bcl-2 protein expression is associated with better prognosis in colorectal cancer.

AIMS: To investigate the expression of bcl-2 in colorectal carcinoma and to examine its association with mediators of apoptosis (p53 and mdm-2), clinicopathological features and long-term outcome. METHODS AND RESULTS: We determined by immunohistochemistry the expression of bcl-2 in 102 colorectal carcinomas with 10-year follow-up. In 66 of these cases in which we had previously assessed p53 status, no correlation was seen between bcl-2 and p53. The mdm-2 protein was not detected in any of the 66 cases. Cytoplasmic staining of the bcl-2 gene product was seen in the tumour cells of 22 cases (22%). Using a polymerase chain reaction technique we showed that overexpression of bcl-2 was not due to rearrangement of the bcl-2 gene. Expression of bcl-2 protein was related to tumour grade but was unrelated to patient age, sex, tumour site, tumour size or Dukes' stage. There was a trend towards increased survival in those whose tumours expressed bcl-2 protein (P = 0.055). When entered into a multivariate analysis, this survival difference was independent of tumour stage (P = 0.05). CONCLUSIONS: These results suggest that bcl-2 expression in colorectal carcinoma is associated with a better long-term prognosis.

The relationship between cyclooxygenase-2 expression and colorectal cancer.

CONTEXT: Epidemiological studies have implicated the inducible form of cyclooxygenase (COX-2) in the pathogenesis of colorectal cancer; however, its role is not fully understood. OBJECTIVE: To examine the relationship between the expression of COX-2 in human colorectal cancer and patient survival. DESIGN: Patients diagnosed as having colorectal cancer were evaluated and followed up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were stained for COX-2 using a rabbit polyclonal antibody raised against human COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome. Preabsorption of the anti-COX-2 antibody with a COX-2 peptide abolished the staining, demonstrating the specificity of the assay. SETTING: Gastrointestinal unit of a large general teaching hospital in Dublin, Ireland. PARTICIPANTS: Seventy-six patients (median age, 66.5 years) with colorectal cancer (Dukes tumor stage A, n = 9; Dukes B, n = 30; Dukes C, n = 25; Dukes D, n = 12) whose diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were stained for COX-2 as controls. MAIN OUTCOME MEASURES: Survival in years following diagnosis compared by extent of COX-2 epithelial staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, > or = 50%), Dukes stage, tumor size, and lymph mode metastasis. RESULTS: COX-2 was found in tumor epithelial cells, inflammatory cells, vascular endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous, varying markedly among different tumors. Normal tissue adjacent to the tumors also stained weakly for COX-2. No COX-2 was detected in control tissue samples. The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor epithelial staining compared with 35% in those with higher grades combined (log-rank chi2 = 5.7; P = .02). Greater expression of COX-2 correlated with more advanced Dukes stage (Kendall tau-b, 0.22; P = .03) and larger tumor size (Kendall tau-b, 0.21; P = .02) and was particularly evident in tumors with lymph node involvement (Kendall tau-b, 0.26; P = .02). CONCLUSIONS: Our data indicate that COX-2 expression in colorectal cancer may be related to survival. These data add to the growing epidemiological and experimental evidence that COX-2 may play a role in colorectal tumorigenesis.

Berberine inhibits ion transport in human colonic epithelia.

The effects of berberine on ion transport in both human colonic mucosal epithelia and an intestinal epithelial cell line (T84) were examined. Berberine (concentration range 0-500 microM) reduced both basal and stimulated ion transport responses in human colonic mucosae in a manner which was non-specific for Ca2+ -or cAMP-mediated signals. Similarly, in cultured intestinal epithelial monolayers, berberine inhibited Ca2+ -and cAMP-mediated responses indicating an inhibitory activity directly at the level of the epithelium rather than an indirect effect through other mucosal element(s). Berberine did not alter the rate of generation of cAMP by adenylyl cyclase or the activity of protein kinase A, the effector enzyme of the cAMP pathway. Berberine inhibited carbachol-stimulated 86Rb+ efflux from T84 monolayers. Berberine also inhibited K+ conductance in apically-permeabilised re-sected mucosae. These results indicate i) that berberine exerts an anti-secretory action directly upon epithelial cells and ii) the mechanism of action may be at the level of blockade of K+ channels.

Crohn's colitis: the fate of the rectum.

Previous reports suggest that up to 70% of patients undergoing surgery for Crohn's disease of the large bowel do not have gastrointestinal continuity restored and require a permanent ileostomy. In this study the experience with patients requiring surgical treatment of large bowel Crohn's disease is reviewed with particular reference to the management of the rectum. The records of 19 elective and 25 urgent colonic resections performed for large bowel Crohn's disease in 44 patients (16 males, 28 females; mean age 41 years, range 17-76) between 1983 and 1995 were reviewed. Staged proctectomy was performed in 5 of 12 patients who had colectomy for acute colitis and in one patient who had had an elective colectomy. Permanent ileostomy was required in 72% of patients with acute Crohn's colitis and 84% of patients who had elective surgery for large bowel Crohn's. Over 70% of patients having surgical treatment of Crohn's disease of the large bowel required permanent ileostomy. No cases of cancer developed in patients with retained rectal stumps.

Fulminant colitis in inflammatory bowel disease: detailed pathologic and clinical analysis.

PURPOSE: The morphologic features of fulminant colitis may be nonspecific, making differentiation between ulcerative colitis and Crohn's disease difficult, even after colectomy. The aims of this study were 1) to identify histologic features that accurately differentiated ulcerative colitis, Crohn's disease, and indeterminate colitis in fulminant colectomy specimens; 2) to determine how frequently subsequent clinical course altered the pathologic diagnosis; and 3) to evaluate the natural history of histologically diagnosed indeterminate colitis. METHODS: Ninety-five fulminant colectomy specimens were evaluated, of which 85 had an original diagnosis of fulminant inflammatory bowel disease. Complete pathologic material and comprehensive clinical follow-up information was available on 67 cases of inflammatory bowel disease. These were re-evaluated in a blinded fashion, and histopathologic features were compared with the original diagnosis and reviewed in the light of subsequent clinical behavior to reach a final diagnosis. RESULTS: Evaluation of macroscopic features was not helpful in differentiating ulcerative colitis from Crohn's disease. Microscopic examination correctly diagnosed ulcerative colitis or Crohn's disease in only 58 of 67 (87 percent) cases. A further three cases (4 percent) were definitively classified after correlation with clinical data, leaving a residual six cases that were diagnosed as indeterminate colitis. Granulomas and lymphoid aggregates were the two most specific indicators of Crohn's disease. CONCLUSIONS: Histopathologic evaluation alone has limitations in the accurate classification of fulminant inflammatory bowel disease. Histologically diagnosed indeterminate colitis is a heterogeneous group that may include some patients who subsequently prove to have ulcerative colitis or Crohn's disease.

Duration of colorectal cancer symptoms and survival: the effect of confounding clinical and pathological variables.

The relationship between symptom duration and long-term survival following colorectal cancer is complex, and a number of factors may influence the length of time from onset of symptoms of cancer diagnosis. We prospectively studied 777 consecutive colorectal cancer patients to determine the association between symptom duration and survival independent of other clinical and pathological features. We used survival curves, the logrank test and Cox's proportional hazards model to assess possible changes in relative risk of death with increasing symptom duration, without making any a priori assumptions. We found that symptom duration shortened with advanced tumour stage (P < 0.0006) and was also shorter for patients presenting with bowel obstruction (P < 0.0001). Univariate survival analysis showed that long-term survival increased consistently with symptom duration (P < 0.001). However, when the effect of tumour stage and bowel obstruction were accounted for in a multivariate analysis, no decrease in the relative risk of death was seen as symptom duration increased. The addition of other variables to the proportional hazards model such as age, sex or tumour site did not further influence the risk function form of symptom duration. Our results suggest that early diagnosis of colorectal cancer should remain our goal when assessing patients with suggestive gastrointestinal symptoms.

Identifying stage B colorectal cancer patients at high risk of tumor recurrence and death.

PURPOSE: This study was designed to determine clinical and pathologic variables associated with poor outcome following resection of Stage B colorectal cancer. METHODS: This was a retrospective study of 117 patients with Stage B cancer who underwent curative surgery and survived the postoperative period. Fourteen clinical and pathologic features were studied. Clinical data were extracted from a prospective colorectal cancer database, and histologic slides were retreived and examined by a pathologist blinded as to clinical details and outcome. RESULTS: After a median follow-up period of 8.2 years, bowel obstruction was significantly related to a poor prognosis (log-rank test; P = 0.03). Extensive necrosis (P = 0.01) and perineural invasion (P = 0.03) were also associated with decreased survival. Vascular invasion was associated with poor long-term outcome in the subgroup of patients with rectal (P = 0.07) but not colonic (P = 0.57) cancer. Multivariate regression analysis identified both tumor necrosis (P = 0.01) and perineural invasion (P = 0.03) as independently related to outcome. CONCLUSION: Further study of prognostic indicators might result in an algorithm to distinguish Stage B cases at high risk of tumor recurrence and death. Such patients could be included in future trials of adjuvant therapies.