Abstract: BACKGROUND Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

Abstract: The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon.

Abstract: Background and Objectives Simple methods to identify colorectal cancer patients at risk of recurrence are needed. This study aimed to determine if neutrophil-to-lymphocyte ratio (NLR) predicts survival in colorectal cancer patients. Methods Two-hundred thirty patients diagnosed with colorectal cancer over a two-year period were identified from a prospectively maintained colorectal cancer database. NLR was calculated from pre-operative full blood counts. In the case of patients who did not undergo surgery, the full blood count from their out-patient visit was used. Known prognostic factors were recorded. Overall and cancer-specific survival were calculated. Results Pre-operative NLR greater than 5 correlated with overall and cancer-specific survival in univariate analyses. NLR was not independent of Dukes stage. Conclusions Pre-operative NLR may represent a simple method of identifying colorectal cancer patients with a poor prognosis pre-operatively. J. Surg. Oncol. 2005;91:181–184. © 2005 Wiley-Liss, Inc.

Abstract: Background Diabetes has been associated with an increased risk of colorectal cancer in most, but not all, studies. Findings have also been inconclusive with regard to sex and subsite in the colorectum. To resolve these inconsistencies, we conducted a meta-analysis of published data on the association between diabetes and the incidence and mortality of colorectal cancer. Methods We identified studies by a literature search of Medline from January 1, 1966, through July 31, 2005, and by searching the reference lists of pertinent articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. All statistical tests were two-sided. Results Analysis of 15 studies (six case-control and nine cohort studies), including 2 593 935 participants, found that diabetes was associated with an increased risk of colorectal cancer, compared with no diabetes (summary RR of colorectal cancer incidence = 1.30, 95% CI = 1.20 to 1.40), without heterogeneity between studies (P(heterogeneity) = .21). These results were consistent between case-control and cohort studies and between studies conducted in the United States and in Europe. The association between diabetes and colorectal cancer incidence did not differ statistically significantly by sex (summary RR among women = 1.33, 95% CI = 1.23 to 1.44; summary RR among men = 1.29, 95% CI = 1.15 to 1.44; P(heterogeneity) = .26) or by cancer subsite (summary RR for colon = 1.43, 95% CI = 1.28 to 1.60; summary RR for rectum = 1.33, 95% CI = 1.14 to 1.54; P(heterogeneity) = .42). Diabetes was positively associated with colorectal cancer mortality (summary RR = 1.26, 95% CI = 1.05 to 1.50), but there was evidence for heterogeneity between studies (P(heterogeneity) = .04). Conclusions Our findings strongly support a relationship between diabetes and increased risk of colon and rectal cancer in both women and men.

Abstract: Colorectal cancer is one of the most commonly diagnosed malignant diseases, with an estimated 1,023,000 new cases and 529,000 deaths worldwide each year. This review considers recently developed cytotoxic chemotherapies and biologic agents that are effective against colorectal cancer and assesses their use as treatments for metastatic disease and as components of adjuvant therapy.

Abstract: Summary Background The antiepidermal growth factor receptor (antiEGFR) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10% of patients with metastatic colorectal cancer that is resistant to chemotherapy. The molecular mechanisms underlying clinical response or resistance to these agents are unknown. Methods Tumours from 31 patients with metastatic colorectal cancer who had either an objective response (n=10) or stable disease or progressive disease (n=21) after treatment with cetuximab or panitumumab were screened for genetic changes in EGFR or its immediate intracellular effectors. Specifically, we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS , BRAF , and PIK3CA . Results Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation (FISH) had an increased EGFR copy number. By contrast, one of 21 non-responders assessable by FISH had an increased EGFR copy number (p vs non-responders, Fisher's exact test). The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA , KRAS , and BRAF did not correlate with disease response. In colorectal-cancer cell lines, the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR . Interpretation We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number. Published online April 14, 2005 DOI 10.1016/S1470-2045(05)70102-9

Abstract: Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).

Abstract: Purpose Preoperative short-term radiotherapy improves local control in patients treated with total mesorectal excision (TME). This study was performed to assess the presence and magnitude of long-term side effects of preoperative 5 × 5 Gy radiotherapy and TME. Also, hospital treatment was recorded for diseases possibly related to late side effects of rectal cancer treatment. Patients and Methods Long-term morbidity was assessed in patients from the prospective randomized TME trial, which investigated the efficacy of 5 × 5 Gy before TME surgery for mobile rectal cancer. Dutch patients without recurrent disease were sent a questionnaire. Results Results were obtained from 597 patients, with a median follow-up of 5.1 years. Stoma function, urinary function, and hospital treatment rates did not differ significantly between the treatment arms. However, irradiated patients, compared with nonirradiated patients, reported increased rates of fecal incontinence (62% v 38%, respectively; P < .001), pad wearing as a ...

Abstract: Background Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, but not all, clinical trials suggest that they reduce the risk of colorectal cancer. Methods The Molecular Epidemiology of Colorectal Cancer study is a population-based case–control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available. Results In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal ...

Abstract: The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large population-based sample of individuals with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer [odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84]. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site [hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32]; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatellite-unstable tumors.

Abstract: Background: Inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD) may have a high prevalence of rectal sparing, backwash ileitis, and colorectal neoplasia. Aims: To describe the clinical features and outcomes of PSC-IBD and compare these to a group of chronic ulcerative colitis (CUC) patients. Methods: The medical records of all patients with PSC-IBD evaluated at the Mayo Clinic Rochester between 1987 and 1992 were abstracted for information on endoscopic and histological features, colorectal neoplasia, surgery, and other clinical outcomes. Patients referred for colorectal neoplasia and those who did not undergo colonoscopy with biopsies were excluded. A control group of CUC patients matched for sex, duration of IBD at first clinic visit, and calendar year of first clinic visit was identified, and similar information was abstracted. Results: Seventy one PSC-IBD patients and 142 CUC patients without PSC were identified. Rectal sparing and backwash ileitis were more common in the PSC-IBD group (52% and 51%, respectively) than in controls (6% and 7%, respectively). Overall, colorectal neoplasia developed in 18 cases and 15 controls, including 11 cancers (seven cases and four controls). An increased risk of colorectal neoplasia or death was not detected in a matched analysis. Although the cumulative incidence of colorectal neoplasia was higher in cases (33%) than in controls (13%) at five years, this was of borderline statistical significance (p = 0.054, unmatched log rank test). Overall survival from first clinic visit was significantly worse among cases (79% v 97%) at five years (p Conclusion: PSC-IBD is frequently characterised by rectal sparing and backwash ileitis. Colorectal neoplasia develops in a substantial fraction and overall survival is worse. PSC-IBD may represent a distinct IBD phenotype.

Abstract: Purpose To update the 2000 American Society of Clinical Oncology guideline on colorectal cancer surveillance. Recommendations Based on results from three independently reported meta-analyses of randomized controlled trials that compared low-intensity and high-intensity programs of colorectal cancer surveillance, and on recent analyses of data from major clinical trials in colon and rectal cancer, the Panel recommends annual computed tomography (CT) of the chest and abdomen for 3 years after primary therapy for patients who are at higher risk of recurrence and who could be candidates for curative-intent surgery; pelvic CT scan for rectal cancer surveillance, especially for patients with several poor prognostic factors, including those who have not been treated with radiation; colonoscopy at 3 years after operative treatment, and, if results are normal, every 5 years thereafter; flexible proctosigmoidoscopy every 6 months for 5 years for rectal cancer patients who have not been treated with pelvic radiation; history and physical examination every 3 to 6 months for the first 3 years, every 6 months during years 4 and 5, and subsequently at the discretion of the physician; and carcinoembryonic antigen every 3 months postoperatively for at least 3 years after diagnosis, if the patient is a candidate for surgery or systemic therapy. Chest x-rays, CBCs, and liver function tests are not recommended, and molecular or cellular markers should not influence the surveillance strategy based on available evidence.

Abstract: Protein kinases are enzymes that are important for controlling cellular growth and invasion, and their malfunction is implicated in the development of some tumours We analysed human colorectal cancers for genetic mutations in 340 serine/threonine kinases and found mutations in eight genes, including in three members of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for therapeutic intervention

Abstract: The idiopathic inflammatory bowel diseases, ulcerative colitis and Crohn's colitis, are associated with an increased risk for developing colorectal cancer. To reduce colorectal cancer mortality in inflammatory bowel disease, most patients and their physicians choose to follow a program of surveillance colonoscopy in an attempt to detect early neoplastic lesions at a curable stage. Colectomy is typically reserved for patients whose biopsy findings are indicative of heightened cancer risk based on interpretation by pathologists. Despite the absence of prospective controlled clinical trials to formally evaluate the benefits, risks, and costs of this approach, enough circumstantial evidence has accrued to warrant its widespread adoption in practice. Nevertheless, no standardized guidelines have yet been set forth to guide the gastroenterologist in performing surveillance. A panel of international experts was assembled to develop consensus recommendations for the performance of surveillance. The findings are presented herein.

Abstract: ContextApproximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown.ObjectiveTo determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities.Design, Setting, and ParticipantsIdentification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses.Main Outcome MeasuresCancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data.ResultsGroup A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001).ConclusionsFamilies who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of “familial colorectal cancer type X” is suggested to describe this type of familial aggregation of colorectal cancer.

Abstract: Purpose Surgical resection of liver-only metastases from colorectal cancer has undergone extensive evaluation and review. The use of neoadjuvant chemotherapy to improve the likelihood of resection in disease that is not optimally resectable has not been as well studied. Patients and Methods Patients with liver-only metastases from colorectal cancer deemed not optimally resectable by a surgeon with expertise in liver surgery received fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). Patients were periodically reassessed for resectability. Surgical response was classified as completely resectable (S-CR), partially resectable (S-PR), or unresectable (S-UR). Study design specified the accrual of 39 patients, with two or more S-CRs considered evidence of promising activity with respect to increasing the S-CR rate. Results Forty-two of 44 patients were assessable for this analysis. Twenty-five patients (60%) had tumor reduction by serial imaging. Seventeen patients (40%) underwent surgery (S-CR, n = 14; S-PR...

Abstract: Purpose Colorectal cancer is the second leading cause of cancer deaths in the United States, with poor survival predicted by regional lymph node (LN) metastasis. The impact of LN ratio (LNR) on survival is unknown in this disease. Patients and Methods We analyzed data from Intergroup trial 0089 of adjuvant chemotherapy for stage II and III patients with colon cancer, in which all patients received fluorouracil-based therapy. Survival was similar for all arms of the study, allowing us to evaluate all patients together. End points included overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Multivariate analyses were performed on all patients and on groups according to LNR quartiles (LNR: < 0.05, 0.05 to 0.19, 0.2 to 0.39, and 0.4 to 1.0). Covariates included in the models were age, sex, tumor stage, grade, histology, number of positive LNs, number of LNs removed, and LNR. Results The median age was 63.7 years, and the median number of LNs removed was 11. In the multivari...

Abstract: background Veterans Affairs (VA) Cooperative Study 380 showed that some advanced colorectal neoplasias (i.e., adenomas at least 1 cm in diameter, villous adenomas, adenomas with high-grade dysplasia, or cancer) in men would be missed with the use of flexible sigmoidoscopy but detected by colonoscopy. In a tandem study, we examined the yield of screening colonoscopy in women. methods To determine the prevalence and location of advanced neoplasia, we offered colonoscopy to consecutive asymptomatic women referred for colon-cancer screening. The diagnostic yield of flexible sigmoidoscopy was calculated by estimating the proportion of patients with advanced neoplasia whose lesions would have been identified if they had undergone flexible sigmoidoscopy alone. Lesions were considered detectable by flexible sigmoidoscopy if they were in the distal colon or if they were in the proximal colon in patients who had concurrent small adenomas in the distal colon, a finding that would have led to colonoscopy. The results were compared with the results from VA Cooperative Study 380 for age-matched men and women with negative fecal occult-blood tests and no family history of colon cancer. results Colonoscopy was complete in 1463 women, 230 of whom (15.7 percent) had a family history of colon cancer. Colonoscopy revealed advanced neoplasia in 72 women (4.9 percent). If flexible sigmoidoscopy alone had been performed, advanced neoplasia would have been detected in 1.7 percent of these women (25 of 1463) and missed in 3.2 percent (47 of 1463). Only 35.2 percent of women with advanced neoplasia would have had their lesions identified if they had undergone flexible sigmoidoscopy alone, as compared with 66.3 percent of matched men from VA Cooperative Study 380 (P<0.001). conclusions Colonoscopy may be the preferred method of screening for colorectal cancer in women.

Abstract: Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a reduction of levels of the oxidative DNA adduct 3-(2-deoxy-beta-di-erythro-pentafuranosyl)-pyr[1,2-alpha]-purin-10(3H)one (M(1)G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacologically active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M(1)G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, respectively, were obtained at diagnosis and at 6 to 7 hours after the last dose of curcumin. Blood was taken 1 hour after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liquid chromatography with detection by UV spectrophotometry or mass spectrometry. M(1)G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, respectively. The concentrations of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 +/- 5.7 and 7.7 +/- 1.8 nmol/g, respectively. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M(1)G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M(1)G levels from 4.8 +/- 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 +/- 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacologically efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.

Abstract: Background: Chronic inflammation is associated with processes that contribute to the onset or progression of cancer. This study examined the relationships between circulating levels of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and total as well as site-specific cancer incidence. Methods: Study subjects ( n = 2,438) were older adults (ages 70-79 years) participating in the Health Aging and Body Composition study, who did not report a previous cancer diagnosis (except for nonmelanoma skin cancer) at baseline. Incident cancer events ( n = 296) were ascertained during an average follow-up of 5.5 years. Inflammatory markers were measured in stored baseline fasting blood samples. Results: The adjusted hazard ratios (95% confidence intervals) for incident cancer associated with a 1-unit increase on the natural log-scale were 1.13 (0.94-1.37), 1.25 (1.09-1.43), and 1.28 (0.96-1.70) for IL-6, CRP, and TNF-α, respectively. Markers were more strongly associated with cancer death: hazard ratios were 1.63 (1.19-2.23) for IL-6, 1.64 (1.20-2.24) for CRP, and 1.82 (1.14-2.92) for TNF-α. Although precision was low for site-specific analyses, our results suggest that all three markers were associated with lung cancer, that IL-6 and CRP were associated with colorectal cancer, and that CRP was associated with breast cancer. Prostate cancer was not associated with any of these markers. Conclusions: These findings suggest that ( a ) the associations between IL-6, CRP, and TNF-α and the risk of cancer may be site specific and ( b ) increased levels of inflammatory markers are more strongly associated with the risk of cancer death than cancer incidence.

Abstract: Most sporadic colorectal cancers are initiated by activating Wnt pathway mutations, characterized by the stabilization of beta-catenin and constitutive transcription by the beta-catenin/T cell factor-4 (Tcf-4) complex. EphB guidance receptors are Tcf4 target genes that control intestinal epithelial architecture through repulsive interactions with Ephrin-B ligands. Here we show that, although Wnt signalling remains constitutively active, most human colorectal cancers lose expression of EphB at the adenoma-carcinoma transition. Loss of EphB expression strongly correlates with degree of malignancy. Furthermore, reduction of EphB activity accelerates tumorigenesis in the colon and rectum of Apc(Min/+) mice, and results in the formation of aggressive adenocarcinomas. Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression.

Abstract: Purpose Colorectal cancer is the second leading cause of cancer deaths in the United States, with poor survival predicted by regional lymph node (LN) metastasis. The impact of LN ratio (LNR) on survival is unknown in this disease. Patients and Methods We analyzed data from Intergroup trial 0089 of adjuvant chemotherapy for stage II and III patients with colon cancer, in which all patients received fluorouracil-based therapy. Survival was similar for all arms of the study, allowing us to evaluate all patients together. End points included overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Multivariate analyses were performed on all patients and on groups according to LNR quartiles (LNR < 0.05, 0.05 to 0.19, 0.2 to 0.39, and 0.4 to 1 0) Covariates included in the models were age, sex, tumor stage, grade, histology, number of positive LNs, number of LNs removed, and LNR. Results The median age was 63.7 years, and the median number of LNs removed was 11 In the multivariate analysis, LNR was a significant factor for OS, DFS, and CSS in patients with 10 to 15 LN and more than 15 LN removed but not for patients with less than 10 LN removed. Using quartiles, LNR maintained its significance for all three end points when patients were grouped by node status Conclusion After curative resection for colorectal cancer, the LNR is an important prognostic factor and should be used in stratification schemes for future clinical trials investigating adjuvant treatments.

Abstract: Purpose: To examine the relationship between tumor regression grade (TRG) and outcomes in patients with rectal cancer treated with preoperative therapy. Methods and Materials: Specimens from 144 patients with cT3,4 rectal cancer who had received preoperative radiation ± chemotherapy and had a minimum follow-up of 3 years were retrospectively reviewed. TRG, which involves examining the residual neoplastic cells and scoring the degree of both cytological changes, including nuclear pyknosis or necrosis and/or eosinophilia, as well as stromal changes, including fibrosis (either dense or edematous) with or without inflammatory infiltrate and giant-cell granulomatosis around ghost cells and keratin, was quantified in five grades according to the Mandard score ( Cancer 1994;73:2680–2686). The greater the response, the lower the TRG score. The median follow-up was 72 months (range, 40–143 months). Results: Of the 144 patients, 19% were TRG1, 12% were TRG2, 21% were TRG3, 46% were TRG4, and 1% were TRG5. To simplify the analysis, TRG was combined into two groups: TRG1–2 and TRG3–5. By univariate analysis, none of the pretreatment factors examined, including age, circumference, length, distance from the anorectal ring, pretreatment T and N stage, and INDpre (defined as the pretreatment reference index size based on digital rectal examination), had an impact on 5-year outcomes, including local control, metastases-free survival, disease-free survival, and overall survival. Postoperative parameters, including pathologic T stage (pT), pathologic N stage (pN), and TRG, did significantly influence 5-year outcomes. These included local failure: pT0–2: 5% vs. pT3–4: 19%, p = 0.007; pN0: 7% vs. pN1–3: 26%, p = 0.002; TRG1–2: 2% vs. TRG3–5: 17%, p = 0.013; metastasis-free survival: pT0–2: 86% vs. pT3–4: 62%, p = 0.005; pN−: 86% vs. pN*: 42%, p p = 0.004; disease-free survival: pT0–2: 83% vs. pT3–4: 54%, p = 0.001; pN0: 80% vs. pN1–3: 39%, p p p = 0.007; pN0: 86% vs. pN1–3: 45%, p p = 0.004. By multivariate analysis combining all pre- and posttreatment parameters, only pN ( p p = 0.005) significantly predicted disease-free survival. Furthermore, TRG predicted the incidence of pathologic nodal involvement ( p Conclusions: By univariate analysis, TRG is a predictor for local failure, metastases-free survival, and overall survival. By multivariate analysis, it predicts improved disease-free survival. Given the ability of TRG to predict those patients with N * disease, it may be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure, such as local excision rather than radical surgery, after preoperative therapy.

Abstract: Purpose The aims of the TP53 Colorectal Cancer (CRC) International Collaborative Study were to evaluate the possible associations between specific TP53 mutations and tumor site, and to evaluate the prognostic and predictive significance of these mutations in different site, stage, and treatment subgroups. Patients and Methods A total of 3,583 CRC patients from 25 different research groups in 17 countries were recruited to the study. Patients were divided into three groups according to site of the primary tumor. TP53 mutational analyses spanned exons 4 to 8. Results TP53 mutations were found in 34% of the proximal colon tumors and in 45% of the distal colon and rectal tumors. They were associated with lymphatic invasion in proximal tumors. In distal colon tumors, deletions causing loss of amino acids were associated with worse survival. In proximal colon tumors, mutations in exon 5 showed a trend toward statistical significance (P < .05) when overall survival was considered. Dukes' C tumors with wild-type ...

Abstract: CEA is a complex glycoprotein produced by 90% of colorectal cancers and contributes to the malignant characteristics of a tumor. It can be measured in serum quantitatively, and its level in plasma can be useful as a marker of disease. Because of its lack of sensitivity in the early stages of colorectal cancer, CEA measurement is an unsuitable modality for population screening. An elevated preoperative CEA is a poor prognostic sign and correlates with reduced overall survival after surgical resection of colorectal carcinoma. A failure of the CEA to return to normal levels after surgical resection is indicative of inadequate resection of occult systemic disease. Frequent monitoring of CEA postoperatively may allow identification of patients with metastatic disease for whom surgical resection or other localized therapy might be potentially beneficial. To identify this group, serial CEA measurement appears to be more effective than clinical evaluation or any other diagnostic modality, although its sensitivity for detecting recurrent disease is not as high for locoregional or pulmonary metastases as it is for liver metastases. Several studies have shown that a small percentage of patients followed postoperatively with CEA monitoring and who undergo CEA-directed salvage surgery for metastatic disease will be alive and disease-free 5 years after surgery. Furthermore, CEA levels after salvage surgery do appear to predict survival in patients undergoing resection of liver or pulmonary metastases. However, several authors argue that CEA surveillance is not cost-effective in terms of lives saved. In support of this argument, there is no clear difference in survival after resection of metastatic disease with curative intent between patients in whom the second-look surgery was performed on the basis of elevated CEA levels and those with other laboratory or imaging abnormalities. There is also no clear consensus on the frequency or duration of CEA monitoring, although the ASCO guidelines currently recommend every 2-3 months for at least 2 years after diagnosis. In the follow-up of patients undergoing palliative therapy, the CEA level correlates well with response, and CEA is indicative of not only response but may also identify patients with stable disease for whom there is also a demonstrated benefit in survival and symptom relief with combination chemotherapy. More recently, scintigraphic imaging after administration of radiolabeled antibodies afforded an important radionuclide technique that adds clinically significant information in assessing the extent and location of disease in patients with colorectal cancer above and beyond or complementary to conventional imaging modalities. Immunotherapy based on CEA is a rapidly advancing area of clinical research demonstrating antibody and T-cell responses.