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PubMed1996

Microsatellite instability in early onset and familial colorectal cancer.

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer.

Adult↗
PubMed1993

Extracolonic cancer in hereditary nonpolyposis colorectal cancer.

BACKGROUND: It has been hypothesized that in some but not all families with hereditary nonpolyposis colorectal cancer (HNPCC) there is a high risk of certain cancers other than colon cancer. METHODS: The authors compared the observed frequency of cancer at specific sites in more than 1300 high-risk members of 23 kindreds with HNPCC with expectations based on general population incidence and evaluated the hypothesis that there was heterogeneity in cancer frequency among families. RESULTS: The authors observed significantly increased numbers of cancers of the stomach, small intestine, upper urologic tract (renal pelvis and ureter), and ovary. No excess was seen in other cancer types that have been associated previously with HNPCC, including cancer of the breast, pancreas, and urinary bladder. Significant heterogeneity among families was observed in the frequencies of endometrial, ovarian, and upper urologic system cancer. CONCLUSION: In addition to early onset cancers of the colorectum, HNPCC family members are at increased risk for cancers of other gastrointestinal tract organs, and, especially in some families, cancers of the upper urologic and female genital tract.

Adenocarcinoma↗
PubMedDate not supplied

Location and age at onset of colorectal cancer in Hungarian patients between 1993 and 2004. The high number of advanced cases supports the need for a colorectal cancer screening program in Hungary.

BACKGROUND: In recent decades, the incidence of proximal colorectal cancer (CRC) in North America and Western Europe has steadily increased, while that of the distal tumors has shown a corresponding decrease. Our aim was to investigate the change in age at diagnosis, the gender, location and cancer stage of CRC cases over the last 12 years in a large number of Hungarian patients. PATIENTS AND METHODS: The clinical and histological data of 1694 CRC patients (M/F: 917/777, age at diagnosis: 65.2 +/- SD 12.5 years), diagnosed at the First Department of Medicine and the First Department of Surgery of Semmelweis University, Budapest, Hungary, between January 1, 1993 and December 31, 2004, were analyzed retrospectively. RESULTS: CRCs were rectal or left-sided in 70% and proximal (transverse, ascending or cecum) in 30% of the cases. The proportion of rectal carcinomas increased over the observed period (1993-1998: 31.6% vs. 1999-2004: 42.1%, p=0.001), while the proportion of proximal tumors remained stable. Eleven percent of CRCs were diagnosed under the age of 50 years. The age at diagnosis did not differ between males and females, but was lower in patients with rectal tumors compared to other localizations (p=0.02); 75.7% of the CRCs were T3-T4 at diagnosis and lymph node metastases could be detected in 47.7%. CONCLUSION: In contrast to Western European and North American trends, the proportion of proximal CRCs did not increase in Hungary over the observed period. Almost two-thirds of all cancers were left-sided. The high percentage of locally advanced tumors and lymph node metastases supports the need for colorectal screening programs.

Adult↗
PubMed2004

Atrial fibrillation and survival in colorectal cancer.

BACKGROUND: Survival in colorectal cancer may correlate with the degree of systemic inflammatory response to the tumour. Atrial fibrillation may be regarded as an inflammatory complication. We aimed to determine if atrial fibrillation is a prognostic factor in colorectal cancer. PATIENTS AND METHODS: A prospective colorectal cancer patient database was cross-referenced with the hospital clinical-coding database to identify patients who had underwent colorectal cancer surgery and were in atrial fibrillation pre- or postoperatively. RESULTS: A total of 175 patients underwent surgery for colorectal cancer over a two-year period. Of these, 13 patients had atrial fibrillation pre- or postoperatively. Atrial fibrillation correlated with worse two-year survival (p = 0.04; log-rank test). However, in a Cox regression analysis, atrial fibrillation was not significantly associated with survival. CONCLUSION: The presence or development of atrial fibrillation in patients undergoing surgery for colorectal cancer is associated with worse overall survival, however it was not found to be an independent factor in multivariate analysis.

Journal Article↗
PubMed2003

Expression of cyclooxygenase-2 parallels expression of interleukin-1beta, interleukin-6 and NF-kappaB in human colorectal cancer.

Elevated expression of cyclooxygenase-2 (COX-2), the inducible isoform of prostaglandin H synthase, has been found in several human cancers, including colorectal cancer (CRC). This appears as a rationale for the chemopreventive effects of non-steroidal anti-inflammatory drugs in CRC. However, the reason for COX-2 overexpression is not fully understood. In cell culture experiments, COX-2 can be induced by proinflammatory cytokines, such as interleukin (IL)-1beta and IL-6. A crucial step in this signalling pathway is thought to be activation of transcription factor NF-kappaB. Based on these findings, we hypothesized an association between COX-2 overexpression and expression of IL-1beta, IL-6 and the NF-kappaB subunit p65 in human CRC. To test the hypothesis, we performed immunohistochemistry for the respective antigens on colorectal cancer specimens, obtained by surgical resections from 21 patients with CRC. Immunohistochemical results were confirmed by examination of protein levels in tissue lysates and nuclear extracts using western blotting. Non-neoplastic tissue specimens resected well outside the tumour border served as controls. COX-2 expression was found to be markedly enhanced in the neoplastic epithelium compared with controls. This was paralleled by a significantly higher expression of IL-1beta, IL-6 and p65. Serial sections revealed consistent cellular colocalizations of respective antigens in the neoplastic epithelium. Statistically, a significant correlation between expression of COX-2 and IL-1beta, IL-6 and p65 was found. Comparable results were obtained for stromal cells like macrophages and myofibroblasts. Further examination of nuclear extracts from CRC-specimens by western blotting confirmed a higher content of p65 protein compared with non-neoplastic control tissues. Therefore, our study provides evidence for an association between expression of COX-2 and IL-1beta, IL-6 and p65 in human CRC. The results are consistent with the thesis that proinflammatory cytokines such as IL-1beta and IL-6 may be accountable for the overexpression of COX-2 in CRC. Finally, the study corroborates a role for NF-kappaB in the control of COX-2 gene transcription in CRC. Given an antiapoptotic role for COX-2 in tumour cells, inhibition of NF-kappaB may offer an important strategy to interfere with the development and progression of CRC.

Aged↗
PubMed2000

Preventable cancers: the role of obstetrician gynecologists in colorectal cancer screening.

Colorectal cancer is second only to lung cancer as a cause of cancer deaths in the United States, and is the third most common cause of cancer deaths in U.S. women. Effective screening and intervention programs exist and, if followed, could halve the number of annual deaths from this disease. Detection of early-stage disease and, more important, premalignant polyps, is possible by following the recommendations of several national societies, including the American College of Obstetricians and Gynecologists. Recommended screening consists of identification of special risk factors, annual fecal occult blood testing, and flexible sigmoidoscopy every 5 years. Alternatively, a dual-contrast barium enema every 5 to 10 years or colonoscopy every 10 years are options. This article reviews the evidence underlying current screening guidelines, highlights emerging trends in screening, and analyzes the growing need for women's health care providers to understand and promote colorectal cancer screening as part of an optimal health maintenance program.

Journal Article↗
PubMedDate not supplied

Tailored computer-based cancer risk communication: correcting colorectal cancer risk perception.

We developed a computer-based tailored risk presentation and risk communication aid for colorectal cancer prevention. To evaluate the effectiveness of the tool, we randomized 353 participants to receive different risk presentation formats (relative plus absolute risk vs. absolute risk only vs. none) and different levels of engagement with the risk communication (active vs. passive). Findings suggest the tool to be useful for correcting misperceptions about personal risk. Of those with inaccurate risk perception at baseline, more than half of the participants in intervention groups had corrected risk perceptions at post-test, compared to only 12% in the control group.

Adult↗
PubMed2004

Screening for defective DNA mismatch repair in stage II and III colorectal cancer patients.

BACKGROUND & AIMS: Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome usually present in younger patients, show loss of mismatch repair (MMR) gene expression, and exhibit microsatellite instability (MSI). About 12% of sporadic colorectal cancers also show MMR loss and MSI. The aims of this study were to evaluate MMR loss and MSI in relation to patient age, sex, tumor stage, and site in the large bowel. METHODS: Tissue microarrays were created from 1020 stage II and III colorectal cancer cases and immunohistochemical staining performed to detect expression of the 2 major MMR proteins, hMLH1 and hMSH2. MSI was determined using the BAT-26 mononucleotide repeat. RESULTS: Ten percent of tumors showed loss of hMLH1 expression and 1.2% showed loss of hMSH2 expression. hMLH1 loss was more frequent in women (P < .001), older patients (P = .004), earlier stage tumors (P = .0001), and proximal colon tumors ( P < .0001). In contrast, tumors showing hMSH2 loss were more frequent in younger (P < .001), male (P = .05) patients and were distributed evenly between the proximal colon and distal colon/rectum. Eleven percent of tumors were MSI+ and these showed similar age, sex, stage, and site characteristics as tumors with hMLH1 loss. Discordance between MMR loss and MSI+ was found in 24 of 983 (2.4%) tumors. Of the 231 patients aged <60 years at diagnosis, 12 (5.2%) showed loss of hMLH1 and 8 (3.5%) showed loss of hMSH2. CONCLUSIONS: Routine immunohistochemical screening for MMR loss in younger colorectal cancer patients may provide a useful, first-step screening tool for the population-based detection of HNPCC.

Adaptor Proteins, Signal Transducing↗
PubMed1994

The National Cancer Data Base report on colorectal cancer.

BACKGROUND: Previous Commission on Cancer studies have examined time trends in stage of disease, treatment patterns, and survival for colorectal cancer. Reported herein are the most current 1993 National Cancer Data Base (NCDB) data on colorectal cancer. METHODS: Two "calls for data," one in 1990 and one in 1991, have yielded a total of 71,560 colon cancer reports and 33,409 rectal cancer reports from hospital registries across the country. RESULTS: For colon cancer, continuation of the time trend toward proximal migration was reported. For both colon and rectal cancer, American Joint Committee on Cancer staging was used increasingly as the standard of appropriate cancer diagnosis. Increased use of multimodal treatment was reported for both colon and rectal cancers. African-American and non-Hispanic white, low-income patients were reported to have later stages of both colon and rectal cancers. CONCLUSIONS: The NCDB provides a useful longitudinal perspective on the diagnosis and treatment of colon and rectal cancers.

Adult↗
PubMed2002

Induction of p53-specific immune responses in colorectal cancer patients receiving a recombinant ALVAC-p53 candidate vaccine.

PURPOSE: The tumor-associated auto-antigen p53 is commonly overexpressed in various types of human cancer, including colorectal cancer. Experiments in preclinical models have shown that it can serve as a target for T-cell-mediated tumor-eradication. The feasibility of a p53-specific therapeutic vaccination was investigated in cancer patients. EXPERIMENTAL DESIGN: A Phase I/II dose-escalation study was performed that evaluated the effect of a recombinant canarypoxvirus (ALVAC) vaccine encoding wild-type human p53 in 15 patients with advanced colorectal cancer. Each group of five patients received three i.v. doses of one-tenth of a dose, one-third of a dose, or 1 dose of the vaccine [1 dose = 1 x 10(7.5) cell culture infectious dosis (CCID)50]. RESULTS: Potent T-cell and IgG antibody responses against the vector component of the ALVAC vaccine were induced in the majority of the patients. Enzyme-linked immunosorbent-spot assay (ELISPOT) analysis of vaccine-induced immunity revealed the presence of IFN-gamma-secreting T cells against both ALVAC and p53, whereas no significant interleukin-4 responses were detected. Vaccine-mediated enhancement of p53-specific T-cell immunity was found in two patients in the highest-vaccine-dose group. CONCLUSIONS: This study demonstrated the feasibility, even in patients with advanced cancer, to elicit immune responses against the ubiquitously expressed tumor-associated auto-antigen p53. Our results form the basis for additional studies that will explore the antitumor capacity of p53 containing multivalent vaccines in cancer patients with limited tumor burden.

Adult↗
PubMedDate not supplied

Cancer genetics of sporadic colorectal cancer: BRAF and PI3KCA mutations, their impact on signaling and novel targeted therapies.

Novel activating mutations in sporadic colorectal cancer (CRC) have recently been identified on major kinase encoding genes such as BRAF and PI3KCA. The presence of these activating point mutations, including the well characterized KRAS oncogene mutations, represent up to 75% of cases in CRC. These genes, that have been implicated in the adenoma-carcinoma transition, cause deregulation and constitutive activation of the MAP AKT/kinase pathways, rendering growth advantages to colon tumor cells. This review focuses on the key genetic alterations underlying the cumulative effect of multiple mutations within the colon cancer cell. Moreover, the currently available and alternative treatment approaches that may target these different genetic alterations are discussed, such as the novel BRAF inhibitor. Identification of novel mutations as well as differential gene expression analyzed by microarray reveal potential targets for combined therapeutic protocols which will result in personalized treatments in the near future.

Animals↗
PubMed2001

Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent. Remarkably, among MLH1 mutation carriers, 54% of ECs (21 of 39), but none of the CRCs (0 of 32), lacked the MSH2 and/or MSH6 protein in addition to lacking MLH1 protein expression. These results demonstrate a marked difference between hereditary nonpolyposis colorectal cancer-related CRCs and ECs and suggest that the development of the latter tumors is selectively associated with the MSH2/MSH6 protein complex deficiency.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Cancer risk in relatives of patients with common colorectal cancer.

OBJECTIVE: To quantify any risk for colorectal cancer in first-degree relatives of patients with common colorectal cancer and to define possible markers for increased risk. DESIGN: Case-control family study. PATIENTS: Relatives of colorectal cancer patients and of matched control patients from a one-surgeon practice. METHODS: Family medical histories were obtained for 7493 first-degree relatives and 1015 spouses of 523 case-control pairs. Reported diagnoses of colorectal cancer in relatives were verified in 79% of instances. RESULTS: By case-control analysis, the odds ratio was 1.8 (95% CI, 1.2 to 2.7) for one and 5.7 (CI, 1.7 to 19.3) for two affected relatives. By matched analysis of risk in relatives, the increased risk to parents and siblings was 2.1 times greater for case patients than for control patients (CI, 1.4 to 3.1); 3.7 times greater (CI, 1.5 to 9.1) with case patients diagnosed before 45; and 1.8 times greater (CI, 1.2 to 2.9) with case patients diagnosed at 45 years or older; and was independent of gender, type of relative, site of cancer, and type of cancer (single or multiple). The cumulative incidence among first-degree relatives was greater for case patients than for control patients (P < 0.001), and in case patients, greater for those diagnosed before 55 years of age (P < 0.001). The cumulative incidence (+/- S.E.) to age 80 was 11.1% +/- 1.3%, 7.3% +/- 0.8%, and 4.4% +/- 1.0% among relatives of case patients diagnosed before age 45 years, between 45 and 54 years, and at 55 years or older, respectively, and was 2.4% +/- 0.6% in relatives of control patients. CONCLUSIONS: First-degree relatives of patients with common colorectal cancer have an increased risk for colorectal cancer. This risk is greater if diagnosis was at an early and is greater when other first-degree relatives are affected. This increased risk should be considered when formulating screening strategies.

Adult↗
PubMed2003

[Selected risk factors and primary prevention of colorectal cancer].

Incidence rates of colorectal cancer vary around 20-fold between industrialized and developing countries. Colon cancer is one of the most common cancers and very important public health problem in the Western world. Each year about 7000 patients in Poland die from colorectal cancer. Most cases of this cancer are possibly related to lifestyle or environmental factors. It is estimated that about 13% of colorectal cancer is attributable to low physical activity, 12% to diet and about 10-15% to genetic susceptibility. The aim of this work was to analyze the relationship between diet, physical activity and colorectal cancer risk. Current data suggest that lifestyle modification including proper diet, regular physical activity and maintaining an appropriate body weight may lead to 50-75% decrease of colorectal cancer cases. Therefore, effective management should include effective educational programs including dietary and other lifestyle behavior guidelines as well as early diagnostic of colorectal cancer.

Adult↗
PubMed1993

Surgical treatment of liver metastases in patients with colorectal cancer.

The incidence of colorectal cancer in the United States is increasing. Because more than half of patients with colorectal cancer have liver metastases develop, the number of patients with hepatic metastases also is increasing. Unfortunately, metastatic disease will be limited to the liver in perhaps 25% of these patients and confined to only one lobe of the liver 25% of this subgroup. Consequently, solitary or unilobar colorectal metastases are found in as few as 5% of patients with colorectal cancer. The median survival of patients with unresected hepatic metastases is approximately 10.6 months. Patients with solitary lesions or small tumor burdens may attain a median survival of 16-20 months, but 5-year survivors are extremely rare. In contrast, rates of 5-year survival average approximately 36% after resections of solitary hepatic lesions and may approach the same level in selected patients with multiple lesions. Factors that appear to adversely effect survival include detection of metastatic disease because of signs or symptoms of disease, an elevated carcinoembryonic antigen (CEA) level, elevated liver function tests, poorly differentiated primary lesions, lymph node-positive primary lesions, extrahepatic sites of metastases, more than four hepatic lesions, bilobar disease, a satellite pattern of metastases in the liver, positive margins of the liver resection, positive extrahepatic lymph nodes, and more than 10 units of blood transfusion during the perioperative period. Operative mortality for liver resections should remain approximately 4%, and major morbidity should be in the range of 20-30%. Modalities other than surgical resection have not improved survival in patients with colorectal hepatic metastases. Thus, when feasible, patients with metastatic colorectal cancer limited to one lobe of the liver should undergo hepatic resection. Unfortunately, only approximately 5% of patients with colorectal cancer fall into this category, so resection of hepatic metastases can improve overall survival of patients with colorectal cancer by only 1-2%.

Colonic Neoplasms↗
PubMed1998

Screening for colorectal cancer reduces emergency admissions.

AIMS: Colorectal cancer is common and accounts for over 15,000 deaths annually in England and Wales. Up to 30% of these patients require emergency surgery. Screening for colorectal cancer can reduce the mortality of colorectal cancer. This study addresses the impact of a population-based screening study on emergency admissions with colorectal cancer. METHOD: From 1981 a randomized trial of Faecal Occult Blood (FOB) screening has been undertaken in the Nottingham area, recruiting over 150,000 patients. The present study examined the records of patients enrolled in this study who presented as an emergency with colorectal cancer. RESULTS: Colorectal cancer was identified in 1962 cases, of which 468 (23.9%) presented as emergencies. The overall compliance was 60% (proportion of individuals completing at least one test). There were significantly fewer emergencies in the Screen-detected group compared with the Control group (P = < 0.0001). This group also had a significantly reduced 30-day mortality and a lower stoma rate than the Control group. Conversely the Non-responders had a significantly greater proportion of emergency admissions and a significantly increased stoma rate compared with the Control group. CONCLUSIONS: Screening for colorectal cancer using a faecal occult blood test can significantly reduce the number of emergency presentations with colorectal cancer. It is likely that the introduction of a national programme of screening for colorectal cancer would lead to increased compliance and that this would lead to a significant reduction in the emergency workload on the National Health Service from colorectal cancer.

Actuarial Analysis↗
PubMed1987

[Cooperative study of surgical adjuvant chemotherapy of colorectal cancer (first report): Investigation of background factors and adverse effects. Cooperative Study Group of Surgical Adjuvant Chemotherapy of Colorectal Cancer in Japan].

In order to evaluate the efficacy of surgical adjuvant chemotherapy in patients undergoing gross curative resection for colorectal cancer (excluding m and sm cancer), a randomized controlled study was conducted from January, 1982 to October, 1983. Four hundred and ninety-one institutions participated in this study. The schedules for drug administration differed according to each district. In the Hokkaido and Shikoku districts, the patients were divided into the following two groups, one was a combination of ACNU and Futraful (FT) and the other was FT only. In the Chubu and Kinki districts, three groups were studied, namely those receiving a combination of ACNU and FT, those receiving FT only and those given no adjuvant chemotherapy. In the Tohoku and Kanto districts, a combination of MMC and FT and administration of FT only were studied. In the Chugoku and Kyushu districts, the patients were divided into a combination of ADM and FT, and FT only group. Among the 3,926 registered cases, 3,421 cases were valid for the study. As to the background factors, there were no significant differences among the groups in each district. There were no significant differences in one-year survival rates and one-year disease-free rates. No serious adverse effects were observed in any of the groups.

Alopecia↗