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PubMed2005

Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study.

OBJECTIVE: To determine to what extent individuals with various family histories of colorectal cancer (from one to three or more affected first degree relatives) benefit from colonoscopic surveillance. DESIGN: Prospective, observational study of high risk families, followed up over 16 years. SETTING: Tertiary referral family cancer clinic in London. PARTICIPANTS: 1678 individuals from families registered with the clinic. Individuals were classified according to the strength of their family history: hereditary non-polyposis colorectal cancer (if they fulfilled the Amsterdam criteria), and one, two, or three affected first degree relatives (moderate risk). INTERVENTIONS: Colonoscopy was initially offered at five year intervals or three year intervals if an adenoma was detected. MAIN OUTCOME MEASURES: The incidence of adenomas with high risk pathological features or cancer. This was analysed by age, the extent of the family history, and findings on previous colonoscopies. The cohort was flagged for cancer and death. Incidence of colorectal cancer and mortality during over 15,000 person years of follow-up were compared with those expected in the absence of surveillance. RESULTS: High risk adenomas and cancer were most common in families with hereditary non-polyposis colorectal cancer (on initial colonoscopy 5.7% and 0.9%, respectively). In the families with moderate risk, these findings were particularly uncommon under age 45 (1.1% and 0%) and on follow-up colonoscopy if advanced neoplasia was absent initially (1.7% and 0.1%). The incidence of colorectal cancer was substantially lower-80% in families with moderate risk (P = 0.00004), and 43% in families with hereditary non-polyposis colorectal cancer (P = 0.06)-than the expected incidence in the absence of surveillance when the family history was taken into account. CONCLUSIONS: Colonoscopic surveillance reduces the risk of colorectal cancer in people with a strong family history. This study confirms that members of families with hereditary non-polyposis colorectal cancer require surveillance with short intervals. Individuals with a lesser family history may not require surveillance under age 45, and if advanced neoplasia is absent on initial colonoscopy, surveillance intervals may be lengthened. This would reduce the demand for colonoscopic surveillance.

Adult↗
PubMedDate not supplied

Multidisciplinary management of metastatic colorectal cancer.

When colorectal cancer metastasizes to distant organs, usually multiple sites are involved and treatment consists primarily of systemic chemotherapy and supportive care. Chemotherapeutic agents effective against metastatic colorectal cancer include 5-fluorouracil, often used in combination with leucovorin or methotrexate, and irinotecan (CPT-11). Median survival with optimal chemotherapy regimens ranges from 10 to 15 months. Less frequently, colorectal cancer metastasizes only to the liver or lung. In a minority of these cases, surgical resection can be performed and results in a median survival of 28-46 months for hepatic resections and 24-25 months for pulmonary resections. Five-year survival rates range from 24 to 38% and 21 to 44% for hepatic and pulmonary resections, respectively. For isolated liver metastases that are not surgically resectable, other regional therapies that can be considered are hepatic cryosurgery, radiofrequency ablation, and hepatic arterial infusion chemotherapy. Median survival following cryosurgery is between 26 and 30 months, while median survival following radiofrequency ablation has not been established in large series. Hepatic arterial infusion chemotherapy, especially with newer combination drug regimens, may increase survival in patients with isolated liver metastases compared to systemic chemotherapy, but this must be confirmed in randomized, prospective trials. Colorectal cancer metastases to the brain can be treated with radiation therapy or surgical resection, but median survival with treatment is less than one year.

Antineoplastic Agents↗
PubMedDate not supplied

Histochemically demonstrable protein tyrosine phosphatase in human breast and colorectal cancer: large decrease in its activity in colorectal cancer suggests a tumor suppressor role in colorectal mucosal cells.

Many oncogene products and growth factor receptors are protein tyrosine kinases, and exert their cellular effects by the phosphorylation of tyrosyl residues of effector proteins. The balance and dynamic renewal of phosphotyrosine proteins are also regulated by protein tyrosine phosphatases (PTPs), whose inhibition under experimental conditions causes cellular proliferation and transformation, with a concomitant increase in phosphotyrosine protein content. Inverse effects are obtained by increasing PTP activity. On the basis of these effects, PTPs might also function as tumor suppressors in human tissues. This possibility was further investigated here by demonstrating PTP and phosphotyrosine protein content with histochemical techniques. In normal human breast tissue PTP activity was low and in the majority of breast cancers the activity was increased and exhibited great variation between different cases. When the relationship of phosphotyrosine protein content with PTP was evaluated, no inverse dependence was detected, suggesting that in human breast tissue and cancer PTP may not show tumor suppressor activity. In normal colorectal mucosae PTP activity was high, while in all colorectal cancers it was very low, constituting only 14% of the activity present in normal mucosal cells. The great drop in PTP activity together with reported alterations in a gene encoding a PTP and in a chromosome containing a PTP gene in colorectal cancer strongly suggest that PTP may function as a tumor suppressor in human colorectal mucosae. The decrease in PTP activity may be one factor stimulating or causing neoplastic proliferation in multistep colorectal carcinogenesis.

Adenocarcinoma↗
PubMed2005

Loss of heterozygosity: an independent prognostic factor of colorectal cancer.

AIM: Colorectal cancers result from the accumulation of several distinct genetic alterations. This study was to investigate the frequency and prognostic value of loss of heterozygosity (LOH) and microsatellite instability (MSI) at 14 genetic loci located near or within regions containing important genes implicated in colorectal tumorigenesis. METHODS: We studied colorectal cancers with corresponding normal mucosae in 207 patients (139 males and 68 females, mean age at the time of tumor resection 66.2+/-12.4 years, range 22-88 years). There were 37 right-sided colonic tumors, 85 left-sided colonic tumors and 85 rectal tumors. The distribution of tumor staging was stage I in 25, stage II in 73, stage III in 68, and stage IV in 41. We analyzed the LOH and MSI of HPC1, hMSH2, hMLH1, APC, MET, P53, NH23-H1, DCC, BAT25, BAT26, D17S250, MYCL1 and D8S254 with fluorescent polymerase chain reaction and denatured gel electrophoresis. High-frequency LOH was determined to be greater than three, or more than 50% of the informative marker with LOH. High-frequency MSI (MSI-H) was determined as more than four markers with instability (>30%). Correlations of LOH and MSI with clinical outcomes and pathological features were analyzed and compared. RESULTS: The occurrence of MSI-H was 7.25%, located predominantly in the right colons (7/15) and had a higher frequency of poor differentiation (6/15) and mucin production (7/15). LOH in at least one genetic locus occurred in 78.7% of the tumors and was significantly associated with disease progression. Of the 166 potentially cured patients, 45 developed tumor recurrence within 36 mo of follow-up. Clinicopathological factors affecting 3-year disease-free survival (DFS) were TNM staging, grade of differentiation, preoperative CEA level, and high LOH status. Patients with high LOH tumors had a significantly lower DFS (50%) compared with patients with low LOH tumors (84%). Of the patients developing subsequent tumor recurrence, the number and percentage of LOH were 2.97 and 46.8% respectively, similar to the stage IV disease patients. TNM staging had the most significant impact on DFS, followed by high LOH status. CONCLUSION: Clinical manifestations of LOH and MSI are different in colorectal cancer patients. High-frequency LOH is associated with high metastatic potential of colorectal cancers.

Adult↗
PubMed1992

Colorectal cancer screening.

Colorectal cancer is a common and devastating disease. Many authorities recommend screening asymptomatic person, although the benefit of such screening is without scientific validation. Each of the screening modalities available has been examined, and their merits and shortcomings have been discussed. Surveys have indicated that primary care physicians generally agree with screening asymptomatic patients, but only a minority actually comply with the recommendations. Patient acceptance also varies. Thus, while specialty boards and panels of experts attempt to arrive at policies for the general population, primary care physicians must interact with the individual patient. Until data from ongoing prospective screening studies are available and cost-benefit issues are resolved, screening for colorectal cancer will remain at the discretion of physicians and their patients. There is insufficient evidence to support either continuing or discontinuing the recommended examinations for asymptomatic patients. The screening examinations can be recommended on the basis of a theoretical benefit, however. They can be performed with a minimum of risk of injury or side effects. Certain patients can be identified as being at above-average risk and deserving of more consideration. If aware of the benefits and limitations of colorectal cancer screening, primary care physicians can decide how to implement colorectal cancer screening in their clinical practice.

Barium Sulfate↗
PubMed2000

Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer.

In colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms, which contain a site for HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.

Colorectal Neoplasms↗
PubMed1998

Up-regulation of a set of glycosyltransferase genes in human colorectal cancer.

The carbohydrate structures of glycoconjugates of cancer cells change markedly in comparison with those of noncancerous cells. We aimed to determine which glycosyltransferases are up-regulated or down-regulated in human colon cancer tissues in order for the dramatic change in carbohydrate structures to occur. The transcript levels of 12 glycosyltransferase genes were measured by a competitive reverse-transcription-PCR method in noncancerous and cancerous colorectal tissues. Eight well- to moderately differentiated and three poorly differentiated carcinomas were examined in comparison with noncancerous colon epithelial tissues adjacent to the carcinoma tissues. Two of the twelve glycosyltransferase genes, Fuc-TIV and ST3Gal II, were significantly up-regulated in all cancerous tissues regardless of the histologic features. Four genes, ST3Gal I, ST6Gal I, beta1,4GalT, and Core2 GnT, showed a tendency toward up-regulation, and a ST3Gal III gene showed a tendency toward down-regulation. The other genes, Fuc-TIII, Fuc-TVI, and ST3Gal IV, which were most abundantly expressed in colorectal tissues, did not show significant up-regulation except in the poorly differentiated carcinomas. The Fuc-TVII gene was expressed at a very low level and was not up-regulated, and the Fuc-TV gene was not expressed at all in the colorectal tissues. Interestingly, all of the 12 glycosyltransferase genes examined, except the Fuc-TV, Fuc-TVI, Fuc-TVII, and ST3Gal III genes, were markedly up-regulated in all of the poorly differentiated carcinomas. We concluded that multiple glycosyltransferase genes are up-regulated, probably leading to extensive glycosylation of glycoconjugates in colorectal cancer cells. Lastly, sialyl Lewis antigens, ie, sialyl Lewis x and a antigens, which are terminal epitopes of sugar chains and well known as tumor-associated antigens, were quantified by Western blotting analysis. Based on the levels of transcripts of the 12 enzymes together with the amounts of sialyl Lewis antigens, we concluded that Fuc-TIII, Fuc-TVI, and ST3Gal IV are mainly responsible for synthesis of the sialyl Lewis antigens in colon tissues, but are not responsible for the augmented expression of the antigens in colorectal cancers. The amounts of sialyl Lewis x and a epitopes on mucins in colon cancer tissues can thus be determined through combinatorial up-regulation of the multiple glycosyltransferase genes.

Adult↗
PubMed2002

Perspectives on the role of sequential or combination chemotherapy for first-line and salvage therapy in advanced colorectal cancer.

Metastatic colorectal cancer is a major cause of cancer-related mortality. Surgical resection of all known metastatic disease can be curative in selected patients. The majority of patients, however, require the consideration of systemic chemotherapy as optimal palliative treatment for their diseases. Using new effective chemotherapeutic agents such as irinotecan and oxaliplatin has resulted in a clear and clinically significant improvement in survival for patients with metastatic colorectal cancer. The optimal sequences and combinations of these agents as initial and salvage chemotherapy along with 5-fluorouracil (5-FU) and leucovorin are controversial. It seems clear that it is important for all patients to have access to all 3 drugs at some point in their therapy for optimal results. Recent randomized trials of first-line chemotherapy for metastatic colorectal cancer in which patients were likely to have access to all 3 effective drugs demonstrated median survivals of 18-20 months. This compares favorably to median survivals of approximately 12 months for patients treated with 5-FU-based regimens alone prior to the availability of effective salvage therapy. A small but meaningful number of patients might develop resectable disease with curative intent as the result of significant tumor response to combination chemotherapy. Herein, we review recent developments in combination and sequential chemotherapy for metastatic colorectal cancer and the implications for the optimal treatment in these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Molecular basis and diagnostics of hereditary colorectal cancers.

Hereditary colorectal cancer syndromes are classified according to the presence of unusually large number of adenomatous or hamartomatous polyps, or their absence. The latter category includes hereditary non-polyposis colorectal cancer (Lynch syndrome) and its variants Muir-Torre and Turcot's syndromes. Adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and its variants, and the recently identified MYH- (mutY homolog)-associated polyposis. Hamartomatous polyposis syndromes include juvenile polyposis, Peutz-Jeghers syndrome, and Cowden syndrome, which is now included within the broader category 'PTEN (phosphatase and tensin homolog) hamartoma tumour syndrome'. Other syndromes such as the 'hereditary breast and colon cancer' and 'familial colorectal cancer' are not yet fully characterized. This review addresses the molecular basis of these syndromes with particular reference to the recent advances in this rapidly progressive field and the applications of such knowledge in diagnosis and management.

Adenomatous Polyposis Coli↗
PubMed2002

A population-based, community estimate of total colon examination: the impact on compliance with screening for colorectal cancer.

OBJECTIVE: Colorectal cancer screening is underutilized. Total colon examination (TCE), such as with colonoscopy, can have a significant effect on the measured compliance with screening, as colonoscopy may be able to be performed as infrequently as once every 10 yr. In a population-based survey we determined the prevalence and validated the self-reporting of TCE and assessed its impact on compliance with screening. METHODS: We interviewed an age- and sex-stratified random sample of 50- to 79-yr-old residents in two communities in southwestern Pennsylvania. Subjects reported ever having had and duration since last use of fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), rigid proctoscopy, barium enema, and colonoscopy. Self-reports of colorectal testing were validated via retrieval of procedure reports. RESULTS: Out of 1223 individuals sampled, 496 completed a telephone interview (40.6% overall and 58.3% of eligible contacts). In those without personal or family histories of colorectal cancer or personal histories of polyps (n = 377), 50%, 19.6%, 39.8%, and 17.5% reported ever having had FOBT, FS, barium enema, and colonoscopy, respectively. Thirty-one percent reported having FOBT within the previous year or FS within the previous 5 yr. Including TCE within the previous 5 yr increased the measured compliance to 39.7%. Compliance was significantly greater among subjects with family histories of colorectal cancer (62.9% vs 39.7%, odds ratio = 2.6, 95% CI = 1.3-5.2). Self-reports of recent colonoscopy were verified in 29 of 35 instances (83%). CONCLUSION: The prevalence of TCE in this population was significant, and including TCE substantially increased measured compliance with colorectal cancer screening. Self-reported use of colonoscopy was validated as accurate.

Age Distribution↗
PubMed1999

[Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer].

About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.

Adenomatous Polyposis Coli↗
PubMed2006

The effects of promoting colorectal cancer screening on screening utilisation: evaluation of the German Campaign "Aktiv gegen Darmkrebs" (Action against Colorectal Cancer).

BACKGROUND: Although colorectal cancer is the second leading cause of cancer death in Germany, screening rates remain low. It is unknown whether local approaches to promoting colorectal cancer screening are effective. This study evaluates the effectiveness of a regional awareness campaign consisting of public information sessions and leaflet distribution, upon the use of colorectal cancer screening by faecal occult blood test (FOBT) and colonoscopy. METHODS: Data on FOBT and colonoscopy were collected by doctors for 12 months following the campaign, including reason for and result of the testing. 37 % (n = 43) of all physicians and practitioners in two administrative districts (249 632 inhabitants) that were exposed to the campaign participated in the study. It was recorded whether the individuals requesting colorectal cancer screening had been prompted by the campaign, so the number and outcome of campaign-related tests was determined. RESULTS: 3398 individuals (male: 54.6 %, female: 45.4 %, age: 64.3 +/- 8.3 years) underwent 3551 screening tests (2446 FOBT, 819 colonoscopy, 133 both). 141 additional diagnostic colonoscopies were performed because of a positive result in the FOBT. Adenomas were detected in 279 individuals, malignancies in 11 individuals. 225 FOBT (8.7 %) and 176 colonoscopies (18.5 %) were performed due to the campaign; among these individuals, 49 had adenoma(s), 1 had carcinoma. The effect could be attributed both to leaflets and to information sessions. The proportion of campaign-related screening tests declined over time. CONCLUSION: The regional information campaign could reach target individuals and motivate them to utilise colorectal cancer screening. The combination of mass media and personal communicative elements seems useful.

Colonoscopy↗
PubMed2001

Microsatellite instability of colorectal cancer and adenoma in synchronous multiple colorectal cancer patients with associated extracolonic malignancies.

We examined microsatellite instability (MSI) in nonfamilial multiple synchronous colorectal cancer (multiple CC) patients. We divided the patients into two groups, those with and without extracolonic primary malignancies, and compared the frequency of MSI between the two groups. A colectomy was performed in 52 multiple CC patients between 1985 and 1998. Of them, 10 patients had extracolonic malignancies, while the other 42 patients did not. The MSI frequency was higher in the patients with extracolonic malignancies than in those without extracolonic malignancies, although it was not statistically significant (40% vs 19%, P = 0.21). Regarding the lesions, MSI frequency of cancers was higher in the multiple CC with extracolonic malignancies than in those without extracolonic malignancies (33% vs 13%, P = 0.033). From our results, there was statistically no difference in the existence of extracolonic malignancies between the patients with at least one MSI-positive cancer and those patients without any MSI-positive cancers. On the other hand, there was a significant correlation between MSI-positivity and the existence of extracolonic malignancies.

Adenoma↗
PubMed1997

[Effect of acupoint irradiation with Q-wave millimeter microwave on peripheral white blood cells in post-operational treatment with chemotherapy in stomach and colorectal cancer patients].

OBJECTIVE: To explore the biological effect of Q-wave millimeter microwave (QWMM). METHODS: The QWMM was used to irradiate the acupoints Xuehai (Sp10) and Geshu (B17) in treating post-operational and chemotherapy treated stomach cancer and colorectal cancer patients. The effect of irradiation on chemotherapy affected peripheral white blood cells was observed. 62 cases (stomach cancer 42, colorectal cancer 20) in total were divided into two groups: group A, 21 cases (stomach cancer 15, colorectal cancer 6) the irradiation began 10 days after operation, and on the 16th day the chemotherapy combined with irradiation started. Group B had 41 cases (stomach cancer 27, colorectal cancer 14), in which the irradiation began immediately after the occurrence of chemotherapy induced peripheral WBC reduction, which persisted for at least 12 days. RESULTS: The effective rate for the group A and B was 85.7% (18/21) and 73.2% (30/41) respectively. The total effective rate of the two groups was 77.4% (48/62). The effective rate of group A was significantly higher than that of group B, P < 0.01. CONCLUSION: GWMM irradiation at acupoints could promote the hematopoietic function of bone marrow, and the irradiation performed 1 week before chemotherapy yielded even better protection on bone marrow.

Acupuncture Points↗
PubMed2005

Colorectal cancer prevention.

Colorectal cancer is the second leading cause of mortality in the United States. In the United States, the cumulative lifetime risk of developing colorectal cancer for both men and women is 6%. Despite advances in the management of this disease, the 5-year survival rate in the United States in only 62%. Because only 38% of patients are diagnosed when the cancers are localized to the bowel wall, it is likely that widespread implementation of screening could significantly improve the outcome. Colorectal cancer screening is cost effective, irrespective of the methods used. In addition to currently available methods (fecal occult blood, flexible sigmoidoscopy, colonoscopy, and double contrast barium enema), computed tomographic colonography (virtual colonoscopy) and stool-based molecular screening are under development. Four classes of chemopreventive compounds have demonstrated efficacy in reducing recurrent colorectal adenomas and/or cancer in randomized, controlled trials. They are selenium, calcium carbonate, hormone replacement therapy, and nonsteroidal anti-inflammatory drugs. The mechanisms of action of nonsteroidal anti-inflammatory drugs include inhibition of the cyclooxygenase system as well as cyclooxygenase-independent effects. Considerable effort is being expended to define chemopreventive activity, optimal dose, administration schedule, and toxicity for the coxibs in adenoma recurrence prevention trials. The threshold for tolerating toxicities is very low in asymptomatic individuals at minimally increased risk for colorectal neoplasia.

Adenomatous Polyps↗
PubMed2005

Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is clinically defined by familial clustering of colorectal cancer and other associated tumours. METHODS: By thorough molecular and clinical evaluation of 41 families, two different groups were characterised: group 1, 25 families with truncating mutations in MLH1 or MSH2 (12 novel mutations); and group 2, 16 Amsterdam positive families without mutations in these genes and without microsatellite instability in their corresponding tumours. RESULTS: Significant clinical differences between these two groups were found. Firstly, earlier age of onset for all colorectal cancers (median 41 v 55 years; p < 0.001) and all tumours (median 43 v 56 years; p = 0.022) was observed, comparing groups 1 and 2. Secondly, 68% of the index colorectal cancers were localised proximally of the splenic flexure in group 1 compared with 14% in group 2 (p < 0.010). Thirdly, more synchronous and metachronous colorectal (p = 0.017) and extracolorectal tumours (p < 0.001) were found in group 1. Fourthly, a higher colorectal adenoma/carcinoma ratio (p = 0.030) and a tendency towards more synchronous or metachronous adenomas in group 2 (p = 0.084) was observed, indicating a slower progression of adenomas to carcinomas. As three mutation negative tumours revealed chromosomal instability after comparative genomic hybridisation, these tumours may be caused by one or more highly penetrant disease alleles from the chromosomal instability pathway. CONCLUSION: These data show that HNPCC includes at least two entities with clinical and molecular differences. This will have implications for surveillance programmes and for cancer research.

Adaptor Proteins, Signal Transducing↗