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PubMed2004

Molecular genetics of colorectal cancer.

Colorectal tumours constitute an excellent system to study carcinogenesis and the molecular events implicated in the development of cancer. Attending to the way it is transmitted, colorectal cancer may appear in one of three forms: sporadic, familial, and hereditary. The sporadic form is most common and has no familial or hereditary associated factor thus far, while familial and hereditary forms show the same inheritance pattern. Hereditary colorectal cancers develop by means of defined stages that go from lesions in the crypt of the colon through adenomas to manifest cancer. They are characterised by the accumulation of multiple mutations in tumour suppressor genes and oncogenes that affect the balance between cell proliferation and apoptosis. The colorectal carcinogenesis pathway is not unique and there are probably several ways for the initiation, development and progression of colorectal tumours.

Clinical Trials as Topic↗

PubMed1997

Attitudes and practice in the management of metastatic colorectal cancer in Britain. Colorectal Cancer Working Party of the UK Medical Research Council.

Evidence-based medicine is widely held to be the essential basis of modern therapeutics. The principle of adopting into clinical practice those treatments proved to be of value in randomized trials, or in the systematic review of several trials, in encouraging a welcome proliferation of clinical research and meta-analysis. However, many things affect clinical practice; quantifiable therapeutic benefit is only one of them. Furthermore, in many situations, clear evidence of the best treatment is not available. When discussing ideas for a new trial in advanced colorectal cancer that was launched in 1996, the MRC Colorectal Cancer Working Party carried out a survey of the attitudes and practice of surgeons and oncologists who were treating this condition. This revealed substantial diversity of practice amongst experts in the treatment of this common disease, and prompted us to review the factors that affect clinical practice and to discuss the implications.

Antineoplastic Agents↗

PubMed2004

[Epidemiology and screening of colorectal cancer].

Colorectal is a major health problem in industrialized countries. Cancer registries have reported relatively large variations in incidence throughout the world. The incidence has been increasing over time. Colorectal cancer fulfills the conditions required by mass screening. Data from randomized studies indicate that it is possible to reduce colorectal cancer mortality in people who accept screening with faecal occult blood test. Time has come to implement well-organised population-based faecal occult blood screening in subjects aged between 50 and 74 despite current limitations of available tests.

Adult↗

PubMed1988

[Surgical treatment of metastatic lung cancer from colorectal cancers].

Based on conclusions obtained after the observation of 61 colorectal cancer patients with a lung metastasis, the resection of lung metastasis as a therapy was evaluated. Among these 61 patients, only 5 patients had been identified as having a lung metastasis at the time of resection of the primary lesion, whereas the other 56 patients developed the lung metastasis after the curative resection of the colorectal cancer. Only one patient with a synchronous lung metastasis and twelve patients (eleven with a solitary metastatic lesion and one with multiple metastatic lesions) with metachronous lung metastasis underwent removal of the lung metastasis. The three-year survival rate was 65.2% in the metachronous group.

Adult↗

PubMed1994

[Studies on adjuvant chemotherapy using subserosal or submucosal administration of neocarzinostatin for gastric cancer and colorectal cancer].

The significance and effectiveness of adjuvant intraoperative chemotherapy using subserosal or submucosal administration of Neocarzinostatin (NCS) and CH 40 for gastric cancer and colorectal cancer were studied. Tissue NCS concentration of proximal lymph nodes were higher than for distant lymph nodes, while the immunocompetency of distant lymph nodes (lower NCS concentration) showed slightly higher activity than that of proximal lymph nodes. From these results, it is suggested that loco-regional administration of NCS might be effective for chemical lymph node cleaning of the cancer.

Carbon↗

PubMed1998

[Clinics for counseling on cancer genetics. Experiences with genetic studies and counseling on familial breast cancer and colorectal cancer].

Five to ten percent of cases of breast cancer and colorectal cancer are familial. These families can be divided into high-risk families and moderate-risk families. Cancer in high-risk families can often be explained by dominant inheritance of a gene causing increased susceptibility to cancer. There is a great demand for genetic counseling in these families, and the structure of and experiences from a familial cancer clinic at Odense University Hospital is described. The establishment of a familial cancer clinic involves three steps: 1) Identification of families with increased cancer susceptibility; 2) Molecular tests to identify gene carriers; 3) Clinical examinations for early detection of tumors. Achievement of these three steps requires the involvement of several medical specialties to ensure patient care. Experience with familial cancer clinics is still limited and the involvement of genetic testing and clinical examination programs at risk individuals are insufficiently examined. The rapidly improving techniques for genetic testing make it urgent that it is implemented as part of already established clinical programs.

Adult↗

PubMed2006

Role of detection of microsatellite instability in Chinese with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer.

AIM: To detect microsatellite instability (MSI) in patients with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer and to provide criteria for screening the kindreds with hereditary nonpolyposis colorectal cancer at molecular level. METHODS: MSI was detected in the specimens from 20 cases with HNPCC, 20 cases with ordinary hereditary colorectal cancer and 20 cases with sporadic colorectal cancer by means of polymerase chain reaction-single strand conformation polymorphism. RESULTS: The positive rate of MSI was 85% (17/20) in HNPCC group, 40% (8/20) in ordinary hereditary colorectal cancer group and 10% (2/20) in the sporadic colorectal cancer group respectively. The differences were significant. The mean ages of the three groups were 43.6, 52.2, and 61.8 years respectively, which increased gradually. The incidence of right hemicolon cancer was 64.7%, 37.5%, and 0% respectively, which decreased gradually and had significant difference. The expression ratio of BAT26 and BAT25 was 94.1% respectively, which was highest in the 5 gene sites studied. The incidence of poorly differentiated adenocarcinoma was 70.6% in HNPCC group among high frequency microsatellite instability (MSI-H), which was higher than the other two groups, which had 50% and 50% respectively. CONCLUSION: The incidence of MSI-H is higher in HNPCC group. The detection of MSI is simple and economical and has high correlation with the clinicopathologic feature of HNPCC and can be used as a screening method to detect the germ line mutation of the mismatch repair gene.

Adult↗

PubMed1997

Endoscopic diagnosis and treatment of early colorectal cancer.

Colorectal adenomas and early cancers are grossly classified into three groups: protruded, flush or slightly elevated (so-called flat adenomas), and depressed. Protruded lesions and flat adenomas are not invasive until they are rather large, whereas depressed lesions can invade the submucosa even when very small. It is not difficult to detect protruded and flat adenomas, but depressed carcinomas are often overlooked. Keys to the detection of depressed carcinomas are a slight color change, bleeding spots, interruptions of the capillary network pattern, slight deformation of the colonic wall, shape change of the lesion with insufflation and deflation of air, and interruption of the innominate grooves by the lesion. Spraying of indigo carmine dye helps to clarify the lesions. Pit pattern analysis with magnifying colonoscopy is useful for diagnosis of early colorectal cancer. Pit pattern analysis and histologic examination suggest that depressed carcinomas probably have arisen de novo, without going through an adenomatous step. Some adenomas appear at first to have a depression, but such cancer-mimicking adenomas with pseudodepression must be distinguished from depressed carcinomas because they are quite different in nature. Protruded and flat adenomas can usually be removed with polypectomy or hot biopsy techniques. Depressed carcinomas are treated with an endoscopic mucosal resection (EMR) technique; but when they massively invade the submucosa, surgical resection is indicated. Some neoplastic lesions, which we call laterally spreading tumors, extensively and circumferentially spread along the colonic wall, although they are short in height. They tend to have a rather benign nature despite their large size; therefore EMR or a piecemeal EMR method is indicated.

Adenoma↗

PubMedDate not supplied

Phase II trial of 150-minute weekly infusion of gemcitabine in advanced colorectal cancer: minimal activity in colorectal cancer.

Metastatic colorectal cancer is very common in the Western hemisphere and current treatment modalities are not effective. In this study a prolonged (150-minute) infusion of gemcitabine at a constant dose rate of 10 mg/m2/min administered weekly for 3 consecutive weeks repeated every 4 weeks revealed a response rate of 4% (90% CI < 1%-18%). There were no complete responses. Treatment with gemcitabine produced moderate to severe toxicity as grade 3-4 neutropenia requiring dose modification was seen in 40% of patients treated. When used in this dose and schedule, gemcitabine does not appear to be effective for patients with metastatic colorectal cancer.

Adult↗

PubMed1999

A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer.

Colorectal carcinoma is an important cause of cancer morbidity and mortality. 5-fluorouracil has been the major chemotherapeutic agent for the treatment of colorectal carcinoma for the past four decades. This regimen is noncurative, and its impact on survival is unclear. Attempts at identifying more effective chemotherapeutic agents for colorectal cancer have yielded oral formulations and prodrugs of 5-fluorouracil with apparently equivalent efficacy. Specific thymidylate synthase inhibitors are now available. Platinum analogues with activity in colorectal carcinoma, and no cross-resistance to the antimetabolites have also been developed. The topoisomerase I inhibitors represent a new class of agents with a novel mechanism of action. These agents are in phase II and Phase III clinical trials, others have been approved for clinical use within the last 3 years.

Antineoplastic Agents↗

PubMed2000

[Colorectal cancer in spouses of colorectal cancer patients].

Married couples share home environments and life style for years. In the case of colorectal cancer, an association with insulin resistance was reported. We determined the presence of the insulin-resistance syndrome (IRS, 1 or more of the following: body mass index of > 25 kg/m2, diabetes, or hyperlipidemia) in 84 colorectal cancer patients, of whom 61 patients (73%) had IRS. The incidence of the distal colorectal cancer, which has been declining in the United States, was significantly higher in the IRS group than in the non-IRS group (75.4 vs 52.2%, p = 0.0400). Some mechanisms may promote the progression of mucosal lesions to invasive cancers in the distal colorectum. There were no significant differences with respect to the age (64.6 +/- 9.4 vs 64.3 +/- 11.3 yr, p = 0.8298), height (159 +/- 9 vs 157 +/- 8 cm, p = 0.1375), and body mass index (22.2 +/- 3.6 vs 22.4 +/- 2.7 kg/m2, p = 0.6364) between the patients and their spouses. In 84 couples in whom colorectal cancer develops at least in one may then not illustrate the nursery rhyme: "Jack Sprat could eat no fat, His wife could eat no lean...". The spouses had been married for an average of 38 years, and in 30 spouses who had been followed in a colorectal cancer screening, 5 developed colorectal cancer. To diminish the incidence of colorectal cancer in Japan, we might advise screening colonoscopy to the spouses of colorectal cancer patients, or déjà vu all over again?

Aged↗

PubMedDate not supplied

Colorectal cancer: future population screening for early colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent cancers in Western countries. The identification of individuals at risk and the early diagnosis of CRC are of critical importance since a large proportion can be prevented or cured by surgical removal before metastasis has occurred. With increasing understanding of the genetic basis of hereditary and sporadic (non-hereditary) CRC, it becomes feasible to detect genetic alterations by molecular techniques. Familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), as well as early stages of spontaneous CRC, can be diagnosed by molecular characterisation of the adenomatous polyposis coli (APC) gene, the RAS oncogene and other genes in DNA from peripheral blood, stool or intestinal biopsies. With a better understanding of the genetic events leading to malignant transformation, molecular population screening should allow us to identify individuals at risk as well as patients with an early and potentially curable CRC. At present, careful patient and family history, physical examination and testing for occult blood as well as colonoscopy are still the key elements for clinical patient management. Molecular diagnosis will hopefully soon complement these analyses and should result in a reduction of morbidity and mortality from CRC.

Adenomatous Polyposis Coli↗

PubMed1988

Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II).

Approximately 5 to 6 percent of the total colorectal cancer burden is accounted for by hereditary nonpolyposis colorectal cancer (HNPCC). Because clinical premonitory signs such as those seen in familial polyposis coli (FPC) are lacking, the clinician must recognize clinical findings and family history typical of HNPCC. The authors have described colorectal cancer expression from a survey of ten HNPCC kindreds. Kindred members with colorectal cancer differed significantly (P less than .05) from patients with sporadic colorectal cancer: 1) mean age of initial colon cancer diagnosis was 44.6 years; 2) 72.3 percent of first colon cancers were located in the right colon, and only 25 percent were in the sigmoid colon and rectum; 3) 18.1 percent had synchronous colon cancers; and 4) 24.2 percent developed metachronous colon cancer, with a risk for metachronous lesions in ten years of 40 percent. Affecteds and their first-degree relatives should undergo early intensive education and surveillance. In families with an early age of onset, colonoscopy should begin at age 25, and biannually thereafter, with fecal occult blood testing of the stool semiannually. Third-party carriers must become more responsive to the costly surveillance measures required for these otherwise healthy patients.

Adult↗

PubMed2005

[Hereditary predisposition of colorectal cancer and prevalence of hereditary nonpolyposis colorectal cancer in general population of colorectal cancer patients in China].

OBJECTIVE: To analyze hereditary predisposition of CRC and the prevalence of HNPCC in general population of CRC patients in China. METHODS: CRC patients were from two sources. One is that we consecutively investigated 594 patients by ourselves. They were proved to be colorectal cancer by histology. The following data of all patients should be registered: sex, age diagnosed colorectal cancer, site, number and histological type of primary cancer. The other was the published Chinese and foreign literatures related to Chinese HNPCC prevalence, and there were cumulatively 3596 patients in all. Hereditary predisposition of CRC (or malignant tumors) is that CRC patients have two or more first- or second-degree relatives (or both) with CRC (or malignant tumors). HNPCC was diagnosed by Amsterdam Criteria I (AC I) or Amsterdam Criteria II (AC II), Japanese Criteria of HNPCC (JC). RESULTS: Hereditary predisposition of both malignant tumors and CRC were 17.2% and 5.2% in 594 patients with CRC, respectively. Multiple primary cancers and multiple CRC were 13.1% and 10.1% , respectively. Among them, multiple primary cancers and multiple CRCs without familial history were 9.1% and 6.7%, respectively. There was a correlation between familial history of malignant tumors and multiple primary cancers and multiple CRCs (both P < 0.01). Patients with familial history of malignant tumors had more frequently multiple primary cancers and multiple CRCs than patients without history of malignant tumors. Younger patients (< or = 50) were 21.4% in all CRC patients. there was a correlation between younger patients (< or =50) and familial history of malignant tumors and familial history of CRC (both P < 0.05). When CRC was diagnosed, patients with familial history of malignant tumors and familial history were younger than patients without them. In the population of CRC patients in China, prevalence of HNPCC diagnosed AC I, AC II and JC were 1.24%, 2.15% and 2.93%, respectively. CONCLUSIONS: Hereditary predispositions of malignant tumors and CRC were 17.2% and 5.2% in CRC patients, respectively. Familial history of malignant tumors, multiple primary cancers and younger patients with CRC (< or =50) were the clinical markers of hereditary predisposition of malignant tumors including CRC. Multiple primary cancers and younger patients with CRC (< or =50) were all correlated with familial history of malignant tumors. The prevalence of HNPCC in China was similar to that in Western countries.

Adult↗

PubMed2006

Clinical and immunologic responses to active specific cancer vaccines in human colorectal cancer.

Colorectal cancer is a common malignant disease, which, despite some progress, still requires improved therapeutic options. Several clinical studies have used active specific immunotherapy (i.e., vaccination) in colorectal cancer. However, the literature still lacks a comprehensive meta-analysis of this approach in advanced colorectal cancer. We did a systematic review with a meta-analysis of clinical studies to evaluate the objective clinical and immunologic response to active specific immunotherapy in patients with colorectal cancer. We conducted a search of Medline and the Web of Science, manually reviewed the literature, and consulted with experts. Criteria for including studies were colorectal cancer patients, active specific immunotherapy to induce a response directed against cancer or cancer antigens, an evaluable tumor burden (i.e., advanced or metastatic colorectal cancer), and precise classification of the patient, disease, and response. Response rates were assessed according to WHO criteria. Primary end points were the objective clinical response rate and the rate of immunologic responses. The secondary end point was the distribution of immune and clinical responses in relation to the route of vaccination and the type of vaccine. Thirty-two phase I/II studies reporting on 527 patients with advanced or metastatic colorectal cancer met all inclusion criteria. Pooled analysis showed an overall response rate (complete response + partial response) of 0.9% for advanced/metastatic colorectal cancer patients who underwent active specific immunization with a broad variety of substances (e.g., autologous tumor cells, peptide vaccine, dendritic cells, idiotypic antibody, and virus-based vaccine). Humoral immune responses were reported in 59%, and cellular ones were reported in 44% of the cases. Mixed or minor responses and disease stabilization are described in 1.9% and 8.3% of colorectal cancer patients, respectively. Pooled results of clinical trials reveal a very weak clinical response rate of <1% for active specific immunization procedures currently available for advanced colorectal cancer. Immune response induction is described in approximately half the patients.

Antibody Formation↗

PubMed2002

Radiologic imaging modalities in the diagnosis and management of colorectal cancer.

Colorectal carcinoma poses a serious public health threat. Detection in its early stages in the best predictor for long-term survival, which is the impetus for population-based screening programs. We believe that full-colon imaging by either DCBE or colonoscopy is necessary for colon cancer screening because flexible sigmoidoscopy, even if perfect, only detects 50% to 60% of colon cancers, a rate far worse than even the worst rate reported for single-contrast barium enema. Screening for colon cancer with flexible sigmoidoscopy is equivalent to performing a "left" mammogram for the detection of breast cancer. The role of CT colonography is still to be determined. When confronted with a symptomatic patient, barium enema is applied in conjunction with CT to detect primary colorectal carcinoma, to differentiate it from other benign and malignant processes involving the colon, and to assess for disease extent before surgery in selected high-risk patient populations. Pelvic MRI may be useful in the preoperative assessment of patients with rectal carcinoma as a means for assisting surgical planning. CT, MRI, and barium enema are used in postoperative follow-up for detecting local recurrence and distant spread. In response to known difficulty in discriminating between normal postoperative changes and tumor recurrence and in determining the nature of certain liver lesions, FDG-PET has been approved for the detection and localization of recurrent colorectal cancer in patients with rising CEA levels and indeterminate findings on standard imaging studies. Given its current promise of offering high sensitivity, specificity, and accuracy, the indications for PET may well expand in the future, but its final role in still to be determined.

Aged↗

PubMed2006

Cancer genetics: colorectal cancer as a model.

Cancer is essentially a somatic evolutionary process and is, therefore, effectively defined by the genetic and epigenetic changes underlying this process. An understanding of the function of these changes is fundamental to devising new approaches to prevention and treatment. Colorectal cancer (CRC), apart from its obvious importance as one of the most frequent cancers, provides an excellent model for such studies because of the availability of precursor adenoma lesions and the existence of several clear-cut familial inherited susceptibilities. These include familial adenomatous polyposis (FAP), which led to the identification of the APC gene and the importance of the Wnt pathway, and hereditary non-polyposis CRC (HNPCC), which identified the role of the mismatch repair genes in colorectal and other cancers. The presently known range of genetic and epigenetic changes in CRCs and adenomas is reviewed in this paper and the evidence against a requirement for genomic instability presented, together with a discussion of patterns of gene methylation, including especially our work on the homeobox gene, CDX1. Clearly, familial cancers, such as FAP and HNPCC, cannot account for more than perhaps 5% of the incidence of CRC. There is, however, evidence that approximately a further 25-30% have some inherited susceptibility. Based on the association of APC missense variants with multiple adenomas, we proposed that much of this may be due to the cumulative effects of low frequency, low penetrance variants, and the "rare variant hypothesis". The evidence for this from our work on multiple adenoma cases, and certain other examples, is discussed.

Adenoma↗

PubMed2006

Proportion of de novo cancers among colorectal cancers in Japan.

BACKGROUND & AIMS: Adenomatous polyps are main precursors of colorectal cancers (CRCs). In Japan, de novo cancers, which do not arise from preexisting adenomas, are considered to account for a substantial number of CRCs, but the relative importance of de novo carcinogenesis remains controversial. This study estimated the proportion of de novo cancers among CRCs in Japan. METHODS: The subjects were persons 40-79 years of age who were relatively similar to those in the general population. The subjects underwent colonoscopy between 1997 and 2001. Early cancers among CRCs detected in this study were classified as de novo cancers or polyp cancers derived from adenomas. The age-specific incidence of the early CRCs was calculated, and the proportion of de novo cancers was estimated. The lifetime risk of early CRCs was estimated. RESULTS: The study group comprised 14,817 persons. CRCs were diagnosed in 189 subjects, including 83 early cancers. There were no differences with regard to size and location between de novo cancers and polyp cancers, but morphology differed. Eighty-four percent (16/19) of de novo cancers were flat elevated or depressed. The expected lifetime risk of developing early CRCs was 5.27% for men and 3.21% for women. Among persons with early cancers, the expected probabilities of developing de novo cancer were 18.6% for men, 27.4% for women. CONCLUSIONS: De novo cancers account for a considerable proportion in Japan. This information suggests that the recommended interval for colonoscopic examination in Japan should be shorter than that in the United States.

Adult↗