Calcium chemoprevention in colorectal cancer

BACKGROUND/AIMS: There are genetic, endoengenous, and exogenous factors responsible for colorectal cancer. Calcium may play a chemopreventive role in high risk groups. Binding fatty and biliary acids and their reduced absorbtion, with a consequent decrease of proliferative stimulation and reduction of secondary carcinogenic compounds, may explain this role. MATERIAL AND METHODS: 175 patients with adenomatous polyps after polypectomy and with calcium chemoprevention were evaluated for polyps recurrence. Another three groups of patients with colorectal cancer without chemoprevention (A,B) and with chemoprevention (group C) were followed concerning survival after surgery. RESULTS: The cumulative survival rate of patients after surgery due to colorectal carcinoma is significantly higher in a calcium chemopreventive group. Adenomatous polyps recurrences after polypectomy are lower (12.9%) in the chemoprevention group than in the group without prevention (55%) with a mean time of follow-up 3.1 yrs. CONCLUSIONS: Calcium is an important chemopreventive agent in adenomatous polyps after polypectomy and after colorectal surgery for colorectal cancer.     

Improving the treatment of colorectal cancer: the role of EUS

The two most important factors for determining the risk of local failure and overall prognosis in colorectal carcinoma are nodal status and the depth of tumor penetration into or through the bowel wall. These features have traditionally been determined pathologically because the clinical-staging accuracy of other imaging modalities such as computed tomography (CT) has not proven sufficiently predictive of surgical staging. However, endorectal or endoscopic ultrasonography (EUS) can be used to preoperatively evaluate nodal involvement with an accuracy of up to 86% (median: 80%) and depth of tumor penetration through the bowel wall with an accuracy of up to 97% (median: 85%) for effective clinical staging. This high staging accuracy is useful in managing colorectal cancer. Through clinical evaluation of the initial stage of colorectal cancer with EUS, a patient's risk of disease recurrence can best be determined and patients stratified for the most appropriate treatment. EUS can be used to select patients with lesions that can be treated with local excision or sphincter-sparing surgery, often combined with radiation therapy, in situations otherwise requiring an abdominoperineal resection. EUS can also be used to preoperatively identify patients with locally advanced or unresectable disease. Chemoradiation can then be given preoperatively, when it appears to be better tolerated and more effective than postoperative treatment. Unresectable tumors can often be downstaged sufficiently to allow their excision. In resectable disease, EUS can also identify patients at high risk for recurrence who would benefit from adjuvant chemoirradiation. EUS for precise staging or for earlier diagnosis of recurrence will further improve the clinical outcome of patients with colorectal tumors as significant advances both in surgical techniques and in combined chemotherapy/radiotherapy continue to be made and applied selectively in a stage-dependent manner.     

Deep vein thrombosis complicating colorectal surgery in the Chinese in Singapore

It has been reported that the risk of thromboembolism after general surgery in Chinese is negligible, thus, prophylaxis has not been used. This study examined the incidence in the high risk subgroup of patients undergoing colorectal operations. In a two-year retrospective review, 35 rectum resections for cancer, 72 colon resections for cancer, and 22 colon resections for benign disease were analysed. The clinical incidence of deep vein thrombosis (DVT) in patients with malignancy was 4.7% (5/107). None of the patients with benign disease had DVT. Three of the five patients with DVT had pulmonary embolism, of which one died. Rectal surgery incurred a higher risk (11.4%) compared to colonic resection (1.4%) (p = 0.038). Postoperative wound infection was an important predisposing factor (p = 0.027). In view of these findings, a prospective trial has been planned to further evaluate the need for prophylaxis in selected high risk patients.     

Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac

BACKGROUND: Recent work has demonstrated a correlation between frequency of aspirin ingestion and colorectal cancer prevention. Sulindac, another nonsteroidal anti-inflammatory drug (NSAID), has been shown to cause polyp regression and a fall in cell proliferation in patients with familial adenomatous polyposis, who are destined to develop colorectal cancer unless the colon is removed. However, the mode of action of NSAIDs in colorectal carcinogenesis prevention remains to be determined, although a prostaglandin-mediated mechanism seems likely. METHODS: Rectal or duodenal biopsies from 20 patients with familial adenomatous polyposis, who had been randomized to sulindac or placebo, were analyzed for prostaglandin (PG) E2 and F2 alpha levels before and after treatment. RESULTS: A significant fall in prostaglandin E2 and F2 alpha levels was seen in patients who were on sulindac; this correlated with a visual improvement in number and size of polyps in the same patients (P = 0.0096; PGE2, P = 0.036; PGF2 alpha, Spearman's rank correlation). CONCLUSIONS: Nonsteroidal anti-inflammatory drugs may prevent colorectal cancer by their inhibition of prostaglandin synthesis. Prostaglandins may be implicated in carcinogenesis through an increase in cell proliferation, through immunosuppression, by increasing neovascularization, or via a mutagenic effect.     

An outbreak of urticarial form of swine erysipelas in a medium-scale piggery in Kiambu District, Kenya

The influence which female sexual steroids, especially estrogen, have on the development of cancer has not only been shown epidemiologically, but also by experimental findings. Hormones, in spite of a known marginal increase in the risk of thrombosis and endometrial cancer, play an important role in the preventive cancer medication (oral contraceptives: ovarian and endometrial cancer; chemoprevention: high-risk breast cancer patients). Basically, hormone replacement therapy should be administered to all patients suffering from gynecological malignomas. In the case of patients suffering from breast cancer, the advantages of hormone replacement therapy (e.g., less risk of cardiovascular complications) need to be weighed against the disadvantages.     

Colorectal lesions predisposing to cancer

Precursors of colorectal carcinoma are adenomatous polyps, sporadic or arising in familial adenomatous polyposis and Lynch syndrome and chronic inflammatory lesions related to ulcerative colitis and Crohn's disease. The adenoma-carcinoma sequence is well established and early detection and removal of colorectal adenomas is thought to prevent colorectal cancer in high risk asymptomatic persons, i.e. subjects over 45 years, with personal or familial history of adenomas and colorectal cancers. The precancerous potential of adenomatous polyps varies according to tissue type, with increased risk with the extent of the villous component, high grade of dysplasia, large size greater than 1 cm and multiple adenomas. The development of de novo colorectal cancer from normal mucosa with flat adenomas has been recently emphasized. The risk of colonic cancer in patients with ulcerative colitis and Crohn's disease is controversed.     

Clinical implications of microsatellite instability in colorectal cancers

BACKGROUND: Microsatellite instability (MI) has been reported in some sporadic colon tumors and in cases of hereditary nonpolyposis colorectal cancer (HNPCC). The criteria for HNPCC have not been fully defined, and clinical criteria are used to identify as many HNPCC patients as possible. To clarify the conformity of these criteria with the identification of eligible HNPCC cases, we analyzed MI in HNPCC patients diagnosed using clinical criteria. METHODS: Genomic DNA was extracted from surgical specimens of 56 colorectal cancers, including 36 from patients diagnosed with HNPCC using the clinical criteria. We analyzed four microsatellite loci using 32P-labeled primers. RESULTS: Among HNPCC patients diagnosed using clinical criteria, patients who were positive for MI accounted for 62% of Group A (a confirmed group) and 35% of Group B (a high risk group); only 5% of randomly selected colorectal cancer patients (Group C), were positive for MI. Furthermore, MI-positive tumors were found in patients who had a tendency for tumors to involve the right side of the colon, an association with cancers in other organs, a lower incidence of p53 protein positivity, and a higher proportion of poorly differentiated cancers. CONCLUSIONS: The presence of MI, in concert with modified clinical criteria, may identify legitimate cases of HNPCC in patients who might otherwise be excluded by the minimum criteria.     

Genetics of colonic cancer

Research in hereditary forms of colorectal cancer (CRC) has increased almost logarithmically thanks in a major way to momentous discoveries in molecular genetics during the past decade. Between 10 and 20% of the total CRC burden is due to Mendelian-inherited CRC syndromes. The paradigm for hereditary CRC is familial adenomatous polyposis (FAP), wherein the APC germ-line mutation has been identified. This has contributed to the elucidation of genomic and clinical heterogeneity within the syndrome, wherein an attenuated form of FAP has been identified as a result of intragenic mutations within this large APC gene. The most common form of hereditary CRC is hereditary nonpolyposis colorectal cancer (HNPCC). Several mutator genes, namely hMSH2, hMLH1, hPMS1, hPMS2 and, more recently, hMSH6/GTBP, have been identified. These molecular genetic discoveries are providing new insights into the pathogenesis of CRC. Individuals within these kindreds who are harbingers of these germ-line mutations will benefit from screening and, one day, chemoprevention.     

Nonsteroidal antiinflammatory agents in chemoprevention of colorectal cancer. At what cost?

The objective was to provide a comparison of the known toxicities of nonsteroidal antiinflammatory drugs (NSAIDS) and the likelihood of benefit from colorectal cancer (CRC) chemoprevention attributed to them. Chemoprevention trials require large numbers of subjects followed over many years and are therefore very expensive and difficult. Hence, it is important that agents tested in these trails have a realistic expectation of actual use in the population. Data sources were published literature on the toxicity and CRC chemopreventive activity of NSAIDS. Presently available NSAIDS, used at their usual therapeutic doses, have a serious toxicity rate that quickly exceeds any benefit from CRC prevention. In contrast, low-dose aspirin is worth evaluating, especially because of the potential for simultaneous cardiovascular risk reduction. Possibly, low doses of other NSAIDS may have benefit, but this remains unproven. Synthesis of other NSAIDS, with less toxicity, is another approach towards making the toxicity-benefit ratio more favorable for the use of these agents for CRC prevention.     

Mass screening of colorectal cancer by general practitioners in France: what is the real target population?

OBJECTIVES: People at high risk of colorectal cancer, due to familial or personal history, or to specific symptoms, are considered not to be concerned by mass screening by Haemoccult test. The aim of this study was to investigate people aged 50 to 74 with high risk of colorectal cancer among general practitioners' practices in the department of Calvados (France). METHODS: A random sample of 200 general practitioners were asked to systematically fill out a questionnaire on Haemoccult II proposal for 50-74 year-old patients for a whole week. RESULTS: Participation rate of general practitioners was 58.5%. According to our findings, 13% of 50-74 years patients are considered not be concerned by mass screening, due to familial or personal history, or to specific symptoms. CONCLUSIONS: Colorectal cancer screening protocol have to be fit to level of risk of colorectal cancer. Involvement of general practitioners in colorectal cancer mass screening allows identification of high risk people who can then be managed with a more suitable screening protocol.     

Colorectal cancer: another complication of diabetes mellitus?

Delayed stool transit and other gastrointestinal abnormalities are commonly observed in persons with diabetes mellitus and are also known to be associated with colorectal cancer. Previous studies of the contribution of diabetes to colorectal cancer incidence and mortality have been limited by small sample sizes and failure to adjust for covariates. With more than 1 million respondents, the 1959-1972 Cancer Prevention Study provided a unique opportunity to explore whether persons with diabetes (n=15,487) were more likely to develop colorectal cancer during a 13-year follow-up period than were persons without diabetes (n=850,946). After adjustment for colorectal cancer risk factors, such as race, educational level, body mass index, smoking, alcohol use, dietary intake, aspirin use, physical activity, and family history of colorectal cancer, the incidence density ratio comparing colorectal cancer in those with diabetes and those without diabetes was 1.30 (95% confidence interval 1.03-1.65) for men and 1.16 (95% confidence interval 0.87-1.53) for women. However, diabetes was not associated with greater case fatality. Future studies should explore the possibility of a cancer-promoting gastrointestinal milieu, including delayed stool transit and elevated fecal bile acid concentrations, associated with hyperglycemia and diabetic neuropathy.     

Nosologic and anatomy pathological study of flat adenoma and associated lesions

Flat adenomas can be dysplastic from onset, whereas for polyps the risk of malignant transformation increases over time and with the size of the polyp. A dominant autosomal syndrome characterized by the development of flat adenomas has been reported. In a retrospective study of operative specimens from high-risk patients who had surgery for colorectal cancer, the author found that flat adenomas, which had been overlooked at initial evaluation, were a potentially useful phenotype. The mucosa adjacent to the flat adenomas showed hyperplasia and increased proliferation reminiscent of the morphologic abnormalities in aberrant crypts described by Pretlow; the latter have been found to occur rapidly in rats exposed to carcinogens and have also been demonstrated in patients at high risk for colon cancer. Aberrant crypt abnormalities and flat adenomas may be premalignant lesions.     

Current surgical practice in screening for colorectal cancer based on family history criteria

BACKGROUND: As awareness about colorectal cancer increases there has been a steady rise in the number of referrals of relatives of patients with colorectal cancer to colorectal surgeons for screening investigations based on family history criteria. Surgeons are generally not trained in either risk assessment of inherited colorectal cancer or genetic counselling. As this is a relatively new area of service, there is likely to be variation in the management of these individuals. METHODS: This study investigated the family history criteria used and the colonic screening practices employed by a group of consultant colorectal surgeons by means of a postal questionnaire distributed and collected through their specialist association. RESULTS: The results show not only wide variation in the practice of colorectal screening based on family history criteria, but also a considerable waste of resources in the provision of illogical and inappropriate investigations. CONCLUSION: Given the lack of evidence on which to base this clinical practice and the current financial difficulties in the health service, the authors question whether it is appropriate for surgeons to continue to provide such a service.     

Superficial bladder cancer: decreasing the risk of recurrence

Bladder cancer appears to develop through two alternative pathways. Papillary bladder cancer, the most common pathway, has a less aggressive course and is frequently heralded by hematuria, whereas carcinoma in situ appears to be more aggressive and is more difficult to detect. Superficial bladder cancer has a high propensity for recurrence but a low rate of progression. Transurethral resection is frequently employed for both diagnosis and treatment. The risk of tumor recurrence is related to the number of tumors at presentation and the findings on the first follow-up cystoscopy. Even patients with a low risk of recurrence need periodic cystoscopic examinations. Patients with a higher risk of recurrence may benefit from adjuvant intravesical chemotherapy or immunotherapy. Bacillus Calmette-Guérin (BCG) appears to be the most effective drug for intravesical therapy but has the highest rate of side effects. It is the treatment of choice for carcinoma in situ. Newer treatment strategies include perioperative intravesical chemotherapy and chemoprevention.     

Prognostic significance of tumor markers in colorectal cancer patients: DNA index, S-phase fraction, p53 expression, and Ki-67 index

Risk of colorectal cancer recurrence has traditionally been determined by use of pathologic staging. However, it is apparent that subgroups of patients exist within tumor stages whose clinical behavior differs. This study was undertaken to identify tumor-associated factors that might be predictive of outcome in patients with intermediate stages who will benefit the most from postsurgical adjuvant therapy. Seventy patients with stage II and III colorectal cancer were assessed for DNA index, S-phase fraction, p53 expression, and Ki-67 index. Tumor recurrence was analyzed by means of nonparametric tests and Cox proportional hazard models incorporating standard clinical and pathologic criteria. Of the four prognostic markers evaluated, Ki-67 index was significantly associated with disease recurrence (P = 0.02), whereas DNA index, S-phase fraction, and p53 expression were not. After stratification by tumor stage, significant associations between Ki-67 index and disease recurrence were retained in stage II tumors (P = 0.01) but not in stage III tumors (P = 0.23). Cox proportional hazard regression analysis indicated that among stage II patients, those with a Ki-67 index >45% were associated with 6.5 times greater risk for disease recurrence than those with a Ki-67 index >/=45%. It was concluded that an elevated Ki- 67 index is associated with an increased risk of tumor recurrence in stage II colorectal cancer.     

Contribution of plasminogen activators and their inhibitors to the survival prognosis of patients with Dukes' stage B and C colorectal cancer

Despite the advances in pre-, peri- and post-operative medical care of colorectal carcinoma patients, the prognosis has improved only marginally over recent decades. Thus, additional prognostic indicators would be of great clinical value to select patients for adjuvant therapy. In previous studies we found that colorectal carcinomas have a marked increase of the urokinase-type of plasminogen activator (u-PA), and the inhibitors PAI-1 and PAI-2, whereas the tissue-type plasminogen activator (t-PA) is found to be decreased in comparison with adjacent normal mucosa. In the present study we evaluated the prognostic value of several plasminogen activation parameters, determined in both normal and carcinomatous tissue from colorectal resection specimens, for overall survival of 136 Dukes' stage B and C colorectal cancer patients, in relation to major clinicopathological parameters. Uni- and multivariate analyses indicated that a high PAI-2 antigen level in carcinoma, a low t-PA activity and antigen level and a high u-PA/t-PA antigen ratio in adjacent normal mucosa are significantly associated with a poor overall survival. A high ratio of u-PA antigen in the carcinomas and t-PA antigen in normal mucosa, i.e. u-PA(C)/t-PA(N), was found to be predictive of a poor overall survival as well. All these parameters were found to be prognostically independent of the clinicopathological parameters. Multivariate analysis of combinations of these prognostically significant plasminogen activation parameters revealed that they are important independent prognostic indicators and have in fact a better prognostic value than their separate components. Based on these combined parameters, subgroups of patients with Dukes' stage B and C colorectal cancer could be identified as having either a high or a low risk regarding overall survival. In conclusion, these findings emphasize the relevance of the intestinal plasminogen activation system for survival prognosis of patients with colorectal cancer and, in the future, might constitute a patient selection criterion for adjuvant therapy.     

NSAID-induced polyp regression in familial adenomatous polyposis patients

NSAIDs inhibit prostaglandin synthesis. In 1983, Waddell et al first reported that sulindac, a NSAID (Clinoril), caused regression of rectal adenomatous polyps in several patients with familial adenomatous polyposis, an inherited form of colorectal cancer. Subsequently, NSAIDs have been used as chemopreventive agents in animal carcinogenesis models and adenoma regression had been confirmed in human trials with sulindac. This article summarizes these developments and describes possible mechanisms of colorectal neoplasia chemoprevention.     

Molecular biology of colorectal cancer and clinical consequences for colorectal cancer syndromes

Because of the accomplishments in biotechnical research in the past few decades our knowledge about the molecular mechanisms of carcinogenesis has grown rapidly. Colorectal cancer has been one of the most intensively investigated tumor entities, and it seems to be well established that colorectal tumor growth is associated with an accumulation of acquired somatic mutational events in tumor suppressor genes and oncogenes. Recent progress in our understanding of the molecular basis of the most prevalent colorectal cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), is reflected by modifications in diagnosis and therapy. Identification and characterization of the causative genes for these colorectal cancer syndromes have enabled precise presymptomatic detection of mutations in individuals who bear an a priori risk of about 50% of developing colorectal cancer. Genotype-phenotype correlations might further increase the clinical management of hereditary colorectal cancer. Even though developments in cancer research are restricted to the minority of individuals with hereditary cancer syndromes, growing knowledge about the effect of low penetrance variations in tumor suppressor genes may affect the diagnosis and therapy of sporadic colorectal cancer.     

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.