Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors.

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.

Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Effects of acute changes of bile acid pool composition on biliary lipid secretion.

To elucidate the mechanism responsible for the bile acid-induced changes of biliary lipid secretion, we evaluated bile flow and biliary output of bile acids, cholesterol, phospholipids, and alkaline phosphatase activity in seven cholecystectomized subjects with a balloon occludable T-tube during two experimental periods: (a) depletion of the endogenous bile acid pool and (b) replacement of the pool by means of duodenal infusion with individual bile acids, such as deoxycholic (DCA), chenodeoxycholic (CDCA), cholic (CA), and ursodeoxycholic (UDCA) acids. Bile flow, cholesterol, and phospholipid output were linearly related to bile acid secretion in all experimental periods. During the replacement periods, the amount of cholesterol and phospholipids coupled to bile acids was significantly different (at 1% level at least) for each individual bile acid secreted; it was the highest during DCA secretion (slope value: 0.209 for cholesterol and 0.434 for phospholipids) followed, in the order, by CDCA (0.078 and 1.794), CA (0.044 and 0.127), and UDCA (0.030 and 0.122). The phospholipid to cholesterol ratio was higher during secretion of CA and UDCA as compared with DCA and CDCA. The secretion of CA seemed to stimulate a greater bile flow than the other bile acids did. The infusion of all bile acids, except UDCA, induced an increase of biliary alkaline phosphatase activity as compared with the values of the depletion period. The mean highest increase (13-fold the pretreatment value) was observed during DCA secretion followed by CDCA (fivefold) and CA (1.5-fold). These results would suggest that the physical chemical properties, namely the lipid-solubilizing capacity, of bile acids could directly contribute to the regulation of biliary lipid secretion. The observed changes in biliary alkaline phosphatase activity lend support to the view that bile acid-induced lipid secretion may be, at least in part, contributed by membrane solubilization.

Epithelial cell kinetics in the remaining colorectal mucosa after surgery for cancer of the large bowel.

We used microautoradiography in order to evaluate cell replication of the remaining colorectal mucosa in 20 patients previously operated on for cancer of the large bowel. The results were compared to those of 24 controls without neoplasms or other relevant colorectal disease. Samples of colorectal mucosa were taken during endoscopy. At histological examination each labeled intestinal hemicrypt was divided into 5 longitudinal compartments, from the base to the surface, and S-phase cells in each compartment were counted. Total labeling index (LI, ratio of labeled to total cells x 100) and labeling index per crypt compartment were similar in surgical patients and in controls. In contrast, both total LI and labeling index in the upper portions of the crypt (compartments 3, 4, and 5) were significantly higher in the 9 patients who showed recurrence of polyps than in those (n = 11) without recurrence. The LI in compartments 4 and 5 (the "high crypt region") was 4.37 +/- 0.95 (SEM) in patients with recurrence versus 0.88 +/- 0.21 (P less than 0.001) in patients with negative endoscopy finding and 1.47 +/- 0.22 in controls. Moreover, the fifth compartment was labeled in 8 of 9 individuals in whom polyps recurred but in only 2 of 11 patients without recurrence and 3 of 24 controls. In conclusion, after resection for large bowel cancer colonic epithelial cell proliferation tends to become more quiescent and similar to that of controls. However, in the subgroup of patients in whom polyps reappear, the colorectal mucosa maintains a hyperproliferative state with an expansion of the replicative zone to the most superficial portions of the crypt. These findings support the sequence adenoma-carcinoma and suggest that the evaluation of cell proliferation might be useful in the identification of subjects at increased risk for multiple tumors of the large bowel.

Cell kinetic evaluation of human colonic aberrant crypts. (Colorectal Cancer Study Group of the University of Modena and the Health Care District 16, Modena, Italy).

Foci of aberrant crypts (ACF) have been observed on the unsectioned, methylene blue-stained mucosal surface of the human colon. Experimental evidence and the histological features of the lesions suggest that they might be early events in colon cancer development. The main objective of the present study was to evaluate cell kinetic properties of ACF in the human colon. Five samples of colon mucosa were collected immediately after operation following the administration of 500 mg of 5'-bromo-2'-deoxyuridine prior to surgery. ACF were then identified on the fixed, unsectioned, methylene blue-stained mucosal surface under a light microscope. Some specimens containing ACF were serially sectioned perpendicular to the luminal surface of the intestine, along with specimens of normal-appearing mucosa. Several sections were prepared for the immunohistochemical identification of 5'-bromo-2'-deoxyuridine-incorporating cells (in the S phase of the cell cycle). The results of this study demonstrated that aberrant crypts have more cells per crypt than normal glands. Total labeling index and labeling index values in each of the five longitudinal compartments in which each crypt was divided showed an increased total proliferative activity in all ACF examined, although limited to the lower crypt compartments in almost all aberrant crypts evaluated. These findings are in keeping with previous cell kinetic studies and observations in experimental animals and provide evidence of the involvement of human aberrant crypts in the stepwise process leading from normal mucosa to colon cancer.

Familial aggregation of tumors in the three-year experience of a population-based colorectal cancer registry.

The familial occurrence of tumors has been investigated in 389 subjects with colorectal cancer by reviewing the clinical data and the genealogical tree of all patients registered in 1984-1986, in the Local Health District, for malignancies of the large bowel. Among first-degree relatives of the registered patients there were 89 cases of colorectal cancer as opposed to 19 in a hospital-based control group matched for age and sex [odds ratio (OR), 7.5, P less than 0.001]. This excess of neoplasms among relatives was particularly evident in siblings (60 versus 7, OR 14.7, P less than 0.001) but it was observed also in parents (27 versus 12, OR 4.2, P less than 0.01). Besides colorectal cancer there was no significant excess of other types of tumor in case families, whereas lung tumors tended to be more frequent in control relatives (32 versus 17). Almost half of the registered patients (182 out of 389) had one or more cases of cancer of any sites among relatives; similarly, in 68 there were one or more relatives affected by (or deceased for) colorectal cancer. Moreover, in 27 patients (7.0%) there were at least three cancers of any sites among relatives and in 15 the excess (two or more) was limited to neoplasms of the large bowel. In patients without or with only one neoplasm among relatives, cancers were mainly located in the left colon; however, cancer of the right colon became relatively more frequent in patients with two or more tumors in close relatives. In conclusion, the present study suggests that in approximately 15-20% of patients registered for colorectal cancer one or more first-degree relatives are affected by neoplasms of the large bowel. This familial occurrence of intestinal malignancies (but not of tumors of other organs) strongly suggests a genetic susceptibility to colorectal cancer in a fraction of these patients. Moreover, in a further subgroup of individuals (approximately 5% of all cases) the familial aggregation of two or more cases of colorectal cancer among relatives (besides the proband) and the frequent location of tumors in the right colon make the diagnosis of Lynch syndrome extremely probable.

Fecal neutral steroids in normal conditions and in patients with polyps or cancer of the large bowel.

There is evidence suggesting that the excretion and conversion of neutral sterols in the human large bowel might be somewhat related to the development of colorectal cancer. Therefore, our objectives were: to characterize the excretion and the major pattern of sterol degradation in normal conditions, both in children and in adults; and to investigate if abnormalities of these parameters are frequent in patients with colorectal cancer or polyps. The study has been carried out in: 38 adult volunteers; 29 children divided into 4 age groups; 22 patients with colorectal cancer; 16 members of 6 families with adenomatosis coli; 15 members of 2 families with a high prevalence of multiple polyps or cancer of the large bowel; 12 subjects with colorectal polyps without familiality. With the subjects kept under metabolic control, fecal samples were collected for at least 3 days and analyzed by thin layer chromatography and gas-liquid chromatography. Total neutral steroid excretion was lower in children than in adult volunteers; in contrast, there was no significant difference between the latter and the other investigated group of patients with cancer or polyps, with values ranging between 230 and 680 mg/day. All the adult volunteers were "high converters" of cholesterol to its intestinal metabolites coprostanol and coprostanone [89 +/- 10% (SE) of degradation]. Children less than 1 year old degraded little or no cholesterol (10.4 +/- 6% of total neutral sterols), whereas with increasing age the fraction of conversion became more similar to that of adults. In patients with colorectal tumors 2 populations could be defined, one characterized by a large degradation of cholesterol and the other by little or no conversion. Low degradation of cholesterol was found in 3 of 6 families with adenomatosis coli. In conclusion, we did not find any significant difference in total neutral sterol excretion among controls, colorectal cancer patients, or subjects at risk. In adult volunteers the normal pattern of cholesterol degradation is characterized by a large conversion of cholesterol to its intestinal metabolites. In children this process changes with increasing age from an absolute "nonconverter" state (after birth) to the pattern typical of adults. Finally, in a minority of patients with either polyps or cancer of the large bowel and of their first-degree relatives, cholesterol is poorly degraded and represents the most abundant fecal sterol.

Rectal cell proliferation and colon cancer risk in ulcerative colitis.

Cell proliferation kinetics of 30 patients affected by extensive ulcerative colitis in remission have been studied with autoradiography of rectal biopsies incubated with tritiated thymidine. The results have been compared with those of 20 control subjects without evidence of colonic diseases, and of 16 patients with multiple nonfamilial colonic adenomas. The labeling index was similar in the three groups (P = NS). On the contrary, the labeling frequency (SEM) in the upper 40% of the crypt (phi h value) was 0.04 +/- 0.01 in controls, 0.16 +/- 0.02 in ulcerative colitis, and 0.10 +/- 0.01 in adenoma patients (P less than 0.001 ulcerative colitis versus controls, P less than 0.01 adenomas versus controls, P = NS ulcerative colitis versus adenomas). The distribution of phi h values in ulcerative colitis showed a bimodal trend with 22 patients having mean phi h values similar to adenoma patients (0.10 +/- 0.01) and 8 with higher values (0.30 +/- 0.02). No relationship was found between phi h values and duration of colitis, age of patients, or age at onset of symptoms. These data show that cell kinetics studies can detect patients at particularly high risk of colon cancer, and that additional factors should determine colon cancer risk level in ulcerative colitis.

Pattern of epithelial cell proliferation in colorectal mucosa of normal subjects and of patients with adenomatous polyps or cancer of the large bowel.

Microautoradiography has been largely used to characterize the proliferative activity of colorectal mucosa. We used this technique in a large series of patients with polyps or cancer of the large bowel and in normal controls with the following objectives: (a) to define the normal pattern of cell replication in different tracts of the large bowel; (b) to compare the proliferative activity of colonic crypts in patients with colorectal cancer or polyps with that of controls; (c) to evaluate replicative activity of colorectal mucosa in the close vicinity and at distance from a neoplastic mass. Specimens of colorectal mucosa were taken during endoscopy (controls and polyps) or at surgery (cancer). During histological examination each intestinal hemicrypt was divided into five equal longitudinal compartments from the base to the surface and the labeled cells in each compartment were counted. In controls, total labeling index (ratio of labeled to total cells) and labeling index per crypt compartment showed only minor differences between the various large bowel tracts. Total labeling index tended to be higher in patients with polyps or cancer than in controls (13.5 +/- 0.4 and 12.5 +/- 0.4, respectively, versus 11.3 +/- 0.5). Labeling index per crypt compartment in the most superficial portions of the crypt (compartments 3 to 5) was significantly higher in the two groups of patients with tumors than in controls. This was particularly evident in the fifth compartment (the most superficial), in which labeled cells were observed in 15.8% (three subjects out of 19) of controls but in 71% (15 out of 21) and 87.5% (14 out of 16) of polyp and cancer patients, respectively. In patients with colorectal cancer there were not significant differences of cell proliferation between mucosal samples taken at various distances from the tumor margin; however, increased cell replication, especially in the most superficial portions of the crypt, has been observed. In conclusion, a significant upwards expansion of the proliferative zone of intestinal glands has been observed in patients with either polyps or cancer of the large bowel. In particular, labeling of the fifth compartment seems to possess the highest discriminatory power between subjects with or without intestinal neoplasms. Hyperproliferation of the entire colonic mucosa seems to be a common feature in patients with colorectal cancer.

The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.

Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability.

Microsatellite instability occurs in 15% of colorectal carcinomas and may be due to replication errors (RER). The pattern of instability--'severe' vs 'mild'--and the tumorigenic pathway, as reflected by the involvement of functionally important genes, may vary according to the underlying gene(s). We defined 'mild' RER as mono- or tetranucleotide repeat instability in the absence of widespread instability at dinucleotide repeats and studied 15 colorectal tumors with this phenotype for mutations in the DNA mismatch repair genes MSH2, MLH1, MSH3, and MSH6. No mutations were found, suggesting that these genes were not implicated. We then compared colorectal cancers with 'mild' RER (n = 15), and those with 'severe' RER without (n = 11) or with (n = 22) detectable mutations in MSH2 or MLH1 to assess the involvement of mononucleotide repeats contained in the coding regions of MSH3, MSH6, BAX, and TGFbeta RII. The combined mutation rates of the above mentioned loci varied significantly between the three groups of tumors, being 0%, 25% and 52%, respectively. Furthermore, the individual genes showed specific patterns of involvement; for example, among tumors with 'severe' RER, TGFbeta RII displayed uniformly high mutation rates while MSH3, MSH6, and BAX were more frequently altered in tumors that also showed MSH2 or MLH1 mutations. Our findings suggest that different subcategories exist among unstable tumors, defined by the RER pattern on the one hand and tumorigenic pathway on the other, and structural changes of MSH2 and MLH1 are likely to explain only a proportion of these cases.

Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.

PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.

Assessment of pathogenicity criteria for constitutional missense mutations of the hereditary nonpolyposis colorectal cancer genes MLH1 and MSH2.

To determine the role played by MLH1 and MSH2 missense variants in cancer susceptibility, we have investigated the following genetic and biological characteristics associated with six MLH1 and four MSH2 missense changes identified in Italian hereditary nonpolyposis colorectal cancer (HNPCC) families: co-segregation with disease phenotype and/or bonafide pathogenetic mutations; presence of the variant in healthy control subjects; evolutionary conservation of the involved aminoacid and type of aminoacid change; and presence/absence of microsatellite instability (MSI) in tumour DNA. Overall, nine variants did not fulfil > or = 2 pathogenicity criteria. MSI was investigated in tumour samples from carriers of nine different missense mutations. Only 3/9 variants were associated with MSI in tumour DNA. In addition, four variants were not present in affected pedigree members, and five variants were observed in the control population. Based upon these results, we conclude that most MLH1 and MSH2 missense changes are unlikely to act as major causative factors in colorectal cancer susceptibility and development.

Argyrophilic nucleolar organizer regions and bromodeoxyuridine and 3[H]-thymidine labelling indices in colorectal cancer.

The count of argyrophilic nucleolar organizer regions (AgNORs) has been proposed as a useful method for evaluating cell replication in human tumours. The current study was undertaken to compare AgNOR values in colorectal cancers with two better established methods for investigating cell proliferation such as bromodeoxyuridine (BrdUrd) and 3[H]-thymidine (3[H]dT) labelling indices (LIs). Because some concern still exists regarding accuracy and reproducibility of AgNOR quantifying methods, we carried out a control study by independently repeating the same measurements (number, area and area per silver-stained NOR particle) in two centres with different operators and computer-assisted image analysers on 40 colorectal carcinomas. AgNOR values recorded in the two centres were strictly correlated (r = 0.75; P < 0.001 for number; r = 0.62, P < 0.01 for area; r = 0.63, P < 0.001 for area per silver-stained NOR particle) and the range of values were almost identical. Then, AgNOR values were compared with BrdUrd and 3[H]dT LIs, respectively obtained by in vivo incorporation and in vitro incubation in the same series of colorectal carcinomas. No correlation was found between AgNOR values and BrdUrd or 3[H]dT LIs. BrdUrd and 3[H]dT LIs were instead reciprocally significantly correlated. No evident correlation was seen between LIs or AgNOR values and clinico-pathological parameters of the tumour. In conclusion, in colorectal neoplasms, AgNOR values did not appear to relate with more direct parameters of cell proliferation. It follows that AgNOR reliability as a biomarker of cell proliferation remains questionable.

Frequency and type of colorectal tumors in asymptomatic high-risk individuals in families with hereditary nonpolyposis colorectal cancer.

In hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome) a close surveillance is usually proposed to high-risk family members with the ultimate goal of reducing cancer incidence and mortality. Through a specialized registry, between 1984 and 1996, we identified 31 families with clinical features of HNPCC. A total of 390 first-degree relatives of affected patients were considered at high risk for colorectal cancer. The main purposes of this study were: (a) to assess overall compliance; and (b) to evaluate the frequency and morphological features of tumors detected at endoscopy. Two hundred twenty-three subjects could be directly interviewed and colonoscopy strongly recommended. Each of the 86 individuals who underwent colonoscopy was matched to a control of the same age (+/-3 years) and sex (control subjects were seeking endoscopy for constipation, rectal bleeding or abdominal discomfort). Of the 390 individuals traced as "at risk," 223 (57.2%) could be contacted, and, of these, 86 (38.6%, or 22.0% of the total) underwent colonoscopy. One or more colorectal lesions were found in 35 of 86 (40.7%) HNPCC asymptomatic family members and in 15 (17.4%; P < 0.001) controls. In the former group, 29 adenomas were detected in 20 individuals as opposed to 11 adenomas in 9 subjects among controls (P < 0.03). Moreover, adenomas in family members were significantly larger [9.1 +/- 5.9 mm (mean +/- SD) versus 5.8 +/- 3.7 mm; P < 0.02] and more frequently showed a tubulovillous histological type and a high degree of dysplasia. Five colorectal carcinomas (in four patients) were detected among cases (four of which were located between the cecum and the hepatic flexure); only one was detected among controls. Surveillance of high-risk subjects in HNPCC families can be carried out only in a fraction of them, because the majority cannot be reached or refuse to collaborate. On the other hand, the frequency of newly detected lesions among family members and the possible aggressive behavior of the lesions render pancolonoscopy necessary at regular intervals of time.

Survival of colorectal cancer patients in Europe during the period 1978-1989. EUROCARE Working Group.

This study concerns the survival of European patients diagnosed between 1978 and 1989 with colorectal cancer. Variations in survival in relation to age, country and period of diagnosis were examined. Data from the EUROCARE study were supplied by population-based cancer registries in 17 countries to a common protocol. Five years after diagnosis, relative survival rates were 47 and 43% for cancers of the colon and rectum, respectively. Survival decreased with increasing age: the relative risk of dying for the oldest patients (75+) was 1.39 for rectum and 1.54 for colon compared with the youngest patients (15-44 years). In 1985-1989 survival from colorectal cancer differed significantly between different European countries: the Nordic countries (Denmark excluded), The Netherlands, Switzerland, France and Austria were characterised by high survival, whilst Eastern European countries, the U.K. and Denmark were characterised by low survival. There was a general improvement in survival over the period 1978-1989: from 40 to 48% for colon cancer and 38 to 46% for rectal cancer. For neither cancer site did between-country survival differences narrow over the study period. Intercountry and time differences in survival differences are probably related to stage at diagnosis and postoperative mortality.

Clinical features, frequency and prognosis of Dukes' A colorectal carcinoma: a population-based investigation.

The main aim of this study was, through the data of a population-based Registry, to establish the incidence of Dukes' A lesions by year of registration and the main clinical features, and to assess cancer-specific survival. One hundred and eighteen Dukes' A colorectal tumours were diagnosed (in 117 patients) out of 1337 registered between 1984 and 1992 in the Health Care District of Modena, Northern Italy; 94 patients were treated with surgery and 23 with endoscopic polypectomy. The frequency of Dukes' A tumours ranged between 4.8% and 18% by year of registration. Dukes' A carcinomas were significantly more frequent in the distal colon. Only 5 patients (4%) died of their cancer, and in all patients the tumour was localised in the rectum. Carcinomas associated with a poor prognosis did not show any of the biological variables usually associated with an unfavourable outcome, but, our data suggest the possibility of incomplete removal of tumours at surgery.

Descriptive epidemiology of colorectal cancer in Italy: the 6-year experience of a specialised registry.

The Colorectal Cancer Registry of Modena recorded 838 malignancies of the large bowel between 1984 and 1989. Crude Incidence rates were 59.5 new cases per 100,000 per year in men and 47.4 in women (age-standardised values 33.1 and 20.6, respectively). 35 incident cases (4.2%) had multiple colorectal tumours, whereas 42 (5.1%) had extraintestinal malignancies (mainly breast, endometrium and stomach). Although 90.5% of the patients underwent surgery, this was "curative" in 634 (77.6% of the total), while 105 individuals (12.8%) had palliative operations; 78 patients (9.5%) were not operated, mainly because of metastatic disease or poor clinical condition. Finally, emergency operations--due to intestinal obstruction, perforation or massive bleeding--were carried out in 46 patients (6.1%). A total of 659 tumours (79%) were accurately staged. Among first-degree relatives of the registered patients a significant excess of cases of colorectal cancer was found in each year of the study. 5-year survival was evaluated in 132 (out of 140) patients registered in 1984 and followed-up until 1989. Overall 5-year survival was 37%, but rose to 43% when only colorectal cancer related deaths were taken into consideration. As expected, survival was strongly influenced by stage (P < 0.0001 by log-rank test). In conclusion, this study confirms previously reported data about incidence and mortality rates for colorectal cancer in northern Italy. The particular approach--limited to the large bowel--allowed the evaluation of the frequency of multiple tumours and of the marked aggregation of cancer among first-degree relatives. Finally, survival figures are comparable to those of many other studies and confirm that the clinical outcome of this neoplasm remains unfavourable in more than 50% of the affected patients.

Survival for colon and rectal cancer in a population-based cancer registry.

Dukes' stage is the most powerful indicator of patient outcome for colorectal cancer. Several cancer survival studies have considered other prognostic variables, but results are often conflicting. We sought to assess the independent value of several clinical and morphological variables in defining colorectal cancer specific survival. 397 colorectal cancer patients diagnosed from 1984 to 1986, and registered in a large bowel cancer registry instituted in a local health district of Northern Italy, were actively followed-up until 31 December 1991. Univariate and multivariate survival analyses were carried out in colon and rectal cancer cases, separately, using the actuarial life-table method and Cox proportional hazard regressions. Crude and specific 5-year survival rates were 37.5 and 41.4%. In univariate analysis, TNM (tumour, nodes and metastases) stage was the strongest predictor of prognosis in both sites. Other variables significantly related to survival were age of patient at diagnosis and pattern of tumour growth in colon cancer, type of differentiation and pattern of tumour growth in rectal cancer. In multivariate analyses, after adjusting for stage, age had a weak but significant negative effect on colon cancer survival, whereas rectal tumours with the infiltrating type of growth had a significantly worse prognosis than those with the expanding type. Colorectal cancer survival should be analysed in the main large bowel subsites in order to define high-risk groups within each TNM stage category.

Correlation between bromodeoxyuridine labelling and ornithine decarboxylase levels in normal rectal mucosa of patients with colorectal adenoma.

We studied rectal cell proliferation by means of bromodeoxyuridine labelling and ornithine decarboxylase activity assay in 16 patients with colorectal adenoma. In each patient, three rectal biopsy specimens taken from normal-appearing mucosa were incubated with bromodeoxyuridine (BrdU), fixed in ethanol and stained with avidin-biotin peroxidase complex using a monoclonal antibody against BrdU. In addition, two biopsies were homogenized and incubated with [1-14C]-ornithine for ornithine decarboxylase (ODC) assay. A direct, significant correlation was found between BrdU-labelling index and ODC levels in the mucosa (r = 0.6511, P less than 0.01). We conclude that BrdU labelling and ODC activity assay give comparable results in the analysis of cell proliferation rate of rectal mucosa. These methods are useful to investigate rectal cell proliferation pattern of patients with increased risk of colorectal cancer.