Endoscopic follow-up after colorectal cancer resection: an Italian multicentre study.

BACKGROUND: Endoscopic follow-up is advised in patients operated for colorectal cancer due to a high risk for both metachronous colorectal cancer and adenomas. Such issue has been scarcely addressed in Italy. This study aimed to evaluate the incidence of neoplastic lesions at a scheduled endoscopic follow-up and to identify the patients at higher risk of recurrence. METHODS: Colorectal cancer patients diagnosed in the three participating hospitals (one North, one Centre and one South Italy) were scheduled for colonoscopies at 1, 3 and 5 years after surgery. Incidence of adenomas, advanced adenomas and colorectal cancer was assessed in all patients. Neoplastic incidence in patients with and without synchronous lesions at entry was also compared. RESULTS: Overall, 318 consecutive patients were prospectively enrolled including 108 (34%, group A) with a synchronous lesion and 210 (group B) without it. A cumulative neoplastic incidence of 20.1, 32.4 and 44% was observed at 1, 3 and 5 years of follow-up, respectively. The cumulative incidence of all the lesions was 70% in group A and 30.2% in group B at 5-year follow-up, being 39.5 and 15.5% after excluding the lesions detected at 1-year examination. A neoplastic lesion was detected more frequently in group A at 1year (30.5% versus 14.7%; p = 0.0013), 3 years (21.4% versus 7.6%; p = 0.0008) and at 5years (18.1% versus 7.8%; p = 0.02). CONCLUSIONS: Our data showed that the incidence of adenomas in patients operated for colorectal cancer is fairly high. Colorectal cancer patients with synchronous lesions are at higher risk of neoplastic recurrence at follow-up as compared to those without them.

Expression of the Met/HGF receptor in normal and neoplastic human tissues.

The MET oncogene encodes a transmembrane tyrosine kinase receptor. Recently, hepatocyte growth factor (HGF), a potent growth factor for hepatocytes involved in liver regeneration, has been proposed as a ligand. In this paper, the physiological role of the human Met/HGF receptor is investigated by studying its specific distribution in normal and neoplastic tissues. Northern blot analysis has shown that the MET gene is selectively expressed in several epithelial tissues. High levels of MET mRNA have been found in liver, gastrointestinal tract, thyroid and kidney. Western blot analysis has shown that the levels of the Met protein generally correspond to those of the mRNA. However, in the thyroid, where there is a high level of MET mRNA, the protein was barely detectable, suggesting translational or post-translational regulation. The protein was also detected in the brain. Normal or increased levels of MET mRNA and Met protein were consistently found in fresh samples of carcinomas as well as in epithelial tumor cell lines. In thyroid carcinomas of a specific histiotype the amount of Met protein, almost undetectable in the normal counterpart, was found to be increased more than 100-fold. The tissue distribution of the Met/HGF receptor indicates that this molecule is involved in growth control of epithelial cells other than hepatocytes and suggests that its increased expression may confer a growth advantage to neoplastic cells.

Cell proliferation of breast cancer evaluated by anti-BrdU and anti-Ki-67 antibodies: its prognostic value on short-term recurrences.

The prognostic value of breast cancer proliferative activity was evaluated in 385 women operated for primary, non-metastasised mammary carcinoma. Cell kinetics was measured using two immunohistochemical techniques. Cells in S-phase of cell cycle were labelled in vitro by incubation of fresh tissue fragments with 5-bromo 2-deoxyuridine (BrdU), a thymidine analogue. Nuclei of cells in active DNA synthesis were stained by an anti-BrdU monoclonal antibody (Mab). Cells in interphase and mitosis were detected with Ki-67, a Mab that is known to react with a nuclear antigen present in G1/S/G2/M phases of cell cycle, but not in resting cells. This reagent provides a means of evaluating the growth fraction of neoplastic cells. BrdU was incorporated in a proportion of tumour cells ranging from 0.1 to 65.5% (median 6.8%). In the panel of tumours presented in this report the median percentage of Ki-67 positive cells (Ki-67 score) was 9.0% (range 0.1-77%). The relationship between disease-free survival (DFS), BrdU labelling index, Ki-67 score and 13 different clinico-pathological variables was investigated by multivariate analysis, using the Cox proportional hazards model. Axillary node status (P = 0.009) and Ki-67 score (P = 0.038) emerged as independent prognostic factors. Nodal status and tumour growth fraction allowed division of patients into groups at different risk of relapse: tumours with a proliferative index below the median value showed a lower recurrence rate than tumours with a high proliferative activity (P < 0.001). In particular, no relapse occurred in pN0 patients bearing carcinomas with a Ki-67 labelling < 9.0% 4 years after surgery. These findings suggest that the evaluation of proliferative activity in breast cancer enhances the probability of correctly predicting outcome after surgery and could be of assistance in the planning of adjuvant therapies.

Screening results in a family cancer clinic: five years experience.

We present our experience so far of screening individuals referred to the Cancer family clinic at St. Mark's Hospital from 1986, with the results of the follow-up of these individuals. 651 individuals from 436 families were offered colonoscopic surveillance at five-yearly intervals. The median age at which the examination was performed was 41 years. Families were subdivided according to family history; 15.8% conformed to the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC). The pathological findings were correlated with the type of pedigree; abnormalities were more often found in males than females (30% of colonoscopies in males revealed adenomas, and 17% in females), and adenoma prevalence increased with age. Adenoma prevalence (27% v.s. 21% at all ages, and 38% v.s. 25% in individuals over the age of 35y.), multiple adenomas and the proportion of proximally sited adenomas were all higher in HNPCC families; however, dysplasia and villous or large adenomas were not more common in individuals from HNPCC families. Four of the 7 carcinoma detected were in HNPCC families (3% v.s. 0.6%).

Primary tumor receptorial status and axillary metastases: their prognostic significance.

Data on the prognostic value of receptorial status are controversial. On the basis of our results, receptorial status has no significance as an independent role; only the number of involved nodes and hormonal therapy have this prognostic role. Free of disease survival curves according Kaplan and Meier show that there are no statistically significant differences either in patients with low neoplastic recurrences (pN0) or in those patients with high risk (pN1) among women with tumor ER+ and ER-. Among 291 pN0 patients there was no relation between receptorial status (negative from 3 to 9 fmol/mg) and results of therapy on the follow-up. Among 248 pN1 patients therapy with tamoxifen had an influence on free interval both in the group with a low receptorial status and in particular in that with high receptorial level; no effects of therapy on the ER- patients. In the group of 248 pN1 patients with high receptorial status, the therapy was more successful in the group with a medium lymph nodal risk (from 1 to 3 positive nodes) and also in the group with G1 or G2. With regard to the study of the relation between lymph nodal metastases and receptorial status, we can state that lymph nodal levels data gives the main prognostic factor of risk. Therefore lymphadenectomy involving the three lymph nodal levels appears to be the crucial point in diagnostic and therapeutic surgical strategy of breast carcinoma.

[The lower esophageal sphincter in gastrectomized patients. Manometric study]. / Lo sfintere esofageo inferiore nel gastrooresecato. Studio manometrico.

New manometric techniques in for examining the lower oesophageal sphincter (LOS) were applied an investigation of the oesophago-gastric junction after partial gastric resection. Pressure and blood gastrin data are reported for eight cases examined before and after surgery, under basal conditions and after stimulation with a protein meal. It was found that gastric resection leads to a decrease in LOS performance (43.6% fall in maximum pressure) and length (-33.3%). There is also a 93.5% decrease in the pressure response to a protein meal, and hence a predisposition to gastroesophageal reflux.

[Long-term effects of gastric resection on the inferior esophageal sphincter]. / Effetti a distanza della resezione gastrica sullo sfintere esofageo inferiore.

The manometric profile of the oesophagogastric junction has been studied in patients subjected one year earlier to partial gastric resection. A reduction in maximum basal pressure (--49.8%) and length of the lower oesophageal sphincter (--35.45%) were noted. These figures agree with what was observed one month after operation in a previous study. It is concluded that gastric resection lead to a non-transitory reduction in sphincter function.

[Postoperative fistulas after gastrectomy: risk factors in relation to incidence and mortality]. / Fistole postoperatorie dopo gastrectomia: fattori di rischio in relazione ad incidenza e mortalità.

The relations between incidence and prognosis of postoperative fistulas after gastrectomy and some different variables were analysed in the present retrospective study. Thirteen digestive fistulas of 113 patients (11.9%) submitted to gastrectomy during the period 1989-1994 represent the study population. The incidence of postoperative fistulas was compared to the kind of gastric pathology, to the extension of gastrectomy, to different nutritional (serum haemoglobin, albumin and transferrin level, weight loss) and immunological factors (serum lymphocytes) and, for oncological patients, to the stage of the disease. Incidence was directly related to the extension of gastrectomy, to serum albumin and haemoglobin level, and to weight loss rate. The results were not statistically significant at Kruskal-Wallis and ANOVA tests. No relation was found between incidence of fistulas and serum transferrin level, number of lymphocytes and adoption of early postoperative enteral nutrition. Six patients had spontaneous closure of the fistula with conservative therapy. Seven patients required reoperation because of abdominal sepsis (53.8%). Three patients died (23%). Although spontaneous closure, reoperation and mortality were related to nutritional and immunological state, no examined variables showed a statistically significative relation. The adoption of early postoperative enteral nutrition was not related to the prognosis, unlike the stage of the disease: patients submitted to reoperation had a TNM III or IV stage; dead patients had a TNM IV stage. Treatment of metabolic-nutritional unbalance can prevent anastomotic failure and fistula after gastrectomy and improve the prognosis. The relation between early postoperative enteral nutrition and incidence and prognosis of postoperative fistulas remains unclear.

The influence of hormone receptors and hormonal adjuvant therapy on disease-free survival in breast cancer: a multifactorial analysis.

The prognostic value of estrogen (ER) and progesterone (PgR) receptor status and the influence of hormonal adjuvant therapy on disease-free survival (DFS) in breast cancer were evaluated in 680 women after radical and modified radical mastectomy. The effect of 17 variables, including clinical data, TNM, hormone receptor status, histology and adjuvant therapy, on the DFS observed was analyzed, using a multivariate proportional hazard model. Multifactorial analysis revealed that DFS was strongly related to the number of positive axillary nodes (P less than 0.001) and the histological grade of the tumor (P = 0.05). Moreover, the DFS of ER-positive patients with node involvement was significantly improved by hormonal adjuvant therapy (tamoxifen). Combination of adjuvant chemotherapy with hormonal therapy did not enhance its effectiveness. Recurrence rates of either node-negative or ER-negative patients were not affected by either adjuvant therapy. When no systemic therapy was given, no significant relationship between ER or PgR content of the tumor and the DFS was observed. These findings suggest that hormone receptor status is not an independent prognostic factor but provides reliable information on responsiveness to adjuvant hormonal therapy which is very effective in patients selected on the basis of ER assay.

The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer. A multifactorial analysis.

Axillary lymph nodes were separated from 492 radical or modified radical mastectomies for primary breast cancer and examined according to their anatomical level corresponding to their position along the theoretical pathway of lymph drainage from the breast. The patterns of metastasis and the relationship between metastatized levels and disease-free survival were investigated to see whether complete axillary dissection is necessary for the staging and the planning of adjuvant therapy in breast cancer. Progressive involvement from level I (proximal) to level III (distal) was found in 206 specimens (80.8% of tumors with axillary metastases), while discontinuous or "skip" metastases were present in 49 (19.2%), including 38 (14.9%) with positive nodes at level II or III but not at level I. "Skip" metastasis was more frequent when fewer than four nodes were positive, and not related to either the size of the primary tumor or its location. The effect of age, menopausal status, tumor size, node status, number of positive nodes, anatomic level of axillary node involvement, estrogen and progesterone receptors, and adjuvant therapies on disease-free survival was evaluated using a multivariate proportional hazard model and life table analysis. This showed that disease-free survival was strongly related to the number of positive nodes (P less than 0.001), tumor size (P = 0.001) and level of node involvement (P = 0.01) as independent prognostic factors. Moreover, the subset of patients with four or more positive nodes and involvements of level III had a higher risk of recurrence (25% recurrence-free patients 5 years after mastectomy). The high frequency of "skip" metastases and the prognostic value of both the level of involvement and the number of metastatic nodes suggest that a complete axillary dissection is needed in the surgical management of breast cancer to obtain all the data useful in the planning of adjuvant therapy.

Prognostic value of CEA and ferritin assay in breast cancer: a multivariate analysis.

The prognostic significance of preoperative serum carcinoembryonic antigen (CEA) and ferritin levels was evaluated in 191 women operated for breast cancer. The influence of CEA, ferritin and another 11 clinical and pathological features on the disease-free survival was investigated in a multivariate analysis, using Cox's proportional hazard model. Axillary node status (P = 0.004), CEA level (P = 0.011), and the histological grade of the tumor (P = 0.029) emerged as independent prognostic factors. By contrast, no significant relationship was found between ferritin and disease-free survival. These three parameters were used to derive a prognostic index (I) for each patient. Multivariate analysis showed that its prognostic value was better than the value of any single factor (P less than 0.0001). The I score was used to divide patients into groups at different risk of recurrence: low, moderate and high (97.5%, 45% and 22.5% of recurrence-free patients at 3 years respectively). The data showed that the prognosis of patients with different combinations of node status and tumor grade was related to the level of CEA. Only women with very good (node-negative with well-differentiated tumors) or very bad prognosis (node-positive with four or more metastatic nodes and poorly differentiated tumors) had a disease-free survival independent of CEA values. These findings suggest that the preoperative measurement of CEA enhances the possibility of correctly predicting outcome and hence could be of assistance in the planning of adjuvant therapies.

The correlation between estrogen receptor status, axillary-node metastases and disease-free interval after surgery in primary breast cancer.

The prognostic value of estrogen receptor (ER) status in primary breast cancer was evaluated in 208 women subjected to Halsted radical mastectomy. The correlation between ER status, node involvement and disease-free interval after surgery was analyzed in detail. Forty-seven out of 127 ER-positive patients received hormonal adjuvant therapy, whereas the 81 ER-negative patients did not. Similar recurrence rates were found in ER-negative and untreated ER-positive patients, suggesting that the natural course of disease was not related to ER status. ER-positive patients who received hormonal adjuvant therapy showed a significantly longer disease-free interval than both ER-negative and untreated ER-positive patients, even though a higher frequency of node involvement was found in ER-positive tumors. Since only hormone-treated ER-positive patients showed a significantly lower recurrence rate, it is felt that ER status cannot be used as an independent prognostic factor.

The correlation between estrogen and progesterone receptors and some clinical and pathological features in human breast cancer.

The correlation between estrogen (ER) and progesterone (PgR) receptor status and some clinical and pathological features was evaluated in a series of 680 breast carcinomas. ER status was significantly related to age, menopause, histological grade and vascular invasion. No relationship was found with tumor size, lymph node involvement, histotype and multicentricity. PgR status was significantly related to vascular invasion only. Despite the relationship between ER and favorable pathological features, ER-positive patients did not show a longer disease-free interval after surgery when no systemic adjuvant therapy was administered. ER status is thus of little prognostic value.

Tachyphylactic action of high doses of pentagastrin.

The study of the human LES was performed with manometrical methods for atropine action on gastrine tachyphylaxis. Our study points out that there is a complex self regulating neuronal circuit in the LES contraction. We discuss some hypothesis for the LES control. In particular ACh could activate an inhibitory adrenergic muscarinic receptor.

Variables associated with the risk of colorectal adenomas in asymptomatic patients with a family history of colorectal cancer.

The results of screening individuals referred to the Family Cancer Clinic at St Mark's Hospital from 1986 are presented. Colonoscopy was performed in 644 asymptomatic individuals (from 436 families) with a family history of colorectal cancer. Sixty nine (15.8%) of the families fulfilled the Amsterdam criteria for the hereditary non-polyposis colorectal cancer syndromes (HNPCC). Seven cases of colorectal cancer were diagnosed at an average age of 49 years; six at Dukes's stage A and one at stage C, four in subjects from Amsterdam criteria families. One hundred and forty four (22.4%) subjects had one or more adenomas. The prevalence of adenomas in the subjects from Amsterdam criteria families was 34 of 127 (26.8%) compared with 110 of 517 (21.3%) in those from other families; the age and sex adjusted odds ratio (OR) was 1.76 (p = 0.02). Factors influencing the prevalence of adenomas in screened individuals were evaluated. Multivariate analysis showed that independent variables significantly related to the risk of adenomas were: age (p < 0.0001), sex (p = 0.0002), and the number of generations (> or = 2 v 1) of relatives affected by either colorectal cancer or adenomas (p = 0.0006). The latter variable was more highly predictive of the probability of finding an adenoma at colonoscopy than a family history of two generations with cancer only (p = 0.056). The OR of having colorectal adenomas increased with age, by about twofold for each decade, and was twice as high in men than women, and in subjects with two or more generations relative to those with one generation affected by colorectal cancer or adenomas. Six of seven patients with cancer and 46 of 144 (31.9%) with adenomas had lesions proximal to the splenic flexure only. The proportion of individuals with proximal adenomas only was 47.1% in Amsterdam criteria families and 27.3% in the others (p=0.03). These findings support the view that colonoscopy rather than sigmoidoscopy is the method of choice for screening high risk groups.

Overexpression of the Met/HGF receptor in ovarian cancer.

The MET oncogene encodes the receptor for Hepatocyte Growth Factor/Scatter Factor, a unique growth factor that induces not only proliferation of epithelial cells, but also cell motility and invasiveness. DNA level and expression of the Met/HGF receptor gene were examined with Southern- and Western-blot analyses, respectively, in human ovary, benign ovarian tumors and epithelial ovarian carcinomas. The Met/HGF receptor was detectable in the surface epithelium of normal ovary. The level of expression was unchanged in benign ovarian tumors of various origins. Fourteen out of 67 malignant carcinomas (20%) showed a 3- to 10-fold increase in expression. In 5 additional cases the Met/HGF protein was overexpressed over 50-fold. This represents a total of 28% of cases. Overexpression was not associated with MET gene amplification. Overexpressing tumors belonged to different histotypic variants, but showed a well-differentiated phenotype. Clinically, overexpression was associated with disease at any pathologic stage, but was significantly correlated with premenopausal status of patients. These data suggest that expression of the Met/HGF receptor may add a selective growth advantage to a narrow subset of differentiated ovarian cancers in premenopausal patients.

Loss of heterozygosity on chromosome 17p13 in breast carcinomas identifies tumors with high proliferation index.

The capacity of breast tumor cells to proliferate is considered a potential prognostic factor together with other histopathologic parameters. The authors determined the proliferation index on a large panel of human primary breast tumors by measuring the levels of incorporation of bromodeoxyuridine (BrdU) by fresh tumor specimens in culture. Previous analysis showed that the percentage of cells entering the S-phase of the cell cycle strongly correlates with tumor grade, tumor size, and estrogen and progesterone receptor status. The capacity of tumor cells to proliferate might be associated with specific genetic mutations in primary tumors. To test this hypothesis, a panel of 96 human breast carcinomas, for which the BrdU labeling index (LI) was known, were tested for loss of heterozygosity (LOH) or increased copy number (ICN) at chromosomes 1q, 3p, 13q, 17p, and 18q. On chromosome 17p, LOH and ICN were observed in 27% and 12%, respectively, of the informative breast tumors. The LOH on chromosome 17p was significantly associated with tumors having an elevated BrdU proliferation index (P = 0.022). No association (P = 0.45) was observed between BrdU LI and tumor size (T2 + T3 compared with T1), tumor grade, and lymph node status. Increased copy number on chromosome 17p, LOH or ICN on 1q, and LOH on 13q14, 18q, and 3p also showed no significant correlation with cell kinetic parameters. These data are consistent with the presence of a gene or genes on chromosome 17p13 near the YNZ22.1 locus whose normal functioning is necessary for controlling breast tumor cells proliferation in vivo.