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M Ponz de Leon

Publications and source records attributed to M Ponz de Leon.

At least 19 recordsLinked to original sources

Cell kinetics evaluation of colorectal tumors after in vivo administration of bromodeoxyuridine.

Although several biomarkers have been tested, Dukes' (or TNM) stage at diagnosis is still considered the only prognostic factor of clinical relevance in colorectal cancer. Among the various biomarkers, the fraction of cells engaged in DNA synthesis has been extensively investigated as an indicator of tumor aggressiveness. Bromodeoxyuridine (BUdR) is a non-radioactive thymidine analogue which is incorporated into DNA during the S-phase of cycling cells. In order to evaluate the relationships between cell kinetics and morphologic variables, 500 mg of BUdR were given i.v. to 46 patients with colorectal cancer prior to surgery. After operation, a large tumor sample was taken and processed for immunohistochemical detection of BUdR-labeled cells in various regions of the neoplasm and in normal colorectal mucosa. Smaller superficial tumor specimens were also incubated with 3H-thymidine (3H-TdR) for the autoradiographic identification of labeled cells. In the 43 evaluable tumors, the overall BUdR labeling index (BLI, percent of labeled cells) was significantly higher in carcinoma (20.30 +/- 0.86%, SEM) than in normal colonic mucosa (6.51 +/- 0.49%). BLIs in central and peripheral regions of carcinoma were closely correlated (r = 0.48, p = 0.003). In 21 neoplasms a high correlation between overall BUdR and 3H-TdR labeling index in the same tumor was observed (r = 0.57, p = 0.007). No evident association between overall BLI and clinical or morphologic parameters of the tumor was seen, including number of capillaries and ras-p21 protein expression. We conclude that BUdR immunostaining after in vivo administration of BUdR is a simple method for studying cell kinetics in various regions of colorectal cancer. BUdR labeling data are comparable to those obtained with in vitro incorporation of 3H-TdR.

Adult

Autoradiographic and flow-cytometric assessment of cell proliferation in primary colorectal cancer: relationship to DNA ploidy and clinico-pathological features.

Two cell-kinetic parameters, the [3H]thymidine-labeling index [3H]dT LI and the flow-cytometric S-phase cell fraction (FCM-S), and DNA ploidy were determined for a prospective series of 110 primary colorectal cancers. Aneuploidy was observed in 66% of tumors and more than one aneuploid peak was present in 12%. The frequency of aneuploid tumors was higher in rectal (80%) and left-colon (70%) cancers than in right-colon cancers (51%), and multiple aneuploid clones were detected more frequently in men than in women (p = 0.03) and more frequently in advanced Dukes' D-stage patients (p = 0.08). The median [3H]dT LI value (17.4%) was similar to the FCM-S value determined by a planimetric model (16.2%) and somewhat higher than the FMC-S value obtained by an optimization procedure (11.2%). However, there was no significant relationship between the [3H]dT LI value and either FCM-S value for individual tumors. Moreover, FCM-S values were higher in aneuploid than in diploid tumors, whereas [3H]dT LI values were independent of DNA-ploidy status; [3H]dT LI and FCM-S were also related differently to some clinical and pathological features such as tumor site and histology. These findings suggest different biological meanings for these 2 cell-kinetic parameters, which should not be used interchangeably.

Adult

Clinical and pathologic prognostic indicators in colorectal cancer. A population-based study.

The institution of a colorectal Cancer Register in a health care district of Northern Italy gave the authors the opportunity to evaluate the prognostic relevance of several morphologic and clinical variables by univariate and multivariate analyses. Of the 134 patients registered in 1984, 132 were followed up until the end of 1989. Overall 5-year survival was 37%, but the figure increased to 43% when only colorectal cancer-related deaths were considered. Univariate analysis for clinical variables showed that TNM staging and age at diagnosis were significantly related to prognosis, whereas none of the other parameters were indicative of the clinical outcome. With a similar analysis, among the various morphologic variables, pattern of growth (infiltrating versus expanding) and extent of fibrosis (extensive versus little or absent) appeared to be indicators of prognosis. When the variables that were significant (stage, age, pattern of growth, and fibrosis) in the univariate analysis were entered into the Cox model of multivariate analysis, TNM staging was the only parameter that maintained an independent prognostic importance. The authors state that their results confirm the importance of stage in predicting survival for cancer of the large bowel and suggest that the possible prognostic value of clinical and morphologic variables should be investigated within each of the major TNM or Dukes' classes.

Age Factors

Genetic transmission of colorectal cancer: exploratory data analysis from a population based registry.

Classical segregation analysis was conducted on 605 families of probands with colorectal carcinoma ascertained through the Cancer Registry of the Province of Modena in Italy. The families were classified as 28 suspected hereditary non-polyposis colorectal cancer (HNPCC) syndromes and 577 presumed non-HNPCC. In 11 of these, both parents had colorectal carcinoma, in 130 one parent was affected, and in 436 both parents were normal. In the suspected HNPCC families, segregation was compatible with dominant transmission of susceptibility to carcinoma. In families with one parent affected, the segregation frequency was almost exactly equal to the frequency of segregation in families where both parents were normal. The model of dominant transmission of susceptibility through a major gene with greatly reduced penetrance in heterozygotes fitted the data acceptably.

Colorectal Neoplasms

Pattern of cell kinetics in colorectal mucosa of patients with different types of adenomatous polyps of the large bowel.

It is generally accepted that adenomatous polyps represent the natural precursor of many colorectal malignancies. The sequence, however, which leads from a normally appearing mucosa to cancer is complex and involves many steps, including a hyperproliferative mucosa with an upward expansion of the replicative compartment. The current study evaluates cell replication in normal colorectal mucosa of patients with adenomatous polyps of various types and relates the observed findings to the main clinical and morphologic features of adenomas. Forty-four patients with polyps and 27 controls entered the study. Samples of colorectal mucosa were taken at endoscopy and cell replication was evaluated with a standard autoradiographic procedure. Cell replication was expressed as labeling index (LI), in the whole crypt and in each of the five longitudinal compartments in which the crypts were divided. Total LI and LI per crypt compartment were significantly higher (P less than 0.02 and P less than 0.01, respectively) than in controls. There was no appreciable difference of LI values between patients with single or multiple, tubular or tubulovillous, small or large adenomas, but in all of these subgroups LI was significantly higher than in controls. In conclusion, in normally appearing colorectal mucosa of patients with adenomatous polyps there was a significant increase of cell replication and a marked upward expansion of the proliferative zone; these changes were more evident in the left colon and in the rectum. Finally, cell replication did not seem to be related to the number of polyps, to the most common histotypes, or to the pattern of recurrence.

Adult

Decrease in plasma tryptophan after a tryptophan-free amino acid solution. A comparison between cirrhotic and control subjects.

In healthy subjects the administration of an amino acid mixture devoid of tryptophan causes a marked decrease of plasma tryptophan. This is because amino acid mixtures induce protein synthesis and tryptophan in blood is incorporated into newly synthesized proteins. We hypothesized that a tryptophan-free mixture could differently affect plasma tryptophan levels in subjects with an impaired protein synthesis such as chronic liver patients. We studied tryptophan levels after a tryptophan-free amino acid solution in controls and cirrhotics fasting 12 hours. Plasma total tryptophan fell to 91% of the initial level 60 minutes after the administration of the diet, to 71% after 120, and to 50% after 210' in controls. In cirrhotics the solution caused a decrease of plasma tryptophan that began significantly later than in controls, the delay being proportional to the severity of the disease. Cirrhotics were subdivided into two groups in accordance to the Pugh modification of the Child-Turcotte criteria. Total plasma tryptophan was 100% of base line levels after 60', 88% after 120', and 65% after 210' in less severe clinical condition; total plasma tryptophan was 102% of base line levels after 60', 98% after 120', and 75% after 210' in more severe clinical condition.

Adult

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.

Adenoma

Reliability of 3H-thymidine labeling index: cell proliferation of colorectal carcinoma in three different centers.

Although the 3H-thymidine labeling index (TLI) has been used extensively as a biologic marker of increased susceptibility to neoplasms or as a prognostic indicator of the clinical outcome in cancer patients, there is still some concern regarding its accuracy and reliability as a marker of cell replication. A study on the prognostic value of TLI in colorectal cancer gave us the ability to evaluate how such a measurement may vary in different laboratories. A total of 150 malignant tumors of the large bowel were studied in the period from 1988 to 1989. Microautoradiography was carried out in tumor fragments taken at surgery. There were only slight differences among the three centers involved in the investigation, mainly as regards the culture medium, exposure time, and the addition of O2 + CO2 during the incubation. No significant difference was observed among TLI values recorded in the three centers (18.3 +/- 0.9; 17.4 +/- 0.9; 15.7 +/- 1.0 mean +/- SE), and the ranges of values were almost identical. Similarly, the numbers of total and of labeled cells counted for each patient were comparable among the three centers. The frequency distribution of TLI showed a peak value between 10 and 19.9% in all three centers. Moreover, more than 80% of the observed values were within the range of 10 to 29.9%. In addition, the neoplastic areas with the highest proliferative activity ("high" TLI) showed a frequency distribution once again rather similar among the three centers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

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 Division

Familial occurrence of gastric cancer in the 2-year experience of a population-based registry.

The authors studied the familial occurrence of tumors in 154 individuals with gastric cancer by reviewing the clinical data and the genealogical tree of all patients registered in 1986 through 1987 in the Local Health Care District of Modena, Italy, for cancer of the stomach. Crude and age-adjusted (world population) incidence rates of gastric cancer were 34.0 and 21.4 new cases/100,000/year, respectively, in men, and 24.5 and 10.9 in women, respectively. Among first-degree relatives of the registered patients there were 30 cases of gastric carcinoma versus 15 cases in a control group matched for age and sex (Mantel-Haenszel odds ratio [M-H OR] 3.14, P less than 0.01). This excess of gastric neoplasms was observed in siblings (17 versus 7, M-H OR 4.33, P less than 0.02) but not in parents (13 versus 8, not significant). Besides gastric cancer, there was no significant excess of other type of tumors in case families. The familial occurrence of gastric cancer tended to be more frequent in patients with "diffuse" carcinoma (52%) than in subjects with "intestinal" cancer (33%), although the difference was not statistically significant. In conclusion, the current investigation suggests that a "family history" for gastric neoplasms is usually observed in approximately 10% to 15% of the registered cases. As already described for other common malignancies, therefore, the familial occurrence of gastric carcinoma suggests the existence of a genetic susceptibility to cancer of the stomach, at least in a fraction of these patients.

Adult

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.

Adenoma

Evidence for the existence of different types of large bowel tumor: suggestions from the clinical data of a population-based registry.

The clinical findings of a population-based colorectal tumor registry have been analyzed to determine elements of supporting or not supporting the existence of different types of large bowel cancer. Age-specific incidence rate of the 409 registered patients rose sharply with increasing age in all segments of the large bowel; however, regarding left colon and rectum, the male: female ratio showed a marked male preponderance, more evident in the more advanced age groups. Histopathology, studied in 87% of patients, revealed adenocarcinoma as the most frequent feature; however, adenocarcinoma with concomitant adenoma (i.e., presumably arising in adenoma) was observed in 14.3% of cancers of the left colon, in 17.7% of rectal tumors, but in only 5.7% of neoplasms of the proximal colon (P less than 0.05 and P less than 0.01, respectively, vs. left colon and rectum). Some histological features (carcinoid and mucinous carcinoma) were observed in right-side tumors only. Analysis of the familial occurrence of cancer showed that a significantly larger proportion of patients with neoplasms located in proximal colonic segments had three or more first-degree relatives affected by (or deceased from) cancer of all sites. Similarly, colorectal tumors among relatives were more frequent in patients with right-side cancer. The location of the 793 polyps observed during 3 years of registration showed that more than 70% of adenomas were located beyond the splenic flexure, overlapping the distribution of cancers. In conclusion, the differences of sex ratio at different colonic subsites, the higher fraction of adenocarcinomas with adenomas in cancer of the more distal tracts of the large bowel, and the more marked familial occurrence of colorectal cancer in patients with right-side neoplasms tend to support the view that cancer of the proximal colon, cancer of the distal colon, and cancer of the rectum may actually be three different types of tumors.

Adenocarcinoma

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.

Colorectal Neoplasms

Hereditary adenomatosis of the colon and rectum: clinical features of eight families from northern Italy.

Adenomatosis coli (or familial polyposis of the large bowel) and related syndromes are relatively rare diseases characterized by an autosomal dominant mode of inheritance. In these diseases, the entire colorectal mucosa is covered by hundreds (often innumerable) polyps of various dimensions. In addition, several extracolonic abnormalities have been reported. In the present study, we describe the clinical features of eight families from northern Italy fulfilling the diagnostic criteria of adenomatosis coli. Information was available on 123 unaffected and 30 affected family members. The most relevant findings of the study can be summarized as follows. 1) Gene frequency was calculated to be between 1:7,300 and 1:19,000. Segregation ratio in affected branches was 0.57, with a gene penetrance of nearly 60% and a male:female ratio of 1.73. 2) Extracolonic manifestations were present in all families and in 15 of 30 affected patients, the most frequent being cutaneous cysts and retinal lesions. No case fulfilling the classical criteria of Gardner syndrome was observed. 3) When the diagnosis of adenomatosis followed the appearance of symptoms, colorectal cancer had usually already developed, whereas no malignant changes were observed in individuals diagnosed in the asymptomatic stage. When colectomy with ileorectal anastomosis was the treatment of choice, polyps tended to recur in the rectal stump, and long-term endoscopic follow-up was necessary. In conclusion, adenomatosis coli may account for a definite proportion of colorectal neoplasms observed in the general population. Taking into consideration the genetic base of the disease, it follows that individuals at risk should be closely monitored for several years. Moreover, clinical investigations should not be limited to the large bowel, but should be extended to the skin, upper digestive tract, fundus oculi, bones, and probably other organs.

Adenomatous Polyposis Coli

The influence of age on colonic epithelial cell proliferation.

Cancer of the large bowel is relatively rare in persons younger than 50 years of age, but its incidence increases sharply in persons older than 60 years of age. We thought that the evaluation of colonic cell proliferation, an accurate biomarker of predisposition to colorectal cancer, might help to elucidate the susceptibility of elderly persons to this common malignancy. Accordingly, 30 persons with normal lower endoscopy results were divided into three age groups (30 to 50,51 to 65, and 66 to 90 years of age; Groups 1, 2, and 3, respectively). Samples of rectal mucosa were taken at endoscopic examination, incubated with [3H]thymidine, and processed with standard autoradiographic techniques. At histologic examination, each intestinal hemicrypt was divided into five equal longitudinal compartments from the fundus (compartment 1) to the surface (compartment 5). The number and the position of labeled cells along the crypt were recorded. The total labeling index (LI) (the ratio of labeled cells to total cells) was significantly higher in Group 3 than in the two other groups. Similarly, the LI per crypt compartment in the most superficial portions of the crypts was consistently higher in persons older than 65 years of age (P less than 0.01 at least), indicating an expansion of the proliferative zone to the most superficial portion of the colonic glands. When the proliferative profiles of the three groups of subjects investigated were compared with those of patients with polyps, an almost complete overlap of values was observed between this population at increased risk for cancer and the subjects in Group 3. We conclude that aging is characterized by an overall increase of epithelial cell proliferation in colorectal mucosa and by an upwards expansion of the proliferative compartment, similar to that observed in a population at risk for cancer of the large bowel.

Adult

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.

Adenoma

Frequency of upper gastrointestinal lesions in patients with liver cirrhosis.

The frequency of gastroduodenal lesions has been investigated in 142 patients with liver cirrhosis of various degrees of severity and in 63 patients with mild liver disease (controls) in whom liver biopsy excluded nodular regeneration. Cirrhotic patients were subdivided in three groups according to the Pugh modification of the Child-Turcotte criteria. Although the frequency of peptic ulcer was not different, gastroduodenal erosions were observed more frequently in cirrhotics than in controls (29.6% vs 11.1%, P less than 0.01). The occurrence of erosions was related to the severity of the disease: in Child A and B patients their frequency was 21 and 26% respectively, but rose to 48.4 (15 of 31 vs 7 of 63 in controls, P less than 0.001) in the Child C group. Both mild and severe gastroduodenitis occurred more frequently, although not significantly, in patients with liver cirrhosis. All together one or more endoscopic lesions were observed in almost 60% of cirrhotics but only in 25.4% of controls (P less than 0.001). In conclusion, our data do not show an increased prevalence of peptic ulcer in cirrhotic patients; in contrast, liver cirrhosis is significantly associated with the endoscopic finding of gastroduodenal erosions, especially in the more advanced stages of the disease. These findings would suggest a cautious use, in cirrhotic patients, of drugs which may damage the gastroduodenal mucosa; moreover, long-term administration of antacids or of other drugs with a protective effect on gastroduodenal mucosa might be taken into consideration for Child C patients.

Aspartate Aminotransferases