C. Rubio - Academia.edu (original) (raw)

Papers by C. Rubio

Cancer research, Jan 15, 2001

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and ... more Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6...

In vivo (Athens, Greece)

A total of 231 flat colorectal neoplasias were investigated at two disparate geographical regions... more A total of 231 flat colorectal neoplasias were investigated at two disparate geographical regions (Stockholm and Tokyo). Of the 141 flat neoplasias seen in Tokyo, 24.8% had HGD, 7.0% intramucosal carcinoma and 9.9% invasive carcinoma. On the other hand, of the 90 flat mucosal neoplasias seen in Stockholm, 13.3% had HGD, 1.1% intramucosal carcinoma and 1.1% invasive carcinoma. The differences between flat adenomas with HGD, intramucosal carcinomas and invasive carcinomas in Japanese patients were significantly higher (p < 0.001) than in Swedish patients. While the causes responsible for this geographic difference remains unclear, possible influences of ethnicity and/or of environmental factors were advanced.

Acta pathologica, microbiologica, et immunologica Scandinavica. Section A, Pathology, 1983

The cellular DNA pattern in 66 colo-rectal adenocarcinomas was studied by means of flow-cytometri... more The cellular DNA pattern in 66 colo-rectal adenocarcinomas was studied by means of flow-cytometric DNA analysis. The degree of ploidy and the proportion of cells in S-phase were related to the clinical stage according to Dukes' classification and to the histological differentiation. Multiple cell populations were found in about 60 per cent of the tumours but more frequently in advanced clinical stages. According to the DNA index the cell populations were bimodally distributed with one peak in the diploid-peridiploid region and one peak in the tri- to tetraploid region. In the second group there was a higher frequency of more advanced tumours as compared to the first. The proportion of cells in S-phase was higher in pure diploid tumour cell populations of all clinical stages as compared to normal mucosa but lower as compared to peridiploid and aneuploid cell populations with high DNA index. High as well as low S-phase values may occur in all clinical stages, but a significant hig...

Scandinavian Journal of Gastroenterology, 1989

The effect of arachidonic acid and its metabolites on the histamine-stimulated acid production in... more The effect of arachidonic acid and its metabolites on the histamine-stimulated acid production in human isolated parietal cells provenient from endoscopic biopsies was examined. 14C-aminopyrine (14C-AP) accumulation in the parietal cells was used for evaluation of acid production. Histamine dose-dependently increased AP uptake. Histamine stimulation (taken as 100% at 10(-5) M) was significantly inhibited by prostaglandin (PG) E2 to 66 +/- 7% at 10(-8) M, 42 +/- 8% at 10(-6) M, and 13 +/- 10% at 10(-4) M (mean +/- SEM, n = 10). PGF2 alpha, PGD2, and PGI2 showed significant inhibitory effects only at very high concentrations (10(-5)-10(-4) M). Leukotriene (LT) B4 and LTC4 were without effect. The basal acid production (taken as 0%) was lowered significantly by 10(-6) M arachidonic acid to -20 +/- 7.4% (p less than 0.02, n = 10), and the histamine-stimulated (10(-6) M) acid production from 100% to 64 +/- 7.2% (p less than 0.001, n = 10). Aspirin (10(-3) M) increased basal (45 +/- 9.6%, p less than 0.001, n = 10) and histamine-stimulated (10(-6) M) acid production (164 +/- 16.3%, p less than 0.001). It is concluded that PGE2, the major product from arachidonic acid metabolism in the human gastric mucosa, is a significant inhibitor of the histamine-stimulated human parietal cell and may, in humans, play a role as a local physiologic inhibitor of acid secretion.

International Journal of Colorectal Disease, 1994

1,2-dimethylhydrazine (DMH) is widely used to induce colorectal tumours in rodents. Some of the a... more 1,2-dimethylhydrazine (DMH) is widely used to induce colorectal tumours in rodents. Some of the animals develop ear as well as colorectal tumours. Rats with large, ulcerated ear tumours are usually sacrificed before the completion of the experiment. In this experiment, fourty-six male Spraque-Dawley rats were injected with 1,2-dimethylhydrazine (21 mg/kg body weight) once a week for 27 weeks to study the histogenesis of colorectal carcinoma. Thirty-six developed ear tumours. Fourteen of the 36 tumours were larger than 2 cm in diameter. These developed between 20-26 weeks and were surgically excised 1-5 weeks later. Four rats died postoperatively. The surgical removal of large ear tumours permitted the completion of the large bowel experiment on schedule (i.e. 27 weeks) in 10 (28%) of the 36 rats with ear tumours.

Gastrointestinal Endoscopy, 2004

Background: Standard videoendoscopy identifies columnar-lined esophagus but cannot distinguish in... more Background: Standard videoendoscopy identifies columnar-lined esophagus but cannot distinguish intestinal metaplasia from other types of epithelium. Enhanced-magnification endoscopy identifies different mucosal pit patterns. A preliminary study suggested that a type 3 pattern is associated with the presence of intestinal metaplasia. This study assesses the value of enhancedmagnification endoscopy for the detection of intestinal metaplasia in the distal esophagus and esophagogastric junction in patients undergoing diagnostic EGD. Methods: Patients undergoing diagnostic endoscopy for upper-GI symptoms underwent enhancedmagnification endoscopy after instillation of 1.5% acetic acid. The enhanced-magnification endoscopy mucosal pattern was classified into 3 types: 1, normal pits; 2, slit-reticular pattern; and 3, gyrus-villous pattern. Preliminary studies indicated that the type 3 pattern was related to intestinal metaplasia. One to 6 biopsies were targeted to areas having a type 3 pattern in columnar-appearing mucosa in the distal esophagus or esophagogastric junction. In the absence of type 3 pattern, one to 8 biopsies were targeted to areas with a type 2 pattern in columnar-appearing mucosa in the distal esophagus or esophagogastric junction. Results: The overall frequency of intestinal metaplasia in the esophagus and esophagogastric junction was 38.8% (26/67 patients). There was a good correlation between the type 3 pattern and intestinal metaplasia in targeted biopsy specimens (sensitivity 88.5%, specificity 90.2%, positive predictive value 85.2%, negative predictive value 92.5%, overall accuracy 90.0%). Conclusions: Enhanced-magnification endoscopy is useful for detection of intestinal metaplasia in distal esophagus and esophagogastric junction. (Gastrointest Endosc 2004;59:15-21.

Gastrointestinal Endoscopy, 1986

European Journal of Clinical Investigation, 1986

The mucosal incorporation and clearance of a DNA precursor was examined in the rat stomach and in... more The mucosal incorporation and clearance of a DNA precursor was examined in the rat stomach and intestine following oral treatment with natural prostaglandin E2 (PGE2) or 15(R) 15 methyl prostaglandin Ez (Me PGE2). Control groups received vehicle or pentagastrin. After five days of treatment animals were labelled with methyl-3H-thymidine. Groups of rats were killed at 0.75, 24,72,96 and 120 h after labelling. Treatments continued until killed. Mucosal scrapings were analysed for radioactivity and DNA. Morphometric measurements were performed and plasma levels of gastrin and somatostatin determined. PGE2 and its stable analogue produced hyperplasia within one week of treatment, in particular of the gastric antrum and changed the incorporation and clearance of radioactive thymidine from gastric and intestinal epithelia. The most consistent finding was a delayed elimination of thymidine from the mucosa, indicating a slowing of the DNA turnover. The DNA synthesis was differently affected along the gastrointestinal tract, being unchanged or reduced in the stomach and moderately increased in the intestine. Prostaglandin treatment was associated with a three-to tenfold increase of the gastric acid contents and with elevated plasma levels of gastrin and somatostatin. It is concluded that E2 prostaglandins produce hyperplasia of gastric and intestinal epithelia in the rat by prolonging the cell survival time rather than by increasing new cell production. Hypergastrinemia is not a likely mediator of trophic actions of E2 prostaglandins, which develop despite elevated plasma levels of somatostatin. the gastrointestinal mucosa in the rat [ I , 21. In man also, treatment with MePGEz for two months increased the height of the gastric mucosa and the number of corporic foveolar cells [3]. Such trophic effects may be related to the peptic ulcer healing properties of E2 prostaglandins [4] and knowledge of the associated changes of epithelial cell kinetics is important for their further clinical development. Results from studies of DNA synthesis during prostaglandin treatment have been inconsistent [5, 6, 71. This study was designed to examine the in vivo incorporation and clearance of radioactive thymidine in gastrointestinal epithelia of the rat during treatment with oral PGEl or 15(R)15 methyl PGE2. Pentagastrin was used as a reference trophic compound and the diaphragm muscle as a reference tissue. Materials and Methods One hundred and eight male Sprague-Dawley rats (120 g) were examined in two studies of identical design. Rats were individually marked and kept in cages with four to six rats in each. They were fed a standard rat chow ad libitum and had free access to water. General protocol Treatments were started five days before in uivo labelling of the rats with a radioactive DNA precursor. On the sixth day, between 9:OO am and 1 1 :00 am, and 1 h after the treatment dose, 1 mCi kg-' methyL3Hthymidine was injected intraperitoneally. During 24 h before labelling, rats were kept in cages with meshed bottoms to avoid coprophagia and were deprived of words* DNA, intestine, methY1-PGE2 (MePGE2), food but had free access to water. Treatments continued until the time of sacrifice. Groups of rats were mucosal scrapings, PGE2, rat, stomach, killed at 0.75, 24, 72, 96 and 120 h after labelling. All sacrifices took place between 1O:OO am and 1 1 :00 am at exactly 1 h after the last treatment dose. Also before thymidine, turnover.

Diseases of the Colon & Rectum, 1994

This study was designed to assess the presence of DNA aneuploidy and mucosal dysplasia, respectiv... more This study was designed to assess the presence of DNA aneuploidy and mucosal dysplasia, respectively, in 63 patients with long-standing ulcerative colitis. The DNA content in colonic biopsies was investigated, using a flow cytometry method, and compared with conventional histology. Patients were subsequently followed each or every second year with colonoscopy and histology. A second flow cytometry examination to monitor the DNA pattern was performed after 10 years. Initially, abnormal DNA pattern (i.e., aneuploidy) was found in 13/63 (21 percent) patients. The colonic mucosa was flat in 10, polypoid in 1, and tumor infiltrated in 2. Eight of the 10 aneuploid cases with a flat mucosa showed no signs of histologic dysplasia. In one of two cases with simultaneous aneuploidy and low-grade dysplasia, a carcinoma Dukes B was found at subsequent colectomy. On the other hand, dysplasia (one low grade and one high grade) without aneuploidy was found in two patients at the initial investigation. After 10 years, 13 had been colectomized, 11 had died (7 noncolitis related), and 3 were lost to follow-up. In the remaining 36 living patients with intact colorectum, no case of histologic dysplasia, but 6 cases of DNA aneuploidy were discovered at the initial investigation. Of the six aneuploid cases, one was later reclassified as diploid and one consisted of an aneuploid adenomatous polyp (removed by polypectomy). At follow-up 10 years later, 3/4 of the other aneuploid cases showed repeated abnormal DNA pattern, now together with histologic low-grade dysplasia (in flat colon mucosa). The 30 patients with initially normal DNA patterns were all still diploid at re-examination 10 years later, but 2 now revealed low-grade dysplasia histologically. DNA aneuploidy in chronic ulcerative colitis seems to be stable and it may precede histologic dysplasia by many years. It appears to be an additional marker for detecting neoplastic transformation in ulcerative colitis.

Acta Radiologica, 1997

To investigate the accuracy of MR imaging in the preoperative staging of patients with clinically... more To investigate the accuracy of MR imaging in the preoperative staging of patients with clinically resectable rectal tumours. Forty-eight consecutive patients with rectal tumours were examined, 29 with a pelvic phased-array coil and 19 with a multi-coil arrangement including a pelvic phased-array coil and an endorectal coil. MR images and histopathological specimens and sections were reviewed independently and tumours were staged according to the TNM classification. A more complete visualisation of the various layers of the rectal wall was achieved on the endorectal MR images than on the pelvic phased-array images. The sensitivity of MR in correctly staging T3 tumours compared with histopathology was 81% with a specificity of 82%. Penetration of the rectal wall was predicted with a sensitivity of 82% and a specificity of 87%. Sensitivity and specificity in predicting lymph node metastases was 83% and 74% respectively. MR imaging with both pelvic phased-array and endorectal coils allowed the preoperative staging of rectal tumours with a high degree of accuracy.

Acta Oncologica, 1984

The effects of oral 16,16 dimethyl prostaglandin E2 on irradiation induced damage of the small in... more The effects of oral 16,16 dimethyl prostaglandin E2 on irradiation induced damage of the small intestine was examined in the rat. Groups of Sprague-Dawley rats received graded doses of the analogue or placebo at 24, 8 and 0.5 hours before and at 16 and 24 hours following whole abdominal exposure to 10 Gy. Rats were killed 72 hours after irradiation. Pretreatment within the lower dose range had a moderate protective effect with better preserved crypts and crypts to villus ratio. Larger doses seemed to increase the intestinal damage. The prostaglandin treated sham irradiated rats had higher villous height and larger epithelial surface compared with controls.

Acta Endoscopica, 1985

ABSTRACT

Journal of Gastroenterology and Hepatology, 2005

Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achl... more Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achlorhydria, gastrinemia and hyperplasia, to cancer risk. To study this, mice lacking the gastric H/K-ATPase (Atp4a(-/-) mice) were used to determine whether chronic loss of acid secretion, with attendant hypergastrinemia, predisposes to cancer phenotype. Atp4a(-/-) and Atp4a(+/+) mice, paired for age and gender, were examined at 3, 8, 12 and 20 months for histopathology, and for expression of the trefoil factor family (TFF)1-3, Reg IIIbeta, gamma and delta, osteopontin, CD44, chromogranin A, Crp-ductin, and galectin, all of which are important in cell growth. By 8 months, the glandular stomach of the Atp4a(-/-) mice doubled in weight and thickness, and several modulators of growth were increased. Female Atp4a(-/-) mice were more hyperplastic than Atp4a(-/-) males at 12 and 20 months. By 1 year, severe mucocystic hyperplasia, incomplete intestinal metaplasia, ciliated metaplasia, a shift in mucins from neutral to acidic, and inflammation were widespread. Cells in the mucus pit zone developed a pyloric-type appearance, containing large hyaline-like, periodic acid-Schiff (PAS)-negative/alcian blue-negative inclusions. But critical characteristics of gastric neoplasia, such as nuclear atypia, invasion into the muscularis mucosa, and metastases were absent. In Atp4a(-/-) mice, chromogranin A and histidine decarboxylase, RegIIIgamma and delta, TFF3, osteopontin and CD44 were upregulated while Reg IIIbeta, and TFF1 were reduced. Chronic achlorhydria and hypergastrinemia in aged Atp4a(-/-) mice produced progressive hyperplasia, mucocystic and incomplete intestinal metaplasia, and the upregulation of growth factors without histological evidence of neoplasia.