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Colonic cell proliferation in normal mucosa of patients with colon cancer.

Cell kinetics parameters have been analysed in colonic mucosa at different distances from a tumour in patients with colon carcinoma. Total cell number (TCN), 3H thymidine labelling index (TLI), mitotic index (MI), Goblet cell index (GCI) and the distribution of labelled cells along the crypt column (cell position frequency plot) were determined in well-aligned crypts. Total cell number, GCI and the labelled cell position frequency plots were similar in different samples from the same individual. A negative linear correlation between TCN and TLI was observed. The analysis of the cell position plots showed two patterns 1) with a high concentration in the bottom fifth of the crypt and 2) with frequent labelled cells at high positions. Whereas a negative correlation between overall TLI and the percent contribution to the TLI of the lowermost fifth was seen, the correlation was positive for the next 3 fifths and labelling was absent in the last part of the crypt.

Aged↗

Evidence for a ras gene mutation in azoxymethane-induced colonic aberrant crypts in Sprague-Dawley rats: earliest recognizable precursor lesions of experimental colon cancer.

The main objective of the present investigation was to understand the molecular events involved in the genesis of aberrant crypt foci. Aberrant crypt foci were induced in Sprague-Dawley rats with a single injection of azoxymethane. Aberrant crypts have been identified topographically in the colon and are hypothesized to represent preneoplastic lesions. In order to understand the molecular events involved in the early stages of colon cancer, PCR-amplified DNA from aberrant crypts was hybridized with oligonucleotide probes specific for the detection of point mutations in codon 12 of K-ras. The mutation identified was a G to A transition resulting in the substitution of the amino acid aspartic acid (asp) for glycine (gly). This mutation was present in 6/19 (32%) of aberrant crypts examined. The identical mutation was also identified in adenomacarcinoma tissue while no mutation could be detected in normal intestinal mucosa. For further confirmation of these results, the presence of the mutated ras protein (rasAsp-12) was detected in aberrant crypts by immunohistochemistry. This investigation provides the first identification of a ras point mutation in aberrant crypt foci.

Adenocarcinoma↗

The effects of small intestinal colonization by fecal and colonic bacteria on intestinal function in rats.

The effects of colonic and fecal bacterial proliferation on jejunal function were studied in normal rats and in low-germ rats after intraperitoneal injections of mecamylamine HCl. Jejunal bacteriology, bile salts, ultrastructure, and transport capacity were assessed. Normal rats given mecamylamine for 3 days had increased anaerobic bacteria in the intestinal fluid, and had high concentrations of deconjugated bile salts in the intraluminal contents. Jejunal bacteria were lodged between microvilli without penetrating the cell cytoplasm. However, there was focal cellular damage, including fused microvilli, dilated endoplasmic reticulum, and secondary lysosomes. In the mecamylamine treated normal rats intestinal glucose transport was reduced with an alteration compatible with noncompetitive inhibition. The absorption rates of galactose, fructose, 3-0-methyl-D-glucose, tyrosine, Na, and K were also decreased. In contrast, low-germ mecamylamine-treated rats showed no evidence of either increased anaerobic bacterial proliferation or deconjugation of bile salts, and had none of the fine structural alterations seen in regularly raised rats. Also, the transport of carbohydrates was unaltered. The findings suggest that non-invasive enteric proliferation of colonic and fecal bacterial anaerobes in rats may be associated with deconjugation of bile salts, ultrastructural alterations of the intestinal epithelial cells, and a diminished jejunal transport capacity of carbohydrates and other solutes.

Anaerobiosis↗

Multifocal leukoencephalopathy associated with 5-fluorouracil and levamisole adjuvant therapy for colon cancer. A report of two cases and review of the literature. The INTACC. Intergruppo Nazionale Terpia Adiuvante Colon Carcinoma.

BACKGROUND: Since 1990 the combination of 5-fluorouracil plus levamisole has been considered the standard therapy for stage B2-C resected colon cancer in the adjuvant setting. Since 1992, 14 cases of multifocal leukoencefalopathy following 5-fluorouracil and levamisole therapy have been reported. PATIENTS AND METHODS: Two cases of this rare but severe neurological syndrome, observed at our Institution within the scope of the INTACC (Intergruppo Nazionale Terapia Adiuvante Colon Carcinoma, Italy) 01 study, are described. CONCLUSIONS: The clinical and radiological features of the syndrome and the relationships between therapy (with the possible pivotal role played by levamisole) and onset of the multifocal leukoencephalopathy are analyzed in light of the literature data.

Chemotherapy, Adjuvant↗

Immunotherapy of a vaccinia colon oncolysate prepared with interleukin-2 gene-encoded vaccinia virus and interferon-alpha increases the survival of mice bearing syngeneic colon adenocarcinoma.

Therapeutic effect of a vaccinia colon oncolysate prepared with interleukin-2 (IL-2) gene-encoded vaccinia virus (IL-2VCO) in combination with recombinant interferon-alpha (IFN-alpha) was studied in a syngeneic murine CC-36 colon hepatic metastasis model. Treatment with this IL-2VCO+IFN-alpha produced a higher survival rate (90% on day 60 after tumor transplantation) in mice having CC-36 hepatic metastases when compared to treatment with IFN-alpha (0%), VCO+IFN-alpha (0%), or IL-2VCO (11%). The only treatment that produced a survival rate similar to the survival rate of IL-2VCO+IFN-alpha was VCO+IL-2 + IFN-alpha (survival rate was 67%). The cause of the prolonged survival with the IL-2VCO+IFN-alpha treatment was identified as the reduction of CC-36 hepatic metastases (mean liver weight 1.31 g and mean tumor nodules 2). This reduction was significant when compared to IL-2VCO (1.58 g and 11), VCO+IFN-alpha (1.96 g and 53), and IFN-alpha (2.24 g and 91) treatments. The mechanism of the induction of antitumor response by the VCO+IL-2+IFN-alpha treatment was analyzed by measuring the direct cytotoxic activity of IFN-alpha on CC-36 tumor cells and by measuring the induction of cytolytic T-cell activity against CC-36 tumor cells. Results suggest that IFN-alpha produced minimal direct cytotoxic activity against CC-36 cells; however, the IL-2VCO+IFN-alpha combination therapy induced an enhanced cytolytic T-cell activity against CC-36 tumor cells (85.1% at E:T 100:1) when compared to other treatments (IL-2VCO 26.3%, VCO+IFN-alpha 13.4%, and IFN-alpha alone 6.3%). In addition, the role of T-cell subsets for the induction of antitumor immune response was analyzed in a survival study that used CD8-positive T cell-depleted mice. It was found that the survival rate was affected in mice depleted with CD8-positive T cells and treated with IL-2VCO+IFN-alpha when compared to control mice which had no T-cell depletion and were treated with IL-2VCO+IFN-alpha. This study suggests that the addition of IFN-alpha along with IL-2VCO increased the survival rate of mice having CC-36 hepatic metastases through the induction of CD8-positive T cells. Furthermore, this study confirms that IL-2VV can be used as a substitute for recombinant IL-2 in cytokine-augmented active specific immunotherapy.

Adenocarcinoma↗

Nonspecific ulcers of the colon: a case presentation of ulceration of the transverse colon.

This paper describes a patient with nonspecific discrete ulcer of the transverse colon. The lesion was responsible for diarrhea which was cured by conservative resection. These uncommon ulcers, which mimic carcinoma radiographically and were previously thought to be uniformly fatal, may occasionally heal spontaneously. The patient has taken several drugs, some of which may have played a role in the pathogenesis of the ulcer, but the etiology of nonspecific colon ulcer remains uncertain.

Colonic Diseases↗

HLA-A, -B, -C expression in colon carcinoma mimics that of the normal colonic mucosa and is prognostically relevant.

Whether human leukocyte antigen (HLA)-A, -B, -C expression has any predictive value on the prognosis of human malignancies remains controversial. Herein, monoclonal antibodies with preferential reactivity for HLA-A, HLA-B, and HLA-C (HCA2, HC10, and L31) were used to stain an archival collection of 291 formalin-fixed/paraffin-embedded tissues, comprising neoplastic lesions from stages II and III colon carcinoma patients (n=165), and the uninvolved, morphologically normal mucosae from a subset (n=126) of these patients. Marked staining variability was detected not only in the tumors as in previous studies, but also in the normal paired mucosae. HLA-A, -B, -C expression was similar in approximately two thirds of the available 126 normal/neoplastic pairs, confirming in vivo our previous observation that most tumor cells mimic the HLA phenotypes of their normal counterparts. Both up and down-regulation occurred in the remaining third of the pairs, but did not coincide with high and low expression, respectively, conventionally evaluated on the tumor lesion only. Remarkably, a "paired" evaluation, but not high or low expression in the tumor, was predictive of the clinical outcome. Deviations from the expression in the normal paired mucosa (both increases and decreases) of HCA2-reactive class I molecules (possibly HLA-A), and down-regulation of L31-reactive class I molecules (possibly HLA-C), particularly in tumors from stage II patients, correlated with poor 5-year overall and disease-free survival, hazard risk ranging from 2 to 6, approximately. Thus, a paired immunohistochemical comparison reveals a novel immune evasion strategy that may impact on the prognosis of colon carcinoma.

Adenocarcinoma↗

Models for investigating the aetiology of cerebral arterial spasm: comparative responses of the human basilar artery with rat colon, anococcygeus, stomach fundus, and aorta and guinea-pig ileum and colon.

1 The pharmacological similarity between human basilar artery and a number of isolated tissues (rat colon, anococcygeus, stomach fundus and aorta and guinea-pig ileum and colon) has been assessed during investigations of the aetiology of cerebral arterial spasm. 2 The responses of each of the six tissues to human normal and abnormal cerebrospinal fluid (CSF) and to human serum were compared with those of the human isolated basilar artery. 3 These studies revealed the presence of a vasodilator factor in CSF from subarachnoid haemorrhage patients and several tissues may be of use for further work in identifying the vasoactive substances in CSF. 4 No tissue displayed exactly the same spectrum of biological reactivity as the human basilar artery. The rat stomach fundus showed the closest similarity and was further studied for similarities in drug-induced responses. 5 The rat stomach fundus, like the human basilar artery, was contracted by 5-hydroxytryptamine, prostaglandin F2alpha and histamine and relaxed by dopamine. However, noradrenaline relaxed the fundus but contracted the basilar artery.

Animals↗

Enhanced expression of iNOS in inflamed colons of IL-2-deficient mice does not impair colonic epithelial barrier function.

On the basis of recently observed high levels of iNOS expression that correlated with intestinal inflammation in interleukin-2-deficient [IL-2(-/-)] mice, it was postulated that nitric oxide may damage colonic epithelial cells or impair intestinal epithelial barrier function. This damage may result in an increased permeability of the colonic epithelium leading to high antigenic exposure of the intestinal immune system, which may perpetuate chronic inflammation. Our data demonstrate that high expression of iNOS in IL-2(-/-) mice is correlated with the length/weight ratio (L/W ratio), a widely accepted marker for intestinal inflammation. However, no reduction of epithelial resistance was observed, as would be expected in case of a damaged, leaky epithelium. Our results suggest that enhanced formation of NO in IL-2(-/-) mice does not cause impairment of epithelial barrier function.

Animals↗

Antibodies to colonic epithelial cells from the serum and colonic mucosal washings in ulcerative colitis.

It has been suggested that antibodies to a colonocyte protein of 40 kD (an intestinal isoform of tropomyosin) are specifically found in the serum and mucosa of patients with ulcerative colitis, which has important pathogenic implications. This study isolated and purified tropomyosin from the colonic mucosa, but no specific binding to this protein has been detected in serum samples or immunoglobulins isolated from mucosal washings of 20 ulcerative colitis (UC) patients by enzyme linked immunosorbent assay (ELISA) compared with 21 controls or 17 Crohn's disease (CD) patients. Samples from a further 12 patients with UC and primary sclerosing cholangitis (it is proposed that cross reactivity against the intestinal tropomyosin isoform accounts for the extraintestinal disease) also did not show binding to tropomyosin, whereas monoclonal antitropomyosin antisera bound both ELISAs and western blots. This study also examined the proteins in the normal colonic biopsy specimens on western blots that are bound by both serum samples and mucosal immunoglobulin preparations from these patients groups; there was no specific IgG or IgA binding to patients with UC or UC/primary sclerosing cholangitis, whereas binding to mitochondrial proteins of 70,000 and 45,000 was seen in samples from 12 primary biliary cirrhosis positive controls. This work does not support the hypothesis that autoimmune activity against the intestinal isoform or tropomyosin is important in the pathogenesis of ulcerative colitis.

Adolescent↗

Platelet activating factor: release from colonic mucosa in patients with ulcerative colitis and its effect on colonic secretion.

Inflammatory mediators have been implicated in the pathophysiology of ulcerative colitis. They may stimulate intestinal secretion and contribute to the production of diarrhoea. Platelet activating factor (PAF) may be responsible for a high proportion of this secretory response. Biopsy specimens from inflamed and quiescent mucosa of patients with ulcerative colitis and normal human colonic mucosa were cultured or co-cultured. The release of PAF, prostaglandin E2, and leukotriene D4 into the culture medium was measured and the ability of this culture medium, from inflamed and normal tissues, to influence secretion in rat colonic mucosa was assessed. PAF was liberated by inflamed tissue. Its release from quiescent but not normal tissue was stimulated by medium in which inflamed mucosal biopsy tissues had been cultured and by exogenous bradykinin and 5-hydroxytryptamine, but not by histamine. PAF stimulated eicosanoid production. The rise in short circuit current produced in vitro by inflamed tissue culture medium was inhibited by the PAF receptor antagonist (CV 6209) (46%) (32.4 (2.9) v 17.5 (1.19) muA.cm-2, p < 0.005) and further by combined cyclooxygenase and lipoxygenase inhibition (indomethacin plus ICI 207968) (58%) (32.4 (2.9) v 13.6 (1.9) muA.cm-2, p < 0.005). Mepacrine and hydrocortisone attenuated considerably the electrical response evoked by medium from inflamed mucosa to a similar extent (32.4 (2.9) v 6.3 (1.2) v 5.1 (0.9) muA.cm-2, p < 0.001). These data suggest that PAF accounted for 46% of the culture medium secretory effect. Thus, any attempt to block its release in patients with ulcerative colitis may have only a partial effect on their symptoms.

Adult↗

Cell density modulates the metastatic aggressiveness of a mouse colon cancer cell line, colon 26.

OBJECTIVE: Although cell density in cultured cells has demonstrated several alterations in the nature of cell kinetics, the changes in the metastatic aggressiveness of cancer lines under different cell densities have not yet been studied. METHODS: In the current study, we investigated the influence of changing the cell density of cultured cancer cells (colon 26 and B16-F10) injected into the tail vein in BALB/c mice on the metastatic activity by evaluating the number of lung metastases, and the possible mechanisms of this phenomenon were discussed based on the basis of the results of an invasion assay and a cell adhesion assay. RESULTS: The number of metastatic nodules was significantly higher in the high-density group than in the low one in colon 26 (p < 0.005), however, this phenomenon was not seen in B16-F10. Next, we performed the same experiment by changing the environment to the opposite conditions for the cells in the low- and high-density groups, and the results showed the metastatic activities to be always higher in the high-density group. Moreover, although no difference was seen regarding the invasive activity between the high- and low-density groups, an adhesion assay showed the difference in the adhesion cell rate to be significantly higher in the high-density group especially in early period after coculture with human umbilical vein endothelial cells (HUVEC) (p < 0.05). CONCLUSION: In some cell types, the metastatic activity could be altered and reversed by changing the environment, such as the cell density, during a relatively short period. As a result, the epigenetic changes of cancer cells are thus suggested to play a certain role in the malignant potentiality.

Animals↗

Ultrasonic assessment of fetal colon by comparing ratios of colon circumference to abdominal circumference in normal pregnancy and two abnormal cases. A preliminary study.

Fetal gastrointestinal malformations occur with an incidence of approximately 6/1,000 births and can often be diagnosed in utero by ultrasound. Antenatal knowledge of these abnormalities can potentially decrease fetal and neonatal morbidity and mortality because the appropriate preparations can be made in advance of delivery. Changes in ultrasonic images of the fetal colon were measured by comparing ratios of colon circumference to abdominal circumference in 136 normal pregnancies. Normal values of these parameters are given for gestational age. Two abnormal case reports are included to exemplify the clinical applications.

Abdomen↗

[Arterial anatomy of the sigmoid colon useful for colon take down techniques].

BACKGROUND: An anatomic study about the arterial vascularization of the sigmoid was performed in order to obtain guidelines for the surgical treatment of rectal carcinoma. AIM: In the proposed technique, the sigmoid is brought down to the perineum, after radical anal-rectal resection, including sphincterectomy. MATERIAL AND METHODS: Thirty-three anatomical pieces were obtained through in situ dissection of formolized corpses (22 were male and 11 female). Turpentine solution, red marking, polyvinyl chloride were the materials used for preparation after catheterization of the inferior mesenteric artery. RESULTS: The inferior mesenteric artery originated in most cases from the left side of the abdominal aorta, approximately 4.3 cm fromits bifurcation point; the left colonic artery, in 25 cases, originated straight from the inferior mesenteric artery below the left colonic artery, after which the sigmoid would be brought down to the perineum. CONCLUSION: Knowledge about arterial vascularization of the sigmoid could be helpful in the surgical management of rectal cancer.

Adult↗

Influence of doxycycline on the normal human flora and colonization of the oral cavity and colon.

Doxycycline was given orally in doses of 100 mg every 24 h for 7 days to 10 subjects. Salivary and faecal specimens were taken up to 16 days for cultivation of aerobic and anaerobic microorganisms and for assay of doxycycline. Doxycycline was detected in both saliva and faeces. Only minor changes were observed regarding the number of aerobic and anaerobic microorganisms in the oral cavity. In the faecal flora a decrease in the number of aerobic microorganisms was observed in most subjects, while only minor changes in the number of anaerobic bacteria were noticed. A marked increase in doxycycline-resistant aerobic and anaerobic bacterial strains was noticed both in the oral cavity and the colon. Only a few patients were colonized with potentially pathogenic microorganisms.

Adult↗

Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform.

Increased expression of nm23/nucleoside diphosphate kinase (NDP kinase) has been reported to be associated with both reduced metastatic potential in breast carcinoma and tumor progression in colon adenocarcinoma and lung adenocarcinoma. We examined effects of expression of nm23-R2 rat NDP kinase alpha isoform on mouse adenocarcinoma cells (Colon 26 line) and found a significant reduction of metastatic potential along with overexpression of c-myc. We also found that the proliferation rate of the transformed cells was the same as that of the control cells in culture. These results indicate that the cell growth potential in vitro is irrelevant to metastatic potential of the cells in vivo.

Adenocarcinoma↗

In vivo growth inhibition of human colon carcinoma cells (HT-29) by all-trans-retinoic acid, difluoromethylornithine, and colon mitosis inhibitor, individually and in combination.

BACKGROUND: An important strategy in experimental chemotherapy of cancer is to combine agents with different mechanisms of action in order to achieve enhanced effect by synergism. We studied the combination of all-trans-retinoic acid (RA), difluoromethylornithine (DFMO) and the tripeptide colon mitosis inhibitor (CMI) on the in vivo growth of human colon carcinoma cells (HT-29) in athymic mice. MATERIALS AND METHODS: DFMO was given as 2% in the drinking water. RA (400 nmol/animal) and CMI (1 pmol/animal) were administered i.p. daily. RESULTS: RA, DFMO or CMI given alone, reduced the tumour growth by 40-60% (P < 0.001). When DFMO was given as a standard therapy, significant synergism was achieved with RA (P = 0.008). In contrast, CMI acted antagonistically with DFMO (P = 0.013). DFMO + RA + CMI was not more effective than DFMO + RA. Without DFMO administration, CMI achieved synergism with RA (P < 0.001). CONCLUSIONS: Synergism was shown between RA and DFMO, and RA and CMI, but not between CMI and DFMO.

Animals↗

[Modern aspects of treatment of colonic cancer, complicated by ileus. Part II. Treatment of colonic cancer, complicated by ileus].

The results of treatment of 364 patients with colonic cancer, complicated by ileus. In 165 patients with partial ileus the radical operative interventions were performed, palliative--in 61 and symptomatic--in 83; with complete ileus--in 30.9 and 16 patients accordingly. Application of the interintestinal anastomoses formation methods, elaborated in the clinic, had permitted to perform primarily-restorational operations in 81.9% of patients with partial ileus and in 61.5%--with complete one, obtaining satisfactory immediate results. Insufficiency of the duplicature anastomosis sutures had occurred in 5 (2.2%) of colonic cancer patients, suffering partial ileus.

Colonic Neoplasms↗