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Production of intestinal and other tumors by 1, 2-dimethylhydrazine dihydrochloride in mice. I. A light and transmission electron microscopic study of colonic neoplasms.

Single or ten weekly subcutaneous injection(s) of 1, 2-dimethylhydrazine dihydrochloride were administered separately to Swiss mice. The repeated application gave rise mainly to high incidences of tumors in the large intestine. These neoplasms occurred most frequently in the colorectal area and in cecum adjacent to ileum. Light microscopically, these lesions were classified as polypoid adenomas and adenocarcinomas. Most of the adenocarcinomas were highly invasive, although they metastasized rarely. The fine structure of the malignant cells exhibited features typical of columnar absorptive cells. A distinctive alteration was the disorderly arrangement and abnormal size and shape of the microvilli. In addition, the cells exhibited numerous free ribosomes, little RER, priminent Golgi bodies, and uniformly dispersed nuclear chromatin. Morphologically, the intestinal tumors were similar to those found in man. In addition, the repeated administration of 1, 2-DMH also induced significant incidences of neoplasms in blood vessels, lungs, anus, and kidneys while the single application produced tumors in blood vessels and liver. The main hypotheses attempting to explain the selective induction of large intestinal neoplasms are discussed.

Adenocarcinoma↗

Characteristics of rectosigmoid adenomas as predictors of synchronous advanced proximal colon neoplasms.

BACKGROUND/AIM: Colonoscopy is recommended to every patient with adenoma in rectosigmoid to disclose synchronous proximal neoplasms. The aim of this study was to determine whether characteristics of rectosigmoid adenomas are associated with proximal advanced neoplasms. PATIENTS/METHODS: One hundred consecutive symptomatic patients who underwent total colonoscopy and had rectosigmoid adenomas were included in the study. Patients with iron-deficiency anemia were excluded. All polyps were removed endoscopically. An adenoma was considered advanced if it had a diameter > 1 cm and/or villous and/or severe dysplasia histology were present. RESULTS: Advanced rectosigmoid adenomas were found in 55 of the 100 patients. Proximal neoplasms were found in 26 (26%) patients. In particular, nonadvanced adenomas were found in 15 (15%), advanced adenomas in eight (8%), and cancer in three (3%) patients. The presence of proximal neoplasms was related to neither sex, age, or presenting symptoms nor to any of the characteristics of rectosigmoid adenomas. On the contrary, the presence of advanced proximal neoplasms (advanced adenoma or cancer) was significantly correlated with the presence of advanced rectosigmoid adenomas, which were detected in 11 (20%) of the 55 patients with advanced and in none of the 45 patients with nonadvanced, rectosigmoid adenomas (odds ratio: 23.5, p = 0.001). Logistic regression analysis revealed that the presence of advanced rectosigmoid adenoma was the main predictor of advanced proximal neoplasms (beta: 1.34, p < 10(-6)). CONCLUSIONS: Among patients with rectosigmoid adenomas, 1) proximal advanced neoplasms appear to exist only in those with advanced adenomas and 2) baseline colonoscopy does not seem necessary in those without advanced adenomas.

Adenoma↗

The role of the barium enema in the detection of colonic neoplasms.

The variability in the published results for colonoscopy and barium enema examinations is confusing. With both, optimum studies depend on meticulous preparation, technical excellence, and operator proficiency. The equivalency of results and the lower cost of the radiologic study indicate that the double-contrast barium enema is the technique of choice for the examination of asymptomatic patients or symptomatic individuals without known antecedent disease. The relatively small difference between the cost of the double-contrast enema examination and sigmoidoscopy ($193 versus $135) suggests that it should replace the latter on the 3-5-year screening schedule because, on average, 50% more of the colon is examined by the barium study. It is a mistake to place colonoscopy and barium enema in competitive positions; the two methods ideally complement one another. The exclusion of significant pathologic findings by the double-contrast enema can be accepted, but the detection of abnormalities should be followed, when necessary, by colonoscopic verification and/or biopsy. The number of times both will be required are few. Radiologically demonstrated colon carcinomas seldom require biopsy verification, and 90% of all polyps are smaller than 5 mm in diameter with a negligible incidence of malignant transformation. When the examinations are used in the proper sequence, they provide a cost-effective approach to the early detection and control of cancer of the large bowel.

Adult↗

Separation and spread of nuclear fragments ("nucleotesimals") in colonic neoplasms.

After multiple fragmentation of neoplastic nuclei into "nucleotesimals," a recently discovered variety of amitosis, some fragments appear to be inflated to full nuclear size; other probably lyse, releasing nucleic acid, which may assist in the synthesis of new cytoplasm around newly formed nuclei. This observation may be useful in elucidating one mechanism of neoplastic growth.

Cell Division↗

Development of colonic neoplasms and expressions of p53 and p21 proteins in experimental colitis of mice induced by dextran sulfate sodium.

The mechanisms underlying the frequent development of colorectal carcinomas in patients with ulcerative colitis (UC) are still not understood. This study was conducted to investigate whether p53 and p21 protein expressions contribute to carcinogenesis in an experimental model with dextran sulfate sodium (DSS) treatment, and to establish if this colitis model is suitable for study of cancer development in UC. A total of 40 mice were subjected to four administration cycles of 4% DSS for 7 days followed by plain water for the subsequent 14 days. The 33-surviving mice were sacrificed to examine the malignant transformation of colonic mucosa morphologically and to determine p53 and p21 expressions immunohistochemically. After DSS treatment periods, there were marked irregularities in the mucosal layer, the thickness of the entire bowel wall and the shortness of the colon. Histologically, tumors were found in 13 out of 33 (39.4%) mice. These 13 cases included 9 with a solitary lesion and 4 with double tumors. There were occurrences of invasive carcinomas in 8 lesions, high-grade dysplasia in 3 lesions and low-grade-dysplasia in 6 lesions. One presented with a polypoid tumor, 5 mm in diameter, while 16 had small flat lesions. There were 13 tumors on the left-sided colon, as opposed to 4 on the right-sided colon. Histological differentiation of invading carcinomas revealed that 6 out of 8 lesions were comprised of well differentiated adenocarcinomas, while 2 were moderately differentiated adenocarcinomas. Overexpression of p53 protein was found in 4 out of 8 invasive carcinomas, 2 out of 3 high-grade dysplasia cases and 2 out of 6 low-grade dysplasia cases, whereas only 1 out of 8 with invasive carcinoma was positive for p21. This experimental colitis model suggests that p53 and p21 protein expressions may contribute to carcinogenesis in DSS-induced colitis in mice and appears suitable to study cancer development in UC.

Animals↗

[Retrospective, comparative study of colonoscopy and irrigoscopy as primary screening for colonic neoplasm suspects].

The diagnostic value of large bowel cancer by endoscopy (796 cases) and X-ray procedures (109) has been compared. A statistical analysis has established colonoscopy to be a more informative and safer procedure to be used in primary examination of patients with "bowel complaints". Irrigoscopy for primary tumor should be recommended for elderly patients with pronounced cardio-vascular and pulmonary pathology.

Colonic Neoplasms↗

[Endoscopic diagnosis of colonic neoplasms].

The work analyzes results of complex examination of 88 patients with cancer of the large intestine. Correct diagnosis was made in 80 patients by fibrocolonoscopy combined with biopsy. The endoscopic method was found to have certain advantages over X-ray analysis for diagnosis of cancer of the large intestine especially in cases with small tumors. Complex employment of these methods was most efficient and allowed to make a true character of the disease in all the examined patients.

Colonic Neoplasms↗

An epitope localized in c-Src negative regulatory domain is a potential marker in early stage of colonic neoplasms.

In previous work, we established a new monoclonal antibody that specifically recognizes the active form of c-Src tyrosine kinase (Kawakatsu et al, 1996). To determine whether c-Src is active in colorectal tumorigenesis, we examined the expression of an active form of c-Src in human normal mucosa, hyperplastic polyps, adenomas, and adenocarcinomas. The tissue distribution of the active form of c-Src was studied by immunohistochemistry using this antibody, termed Clone 28. Among 66 cases of adenoma tested, 61 (92%) showed positive staining (adenoma with mild atypia, 3 of 3; adenoma with moderate atypia, 38 of 42; adenoma with severe atypia, 20 of 21). In contrast to the frequent and intense staining in adenomas, adenocarcinoma showed weak staining with less frequency in 4 of 16 (25%) cases. The number of specimens with positive staining in well- and moderately differentiated adenocarcinomas was limited to an early stage. The active form of c-Src mainly localized to the nuclear membrane and the perinuclear region. These results provide the first direct evidence that the activation of c-Src appears to be an early event in colonic carcinogenesis in situ. The findings of the present study thus allow us to propose a molecular mechanism involving c-Src activation in the process of malignant transformation of the human colonic neoplastic cells.

Antibodies, Monoclonal↗

[Circulating nucleic acids in blood of patients with stomach and colon neoplasms].

Concentrations of extracellular deoxy- and ribonucleic acids in blood plasma and cell-surface-bound of blood cells were investigated in healthy donors and patients with malignant gastrointestinal tumors. Our results indicate that high concentration of extracellular DNA in blood plasma along with decreased level of extracellular RNA on the surface of blood cells correlate with development of gastrointestinal cancer. Ratio of nucleic acids in plasma to total amount of nucleic acids circulated in blood is a characteristic parameter distinguishing cancer patients from healthy persons.

Blood Cells↗

[Colonic neoplasms: long-term survival after surgical treatment. Our experience].

The surgery is still the only treatment for large bowel tumours. The patients who underwent a radical operation and then were treated with chemo and/or radiotherapy have not shown a longer free-disease survival. Palliative resection should be preferred to by pass operation, since the latter has shown less postoperative morbility and mortality. The authors report their experience on 139 patients with large bowel tumours operated between 1979 and 1988, and they analyze the surgical results and the five-years survival according to the stage of disease.

Adult↗

[Usefulness of biochemical tumor markers (CEA, Ca 19-9, ferritin and sialic acid) in diagnosis and prognosis of colonic neoplasms].

The aim of the study was: to determine the value of CEA, Ca 19-9, ferritin and sialic acid in diagnostics, to assess the prognostic role of serum CEA and Ca 19-9 levels before surgery and to evaluate their usefulness in diagnostics of recurrences. The study included 352 patients with colorectal carcinoma (adenocarcinoma). The preoperative level of CEA was elevated in 286 patients, Ca 19-9 in 108, ferritin in 60 and sialic acid in 58 patients. All of them are poor markers in diagnostics because of the low sensitivity, respectively 47.6%, 37.0%, 16.7% and 55.2%. Preoperative high, CEA and Ca 19-9 values are associated with a significantly poorer prognosis and with frequency of recurrences.

Adenocarcinoma↗

Low frequency of bcl-2 expression in large non-polypoid colonic neoplasms.

Large non-polypoid colorectal adenomas that spread over the mucosa and morphologically flat lesions are included in a group called granule-aggregating tumours. These are uncommon in the West. We aimed to clarify the biological differences between granule-aggregating tumours and colorectal polypoid adenomas. We evaluated the extent of apoptotic cell loss and expression of bcl-2 and p53 oncoproteins in 26 granule-aggregating tumours and 19 polypoid adenomas. The mean apoptosis index value of granule-aggregating tumours was significantly higher than that of polypoid adenomas. Only two (7.7%) granule-aggregating tumours and 13 (68.4%) polypoid colorectal adenomas expressed bcl-2, while 12 (46.2%) granule-aggregating tumours and six (31.6%) polypoid colorectal adenomas were p53-positive. Our results show that the higher apoptosis index and frequent expression of bcl-2 oncoprotein differentiates granule-aggregating tumours from polypoid colorectal adenomas. We propose that large non-polypoid granule-aggregating tumours of the colorectum are a biologically distinct entity.

Adenoma↗

Cytomegalovirus colitis mimicking a colonic neoplasm or ischemic colitis 4 years after heart transplantation.

BACKGROUND: Cytomegalovirus (CMV) colitis is a polymorphous disease presenting in immunodepressed patients in a variety of clinical forms that can delay diagnosis and therapy. We report the case of a patient who presented with abdominal pain 4 years after heart transplantation; clinical and x-ray findings were suggestive of a neoplastic or ischemic stenosis, and histopathological examination likewise initially suggested an ischemic etiology. METHODS: Tissue samples were fixed in 10% formaldehyde, embedded in paraffin, cut, and stained with hematoxylin/eosin and periodic acid-Schiff-Alcian Blue. Immunohistochemistry with monoclonal antibodies was performed using an indirect immunoperoxidase method. RESULTS: CMV colitis was eventually diagnosed and resolved with surgery and specific anti-CMV therapy. CONCLUSIONS: CMV colitis should be suspected in any heart transplant patient with signs or symptoms of abdominal pathology, even without classical signs or symptoms of CMV infection. If stenotic lesions are present, surgery may be required not only to remove the obstruction but also to rule out malignancy.

Cardiomyopathy, Dilated↗

Polymerase chain reaction-based approaches for detection of allelic loss in the p53 tumor suppressor gene in colon neoplasms.

OBJECTIVES: Inactivation of the p53 tumor suppressor gene is considered to be a late event involved in the malignant transformation of colorectal adenoma to cancer. Thus, its detection is thought to provide useful information for the clinical management of colorectal neoplasms. We devised a rapid screening test for allelic loss of the p53 gene by non-radioisotopic single-strand conformation polymorphism analysis. METHODS: Biopsy materials from 119 colorectal tumors obtained at endoscopy were examined. Three intragenic polymorphic sites were amplified by polymerase chain reaction using DNA extracted from these materials, and amplified DNA fragments were subjected to non-radioisotopic single-strand conformation polymorphism. RESULTS: This method can detect a loss of heterozygosity (LOH) of the p53 locus from samples containing over 40% tumor derived DNA, and the combination of the three polymorphic markers encompassed 62.4% of Japanese patients as informative. In adenocarcinoma, an LOH was detected in 51.5% (17 of 33) of the samples and in 12.2% (4 of 33) of tubular and/or tubulovillous adenomas. The p53 gene was mutated only in samples carrying an LOH, that is 64.7% (11 of 17) of carcinomas and 25.0% (1 of 4) of adenomas, but there were no mutation in samples retaining both alleles. The presence of an LOH was statistically correlated both with p53 mutation and malignant histology (chi 2 test, p < 0.05). CONCLUSIONS: This method can detect LOH from biopsy material obtained at endoscopy. LOH in the p53 locus precedes mutation of the p53 gene, and its detection provides useful information of malignancy in colorectal tumors.

Adenocarcinoma↗

The cellular response to human colonic neoplasms: macrophage numbers.

Tumour cells and macrophages are thought to interact and the behaviour of tumours may be modified by macrophage activity. Using an immuno-histochemical method for the demonstration of lysozyme and a computerised image analysis system, the number of macrophages was assessed in and around tubulovillous adenomas and the different Dukes grades of adenocarcinomas of the colon. No significant differences were demonstrated and it is concluded that the behaviour of these neoplasms is not related to the number of associated macrophages.

Adenocarcinoma↗

The Muir-Torre syndrome: a disease of sebaceous and colonic neoplasms.

The Muir-Torre syndrome of sebaceous neoplasms of the skin, with or without keratoacanthomas, and multiple low-grade visceral malignancies with prolonged survival is a rare disorder. Colonic polyps are frequently present, and the syndrome appears to be familial. We report 2 unrelated patients with the Muir-Torre syndrome. Each case exhibited sebaceous adenomas. Gastrointestinal findings included colonic adenocarcinomas and a tubulovillous adenoma. Although an unusual disease, the Muir-Torre syndrome requires recognition because these patients are at risk for multiple primary malignancies and may have family members also at risk.

Adenocarcinoma↗