Flat adenoma as a precursor of colorectal carcinoma in hereditary nonpolyposis colorectal carcinoma

BACKGROUND: Because flat adenoma shows a higher malignancy rate compared with other types of polyps, it is considered to play an important role in the carcinogenesis of colorectal carcinoma. In the present study, we examined flat adenomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. METHODS: Nine HNPCC patients who presented with flat adenomas were examined. All patients underwent either surgery or endoscopic polypectomy for colorectal carcinoma and/or adenoma. In all patients, annual colonoscopy had been performed once a year throughout the follow-up period after the initial treatment. When colorectal polyps were detected during follow-up colonoscopy, all lesions were endoscopically excised. Clinicopathologic features and microsatellite instability of both malignant lesions and adenomas were examined. RESULTS: Thirteen malignant lesions were detected: seven advanced carcinomas and six early carcinomas. Among 4 early carcinomas with submucosal invasion, 3 lesions (75%) were categorized as superficial type, with a configuration similar to flat adenoma. The frequency of flat adenoma was strikingly high in HNPCC patients in the present study. Among 73 polyps detected, 37 (50.7%) were flat adenomas. Both malignant lesions and flat adenomas had proximal predominance, 61.5% and 59.5%, respectively. Eleven of 15 lesions (73.3%) showed replication error. CONCLUSIONS: These results suggest the importance of flat adenoma as a precursor of colorectal carcinoma in some groups of HNPCC patients. Further study is essential to elucidate the natural history of flat adenomas in HNPCC patients.     

A study on the changes of DCC and MCC genes in colorectal carcinoma and adenoma

Both deleted in colorectal carcinoma (DCC) and mutated in colorectal carcinomas (MCC) genes are newly found tumour suppresser genes in colorectal carcinomas. In this study mutations of DCC gene and loss of heterozygosity (LOH) of MCC gene were detected with Southern blot and PCR methods respectively. The study consisted of 30 cases of colorectal adenoma (10 with mild, 10 with moderate and 10 with severe dysplasia) and 33 cases of colorectal carcinomas (13 highly, 10 moderately and 10 poorly differentiated, meanwhile 9 in Dukes A, 10 in B and 14 in C stage). Their paired normal colorectal mucosa served as control. The results were as follows: mutation of DCC was not found in any specimen with normal mucosa or with adenoma of mild and moderate dysplaaia, while it was found in one if those with severe dysplasia. Mutation of DCC was, however, found in 7 of the 33 specimens with carcinoma and there was a correlation between the positive rate and the differentiation or staging of the carcinoma. LOH of MCC was not found in normal mucosa, but it was found in 2/10, 3/10 and 4/10 of the adenoma specimens with mild, moderate and severe dysplasia respectively. 18/33 of the carcinoma specimens was found to have LOH of MCC and there was also a correlation between the positive rate and the differentiation or staging of the carcinoma. These results suggest that the frequency of multiple gene changes increase with poor differentiation and increased staging of colorectal carcinoma.     

A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group

BACKGROUND: People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer. METHODS: We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo; beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations. RESULTS: Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location. CONCLUSIONS: The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.     

A comparison of antioxidant enzyme activities in organ-cultured rhesus monkey lenses following peroxide challenge

PURPOSE: To analyze the activities of catalase, glutathione peroxidase and superoxide dismutase, three enzymes involved in the detoxification of reactive oxygen species in organ-cultured Rhesus monkey lenses. METHODS: Lenses freshly obtained from Rhesus monkeys were incubated at 37 degrees C for 2 h and assessed for lens integrity. Lenses were then oxidatively stressed by exposure to a bolus of hydrogen peroxide. The three enzyme activities were assayed 2, 4 and 24 h after exposure to the peroxide challenge. RESULTS: Freshly dissected lenses placed in organ culture exhibited a 20% decrease in catalase activity within 2 h. During the course of a 24 h incubation, catalase activity continued to decrease to a level 58% below that of freshly dissected monkey lenses. In contrast, the activity levels of both glutathione peroxidase and superoxide dismutase increased dramatically within the first 2 h of organ culture, with superoxide dismutase being most affected. Although glutathione peroxidase activity declined with incubation time, its level at the end of 24 h was still 36% greater than that of the fresh lenses. Superoxide dismutase activity remained elevated throughout the 24 h incubation period. The addition of a bolus of 0.25mM H2O2 to monkey lenses in culture had no effect on catalase activity. Two h after the peroxide insult, glutathione peroxidase activity decreased in comparison to control levels while the activity of superoxide dismutase increased by 43%. After 24 h, superoxide dismutase activity returned to values equivalent to the controls. In lenses challenged with 0.50mM H2O2, catalase and glutathione peroxidase activities decreased at 2 h, while superoxide dismutase activity increased 67% above control levels. At subsequent timepoints, catalase activity increased and reached control levels. In contrast, glutathione peroxidase activity continued to decrease with time eventually reaching fresh lens levels. Superoxide dismutase activity levels remained elevated and were equivalent to control values at 24 h. CONCLUSIONS: The data indicate that placement of monkey lenses into an organ culture system represents an environmental change sufficient to cause a response in antioxidant enzyme levels. The addition of H2O2 to this environment caused only superoxide dismutase to be stimulated above control lens levels.     

Studies on hepatic injury and antioxidant enzyme activities in rat subcellular organelles following in vivo ischemia and reperfusion

The activities of rat hepatic subcellular antioxidant enzymes were studied during hepatic ischemia/reperfusion. Ischemia was induced for 30 min (reversible ischemia) or 60 min (irreversible ischemia). Ischemia was followed by 2 or 24 h of reperfusion. Hepatocyte peroxisomal catalase enzyme activity decreased during 60 min of ischemia and declined further during reperfusion. Peroxisomes of normal density (d = 1.225 gram/ml) were observed in control tissues. However, 60 min of ischemia also produced a second peak of catalase specific activity in subcellular fractions corresponding to newly formed low density immature peroxisomes (d = 1.12 gram/ml). The second peak was also detectable after 30 min of ischemia followed by reperfusion for 2 or 24 h. Mitochondrial and microsomal fractions responded differently. MnSOD activity in mitochondria and microsomal fractions increased significantly (p < 0.05) after 30 min of ischemia, but decreased below control values following 60 min of ischemia and remained lower during reperfusion at 2 and 24 h in both organelle fractions. Conversely, mitochondrial and microsomal glutathione peroxidase (GPx) activity increased significantly (p < 0.001) after 60 min of ischemia and was sustained during 24 h of reperfusion. In the cytosolic fraction, a significant increase in CuZnSOD activity was noted following reperfusion in animals subjected to 30 min of ischemia, but 60 min of ischemia and 24 h of reperfusion resulted in decreased CuZnSOD activity. These studies suggest that the antioxidant enzymes of various subcellular compartments respond to ischemia/reperfusion in an organelle or compartment specific manner and that the regulation of antioxidant enzyme activity in peroxisomes may differ from that in mitochondria and microsomes. The compartmentalized changes in hepatic antioxidant enzyme activity may be crucial determinant of cell survival and function during ischemia/reperfusion. Finally, a progressive decline in the level of hepatic reduced glutathione (GSH) and concomitant increase in serum glutamate pyruvate transaminase (SGPT) activity also suggest that greater tissue damage and impairment of intracellular antioxidant activity occur with longer ischemia periods, and during reperfusion.     

Tissue manganese concentrations and antioxidant enzyme activities in rats given total parenteral nutrition with and without supplemental manganese

BACKGROUND: Manganese is an essential but potentially toxic mineral. Parenteral administration of manganese via total parenteral nutrition (TPN) bypasses homeostatic mechanisms (intestinal absorption and presystemic hepatic elimination). Our objective in this study was to determine the effect of supplemental manganese in TPN solutions on manganese status in a rat model. METHODS: Male Sprague-Dawley rats underwent jugular catheterization and were given 61.0 +/- 0.4 g/d TPN solution providing 0.5 +/- 0.2 nmol manganese/g (Mn-; n = 6) or 16 +/- 3 nmol manganese/g (Mn+; n = 7) for 7 days. Reference rats (RF; n = 8) were fed a purified diet containing 1.3 mmol manganese/g. RESULTS: Liver manganese decreased in both TPN groups, but tibia, spleen, and pancreas manganese concentrations were greater in Mn+ rats than in Mn- or RF rats. Although no treatment differences were seen in heart or liver manganese superoxide dismutase activity, heart copper-zinc superoxide dismutase activity was lower in the Mn+ rats than in Mn- or RF rats (p < .05). Glutathione peroxidase activity was depressed in livers of both Mn- and Mn+ rats relative to RF rats (p < .0001), which was not due to selenium deficiency. CONCLUSIONS: Supplemental parenteral manganese is taken up to a greater extent by peripheral tissues than the liver. In this first report of antioxidant enzyme activities in animals maintained with TPN, we found that TPN as well as supplemental manganese can influence antioxidant enzyme activities. We conclude that it is generally unnecessary and potentially toxic to supplement TPN solutions with manganese during short-term usage.     

Telomerase activity and microsatellite instability in colorectal cancer and adenoma

BACKGROUND AND PURPOSE: We investigated the role of actin polymerization in regulating arterial diameter in response to increasing pressure and modulating forced dilatation of cerebral arteries at pressures above the upper limit of autoregulation. METHODS: Posterior cerebral arteries (n = 12) were isolated and pressurized in a special arteriograph that allowed control of intravascular pressure and measurement of lumen diameter. Intact arteries in the absence (control) or presence of 3.0 mumol/L cytochalasin B (CB), an inhibitor of actin polymerization, were subjected to stepwise increases in pressure from 75 to 200 mm Hg. Lumen diameter was continuously recorded, as was the pressure at which forced dilatation (loss of tone) occurred. After a period of time at 200 mm Hg, pressure was returned to 75 mm Hg and the extent of tone recovery was evaluated. RESULTS: Arteries with and without CB developed a similar amount of tone during equilibration at 75 mm Hg: percent tone = 27 +/- 3% for control versus 29 +/- 4% for CB arteries (P > 0.05). However, arteries in the presence of CB could not withstand pressure as well and underwent FD at significantly lower pressures: 168 +/- 5 mm Hg for control versus 142 +/- 5 mm Hg for CB arteries (P < 0.01). The amount of tone that arteries regained after FD when pressure was returned to 75 mm Hg was also less in CB arteries: percent tone = 34 +/- 3% for control versus 11 +/- 2% for CB arteries (P < 0.01). CONCLUSIONS: Cytoskeletal integrity appears important for maintaining cerebral arterial diameter during changing intravascular pressure. In addition, the process of actin polymerization may be a significant contributor to development of myogenic tone after forced dilatation.     

Effects of estradiol and medroxyprogesterone-acetate treatment on erythrocyte antioxidant enzyme activities and malondialdehyde plasma levels in amenorrhoic women

Plasma levels of 17 beta-estradiol (E2) and malondialdehyde and erythrocyte antioxidant enzyme [superoxide dismutase, catalase, and glutathione-peroxidase (GSH-Px)] activities were evaluated in 20 healthy eumenorrhoic women (EW) on day 7 of the menstrual cycle and in 48 secondary hypothalamic amenorrhea patients (AP) (time 0). The AP were randomly divided into four subgroups of 12 subjects and treated with transdermal E2 for 30 days (subgroup A), oral medroxyprogesterone-acetate for 30 days (subgroup B), and transdermal E2 plus medroxyprogesterone-acetate for 30 days (subgroup C). The fourth subgroup acted as control. E2 and malondialdehyde plasma levels and superoxide dismutase, catalase, and GSH-Px activities were evaluated in subgroups A, B, and C on day 30 of therapy and in the control subgroup. GSH-Px activity was significantly higher in EW than in AP at time 0. A statistically significant increase in E2 plasma levels and GSH-Px activity was observed in subgroups A and C on day 30 of treatment, and there was a significant positive correlation between E2 plasma levels and GSH-Px activity in both subgroups. After a month of treatment, erythrocyte GSH-Px activity in subgroups A and C was not significantly different from that observed in EW. After a month of treatment, no significant variation was found in subgroup B nor in the control group. These results strongly suggest that when plasma E2 is restored to physiological levels in AP, it stimulates erythrocyte GSH-Px activity. Progesterone therapy did not induce significant modifications.     

Effect of cadmium on antioxidant enzyme activities and lipid peroxidation in a freshwater field crab, Barytelphusa guerini

The kinetics of efflux of calcium mobilized from intracellular stores following activation of human neutrophils with the synthetic chemotactic tripeptide, fMLP (1 microM), as well as that of the subsequent store-operated influx of this cation, has been measured by radiometric procedures using 45Ca. These procedures enabled distinction between net efflux and influx of 45Ca. Preincubation of neutrophils in medium containing 45Ca as the sole source of Ca2+, followed by activation with fMLP, resulted in a rapid efflux of the cation, which coincided with its release from intracellular stores. Efflux terminated at approximately 30 s after addition of fMLP to neutrophils and resulted in the loss of 42 +/- 3% (P < 0.005) of cell-associated 45Ca. Net influx of 45Ca, which was insensitive to the voltage-dependent Ca2+ channel blockading agent, verapamil (20 microM), could only be detected at 30-60 s after the addition of fMLP to neutrophils, and proceeded for about 5 min, resulting in intracellular concentrations of Ca2+ which were 27 +/- 3% (P<0.05) higher than preactivation levels. These results demonstrate that the efflux of cytoplasmic Ca2+ mobilized from intracellular stores during activation of neutrophils by fMLP, and the subsequent influx of extracellular Ca2+ to replete these stores, are chronologically distinct events in fMLP-activated neutrophils.     

Flow cytometric analysis of DNA ploidy in colorectal adenoma

Flow cytometric measurement of nuclear DNA content in 159 colorectal adenomas was carried out to investigate the relationship between DNA ploidy and the histological findings. DNA aneuploidy was detected in 18 lesions (12.8%). The incidence of DNA aneuploidy was significantly higher in tubulovillous adenomas than in tubular adenomas (30.4% vs. 8.1%; p < 0.01). DNA aneuploidy was not found in any adenoma with mild dysplasia, but was noted in 19.1% of those with moderate dysplasia and in 33.3% of those with severe dysplasia. The mean size of the lesions was significantly larger in adenomas with aneuploidy than in those without aneuploidy (14.0 mm vs. 7.7 mm; p < 0.01). The DNA index values of 18 adenomas with aneuploidy were divided into two groups: one ranged from 1.07 to 1.23 and the other from 1.66 to 1.85. DNA index values correlated with the size of the lesions (p < 0.05), but not with the histologic type and degree of dysplasia.     

Lymphadenectomy in colorectal carcinoma

Recurrence of colorectal carcinomas occurs in about 50% of the cases with localized neoplasia. It is understood that the tumor recurrence is due to residual micrometastases not found during surgery or extraregional (peripheral blood or bone marrow). We developed a procedure to detect non-visible, abdominal metastases using a radiolabeled anti-tumor cell antibody injected before the operation (radioimmunoguided surgery RIGS). However, even with the best technique, it is not possible to remove all micrometastasis if a hematogenic dissemination happens. Based on the knowledge of disturbing humoral immune reaction is mounted against shed tumor associated antigens (TAA), we developed a new method to reduce and correct the B cell response and B cell recruitment due to chronic TAA immun complex presentation on follicular dendritic cells (immune corrective surgery, ICS). This method is based on a selective lymphadenectomy. The target lymph nodes were those loaded with TAA-immune complex. The detection method used was the injection of radiolabeled antibody able to recognize the immune complex. From 20 patients (stage I, II and III) treated with ICS, 17 survived more than 5 years 'showing a statistically significant increase of survival compared to patients treated with standard procedures. In conclusion, these data show that surgery of colorectal cancer should be selectively extended to specific anatomical regions in order to remove hidden micrometastases, and more importantly, correct postoperative immune processes that could suppress the T cell response against residual tumor cells.     

Papillary thyroid carcinoma in a toxic adenoma

The technique of amniocentesis, by which an abnormal fetus can be detected in utero, has brought a technological advance in medical science but attendant medical and moral problems. Dr Seller describes those congenital disabilities which can be detected in the fetus before birth, for which the "remedy" is selective abortion. She then discusses the arguments for and against selective abortion, for the issue is not simple, even in the strictly genetic sense of attempting to ensure a population free of congenital abnormality.     

Genetic changes in colorectal adenoma and cancer in relation to various morphologic aspects

Diffuse hypoxic pneumonia was found to be caused by angiotensin converting enzyme (ACE) inhibitors in two patients given enalapril and fosinopril for hypertension. Both patients developed sub-acute respiratory failure and lost weight. Imaging explorations showed multiple areas of alveolar consolidation, moderate pleural effusion and in one case linear opacities. In both cases, peripheral eosinophila was found and the bronchoalveolar lavage fluid contained lymphocytes. Progressive improvement was achieved after withdrawal of the ACE and corticosteroid therapy for three months. Subsequent x-rays and respiratory function tests returned to normal apart from persistently low CO diffusion in one patient. In view of other cases reported in the literature, ACE inhibitors should probably be included in the list of drugs capable of inducing pneumonia, notably eosinophilic pneumonia.     

脂代谢紊乱及脂质过氧化与结肠腺瘤恶变的关系

Objective:The aim of this study was to investigate lipid disorders and lipid peroxidation associated with the malignant transformation of colorectal adenoma. Methods:Analyses were based on data from 100 subjects with histologically confirmed adenomas (cases) and 50 adenoma-free control subjects, all of whom had colonoscopy. The subjects were divided into two groups:those with no adenoma and those with adenoma. According to subsite of adenomas the subjects with adenoma were divided into group of distal adenoma and group of proximal adenoma. According to histology of adenomas the subjects with adenoma were divided into group of villiform adenoma and group of tubular + tubulo-villous adenoma. Among the groups, the serum levels of triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and lipid peroxidation product malondialdehyde (MDA) were compared in all the patients.Results:Plasma total cholesterol and MDA level in group of adenomas were significantly higher than that in group of control subjects, but plasma HDL-C level was low in group of adenomas (P < 0.05). Plasma total cholesterol and MDA levels were positively related to distal and villiform adenomas (P < 0.05). Conclusion:The findings suggest that altered lipid metabolism may be differentially associated with colorectal adenomas.     

Glutathione and related enzyme activities in the blood of Simmental bulls

Blood glutathione (GSH) concentration and the activities of enzymes associated with glutathione metabolism, namely glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyltransferase (gamma GT) were determined in thirteen intensively-fed Simmental young bulls at seven, 10, 12.5 and 15 months of age. When G6PD activity was highest, the GSH concentration had its lowest value and inversely. This suggests that NADPH is not completely spent on glutathione reduction. gamma GT activity increased significantly during fattening.     

Increased telomerase activities in human pancreatic duct adenocarcinomas

Telomerase is a key enzyme with regard to immortalization of cancer cells and increased activity has been demonstrated in various human malignant neoplasms. Since little is known of its role in pancreatic cancers, we investigated changes in telomerase activity in human pancreatic duct adenocarcinomas and compared the frequency of increased telomerase activity with the presence of K-ras gene mutations. The samples were obtained from 38 pancreatic duct adenocarcinomas and 7 tumor surrounding tissues at surgical resection. Telomerase activity was examined by telomeric repeat amplification protocol assay and terminal restriction fragment (TRF) length was examined by Southern analysis. K-ras mutation was examined by means of polymerase chain reaction-single strand conformation polymorphism analysis. Among 38 pancreatic carcinomas, 32 (84%) exhibited increased telomerase activities with no apparent relation to the histological type of tumor, tumor size, regional lymphnode involvement and distant metastasis or clinical stage. In tissue surrounding the tumor, telomerase activity was not detected. TRF length tended to be reduced in pancreatic carcinomas. Mutations of K-ras gene were found in 24 out of the 38 (63%) cases. Among the 38 cases, 14 showed increased telomerase activity without K-ras mutation and 4 cases showed K-ras mutation without telomerase activity. These results suggest that increased telomerase activity might be a sensitive genetic diagnostic marker and could be a target for future therapy of pancreatic duct carcinomas.     

New drugs in the treatment of colorectal carcinoma

BACKGROUND: Treatment with 5-fluorouracil (5-FU) plus leucovorin has been the unofficial standard therapy for patients with colorectal carcinoma (CRC) for more than a decade; however, the optimal dose and schedule remain a matter of debate. Recently several new drugs have shown activity in this disease. These include irinotecan (CPT-11); oxaliplatin; the thymidylate synthase inhibitors raltitrexed, uracil/tegafur (UFT), capecitabine, and S-1; the biochemical modulators trimetrexate and 5-ethynyluracil; and the monoclonal antibody 17-1A. METHODS: The results of clinical trials with these and other new agents, as well as their current status and main characteristics, were reviewed. RESULTS: Several of these agents, some with a novel mechanism of action, show promising activity in CRC. In combination with 5-FU and leucovorin, trimetrexate showed encouraging response rates in Phase II studies. Other interesting agents include capecitabine, UFT, and S-1. The biochemical modulator 5-ethynyluracil may allow the oral administration of 5-FU; however, results of Phase II clinical trials are not yet available. CPT-11 is in the most advanced stage of development and, based on consistent data generated in extensive Phase II studies, currently appears to be a reasonable choice for 5-FU-resistant or refractory disease. Another promising agent is oxaliplatin, which showed activity as first-line and second-line treatment. CONCLUSIONS: Several new agents have shown promise in the treatment of CRC, and changes in the standard treatment of advanced or high risk CRC appear likely in the near future.     

Role of the barium enema in colorectal carcinoma

Colorectal carcinoma is the second most common cancer that occurs in women and men. To better appreciate the role of the barium enema in the evaluation of colorectal carcinoma, an understanding of its epidemiology, pathologic development, and current methods of detection is needed. Following review of these aspects of colorectal carcinoma, the barium enema is discussed more thoroughly regarding examination techniques, radiologic evaluation of colonic neoplasms, quality of the examinations, and radiologic efficacy.