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PubMedDate not supplied

Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer.

Biological and chemical irritants can be the cause of irritation in a variety of organ sites. It is becoming well understood that chronic irritation in any form can initiate and accelerate the cancer process in these same organs. This understanding comes in part from the many epidemiologic studies which point out that chronic inflammation correlates with increased risk of developing cancer in that organ which is affected. One of the hallmarks of chronic irritation is the increased activity in the arachidonic acid pathway which provides many of the necessary inflammatory biochemical mediators to this process. Arachidonic acid metabolism diverges down two main pathways, the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways. The COX pathway leads to prostaglandin and thromboxane production and the LOX pathway leads to the leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs). These classes of inflammatory molecules exert profound biological effects which enhance the development and progression of human cancers. A large number of synthetic drugs and natural products have been discovered that block many of these key pathways. Much experimental evidence in animals has shown that inhibition of the key enzymes which drive these pathways can, in fact, prevent, slow or reverse the cancer process. The data are convincing in a number of organ sites including colon, breast, lung, bladder and skin. More recently, double-blinded randomize clinical trials in humans have shown the prevention of colonic polyps by anti-inflammatory agents. These studies have primarily used non-steroidal anti-inflammatory drugs (NSAIDS) which block the COX pathways. Recent preclinical studies indicate that the LOX pathway also may be an important target for cancer prevention strategy. The expression of high levels of these enzymes in cancerous tissues make them an obvious first target for cancer prevention strategies. As newer more specific drugs are developed with few adverse effects this important prevention strategy may become a reality.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Seven novel mutations in the APC gene of Portuguese families with familial adenomatous polyposis: correlation with phenotype.

Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). In the present study, we have used the protein truncation test to screen for mutations in exon 15 and exons 1-14 of the APC gene and denaturing gradient gel electrophoresis to analyze exons 1-14. We have studied nine unrelated FAP kindreds, eight with the classical phenotype and one with an atypical phenotype, with several family members exhibiting fewer than 50 colonic polyps. The combined use of these two methodologies allowed the identification of seven novel mutations, with two unrelated families sharing the same mutation. All mutations were chain terminating: six resulted from small deletions, one from a small insertion, and one was a point mutation, resulting in a premature stop codon. Seven mutations were located in exon 15 of the APC gene, one was in exon 10, and the remaining one, which corresponded to the kindred with an atypical phenotype, was located in exon 4.

Adenomatous Polyposis Coli↗
PubMed1998

Mutations of the adenomatous polyposis coli and p53 genes in a child with Turcot's syndrome.

Turcot's syndrome is a rare heritable complex that is characterized by an association between a primary neuroepithelial tumor of the central nervous system and multiple colonic polyps. The aim of this study was to analyze genetic alterations in a case of Turcot's syndrome in a 10.5-year-old boy in whom a colorectal tumor developed 3.5 years following astrocytoma. An APC germline non-sense mutation at codon 1284 leading to a truncated protein was identified, as was a somatic p53 mutation in the colorectal carcinoma in exon 7, codon 244. The latter was not identified in the primary astrocytoma. However, immunohistochemistry revealed high p53 protein expression in both tumors, suggesting an additional p53 mutation in the primary astrocytic tumor. The diverse p53 mutations observed in this unique syndrome in two different sites and stages of the disease may shed light on the multistep progression of the malignant events.

Adenomatous Polyposis Coli↗
PubMed2000

New DNA-based biomarkers for oxidative stress and cancer chemoprevention studies.

Etheno (epsilon) modified DNA bases (epsilond A, epsilond C, epsilond G) are generated from the carcinogens vinyl chloride and urethane, but also by reactions of DNA with products derived from lipid peroxidation (LPO) and oxidative stress via endogenous pathways. Recently developed ultrasensitive methods allowed the detection of these epsilon-adducts in vivo and their role to be studied in experimental and human carcinogenesis. Highly variable background levels of epsilon-adducts were detected in DNA from different organs of unexposed humans and rodents. Several known cancer risk factors increased the level of these DNA lesions in target organs: elevated epsilon-adducts were found in hepatic DNA from patients with metal storage diseases, after overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in a mouse model, and in colonic polyps of familial adenomatous polyposis patients. A high omega-6-polyunsaturated fatty acid diet increased epsilon-DNA adducts in white blood cells of female subjects. In conclusion, epsilon-adducts were found to be elevated in cancer-prone tissues, suggesting that these promutagenic lesions could drive cells to malignancy. Therefore, exocyclic DNA adducts offer new tools in cancer aetiological research and in verifying the efficacy of chemopreventive agents.

Animals↗
PubMed1996

The role of the ET nurse in managing Gardner's syndrome.

Gardner's syndrome is a genetic disease that carries a 100% risk of malignant degeneration if left untreated. The syndrome is characterized by the presence of numerous colon polyps, along with a wide variety of extracolonic manifestations. The presence of these extracolonic manifestations increase morbidity and make treatment more difficult. The surgical procedure commonly used to manage the disease is total colectomy with creation of an ileoanal reservoir. The incidences of intestinal obstruction, genitourinary obstruction, septicemia, and fistula formation increase with the growth of desmoid tumors, which are one of the extracolonic manifestations of the disease. The ET nurse plays an essential role in the care of the patient with Gardner's syndrome. Whether acting as a consultant or primary care provider, the ET nurse provides emotional support, educates, and establishes a plan of care to manage the ostomies, skin problems, complex wounds, and fistulas associated with Gardner's syndrome.

Gardner Syndrome↗
PubMed2001

Cancer chemoprevention by dietary constituents: a tale of failure and promise.

Although the results of clinical intervention trials of beta-carotene to prevent lung cancer, and of dietary augmentation with fibre or fruit and vegetables to reduce the occurrence of colonic polyps have so far been negative, a structured path for the development of diet-derived constituents as cancer chemopreventive agents is emerging. Putative agents are identified on the basis of epidemiological and preclinical mechanistic studies. Some examples of promising diet-derived chemopreventive agents are folate, curcumin, genistein, and tea catechins. Long-term supplementation of the diet with folate seems to lower the risk of colorectal cancer. Curcumin in the spice turmeric, genistein in soya, and catechins in tea have tumour-suppressing properties in rodent models of carcinogenesis, and they interfere with cellular processes involved in tumour promotion and progression. Kinases, telomerase, cyclooxygenase-2, triggers of apoptosis, and transcription factors AP1 and nuclear factor kappaB are among the cellular targets. The investigation of dietary constituents should follow a structured design, incorporating parallel preclinical studies of the food source and the isolated agent in terms of efficacy, toxicity, biological mechanisms, and pharmacokinetics. Either the food source or the isolated agent should be selected for further development on the basis of dose-efficacy and toxicity data. Pilot clinical trials on the pharmacokinetics and mechanism-based markers of efficacy of the selected intervention should precede phase I-III development in suitable populations.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Optical coherence tomography imaging of the pancreas: a needle-based approach.

A novel, high-resolution, needle-based optical coherence tomography (OCT) device for improving the ability to detect early epithelial dysplasia in solid tissues/organs in vivo is currently in development. An instrument capable of real-time imaging of tissue microstructures in vivo could improve the ability to detect pathologic conditions such as dysplasia, and consequently improve patient outcomes. OCT is an emerging technology that can perform real-time cross-sectional imaging of tissue structures at micron-scale resolution in vivo. OCT has been shown to be effective in the imaging of luminal epithelium, capable of detecting epithelial dysplasia in Barrett's esophagus, and colonic polyps. However, OCT imaging depth with conventional probes is limited to the luminal surface (approximately 1-2 mm). The development of a technology and device that enables high-resolution, real-time imaging of solid tissues beyond 1- to 2-mm deep at or near the cellular level in vivo could improve the diagnosis of diseases of the pancreas and other solid organs.

Diagnosis, Differential↗
PubMed2001

Pathology of colorectal cancer.

The earliest phases of colorectal tumourigenesis initiate in the normal mucosa, with a generalised disorder of cell replication, and with the appearance of clusters of enlarged crypts (aberrant crypts) showing proliferative, biochemical and biomolecular abnormalities. The large majority of colorectal malignancies develop from adenomatous polyps. These can be defined as well demarcated masses of epithelial dysplasia, with uncontrolled crypt cell division. An adenoma can be considered malignant when neoplastic cells pass through the muscularis mucosae and infiltrate the submucosa. Definitions like "carcinoma in situ" or "intramucosal carcinoma" should be abandoned, since they lead to confusion. Although several lines of evidence indicate that carcinomas usually originate from pre-existing adenomas, this does not imply that all polyps undergo malignant changes, and does not exclude "de novo" carcinogenesis. Besides adenomas, other types of polypoid lesions include hyperplastic polyps (showing elongated crypts often with cystic dilatation), serrated adenomas (with a serrated glandular pattern], flat adenomas (flat lesions which are difficult to detect in routine lower endoscopy, but may possess malignant potential), hamartomatous polyps (which show a complex branching pattern of smooth muscle supporting normal lamina propria and glands), and inflammatory polyps. Colorectal carcinomas are one of the most frequent neoplasms in Western society; the macroscopic appearance of these lesions may be that of a polypoid vegetating mass or of a flat infiltrating lesion. Most of these tumours are adenocarcinomas (96%), that, in some cases, show a mucinous component. More rare malignancies of the large bowel include signet-ring cell carcinoma, squamous carcinoma, undifferentiated neoplasms and medullary type adenocarcinoma (solid carcinoma with minimal glandular differentiation or slight cellular pleomorphism). Colorectal carcinoma can be graded into well, moderately and poorly differentiated lesions; there is little evidence, however, that grading may be of help in evaluating prognosis of affected patients. In conclusion, colorectal tumours cover a wide range of premalignant and malignant lesions, many of which can easily be removed at endoscopy. It follows that colorectal neoplasms might be prevented by interfering with the various steps of carcinogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas of various dimensions, and eventually evolves into malignancy.

Adenomatous Polyposis Coli↗
PubMed1998

Effect of dietary vitamin A or N-acetylcysteine on ethylnitrosourea-induced rat gliomas.

It is our hypothesis that low grade gliomas are the glial counterparts of other precancerous lesions such as colon polyps and, therefore, suitable targets for chemoprevention. Steps in the molecular progression of gliomas have been described, indicating that an accumulation of abnormalities is required for progression to a high grade and interruption of this progression might be possible. An animal model of chemical glial carcinogenesis was used to test this hypothesis. Pregnant rats were injected intravenously with ENU (ethylnitrosourea) on the 18th day of gestation to induce gliomas in the offspring, which were randomized to receive control diet, diet supplemented with vitamin A palmitate, or diet supplemented with N-acetylcysteine. Animals exposed to ENU and receiving a control diet developed brain tumors and had a shortened life expectancy compared with rats unexposed to ENU. The animals treated with NAC showed no statistically significant delay in the time to tumor and no change in the histologic grade of the tumors when compared with animals receiving control diet, but the time to death from any cause of NAC treated animals differed significantly from untreated animals. Animals receiving high dose VA had statistically significantly prolonged time to tumor, survived significantly longer than untreated animals, but had no reduction in the total number of tumors or change in the histologic grade of their tumors. The theoretical basis of these results is likely due to the putative mechanism of action of these agents. These data indicate that glioma chemoprevention is possible and deserves further exploration.

Acetylcysteine↗
PubMed2004

Agreement of self-reported medical history: comparison of an in-person interview with a self-administered questionnaire.

PURPOSE: To compare history of 22 different diseases reported during an in-person interview with that reported on a mailed self-administered questionnaire. METHODS: 7841 participants of the European Prospective Investigation into Cancer (EPIC)-Potsdam study. The interview at baseline and the questionnaire at follow-up approximately 2 years later included identical questions about whether the participant had ever had a physician diagnosis of each disease. Incident diagnoses occurring in the interval between the interview and questionnaire were excluded from the analysis. RESULTS: Agreement between self-report from the interview and from the questionnaire was highest (kappa = 0.83-0.88) for myocardial infarction, cancer and diabetes mellitus; it was lower (kappa = 0.68-0.77) for gout, hypertension, hay fever, asthma, osteoporosis, ulcer of the duodenum, thyroid disease, stroke, and kidney stones, and was lowest (kappa = 0.39-0.59) for chronic gastritis, ulcer of the stomach, cerebral ischemia, benign tumor, inflammatory bowel disease, angina pectoris, hyperlipidemia, rheumatism, colon polyps and skin disease. The poor agreement for less severe or more transient diseases was primarily a result of disease frequently being reported at the interview but not on the questionnaire. CONCLUSION: Self-administered questionnaires do not generate same information particularly for less severe or transient diseases as personal interviews. For these diseases, self-administered questionnaires are not recommended. Pilot studies that test validity will be necessary.

Adult↗
PubMed2004

Spectroscopic diagnosis and imaging of invisible pre-cancer.

The theme of this paper is the use of optical spectroscopy to diagnose invisible pre-cancer in patients undergoing endoscopy and similar medical procedures. We describe three techniques that provide diagnostic information and two instruments to implement them, the FastEEM for studying small regions of tissue and the LSS (light scattering spectroscopy) imaging system for wide-area surveillance. The FastEEM is an optical fiber clinical device that collects spectra of reflected light and fluorescence at multiple excitation wavelengths from the tissue, all in a fraction of a second. Quantitative information is obtained in real time, without removing the tissue and without the need for staining and fixation. Three types of spectral information are extracted intrinsic fluorescence, diffuse reflectance and elastic light scattering. Each of the three analyses is based on a biophysical model, and each provides complementary quantitative physical and chemical information about cellular/tissue structures. This information is used to make a combined spectral diagnosis, a method we call tri-modal spectroscopy (TMS). Promising clinical studies are being carried out on patients undergoing routine pre-cancer surveillance in the oral cavity, the uterine cervix and the gastrointestinal tract. The LSS imaging system provides wide-area spectroscopic images of the epithelium, typically 2 cm in each dimension, depicting the size distribution and chromatin content of the cell nuclei, which are key parameters in diagnosing pre-cancer. This instrument is in preclinical stages of development, although a laboratory prototype has been used to create diagnostic images in resected colon polyp samples. The combination of the TMS/FastEEM and LSS imaging instrument will constitute a powerful new diagnostic tool, with LSS imaging to provide wide area surveillance and the TMS probe to provide detailed information on suspect tissue sites.

Cervix Uteri↗
PubMed2002

Review article: intestinal metaplasia and gastric carcinogenesis.

Gastric intestinal metaplasia, an intermediate step in Correa's cascade of gastric carcinogenesis, is generally regarded as a pre-malignant lesion. Epidemiological studies suggest that patients with intestinal metaplasia have more than a 10-fold increased risk of developing gastric cancer. Within the subclassification of intestinal metaplasia, incomplete or type III intestinal metaplasia appears to be associated with even higher malignant potential. The topographical distribution of intestinal metaplasia may also have prognostic implications. Certain genetic and epigenetic alterations have been demonstrated in gastric intestinal metaplasia which straddle into gastric cancer. These findings suggest that genetic changes occur early in the multistep gastric carcinogenesis process. Unlike Barrett's oesophagus and colonic polyp, which have well-defined surveillance guidelines, there is no widely accepted surveillance programme for gastric intestinal metaplasia. An annual surveillance programme may allow early detection of gastric cancer, which theoretically may improve survival. It remains elusive whether the treatment of Helicobacter pylori infection may reverse gastric intestinal metaplasia or reduce the subsequent risk of cancer development. Further controlled studies with longer follow-up are needed to resolve this controversy. The role of chemo-prophylactic agents, e.g. cyclo-oxygenase-2 inhibitor, should be investigated.

Disease Progression↗
PubMed2000

Randomization is not the (only) answer: a plea for structured objective evaluation of endoscopic therapy.

Endoscopic therapy clearly has a primary role in many clinical conditions (such as dysphagia, obstructive jaundice, bleeding, and colonic polyps). There is much less certainty about the role of endoscopy in many other clinical contexts (e.g. management of chronic pancreatitis). Randomization is the gold standard for evaluation of competing therapies. Unfortunately, there are many difficulties in mounting meaningful randomized controlled trials of endoscopic methods. Many have been done, but few have provided us with real practical answers. This article argues that the evidence we need to advise patients is often better obtained through very stringent observational studies, provided that all necessary data elements are defined and documented and independent objective arbiters (referees) are fully involved in the process.

Digestive System Diseases↗
PubMed2000

Optical coherence tomography in the gastrointestinal tract.

Optical coherence tomography (OCT) is a high-resolution, cross-sectional optical imaging technique that allows in situ imaging of tissue by measuring back-reflected light. OCT provides images in real time with a resolution approaching that of conventional histopathology, but without the need for tissue removal. OCT imaging can be performed endoscopically to visualize gastrointestinal tissue using a fiberoptic catheter passed through the instrument channel of a conventional endoscope. The resolution of OCT allows visualization of the different layers of gastrointestinal epithelium and the differentiation of Barrett's epithelium from normal gastric and squamous mucosa. OCT has also been used to image esophageal adenocarcinoma and colonic polyps. Recent developments include Doppler OCT, spectroscopic OCT, and ultrahigh-resolution OCT, which can visualize nuclei within single cells. Although still in its infancy as a clinical tool, OCT currently provides high-resolution images over the same imaging depth as conventional mucosal biopsy, and may prove to be a useful and minimally invasive technique for evaluating gastrointestinal tissue, particularly for early neoplastic changes.

Digestive System↗
PubMed2003

Diagnostic yield of wireless capsule enteroscopy in comparison with computed tomography enteroclysis.

BACKGROUND AND STUDY AIMS: It is still difficult to visualize changes in the small intestine. Wireless capsule enteroscopy is a new method that promises to provide new insights into the small intestine. In a prospective study, the diagnostic yield of wireless enteroscopy was therefore compared with computed tomography (CT) enteroclysis. PATIENTS AND METHODS: Twenty-two patients with suspected small-bowel pathology underwent CT enteroclysis and wireless capsule enteroscopy examinations, conducted by two independent blinded investigators. The results of the two investigations (diagnoses and the number, extent, and location of lesions detected) were compared by a third investigator. RESULTS: The patients included in the study had obscure gastrointestinal bleeding (n = 8), Crohn's disease (n = 8), unexplained diarrhea (n = 5), or suspected carcinoid tumor (n = 1). Pathological lesions were detected using capsule enteroscopy in 13 patients (59 %) and using CT enteroclysis in eight (36 %; P = 0.12). In seven patients (one case each of colonic Crohn's disease, diverticulitis, Meckel's diverticulum, carcinoid tumor, mesothelioma, colonic polyps, and irritable bowel syndrome), no pathological changes were found in the small intestine using either method. The diagnosis was established by wireless capsule enteroscopy in four patients with obscure bleeding, whereas CT enteroclysis was positive in only one patient ( P = 0.1). Crohn's disease was found in two patients with unexplained diarrhea. Small-bowel lesions were identified in six patients with known Crohn's disease using capsule enteroscopy or CT enteroclysis. The only side effect of wireless capsule enteroscopy observed was abdominal pain in one patient with Crohn's disease. There were no serious side effects with CT enteroclysis. CONCLUSIONS: Wireless capsule enteroscopy detects more small-bowel lesions than CT enteroclysis in patients with obscure gastrointestinal bleeding and Crohn's disease.

Adolescent↗
PubMed2004

[Precautions for intestinal cancer in the workplace. An initiative for secondary prevention in the BASF joint-stock company].

BACKGROUND AND OBJECTIVE: The annual incidence of colorectal cancer in Germany is estimated at 27000 in men and 30000 in women. If the diagnosis is made early the cure rate is over 90%. Against this background the department of occupational medicine and health protection of the BASF Aktiengesellschaft initiated a study on the potential prevention of colorectal cancer among the staff at its Ludwigshafen site. SUBJECTS AND METHODS: The target group included all 13265 actively working employees aged 45 years or above. Those expressing interest were given a standardized questionnaire concerning risk factors for colorectal cancer and a test for occult fecal blood (FOBT). If the test was positive and/or a positive answer was given to the question on blood in the stool or on a positive family history, coloscopy - to be arranged via the general practitioner - was advised, in line with the recommendations of the German Society of Digestive and Metabolic diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen). RESULTS: At the end of the study 3732 employees (337 women, 3395 men, mean age 52 years) had completed the questionnaire and the FOBT results were available. Coloscopy was recommended to 688 employees, 323 of whom (47%) underwent the investigation. Nine of the subjects already had manifest cancer, six of them in the early stage T1 or T2. Adenomatous polyps were found in an additional 61 and subsequently excised. Cost-benefit considerations at the company level or in the area of the health system, respectively, gave favourable ratios of 1:10 and 1:14. CONCLUSION: It requires considerable expenditure to increase the number of participants in the cancer prevention programme and obtain a consequent clarification of suspicious findings. Health care within a company is a valuable complementation in Germany of medical care provided by general practitioners or specialist, if close cooperation between practitioners in the given region is assured. Initiatives like the one presented here protect people personally affected against pain and distress and are also of economic value.

Adenomatous Polyps↗