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Duodenal neoplasms of gastric phenotype are uncommon epithelial neoplasms. Pyloric gland adenomas should be recognized as neoplasms with risk for transformation into invasive adenocarcinoma (). Here we report the case histories of two male patients, who presented with duodenal polypoid lesion. Endoscopic polypectomy and endoscopic submucosal dissection were carried out, respectively. Histopathologically, both polyps showed features of neoplasms of gastric phenotype. The clinical and endoscopic features, pathologic features, immunophenotype, molecular pathogenesis, clinical management and prognosis of the two cases will be discussed. We will also briefly review the latest literatures on duodenal neoplasms of gastric phenotype.

To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months ( P < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4-15. ©2017 AACR See related editorial by Shureiqi, p. 1 ., (©2017 American Association for Cancer Research.)

Familial adenomatous polyposis (FAP) is a hereditary condition with a near 100 % lifetime risk of colorectal cancer without prophylactic colectomy. Most patients with FAP have a mutation in the adenomatous polyposis coli gene on chromosome 5q22. This condition frequently presents in children with polyps developing most frequently in the second decade of life and surveillance colonoscopy is required starting at age ten. Polyps are found not only in the colon, but in the stomach and duodenum. Knowledge of the natural history of FAP is important as there are several extra-colonic sequelae which also require surveillance. In infants and toddlers, there is an increased risk of hepatoblastoma, while in teenagers and adults duodenal carcinomas, desmoid tumors, thyroid cancer and medulloblastoma are more common in FAP than in the general population. Current chemopreventive strategies include several medications and natural products, although to this point there is no consensus on the most efficacious and safe agent. Genetic counseling is an important part of the diagnostic process for FAP. Appropriate use and interpretation of genetic testing is best accomplished with genetic counselor involvement as many families also have concerns regarding future insurability or discrimination when faced with genetic testing.

Context: In ampullary carcinoma staging, T1 is defined as a tumor limited to the ampulla of Vater or the sphincter of Oddi, and T2 is defined as invasion into the duodenal wall. However, the definition of duodenal wall invasion is vague. Ampullary carcinoma that invades beyond the sphincteric of Oddi (perisphincteric invasion) or into the duodenal submucosa could be considered pT1b because submucosal invasion is classified as pT1b in gastrointestinal tract tumors. However, there are no data regarding T subclassifications for ampullary carcinoma with perisphincteric or duodenal submucosa invasion., Objective: To determine the T subclassification of ampullary carcinoma that invades into perisphincteric or duodenal submucosa., Design: Pathologically proven ampullary carcinomas with T1 or T2 were reviewed (n = 105). We reclassified tumors as pT1a that were limited to within the sphincter of Oddi (n = 40; 38%), as pT1b for tumors that invaded beyond the sphincter of Oddi or into the duodenal submucosa (n = 25; 24%), and as pT2 for tumors that invaded into duodenal proper muscle (n = 40; 38%)., Results: Lymph node metastasis and recurrence were absent in ampullary carcinoma with pT1a, whereas nodal metastasis were noted in 24% (6 of 25) and 40% (16 of 40) of the ampullary carcinomas with pT1b and pT2, respectively. Tumor recurrence/metastasis rate of ampullary carcinoma with pT1b and pT2 was 44% (11 of 25) and 40% (16 of 40), respectively. The 5-year disease-free-survival rates from ampullary carcinoma with pT1a, pT1b, and pT2 were 95% (38 of 40), 56% (14 of 25), and 58% (23 of 40), respectively (P = .003). The 5-year overall survival from ampullary carcinoma with pT1a, pT1b, and pT2 was 98% (39 of 40), 72% (18 of 25), and 60% (24 of 40), respectively., Conclusions: The clinicopathologic outcome of ampullary carcinoma with a pT1b subclassification was worse than it was for T1a and approached the outcome for pT2.

Aim: Duodenal adenomas occur in about 90% of patients with familial adenomatous polyposis (FAP) and are the second cause of death of patients who have had a prophylactic proctocolectomy. Studies suggest that biliary acids have a role in the development of duodenal adenomas. The aim of this study was to evaluate the impact of ursodesoxycholic acid (UDCA) on duodenal adenoma formation in patients with FAP., Method: A randomized, double-blinded, placebo-controlled study was carried out of 71 patients (20-65 years) who already had a restorative proctocolectomy. Subjects received either 10 mg/kg of UDCA orally per day or a placebo tablet for 24 months. The Spigelman severity score was determined after duodenal axial and lateral view endoscopy at 12 and 24 months., Results: At 2 years 55 patients had completed the entire period of treatment. At the end of the follow-up period, nine (25%) patients in the UDCA group and seven (20%) in the placebo group had a decrease in the Spigelman score (P = 0.6142). Patients receiving UDCA had no side-effects (0%) compared with four (14%) in the placebo group (P = 0.0392)., Conclusion: UDCA had no effect on the development of duodenal adenomas in FAP patients (NCT: 00134758)., (© 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.)

Background: Duodenal cancer is a major cause of mortality in patients with familial adenomatous polyposis (FAP). The clinical challenge is to perform duodenectomy before cancer develops; however, procedures are associated with complications. Our aim was to gain insight into the pros and cons of prophylactic duodenectomy., Methods: Patients with FAP from the nationwide Dutch polyposis registry who underwent prophylactic duodenectomy or were diagnosed with duodenal cancer were identified and classified as having benign disease or cancer at preoperative endoscopy. Surveillance, clinical presentation, surgical management, outcome, survival, and recurrence were compared., Results: Of 1,066 patients with FAP in the registry, 52 (5%; 25 males) were included: 36 with benign adenomatosis (median: 48 years old; including two (6%) cancer cases diagnosed after operation), and 16 with cancer (median: 53 years old). Cancer cases had been diagnosed with colorectal cancer more often (6% vs 44%; P < .01). Forty-three patients underwent duodenectomy (35 benign/eight cancer): 30-day mortality was 4.7% (n = 2), and in-hospital morbidity occurred in 21 patients (49%), without differences between patients with benign adenomatosis and cancer. Adenomas recurred in reconstructed proximal small bowel in 14 of 28 patients (50%, median time to recurrence: 75 months), and one patient developed cancer. Median survival of all 18 cancer cases in the registry (1.7%; 12 ampullary/six duodenal) was 11 months., Conclusion: Prognosis of duodenal cancer in patients with FAP is poor, which justifies an aggressive approach to advanced benign adenomatosis. Strict adherence to recommended surveillance intervals is essential for a well-timed intervention. Given the substantial morbidity and mortality of duodenectomy, patients' individual characteristics are to be critically evaluated preoperatively. As adenomas recur, postoperative endoscopic surveillance is mandatory., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Duodenal cancer is the leading cause of cancer death in familial adenomatous polyposis after colorectal cancer. The lifetime risk for developing duodenal cancer is 4% to 10%. Current treatment guidelines recommend endoscopic surveillance with a prophylactic pancreaticoduodenectomy in advanced duodenal polyposis, defined using the Spigelman staging system. Because no clinical trials have assessed this recommendation, a modeling approach was used to evaluate the cost-effectiveness of various treatment strategies., Methods: A Markov model was constructed to estimate the life expectancy and cost of three different strategies: pancreaticoduodenectomy at Spigelman stage III, pancreaticoduodenectomy at Spigelman stage IV, and pancreaticoduodenectomy at cancer diagnosis. A cohort of 30-year-old familial adenomatous polyposis patients with total colectomies was simulated until age 80. The analysis was from a societal perspective. Extensive sensitivity analysis was performed to assess the impact of model uncertainty on results., Results: At all stages of polyposis and all ages <80 years, prophylactic surgery at Spigelman stage IV resulted in the greatest life expectancy. Surgery at stage IV was more effective and more expensive than surgery at cancer diagnosis, with an incremental cost of $3,200 per quality-adjusted life year gained. Surgery at stage III was not a viable option. The results were robust to wide variation in model parameters but were sensitive to the post-pancreaticoduodenectomy quality of life score., Conclusions: Prophylactic pancreaticoduodenectomy at stage IV duodenal polyposis in familial adenomatous polyposis is a cost-effective approach that results in greater life expectancy than surgery at either stage III or cancer diagnosis.

Background: Blueberries may lower relative risk for cancers of the gastrointestinal tract. Previous work indicated an inhibitory effect of consumed blueberry (BB) on formation of aberrant crypt foci (ACF) in colons of male Fisher F344 rats (inbred strain). However, effects of BB on colon tumors and in both genders are unknown., Methods: We examined efficacy of BB in inhibition of azoxymethane (AOM)-induced colon ACF and intestine tumors in male and female Sprague-Dawley rats (outbred strain). Pregnant rats were fed a diet with or without 10% BB powder; progeny were weaned to the same diet as their dam and received AOM as young adults., Results: Male and female rats on control diet had similar numbers of ACF at 6 weeks after AOM administration. BB increased (P < 0.05) ACF numbers within the distal colon of female but not male rats. There was a significant (P < 0.05) diet by gender interaction with respect to total colon ACF number. Colon and duodenum tumor incidences were less in females than males at 17 weeks after AOM. BB tended (0.1 > P > 0.05) to reduce overall gastrointestinal tract tumor incidence in males, however, tumor incidence in females was unaffected (P > 0.1) by BB. There was a tendency (0.1 > P > 0.05) for fewer adenocarcinomas (relative to total of adenomatous polyps plus adenocarcinomas) in colons of female than male tumor-bearing rats; in small intestine, this gender difference was significant (P < 0.05). BB favored (P < 0.05) fewer adenocarcinomas and more adenomatous polyps (as a proportion of total tumor number) in female rat small intestine., Conclusion: Results did not indicate robust cancer-preventive effects of BB. Blueberry influenced ACF occurrence in distal colon and tumor progression in duodenum, in gender-specific fashion. Data indicate the potential for slowing tumor progression (adenomatous polyp to adenocarcinoma) by BB.

The goal of prophylactic surgery is to prevent malignant growth in patients with hereditary tumor predisposition. The pancreas presents as particularly challenging, due to the difficulty of operation and comparatively high risk of morbidity and even mortality. In addition, partial operative procedures and, more significantly, total resection lead to exocrine pancreas insufficiency and secondary diabetes, with grave consequences for the patient. Hereditary tumor predisposition syndromes that can result in pancreaticoduodenal endocrine tumors (PET) include multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau syndrome. As penetrance is maximally 70-80% and the 10-year survival rate over 80%, prophylactic pancreatic resection without evidence of a tumor is not indicated. However, prophylactic extension of a resection would be advised, should a PET be diagnosed. Patients predisposed to developing ductal pancreatic carcinoma (PC) are at risk of familial pancreatic cancer syndrome (FPC), hereditary pancreatitis, and other hereditary tumor predisposition syndromes such as Peutz-Jeghers syndrome and familial atypical multiple mole-melanoma syndrome. As the gene defect responsible for FPC has yet to be identified and the penetrance of PC in the other tumor predisposition syndromes is low or unknown, a prophylactic pancreatectomy based on today's knowledge is not indicated. Prophylactic extension of the resection is advisable should PC or high-grade PanIN lesions be diagnosed, as these patients often present with multifocal dysplasia and even carcinoma.

I-compounds are bulky covalent DNA modifications that are derived from metabolic intermediates of nutrients. Some I-compounds may play protective roles against cancer, aging, and degenerative diseases. Many carcinogens and tumor promoters significantly reduce I-compound levels gradually during carcinogenesis. Colon cancer is the second leading cause of cancer death in the United States, whereas cancer of the small intestine is relatively rare. Here we have studied levels of I-compounds in DNA of colon and duodenum of male Sprague-Dawley rats treated with azoxymethane. The effects of dietary lipids (fish oil or corn oil) on colon and duodenal DNA I-compounds were also investigated. Rats fed a diet containing fish oil or corn oil were treated with 15 mg/kg azoxymethane. Animals were terminated 0, 6, 9, 12, or 24 hours after injection. I-compound levels were analyzed by the nuclease P1-enhanced (32)P-postlabeling assay. Rats treated with azoxymethane displayed lower levels of I-compounds in colon DNA compared with control groups (0 hour). However, I-compound levels in duodenal DNA were not diminished after azoxymethane treatment. Animals fed a fish oil diet showed higher levels of I-compounds in colonic DNA compared with corn oil groups (mean adduct levels for fish and corn oil groups were 13.35 and 10.69 in 10(9) nucleotides, respectively, P = 0.034). Taken together, these results support claims that fish oil, which contains a high level of omega-3 polyunsaturated fatty acids, may have potent chemopreventive effects on carcinogen-induced colon cancer. The fact that duodenal I-compounds were not diminished by azoxymethane treatment may have been due to the existence of tissue-specific factors protecting against carcinogenesis. In conclusion, our observations show that endogenous DNA adducts may serve not only as sensitive biomarkers in carcinogenesis and cancer prevention studies, but are also helpful to further our understanding of the chemopreventive properties of omega-3 fatty acids and mechanisms of carcinogenesis.

Background: The prevalence of duodenal carcinoma is much higher in familial adenomatous polyposis (FAP) than in the background population, and duodenal adenomatosis is found in most polyposis patients., Aims: To describe the long term natural history of duodenal adenomatosis in FAP and evaluate if cancer prophylactic surveillance of the duodenum is indicated., Methods: A prospective five nation study was carried out in the Nordic countries and the Netherlands., Patients: A total of 368 patients were examined by gastroduodenoscopy at two year intervals during the period 1990-2001., Results: At the first endoscopy, 238 (65%) patients had duodenal adenomas at a median age of 38 years. Median follow up was 7.6 years. The cumulative incidence of adenomatosis at age 70 years was 90% (95% confidence interval (CI) 79-100%), and of Spigelman stage IV 52% (95% CI 28-76%). The probability of an advanced Spigelman score increased during the study period (p<0.0001) due to an increasing number and size of adenomas. Two patients had asymptomatic duodenal carcinoma at their first endoscopy while four developed carcinoma during the study at a median age of 52 years (range 26-58). The cumulative incidence rate of cancer was 4.5% at age 57 years (95% CI 0.1-8.9%) and the risk was higher in patients with Spigelman stage IV at their first endoscopy than in those with stages 0-III (p<0.01)., Conclusions: The natural course of duodenal adenomatosis has now been described in detail. The high incidence and increasing severity of duodenal adenomatosis with age justifies prophylactic examination, and a programme is presented for upper gastrointestinal endoscopic surveillance.

The aim of this study is to investigate the chemopreventive effects of the synthetic phenolic antioxidant 1-O-hexyl-2,3, 5-trimethylhydroquinone (HTHQ) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colon carcinogenesis in rats after initiation with 1,2-dimethylhydrazine (DMH) in male F344 rats. Groups of 20-22, 6-week-old male F344 rats were given four subcutaneous injections of 40 mg/kg body wt of DMH during the initial 4 weeks. They were then maintained on powdered basal diet containing 0.03% PhIP alone, PhIP together with 0.5 or 0.125% HTHQ, 0.5 or 0.125% HTHQ alone or basal diet for 32 weeks. A small number (1.1 +/- 1.1/rat) of colon tumors were induced by DMH treatment alone. After initiation with DMH, the number of colon tumors was greatly increased to 8.3 +/- 5.6 by the administration of PhIP. Additional treatment with HTHQ dose-dependently decreased the multiplicity of colon adenocarcinomas to 4.9 +/- 2.8 and 2.6 +/- 1.4 with 0.125 and 0.5%, respectively. This treatment similarly reduced atypical hyperplasias of the ventral prostate. Furthermore, HTHQ significantly reduced the multiplicity of duodenal adenocarcinomas induced by DMH + PhIP or DMH alone. Immunohistochemically, HTHQ was revealed to suppress PhIP-DNA adduct formation in the epithelial cells of the colon and prostate in a separate 2 weeks experiment. The present results clearly showed that HTHQ has chemopreventive potential for PhIP-associated colon and prostate carcinogenesis. The observed inhibition may largely be due to interference with PhIP-DNA adduct formation. In addition, HTHQ has been demonstrated to inhibit duodenal carcinogenesis in the post-initiation stage.

A highly selective, p.o. bioavailable irreversible inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, N-[4-(3-chloro4-fluorophenylamino)-quinazolin-6-yl]-ac rylamide (CFPQA), was evaluated for its ability to prevent intestinal adenoma formation in ApcMin mice. Ten-week continuous dietary exposure to CFPQA at doses sufficient to abolish intestinal EGFR tyrosine phosphorylation failed to affect intestinal tumor multiplicity or distribution but induced flat mucosal lesions in the duodenum characteristic of chronic injury. Intestinal trefoil factor, an intestinal peptide that mediates antiapoptotic effects through an EGFR-dependent mechanism, was notably absent in adenomas but was highly expressed in flat duodenal lesions. We conclude that chronic inhibition of EGFR tyrosine kinase by CFPQA does not prevent adenomas in ApcMin mice but may induce duodenal injury.

Prophylactic colectomy is generally recommended for patients with familial adenomatous polyposis (FAP) who are inevitably affected with large bowel cancer. After prophylactic colectomy has been performed, gastrointestinal malignancy is the leading cause of death. Duodenal adenomas are found in patients with FAP and the adenoma-carcinoma sequence exists in the FAP duodenum, suggesting that treatment of duodenal polyps might be beneficial. Several methods of treatment for duodenal lesions in patients with FAP have been reported, but the current treatment options are not ideal. The nonsteroid anti-inflammatory drugs, sulindac and aspirin, are used for chemoprevention, while recently developed cyclooxygenase-2 inhibitors may be of some use in the future. Endoscopic polypectomy has been attempted for duodenal polyps and open surgical polypectomy has proven to be effective for selected patients. Photodynamic therapy and Argon plasma coagulation may be suitable to treat carpeted polyposis. New methods of duodenal resection, such as pancreas-preserving duodenectomy and pylorus-preserving pancreaticoduodenectomy, might be considered for severe duodenal polyposis; however, because prophylactic duodenal surgery has been considered too aggressive, surveillance duodenoscopy is usually performed to detect duodenal cancer at an early stage.

Previous cancer chemoprevention studies have demonstrated that NSAIDs can be effective in suppressing the development of intestinal tumors. To further explore this issue, we performed cross-over chemoprevention studies using the drug piroxicam in the ApcMin mouse to evaluate the kinetics of NSAID-mediated tumor regression, the effects of genetic background and the incidence of resistance to chemoprevention. Starting at the time of weaning, C57BI/ 6J-ApcMin mice were fed either the control diet (AIN-93G) or AIN-93G plus 200 p.p.m. piroxicam. Tumor multiplicity was significantly reduced in ApcMin mice that were fed 200 p.p.m. piroxicam until 100 or 200 days of age (94.4 and 95.7% reduction in tumor number, respectively; P < 0.001 versus AIN-93G controls). When the administration of piroxicam was delayed until 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 96.2% (P < 0.001 versus controls). Alternatively, when the administration of piroxicam was suspended at 100 days of age and the mice were killed at 200 days of age, tumor multiplicity was reduced by 68.0% (P < 0.001 versus controls). Short-term drug treatment periods for ApcMin animals with established tumors revealed that the kinetics of piroxicam-induced tumor regression were rapid: >90% reduction in tumor multiplicity was observed after 1 week of treatment with 200 p.p.m. piroxicam. The distribution of residual tumors in piroxicam-treated mice suggests that tumors of the duodenum and colon were relatively resistant to chemosuppression. Treatment of interspecific hybrid ApcMin mice with 200 p.p.m. piroxicam revealed that there was a strain-related effect on chemosuppression, suggesting the existence of genetic elements which modulate NSAID chemosensitivity. Finally, whole-genome allelic loss studies showed that there were few unique chromosomal deletions in the NSAID-resistant tumors from F1 mice, implying that loss-of-function mutations secondary to Apc inactivation are not likely to account for the observed difference in chemoresistance.

Almost all patients with familial adenomatous polyposis develop duodenal polyps most of which occur in a cluster around the ampulla of Vater. Between 5 and 10% of FAP patients will die from upper gastrointestinal cancer, usually periampullary in origin. In an attempt to prevent cancer a screening programme has been developed using a well defined staging system to detect those patients most at risk of developing the disease. Treatment options are limited, with endoscopic clearance being contraindicated in most cases. The only certain method of preventing duodenal cancer is prophylactic radical surgery which has its own associated morbidity and mortality. Future developments may include new drug treatments or even gene therapy. Until then patients with FAP should all be considered for clinical trials as research continues.

Rebamipide is a potent antioxidative agent; it increases gastric mucosal PGE2 production and thus protects the gastric mucosa. We hypothesized that the mechanisms of ulcer formation could be extended to carcinogenesis and that an increase in gastric mucosal protection may result in a decrease in gastric carcinogenesis. Therefore, we assessed the inhibitory effects of rebamipide on N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) -induced carcinogenesis in mice. The percentage of tumor-bearing mice in three treatment groups--ENNG + rebamipide 20 mg, ENNG + rebamipide 50 mg, and ENNG alone--was 55%, 42%, and 67%, respectively. The incidence of tumorigenesis tended to decrease with increasing doses of rebamipide. The difference between ENNG + rebamipide 50 mg and ENNG alone was statistically significant (P < 0.05). These results suggest that rebamipide may strengthen the host defense mechanisms related to carcinogenesis in the digestive tract.

Coeliac disease is associated with an increased risk of certain gastrointestinal malignancies, especially of the small bowel. Metachronous malignancies are well established in the colon, where adenocarcinoma is common, but are exceptional in the small intestine. We describe a young woman with a long history of malabsorption who was shown to have coeliac disease complicated by a small-bowel adenocarcinoma. The cancer was resected, and the coeliac disease went into complete remission on a strict gluten-free diet. Fifteen years later she developed iron deficiency anaemia. Investigations showed a metachronous small-bowel adenocarcinoma but continuing remission of the coeliac disease. The case provides strong evidence against a causative role for the enteropathy of active coeliac disease in small-bowel adenocarcinoma and against a protective effect of a gluten-free diet in tumour development. Predisposition to adenocarcinoma in coeliac disease is probably genetic.

Although there have been several reports of hyperplastic gastric polyps associated with persistent Helicobacter pylori gastritis, the association of H. pylori infection with metaplastic polyps in the duodenum has not hitherto been described. After a 52-year-old man had a single episode of hematemesis, endoscopy showed a smooth polyp 1 cm in greatest dimension formed by a proliferation of gastric epithelial cells of fundic and antral type found in the duodenal bulb. The outer surface was entirely covered with a single layer of hyperplastic columnar epithelium with many H. pylori organisms. After administration of metronidazole 500 mg, omeprazole 20 mg for 4 weeks, and clarithromycin 250 mg twice a day for 2 weeks, endoscopy showed a decrease in size of the duodenal polyp. At 12 weeks there was complete regression of the polyp. This report documents a new and unusual finding: resolution of a gastric metaplastic polyp in the duodenum associated with cure of H. pylori.

There are divergent opinions on the effect of ethanol in the carcinogenesis of gastroduodenal tumors. The effect of the synchronous application of 11% ethanol or wine (11% ethanol) and N-methyl-N'-nitro-N-nitrosoguanidine (100 micrograms/ml, MNNG) in a drinking solution on the incidence of gastroduodenal tumors was evaluated. Sixty outbred male Wistar rats were distributed among three groups. The animals drank MNNG and ethanol or wine for six months and consumed the same quantity of MNNG. Then they consumed a normal diet until the 13th month, when the experiment was terminated. The stomach and duodenum were examined histologically. In the stomach, 15 tumors (2 squamous paillomas, 4 squamous carcinomas, 1 sarcoma, and 8 adenocarcinomas) and 4 cases of dysplasia were found; in the duodenum, there were four cases of adenocarcinoma. There were 6 cases of multiple tumors. Incidence of forestomach tumors did not differ among the groups, whereas the incidence of glandular stomach carcinoma and duodenal carcinoma was significantly lower in the groups treated with 11% ethanol or wine than in the control group. MNNG was not inactivated by ethanol in the drinking solutions. We concluded that the inhibitory effect on gastroduodenal carcinogenesis is the result of 11% ethanol ingestion and its protective action on the mucosa and not of the wine's nonethanol components.

Patients with familial adenomatous polyposis (FAP) develop periampullary duodenal tumours, suggesting that bile contributes to their formation. The hypothesis that bile contains carcinogens has been tested by looking for DNA adducts (markers of carcinogen exposure) in the duodenum of patients with or without FAP and by determining whether bile can produce DNA adducts in vitro. Using 32P-postlabelling to detect adducts, there was an excess (compared with unaffected patients) of DNA adducts in the duodenum of FAP patients and an excess of DNA adducts in the small bowel of rats treated with FAP bile, while bile from FAP patients formed significantly more DNA adducts in vitro than did bile from controls. In this study it is shown that the excess of adduct labelling produced by FAP bile in vitro depends on the pH of the incubate. While adduct labelling at pH 6-8 did not differ significantly between bile from six FAP patients and six controls, at pH 4-5 FAP bile, but not control bile, produced a near threefold excess of adduct labelling over that at pH 6-8. Therapy that increases duodenal pH may therefore alleviate duodenal polyposis.

As one of the most promising cancer chemopreventive agents, beta-carotene has been studied extensively. However, other natural carotenoids have also suppressed tumorigenesis, and some are more potent than beta-carotene. For example, alpha-carotene shows higher potency than beta-carotene in suppressing tumorigenesis in mouse skin and lung models. In the two-stage mouse skin carcinogenesis model (initiator, 7,12-dimethylbenz[a]anthracene; promoter, 12-O-tetradecanoylphorbol-13-acetate), topical application of alpha-carotene at a 200 nmol dose per painting twice a week significantly decreased the mean number of skin tumors per mouse. The greater potency of alpha-carotene over beta-carotene in suppression of tumor promotion was confirmed in the two-stage mouse lung carcinogenesis model (initiator, 4-nitro-quinoline-1-oxide; promoter, glycerol). Oral administration of alpha-carotene (0.05% in drinking water) significantly decreased the mean number of lung tumors per mouse. In contrast, beta-carotene showed no suppression of lung tumor formation under the same experimental conditions. Fucoxanthin, a carotenoid as abundant in nature as beta-carotene, was also found to have antitumorigenic activity in mouse skin and duodenum models. Thus, further studies on various natural carotenoids, other than beta-carotene, should be carried out in the field of cancer chemoprevention.

Curcumin (diferuloylmethane), a yellow pigment that is obtained from the rhizomes of Curcuma longa Linn., is a major component of turmeric and is commonly used as a spice and food-coloring agent. The inhibitory effects of feeding commercial grade curcumin (77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin) in AIN 76A diet on carcinogen-induced tumorigenesis in the forestomach, duodenum, and colon of mice were evaluated. Administration p.o. of commercial grade curcumin in the diet inhibited benzo(a)pyrene-induced forestomach tumorigenesis in A/J mice, N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumorigenesis in C57BL/6 mice, and azoxymethane (AOM)-induced colon tumorigenesis in CF-1 mice. Dietary commercial grade curcumin was given to mice at: (a) 2 weeks before, during, and for 1 week after carcinogen administration (during the initiation period); (b) 1 week after carcinogen treatment until the end of the experiment (during the postinitiation period); or (c) during both the initiation and postinitiation periods. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of benzo(a)pyrene-induced forestomach tumors per mouse by 51-53% when administered during the initiation period and 47-67% when administered during the postinitiation period. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumors per mouse by 47-77% when administered during the postinitiation period. Administration of 0.5-4.0% commercial grade curcumin in the diet both during the initiation and postinitation periods decreased the number of AOM-induced colon tumors per mouse by 51-62%. Administration of 2% commercial grade curcumin in the diet inhibited the number of AOM-induced colon tumors per mouse by 66% when fed during the initiation period and 25% when fed during the postinitiation period. The ability of commercial grade curcumin to inhibit AOM-induced colon tumorigenesis is comparable to that of pure curcumin (purity greater than 98%). Administration of pure or commercial grade curcumin in the diet to AOM-treated mice resulted in development of colon tumors which were generally smaller in number and size as compared to the control group of AOM-treated mice. These results indicate that not only did curcumin inhibit the number of tumors per mouse and the percentage of mice with tumors but it also reduced tumor size. Histopathological examination of the tumors showed that dietary curcumin inhibited the number of papillomas and squamous cell carcinomas of the forestomach as well as the number of adenomas and adenocarcinomas of the duodenum and colon.

Fucoxanthin was shown to inhibit chemical carcinogenesis. Fucoxanthin is a natural carotenoid prepared from brown algae which is an ingredient used daily in Japanese food. In this study, all mice were given 0.01% N-ethyl-N'-nitro-N-nitrosoguanidine in their drinking water for 4 weeks. This was followed by 0.005% fucoxanthin in dimethylsulfoxide or the vehicle alone in the drinking water. In the 16-week fucoxanthin-treated group both the percentage of tumor-bearing mice and the average number of tumors per mouse were significantly lower than those of the control group. The results indicate that fucoxanthin inhibited duodenal carcinogenesis induced by N-ethyl-N'-nitro-N-nitrosoguanidine in mice.

Male Wistar rats were treated concurrently with a combination of the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS 70-25-7) and the polyamine-synthesis inhibitor alpha-difluoromethylornithine (DFMO) at two different doses of 0.5% and 1.0% (w/v). Experimental groups were treated with (I) MNNG alone (n = 25), (II) MNNG plus 0.5% (w/v) DFMO (n = 25), (III) MNNG plus 1.0% (w/v) DFMO (n = 25), (IV) 1.0% (w/v) DFMO alone (n = 25). Group V represented untreated controls (n = 20). Both the carcinogen and DFMO were administered in drinking water. The treatment time with the carcinogen and DFMO was 35 weeks. After treatment was completed animals were followed for an additional 50 weeks to cover a total observation time of 85 weeks. Significantly fewer animals developed gastric adenocarcinoma in the two groups of animals that received a combined treatment of MNNG plus DFMO compared to animals treated with the carcinogen alone (P < 0.05 and 0.005). No benign or malignant neoplastic lesions were observed in the stomach or duodenum of animals treated with DFMO alone or in untreated controls. It is concluded that concurrent treatment with DFMO prevents the development of malignant gastric epithelial tumors induced by MNNG in rats.

The effects of palm carotene on chemical carcinogenesis was studied. Palm carotene suppressed mouse epidermal ornithine decarboxylase activity induced by glycocholic acid. In a two-stage mouse epidermal carcinogenesis experiment using 7,12-dimethylbenz(a)anthracene as the initiator, glycocholic acid as the 1st stage promoter, and mezerein as the 2nd stage promoter, palm carotene inhibited the promoting activity of glycocholic acid. Furthermore, in N-ethyl-N'-nitro-N-nitrosoguanidine-induced mouse duodenal carcinogenesis, 0.05% of palm carotene given in drinking water decreased the percentage of tumor-bearing mice significantly.

Helicobacter pylori was implicated in gastric carcinogenesis through the induction of metaplasia of the gastric mucosa. In this experiment a co-carcinogenic effect of H. pylori on chemically induced gastric carcinogenesis was examined. Wistar WKY male rats received drinking water containing 50 mg/l of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and intragastric administration of 10(6) to 10(8) colony forming unit of H. pylori thrice a week for 40 weeks. Thus, 3 groups were assigned as Group I; MNNG alone, Group II; MNNG + vehicle, and Group III; MNNG + H. pylori (n = 30, each). At autopsy, 9 rats (30%) had 7 glandular stomach and 3 duodenal tumors in Group I, and 10 rats (33%) had 8 glandular stomach and 2 duodenal tumors in Group II, whereas in Group III 4 rats (13%) had 2 glandular stomach and 2 duodenal tumors (chi 2 = 4.257, P < 0.15 for the incidences of glandular stomach tumors among 3 groups). The finding seems to suggest that H. pylori has an ambitendency in the gastritis-metaplasia-carcinogenesis sequence as a promoter for the induction of the predisposing mucosa and as an inhibitor against certain carcinogens.

The effects of simultaneous soybean trypsin inhibitor (SBTI) treatment on initiation of pancreatic carcinogenesis by N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Female Syrian golden hamsters were given five weekly s.c. injections of BOP at a dose of 10 mg/kg while being administered a diet containing 5% SBTI for 5 weeks (BOP + SBTI group). Two other groups of 30 animals each received the s.c. injections of BOP or the 5% SBTI diet for the same period, alone (BOP and SBTI groups respectively). Total numbers of pancreatic dysplastic lesions in hamsters of the BOP+SBTI group were significantly decreased as compared to the BOP group values, though the incidences of pancreatic adenocarcinomas were not significantly different. Atrophic changes were, however, more severe in the BOP group than in the BOP+SBTI group pancreatic exocrine tissue, showing that treatment with SBTI was effective for protection of acinar cells from carcinogen toxicity.

The inhibitory effect of murine interferon alpha/beta (Mu-IFN) on the induction of adenocarcinoma of the duodenum in C57BL/6 mice given N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) was examined. ENNG was given continuously in drinking water for 4 weeks and Mu-IFN was given intraperitoneally for 12 weeks. Then, the duodenal tumors of mice were examined stereomicroscopically and histologically. The level of IFN activity and natural killer (NK) activity were evaluated after an intraperitoneal single injection of Mu-IFN, and the level of NK activity was evaluated 2, 5 and 8 weeks after giving ENNG and Mu-IFN. In the mice given Mu-IFN, the incidence of duodenal tumors was significantly decreased (P less than 0.01), compared with that in mice given ENNG alone. Further, anti-asialo GM1 was given intraperitoneally every 5 days for 8 weeks to depress NK function and the incidence and size of duodenal tumors were examined. The results indicated that NK cells also have an important effect on the process of carcinogenesis. These data suggest that chemoprevention with IFN may be feasible.

Familial polyposis coli is characterized by progressive adenomatosis with ultimate progression to colon cancer. It is becoming clear that these patients also have a high incidence of upper gastrointestinal adenomatous polyps, with some developing periampullary malignancies similar to those seen in Gardner's syndrome. This has led to recommendations for periodic endoscopic screening of asymptomatic polyposis patients. We report a patient with familial polyposis coli who developed an adenocarcinoma in the distal duodenum. This case points out the importance of screening the upper gastrointestinal tract in patients at risk.

(-)-Epigallocatechin gallate (EGCG) is the main polyphenolic constituent of green tea infusion and inhibits tumor promotion by teleocidin in two-stage carcinogenesis on mouse skin. In this work, EGCG was found to inhibit tumor promotion in the gastrointestinal tract in a model system of mouse duodenal carcinogenesis with N-ethyl-N'-nitro-N-nitrosoguanidine. The duodenal tumors that developed were studied stereomicroscopically and histologically.

This study applies to the agency of vitamin C on chemical carcinogenesis in the small intestine of rats. Administration of N-Ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in drinking water produced tumors of the small intestine after 18 weeks in more than 90%. The induction of tumors could not be suppressed by a large amount (2-3%) of sodium ascorbate in food, but the depth of tumor infiltration was restricted. Cancer developed in 29 of 36 rats receiving ENNG only. In 25 animals of this group growth of tumor corresponded to a P4 stage. In 24 of 35 animals, additionally receiving vitamin C, P4 stage was observed in only 13 cases. Pathological changes in the small intestine could not be observed after the sole administration of vitamin C.