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Background & Aims: Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. Oral administration of the spice curcumin has been followed by regression of polyps in patients with this disorder. We performed a double-blinded randomized trial to determine the safety and efficacy of curcumin in patients with familial adenomatous polyposis., Methods: This study included 44 patients with familial adenomatous polyposis (18-85 years old) who had not undergone colectomy or had undergone colectomy with ileorectal anastomosis or ileal anal pouches, had at least 5 intestinal adenomatous polyps, and had enrolled in Puerto Rico or the United States from September 2011 through November 2016. Patients were randomly assigned (1:1) to groups given 100% pure curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months. The number and size of lower gastrointestinal tract polyps were evaluated every 4 months for 1 year. The primary outcome was the number of polyps in the curcumin and placebo groups at 12 months or at the time of withdrawal from the study according to the intention-to-treat principle., Results: After 1 year of treatment, the average rate of compliance was 83% in the curcumin group and 91% in the placebo group. After 12 weeks, there was no significant difference in the mean number of polyps between the placebo group (18.6; 95% CI, 9.3-27.8) and the curcumin group (22.6; 95% CI, 12.1-33.1; P = .58). We found no significant difference in mean polyp size between the curcumin group (2.3 mm; 95% CI, 1.8-2.8) and the placebo group (2.1 mm; 95% CI, 1.5-2.7; P = .76). Adverse events were few, with no significant differences between groups., Conclusions: In a double-blinded randomized trial of patients with familial adenomatous polyposis, we found no difference in the mean number or size of lower intestinal tract adenomas between patients given curcumin 3,000 mg/day and those given placebo for 12 weeks. Clinicaltrials.gov ID NCT00641147., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is suboptimal inter-observer agreement, even among expert gastrointestinal pathologists, in the diagnosis of low-grade dysplasia (LGD) in patients with Barrett's esophagus (BE). We analyzed histopathologic criteria required for a diagnosis of LGD using the new subcategories of LGD with inflammatory and dysplastic features. We categorized each diagnosis based on the level of confidence and assessed inter-observer agreement among gastrointestinal pathologists from 5 tertiary centers in the United States and Europe., Methods: In the first phase of the study, 3 pathologists held a consensus conference at which they discussed the diagnostic criteria for LGD. In the second phase, 79 slides from patients with BE (23 samples of non-dysplastic BE, 22 samples of LGD, and 34 samples of high-grade dysplasia) were identified, randomly assigned to 7 pathologists (4 from the United States and 3 from Europe), and interpreted in a blinded fashion. κ Values were calculated for inter-observer agreement. We performed multinomial logistic regression analysis to assess the weighting of histologic features with the diagnosis., Results: The overall κ value for diagnosis was 0.43 (95% confidence interval [CI], 0.42-0.48). When categorized based on degree of dysplasia, the κ value was 0.22 (95% CI, 0.11-0.29) for non-dysplastic BE, 0.11 (95% CI, 0.004-0.15) for LGD, and 0.43 (95% CI, 0.36-0.46) for high-grade dysplasia. When all pathologists made a diagnosis with high confidence, the inter-observer agreement was substantial among the US pathologists (κ, 0.63; 95% CI, 0.61-0.66) and European pathologists (κ, 0.80; 95% CI, 0.74-0.97). The κ values for all diagnoses made by European pathologists were higher than those made by US pathologists., Conclusions: In an analysis of criteria used in histopathologic diagnosis of LGD, we did not observe improvement in level of agreement among experienced pathologists, even after accounting for inflammation. The level of inter-observer agreement increased with level of pathologist confidence. There was also a difference in reading of histopathology samples of BE tissues between US and European pathologists., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC report a family history of CRC. However, only 5% of CRCs arise in the setting of a well-established mendelian inherited disorder. In addition, serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and an increased CRC risk for which the genetics are unknown. This article focuses on genetic and clinical aspects of Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background & Aims: Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice., Methods: Glioma-associated oncogene (Gli1)-CreERT2 and Patched (Ptch)-lacZ reporter mice were crossed with Apc(Min) mice to generate Gli1CreERT2-Rosa26-ZSGreen-Apc(Min) and Ptch-lacZ-Apc(Min) mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc (Apc(HET)) mice, which develop adenomas after administration of β-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. Apc(Min) mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12)., Results: Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from Apc(HET) mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from Apc(HET) mice changed the composition of the adenoma stroma; cells that expressed α-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased., Conclusions: Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: SMAD4 frequently is lost from colorectal cancers (CRCs), which is associated with the development of metastases and a poor prognosis. SMAD4 loss is believed to alter transforming growth factor β signaling to promote tumor progression. However, SMAD4 is also a central component of the bone morphogenetic protein (BMP) signaling pathway, implicated in CRC pathogenesis by human genetic studies. We investigated the effects of alterations in BMP signaling on the invasive and metastatic abilities of CRC cells and changes in members in this pathway in human tumor samples., Methods: We activated BMP signaling in SMAD4-positive and SMAD4-negative CRC cells (HCT116, HT-29, SW480, and LS174T); SMAD4 was stably expressed or knocked down using lentiviral vectors. We investigated the effects on markers of epithelial-mesenchymal transition and on cell migration, invasion, and formation of invadopodia. We performed kinase activity assays to characterize SMAD4-independent BMP signaling and used an inhibitor screen to identify pathways that regulate CRC cell migration. We investigated the effects of the ROCK inhibitor Y-27632 in immunocompromised (CD-1 Nu) mice with orthotopic metastatic tumors. Immunohistochemistry was used to detect BMPR1a, BMPR1b, BMPR2, and SMAD4 in human colorectal tumors; these were related to patient survival times., Results: Activation of BMP signaling in SMAD4-negative cells altered protein and messenger RNA levels of markers of epithelial-mesenchymal transition and increased cell migration, invasion, and formation of invadopodia. Knockdown of the BMP receptor in SMAD4-negative cells reduced their invasive activity in vitro. SMAD4-independent BMP signaling activated Rho signaling via ROCK and LIM domain kinase (LIMK). Pharmacologic inhibition of ROCK reduced metastasis of colorectal xenograft tumors in mice. Loss of SMAD4 from colorectal tumors has been associated with reduced survival time; we found that this association is dependent on the expression of BMP receptors but not transforming growth factor β receptors., Conclusions: Loss of SMAD4 from colorectal cancer cells causes BMP signaling to switch from tumor suppressive to metastasis promoting. Concurrent loss of SMAD4 and normal expression of BMP receptors in colorectal tumors was associated with reduced survival times of patients. Reagents that interfere with SMAD4-independent BMP signaling, such as ROCK inhibitors, might be developed as therapeutics for CRC., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Surveillance of high-risk groups for pancreatic cancer might increase early detection and treatment outcomes. Individuals with germline mutations in p16-Leiden have a lifetime risk of 15% to 20% of developing pancreatic cancer. We assessed the feasibility of detecting pancreatic cancer at an early stage and investigated the outcomes of patients with neoplastic lesions., Methods: Individuals with germline mutations in p16-Leiden (N = 79; 31 male; mean age, 56 years; range, 39-72 years) were offered annual surveillance by magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP). Those found to have neoplastic lesions were offered options for surgery or intensive follow-up. Individuals found to have possible neoplastic lesions were examined again by MRI/MRCP within 2 to 4 months., Results: After a median follow-up period of 4 years (range, 0-10 years), pancreatic cancer was diagnosed in 7 patients (9%). The mean age at diagnosis was 59 years (range, 49-72 years). Three of the tumors were present at the first examination, and 4 were detected after a negative result in the initial examination. All 7 patients had a resectable lesion; 5 underwent surgery, 3 had an R0 resection, and 2 had lymph node metastases. Possible precursor lesions (ie, duct ectasias, based on MRCP) were found in 9 individuals (11%)., Conclusions: MRI/MRCP detects small, solid pancreatic tumors and small duct ectasias. Although surveillance increases the rate of resectability, carriers of a p16-Leiden mutation develop aggressive tumors., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Indian Hedgehog (Ihh) is expressed by the differentiated epithelial cells of the small intestine and signals to the mesenchyme where it induces unidentified factors that negatively regulate intestinal epithelial precursor cell fate. Recently, genetic variants in the Hh pathway have been linked to the development of inflammatory bowel disease., Methods: We deleted Ihh from the small intestinal epithelium in adult mice using Cyp1a1-CreIhh(fl/fl) conditional Ihh mutant mice. Intestines were examined by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction., Results: Deletion of Ihh from the intestinal epithelium initially resulted in a proliferative response of the intestinal epithelium with lengthening and fissioning of crypts and increased Wnt signaling. The epithelial proliferative response was associated with loss of bone morphogenetic protein and Activin signaling from the epithelium of the villus and crypts, respectively. At the same stage we observed a substantial influx of fibroblasts and macrophages into the villus core with increased mesenchymal transforming growth factor-β signaling and deposition of extracellular matrix proteins. Prolonged loss of Ihh resulted in progressive leukocyte infiltration of the crypt area, blunting and loss of villi, and the development of intestinal fibrosis., Conclusions: Loss of Ihh initiates several events that are characteristic of an intestinal wound repair response. Prolonged loss resulted in progressive inflammation, mucosal damage, and the development of intestinal fibrosis. Ihh is a signal derived from the superficial epithelial cells that may act as a critical indicator of epithelial integrity., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The intestinal epithelium is a homeostatic system in which differentiated cells are in dynamic equilibrium with rapidly cycling precursor cells. Wnt signaling regulates intestinal epithelial precursor cell fate and proliferation. Homeostatic systems exist by virtue of negative feedback loops, and we have previously identified the Hedgehog (Hh) pathway as a potential negative feedback signal in the colonic epithelium. Indian hedgehog (Ihh) is produced by the differentiated enterocytes and negatively regulates Wnt signaling in intestinal precursor cells. We studied the role of members of the Hh signaling family in the intestine using a conditional genetic approach., Methods: We inactivated the Hh receptor Patched1 (Ptch1) in adult mice, resulting in constitutive activation of the Hh signaling pathway. Effects on colonic mucosal homeostasis were examined. Colon tissues were examined by immunohistochemistry, in situ hybridization, transmission electron microscopy, and real-time polymerase chain reaction., Results: Ihh but not Sonic hedgehog (Shh) was expressed in colonic epithelium. Expression of Ptch1 and Gli1 was restricted to the mesenchyme. Constitutive activation of Hh signaling resulted in accumulation of myofibroblasts and colonic crypt hypoplasia. A reduction in the number of epithelial precursor cells was observed with premature development into the enterocyte lineage and inhibition of Wnt signaling. Activation of Hh signaling resulted in induction of the expression of bone morphogenetic proteins (Bmp) and increased Bmp signaling in the epithelium., Conclusions: Hh signaling acts in a negative feedback loop from differentiated cells via the mesenchyme to the colonic epithelial precursor cell compartment in the adult mouse.

Background & Aims: The finding of bone morphogenetic protein (BMP) receptor 1a mutations in juvenile polyposis suggests that BMPs are important in colorectal cancer (CRC). We investigated the BMP pathway in sporadic CRC., Methods: We investigated BMP receptor (BMPR) expression using immunoblotting and sequenced BMPR2 in CRC cell lines. We assessed the expression of BMPRs, SMAD4, and pSMAD1/5/8 in 72 sporadic CRCs using a tissue microarray and immunohistochemistry. We assessed the effect of reintroduction of wild-type BMPR2 on BMP pathway activity and the effect of wild-type or mutated BMPR2 3' untranslated region (UTR) sequences on protein expression by attachment to pCMV-Luc., Results: BMPR2 and SMAD4 protein expression is abrogated in microsatellite unstable (MSI) and microsatellite stable (MSS) cell lines, respectively. BMPR2 3'UTR is mutated in all MSI and in none of the MSS cell lines. Mutant BMPR2 3'UTR sequences reduced luciferase expression 10-fold compared with wild-type BMPR2 3'UTR. BMPR2 expression is impaired more frequently in MSI CRCs than MSS (85% vs 29%; P < .0001) and shows a mutually exclusive pattern of impaired expression compared with SMAD4. Nine of 11 MSI cancers with impaired expression of BMPR2 have microsatellite mutations. The BMP pathway is inactivated, as judged by nuclear pSMAD1/5/8 expression, in 70% of CRCs, and this correlates with BMPR and SMAD4 loss., Conclusions: Our data suggest that the BMP pathway is inactivated in the majority of sporadic CRCs. In MSI CRC this is associated predominantly with impaired BMPR2 expression and in MSS CRC with impaired SMAD4 expression.

Epidemiologic and experimental reports suggest that female hormones protect against the development of colorectal cancer, but studies are limited. We describe a patient in the placebo arm of a 4-year primary chemoprevention trial who developed adenomatous polyps and then had eradication of polyps after the administration of oral contraceptives. No change in the prostaglandin levels in the colonic mucosa was noted after polyp elimination, making nonsteroidal anti-inflammatory drug ingestion unlikely as a cause. This report represents the regression of colorectal adenomas with the use of estrogen/progesterone compounds.

Background & Aims: There is limited data on the spectrum and risk for cancer associated with germline serine/threonine protein kinase 11 (STK11) mutations that cause Peutz-Jeghers syndrome (PJS)., Methods: We analyzed the incidence of cancer in 240 individuals with PJS possessing germline mutations in STK11., Results: Fifty-four cancers were found among carriers. Overall, the risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 1%, 3%, 19%, 32%, 63%, and 81%, respectively. Kaplan-Meier analysis showed similar cancer risks between missense and truncating mutation carriers (log-rank chi(2) = 2.48; P = 0.12). There was some evidence that mutations in exon 3 of STK11 were associated with a higher cancer risk than mutations within other regions of the gene. We found no difference in overall cancer risk between male and female carriers (log-rank chi(2) = 1.31; P = 0.25) or between familial and sporadic cases (log-rank chi(2) = 1.16, with 1 df; P = 0.28). The most common cancers represented were gastrointestinal in origin--gastroesophageal, small bowel, colorectal, and pancreatic--and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 10%, 18%, and 42%, respectively. In women, the risk for breast cancer was substantially increased, being 32% by age 60 years., Conclusions: These results quantitatively show the spectrum of cancer risk associated with STK11 germline mutations in the context of PJS and provide a valuable reference for defining surveillance regimens.

Background & Aims: Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated., Methods: A randomized, double-blind, placebo-controlled study of 41 subjects genotypically affected with familial adenomatous polyposis but phenotypically unaffected was conducted. Patients received either sulindac or placebo for 48 months, and development of new adenomas was evaluated. The levels of 5 prostanoids, ornithine decarboxylase, and polyamines were measured serially in normal-appearing rectal mucosa., Results: There were no statistically significant differences between treatment groups in baseline levels of prostanoids, ornithine decarboxylase, or polyamines. At conclusion of the study, 4 of 5 prostaglandin levels were statistically significantly lower in the sulindac group than in the placebo group. Among the subset of patients taking sulindac, 3 of 5 prostaglandin levels were statistically significantly lower in patients who were polyp free than in those who developed polyps. By contrast, there were no statistically significant differences in ornithine decarboxylase or polyamines between treatment groups or in those on sulindac who were polyp free compared with those who developed polyps., Conclusions: Colorectal mucosal prostaglandin levels, but not ornithine decarboxylase or polyamines, may be valuable biomarkers to assess appropriate drug dosage and medication compliance in patients undergoing primary chemoprevention therapy with sulindac. Reduction of mucosal prostaglandin levels may be necessary to achieve chemopreventive benefit from this agent.

Background and Aims: The recent findings of bone morphogenetic protein (BMP) receptor Ia mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer suggest a role for BMPs in the colonic epithelium and colon cancer. We investigated the role of BMP2 in the colon., Methods: We assessed BMP receptor expression in cell lines using the reverse-transcribed polymerase chain reaction and immunoblotting. We investigated the effect of BMP2 on cell lines using the MTT assay and by immunoblotting for markers of differentiation, proliferation, and apoptosis. We assessed the expression of BMP2, its receptors, and signal transduction elements in mouse and human colon tissue using immunohistochemistry. We also investigated the effect of the BMP antagonist noggin in vivo in mice by assessing colon tissue with immunohistochemistry and immunoblotting. Finally, we investigated the expression of BMP2 in microadenomas from familial adenomatous polyposis patients., Results: BMP receptors (BMPR) Ia, BMPR Ib, and BMPR II are all expressed in colonic epithelial cell lines. BMP2 inhibits colonic epithelial cell growth in vitro, promoting apoptosis and differentiation and inhibiting proliferation. BMP2, BMPRIa, BMPRIb, BMPRII, phosphorylated Smad1, and Smad4 are expressed predominantly in mature colonocytes at the epithelial surface in normal adult human and mouse colon. Noggin inhibits apoptosis and proliferation in mouse colonic epithelium in vivo. BMP2 expression is lost in the microadenomas of familial adenomatous polyposis patients., Conclusions: These data suggest that BMP2 acts as a tumor suppressor promoting apoptosis in mature colonic epithelial cells.

Background & Aims: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of cancer in the digestive tract. Cyclooxygenase (COX) is the best-known target of NSAIDs, and expression of the COX-2 isoform is elevated in esophageal carcinomas but its clinical significance remains unclear. We examined COX-2 expression in esophageal adenocarcinomas and its relation to clinicopathologic parameters., Methods: Tumor sections from 145 consecutive patients undergoing intentionally curative surgery for an adenocarcinoma arising from a Barrett's esophagus were immunohistochemically stained using a COX-2-specific anti-human monoclonal antibody. The specimens were scored based on the intensity and extent of COX-2 immunopositivity., Results: COX-2 immunoreactivity was negative to weak in 21% (COX-2 low) and moderate to strong in 79% (COX-2 high) of the carcinomas. Patients with high COX-2 expression were more likely to develop distant metastases (P = 0.02) and local recurrences (P = 0.05), and survival was significantly reduced (P = 0.002, log-rank test) among patients with high COX-2 expression when compared with the COX-2 low group. Five-year survival rates were 35% (95% confidence interval [CI], 23-47) and 72% (95% CI, 53-90) in COX-2 high and COX-2 low categories, respectively. Furthermore, expression of COX-2 was recognized as an independent prognostic factor by multivariate analysis (relative risk, 3.5; 95% CI, 1.6-7.9)., Conclusions: Elevated expression of COX-2 protein is associated with significantly reduced survival of patients undergoing surgery for esophageal adenocarcinoma. These findings support the effort to initiate clinical studies to investigate the effect of COX-2 inhibitors as a novel (adjuvant) chemotherapeutic modality for the treatment of adenocarcinoma arising from Barrett's esophagus.

We describe an uncommon case of adenosquamous carcinoma arising in a Barrett esophagus in a 72-year-old white man who occasionally used alcohol, and was a nonsmoker for 34 years. Polymerase chain reaction-based microsatellite analysis was performed on the adenocarcinoma component (AC) and squamous cell carcinoma component (SC) of the tumor. The metaplastic Barrett epithelium (BE), the AC and the SC all showed loss of the same allele at 4 markers on chromosome 9p. Furthermore, the AC and the SC both showed loss of the same allele at all informative markers tested on chromosomal arms 3p, 5q, 10q, 14q, and 18q. In addition, both the SC and AC component contained the same missense mutation in the p53 tumor-suppressor gene. The only observed difference was a shift at a marker on chromosome 16q in the AC, whereas no shift was found in the BE and the SC. These findings suggest that this biphasic tumor has a monoclonal origin. The divergence presumably occurred late in the tumorigenesis of this carcinoma.

Background and Aims: Obesity increases the risk of colon cancer, whereas physical activity reduces the risk. Plasma levels of leptin increase in proportion to the level of obesity and are reduced by physical activity. Leptin acts as a growth factor for several cell types and thus may provide a biological explanation for the observed epidemiological risk factors. The aim of this study was to investigate whether leptin is a growth factor for colonic epithelial cells., Methods: The presence of the leptin receptor in human colon cancer cell lines was assessed using reverse-transcription polymerase chain reaction and immunoblotting, and its presence in human colonic tissue was assessed by immunohistochemistry. The effects of leptin in vitro on HT29 cells were assessed by assessing p42/44 mitogen-activated protein kinase phosphorylation, thymidine incorporation, and cell numbers and in vivo in C57BL/6 mice by colonic bromodeoxyuridine incorporation., Results: The leptin receptor is expressed in human colon cancer cell lines and human colonic tissue. Stimulation with leptin leads to phosphorylation of p42/44 mitogen-activated protein kinase and increases proliferation in vitro and in vivo., Conclusions: Leptin is a growth factor in colonic epithelial cells and one that may provide a biological explanation for the observed associations between obesity, physical activity, and colon cancer.

The origin and neoplastic potential of gastric epithelial polyps remains an area of great interest, and treatment choices are a topic of controversy. This report describes a patient diagnosed with three concurrent hyperplastic gastric polyps that were studied for genetic alterations. The polyps were investigated for alterations in the K-ras oncogene and the p53 tumor suppressor gene and for p21WAF1/Cip1 and MDM2 protein overexpression. In addition, loss of heterozygosity at several loci that are frequently involved in human cancer was analyzed, microsatellite instability, a hallmark of the "mutator" phenotype, was determined, and Epstein-Barr virus infection was investigated. All separate areas from the three independent polyps harbored the same activating point mutation in codon 12 of the K-ras oncogene, indicating a clonal origin. DNA sequence alterations in p53 were not found, although high p53 protein levels could be shown by immunohistochemistry in areas of carcinoma within the largest polyp. No alterations in any of the other molecular markers were observed. The results strongly favor a clonal origin of the three independent gastric polyps and support the notion that these hyperplastic polyps may carry a risk for malignancy.

Background & Aims: The mouse mdr2 gene encodes a P-glycoprotein expressed in the hepatocanalicular membrane. Inactivation of this gene causes lack of biliary phospholipid and cholesterol secretion and non-suppurative cholangitis. The aim of this study was to investigate the role of bile salt hydrophobicity in induction of liver pathology in mdr2 (-/-) mice., Methods: Mice (+/+) wild type or (-/-) knockout for the mdr2 gene were fed with either purified control diet or this diet supplemented with cholate (0.1%) or ursodeoxycholate (0.5%) for 3, 6, or 22 weeks after weaning. Liver histology was semiquantitatively scored., Results: Each mouse fed bile acid became the major constituent of the bile salt pool. The cholate diet during 22 weeks induced only very mild liver pathology in (+/+) mice. By contrast, lever histology had already deteriorated after 3 weeks in the (-/-) mice and caused pronounced inflammatory nonsuppurative cholangitis and fibrosis in the 75% of mice that survived. Dietary ursodeoxycholate had no effect on histology in (+/+) mice but improved liver pathology significantly in (-/-) mice compared with purified control diet; the decrease of ductular proliferation and portal inflammation was most prominent after 22 weeks., Conclusions: The cholangiolitis and its sequelae in the mdr2 knockout mice depend on bile salt hydrophobicity.

Adenomas with potential for malignancy occur frequently in the upper gastrointestinal tract of patients with familial adenomatous polyposis. However, an assessment of relative risk of upper gastrointestinal cancer in patients with adenomatous polyposis has never been performed. Therefore, the incidence rate of upper gastrointestinal cancer in patients with familial adenomatous polyposis in The Johns Hopkins Registry was compared with the rate of the general population through person-year analysis with adjustment for demographics. There was an increased relative risk of duodenal adenocarcinoma (relative risk, 330.82; 95% confidence limits, 132.66 and 681.49; P less than 0.001) and ampullary adenocarcinoma (relative risk, 123.72; 95% confidence limits, 33.65 and 316.72; P less than 0.001). No significant increased risk was found for gastric or nonduodenal small intestinal cancer. These results indicate that periodic surveillance of the upper gastrointestinal tract for duodenal and periampullary cancer is needed in patients with familial adenomatous polyposis. Prophylactic duodenectomy is a consideration when large adenoma(s) with high-grade dysplasia are identified but awaits risk benefit analysis.

Altered total nuclear DNA content is frequent in colorectal carcinomas, but the mechanisms producing aneuploidy are unknown. Therefore, DNA ploidy by flow cytometry was correlated with molecular genetic alterations and tumor characteristics in 50 colorectal carcinomas. The prognostic value of these alterations was also evaluated because aneuploidy has been associated with poor prognosis. Thirty-nine of the carcinomas (78%) were DNA aneuploid. When compared with diploid carcinomas, aneuploid tumors had greater mean fractional allelic loss, defined as the fraction of evaluable nonacrocentric autosomal arms with deletion (0.25 +/- 0.15, range 0-0.667, vs. 0.12 +/- 0.10, range 0-0.345; P = 0.006). DNA index by flow cytometry correlated with fractional allelic loss (r = 0.38, P = 0.006). Aneuploid tumors also had more frequent allelic loss on chromosome 17p (87% vs. 55%; P = 0.017), but less frequent ras gene mutation (44% vs. 82%; P = 0.025). Among the 25 right-sided and 25 left-sided tumors, DNA diploid tumors were more frequent on the right side (P = 0.002), whereas deletion of 17p was found predominantly on the left side. Aneuploidy was associated with moderate and poor differentiation of the carcinomas but not with distant metastasis. By contrast, high fractional allelic loss, deletion of 17p, and deletion of 18q were associated with distant metastasis. In survival analysis of patients with Dukes' B or C carcinoma, DNA aneuploidy was not a significant discriminator, but patients whose tumor had deletion of 17p or deletion of both 17p and 18q had poorer survival (P = 0.045 and 0.022, respectively). The results suggest that DNA aneuploidy is associated with some of the molecular genetic alterations and phenotypic characteristics of colorectal carcinomas but is not a reliable indicator of metastatic potential.

Decreased life expectancy may occur after remote peptic ulcer surgery, but the cause of shortened survival is unclear. A 50-year follow-up study of an Amsterdam cohort of postgastrectomy patients who underwent ulcer surgery between 1931 and 1960 showed a statistically significant decrease in survival after a postoperative interval of 12 years or more compared with the general population. The shortened life expectancy mainly reflected decreased survival in men. In women, no significant difference in survival compared with the general population was observed. The excess mortality in men was predominantly due to a statistically significant increase in cancer-related deaths. Carcinoma of the lung accounted for the majority of excess mortality. No time relationship between lung cancer death and interval since surgery was observed. Thus, smoking, primarily in men who had undergone surgery for gastric ulcers, seems an important factor contributing to excess mortality and shortened life expectancy. Excess mortality due to tobacco use has also been observed in postmarketing surveillance of H2-receptor antagonists. Therefore, smoking cessation may provide the greatest improvement in the long-term prognosis of peptic ulcer patients, regardless of the treatment.

The purposes of this study were to determine the association, in 10 pedigrees, between adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, and occult radiopaque jaw lesions, and to assess whether these radiodensities are predictors for adenomatous polyposis. In seven kindreds with adenomatous polyposis, all patients with polyps had jaw lesions; in one kindred, no jaw lesions were found. In one of two kindreds with hereditary nonpolyposis colorectal cancer, no affected individuals had jaw lesions. In the other, the 1 affected patient with dental radiographs had generalized jaw lesions. Twelve children less than 16 yr old at risk for adenomatous polyposis were observed. Seven children with jaw lesions developed polyps after a mean interval of 4 yr. Five children without jaw lesions were polyp-free during a 5-10-yr follow-up. Thus, occult jaw lesions are consistently found only in some families with adenomatous polyposis coli, providing support for heterogeneity in polyposis syndromes. Jaw lesions are good predictors for polyp development in kindreds with adenomatous polyposis coli and jaw lesions. Their role as markers in hereditary nonpolyposis colorectal cancer needs exploration.

Histomorphometric, electron microscopic, and cell kinetic studies of gastric mucosa were performed in 12 healthy men treated with 100 micrograms of 15(R)-15-methyl prostaglandin E2 (PGE2) orally q.i.d. for 2 mo followed by 2 mo of placebo. Results were compared with 13 control subjects receiving placebo for 4 mo. After PGE2 administration, total antral mucosal thickness and antral and corpus foveolar thicknesses increased 36%, 44%, and 51%, respectively, over baseline values. The total number and height of the foveolar cells also increased. These morphologic changes reversed completely within 2 mo of stopping PGE2 therapy. After PGE2 administration, no evidence of mucosal inflammation or atypia was observed, nor was there any evidence of ultrastructural changes in the overall appearance of the parietal and gastrin cells. The increased thickness of the gastric mucosa could not be explained by alteration of the proliferative activity, as the labeling index and localization of the proliferative compartment remained unchanged after PGE2 therapy. Presumably PGE2 retards senescence and exfoliation of epithelial cells, which explains the foveolar expansion in the presence of unaltered proliferation.