Peter Lance

Interests

Research

I have been able to sustain my own research program in Tucson while administratively occupied in Phoenix. We completed (I was the PI) a phase III colorectal adenoma prevention trial of celecoxib and selenium in 1,800 patients. Results were published in back-to-back articles in the December 2016 issue of the Journal of the National Cancer Institute. I was also PI of an ancillary study to the SELECT prostate cancer prevention trial looking at colorectal neoplasia in ~7,000 SELECT participants. Results of this study were accepted for publication in 2016 in Cancer Prevention Research.The celecoxib and selenium trial was supported by a P01 (Program Project Grant) and latterly an R01, for both of which I was PI. For the competitive renewal of the R01 I handed over the PI'ship to Elizabeth (Beth) Jacobs, remaining myself as a Co-Investigator. This grant was recently reviewed and received an overall impact 7th percentile score. We have been assured that it is virtually certain this grant will be funded, pending NCI Council decision in June 2017.I am Co-Investigator with Nathan Ellis as PI in a new R01 currently under review to investigate the molecular pathology and gut microbiome (biofilm and luminal) in new cases of early-onset colorectal cancer (patients aged <50 year) from across Arizona.I am PI for a new R01 grant to be submitted in June 2017. This grant is a phase II genotype-specific chemoprevention trial. Participants will be individuals with high-risk colorectal adenomas. The interventions are aspirin, difluoromethylornithine, and sulindac. For each agent there are genotypes thought to enhance efficacy. The formal process for seeking permission from NCI to submit a budget in excess of $500,000 per year direct costs is under way.

Teaching

While shouldering the major administrative load outlined above, I was able to maintain contact with various graduate and postdoctoral basic and translational students at the UACC. Mentees include Monica Yellowhair, PhD, a postdoctoral student in the Native American Cancer Partnership NCI U54 grant program, and Natalia Ignatenko, PhD, Assistant Professor. Dr. Ignatenko is a member of the UACC Cancer Biology Program and has obtained NCI funding as an early investigator.

Courses

Scholarly Contributions

Journals/Publications

• Augustus, G. J., Roe, D. J., Jacobs, E. T., Lance, P., & Ellis, N. A. (2018). Is increased colorectal screening effective in preventing distant disease?. PloS one, 13(7), e0200462.
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  Screening in the average risk population for colorectal cancer (CRC) is expected to reduce the incidence of distant (i.e., metastatic) CRCs at least as much as less advanced CRCs. Indeed, since 2000, during which time colonoscopy became widely used as a screening tool, the overall incidence of CRC has been reduced by 29%.
• Kohler, L. N., Florea, A., Kelley, C. P., Chow, S., Hsu, P., Batai, K., Saboda, K., Lance, P., & Jacobs, E. T. (2018). Higher Plasma Selenium Concentrations Are Associated with Increased Odds of Prevalent Type 2 Diabetes. The Journal of nutrition, 148(8), 1333-1340.
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  Selenium, an essential trace element, has been investigated as a potential cancer prevention agent. However, several studies have indicated that selenium supplementation may be associated with an increased risk of type 2 diabetes (T2D), although an equivocal relation of this nature requires confirmation.
• Kohler, L. N., Foote, J., Kelley, C. P., Florea, A., Shelly, C., Chow, H. S., Hsu, P., Batai, K., Ellis, N., Saboda, K., Lance, P., & Jacobs, E. T. (2018). Selenium and Type 2 Diabetes: Systematic Review. Nutrients, 10(12).
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  Several studies have investigated the potential role of selenium (Se) in the development of type 2 diabetes (T2D) with disparate findings. We conducted a systematic review and meta-analysis to synthesize the evidence of any association between Se and T2D. PubMed, Embase, and Scopus were searched following the Preferred Reporting Items for Systematic Reviews and Meta-analysis Approach (PRISMA). Sixteen studies from 15 papers met inclusion criteria defined for this review. Of the 13 observational studies included, 8 demonstrated a statistically significant positive association between concentrations of Se and odds for T2D, with odds ratios (95% confidence intervals) ranging from 1.52 (1.01⁻2.28) to 7.64 (3.34⁻17.46), and a summary odds ratio (OR) (95% confidence interval (CI)) of 2.03 (1.51⁻2.72). In contrast, among randomized clinical trials (RCTs) of Se, a higher risk of T2D was not observed for those who received Se compared to a placebo (OR = 1.18, 95% CI 0.95⁻1.47). Taken together, the results for the relationship between Se and T2D differ between observational studies and randomized clinical trials (RCTs). It remains unclear whether these differences are the result of uncontrolled confounding in the observational studies, or whether there is a modest effect of Se on the risk for T2D that may vary by duration of exposure. Further investigations on the effects of Se on glucose metabolism are needed.
• Kohler, L. N., Harris, R. B., Oren, E., Roe, D. J., Lance, P., & Jacobs, E. T. (2018). Adherence to Nutrition and Physical Activity Cancer Prevention Guidelines and Development of Colorectal Adenoma. Nutrients, 10(8).
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  Adherence to the American Cancer Society's (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines is associated with reductions in overall cancer incidence and mortality, including site-specific cancers such as colorectal cancer. We examined the relationship between baseline adherence to the ACS guidelines and (1) baseline adenoma characteristics and (2) odds of recurrent colorectal adenomas over 3 years of follow-up. Cross-sectional and prospective analyses with a pooled sample of participants from the Wheat Bran Fiber ( = 503) and Ursodeoxycholic Acid ( = 854) trials were performed. A cumulative adherence score was constructed using baseline self-reported data regarding body size, diet, physical activity and alcohol consumption. Multivariable logistic regression demonstrated significantly reduced odds of having three or more adenomas at baseline for moderately adherent (odds ratio [OR] = 0.67, 95% confidence intervals [CI]: 0.46⁻0.99) and highly adherent (OR = 0.50, 95% CI: 0.31⁻0.81) participants compared to low adherers (-trend = 0.005). Conversely, guideline adherence was not associated with development of recurrent colorectal adenoma (moderate adherence OR = 1.16, 95% CI: 0.85⁻1.59, high adherence OR = 1.23, 95% CI: 0.85⁻1.79).
• Martinez, J. A., Yang, J., Wertheim, B. C., Roe, D. J., Schriewer, A., Lance, P., Alberts, D. S., Hammock, B. D., & Thompson, P. A. (2018). Celecoxib use and circulating oxylipins in a colon polyp prevention trial. PloS one, 13(4), e0196398.
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  Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P
• Gruber, M., & Lance, P. (2017). Colorectal cancer detection and screening. Lippincott's primary care practice, 2(4), 369-76; quiz 377-8.
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  Colon cancer is a leading cause of death in the United States and is estimated to cause 56,500 deaths during 1998. Most cancers evolve from adenomatous polyps. Screening asymptomatic average-risk individuals is recommended to reduce colorectal cancer mortality by detection and removal of adenomatous polyps.
• Gruber, M., Marshall, J. R., Zielezny, M., & Lance, P. (2017). A case-control study to examine the influence of maternal perinatal behaviors on the incidence of Crohn's disease. Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates, 19(2), 53-9.
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  This case-control study, which examines maternal perinatal characteristics and behaviors during pregnancy, was an initial step to determine whether an association exists between breast feeding, oral contraceptive use, smoking habits during pregnancy, and the incidence of Crohn's disease. The population studied was mothers whose children were diagnosed with Crohn's disease before the age of 22. Population controls were selected by each case mother, who solicited two friends or neighbors with a child of similar age. Case mothers differed significantly on the variables of allergies (p = .05) and family history of inflammatory bowel disease (p = .001). No significant differences were found regarding feeding, oral contraceptives, or smoking. Using a forward step-wise logistic regression method, only family history remained in the equation.
• Hale, V. L., Chen, J., Johnson, S., Harrington, S. C., Yab, T. C., Smyrk, T. C., Nelson, H., Boardman, L. A., Druliner, B. R., Levin, T. R., Rex, D. K., Ahnen, D. J., Lance, P., Ahlquist, D. A., & Chia, N. (2017). Shifts in the Fecal Microbiota Associated with Adenomatous Polyps. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 26(1), 85-94.
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  Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas.
• Lance, P. (2017). Colorectal cancer--to screen or not to screen?. HMO practice, 3(4), 137-41.
• Lance, P. (2017). Recent developments in colorectal cancer. Journal of the Royal College of Physicians of London, 31(5), 483-7.
• Lance, P., Alberts, D. S., Thompson, P. A., Fales, L., Wang, F., San Jose, J., Jacobs, E. T., Goodman, P. J., Darke, A. K., Yee, M., Minasian, L., Thompson, I. M., & Roe, D. J. (2017). Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention. Cancer prevention research (Philadelphia, Pa.), 10(1), 45-54.
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  Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as α-tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative Risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90-1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared with placebo (RR = 1.03; 95% CI, 0.96-1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention. Cancer Prev Res; 10(1); 45-54. ©2016 AACR.
• Lev, R., Lebenthal, E., Rossi, T., & Lance, P. (2017). Histochemical and morphological analysis of colonic epithelium from children with Gardner's syndrome and adults bearing adenomatous polyps. Journal of pediatric gastroenterology and nutrition, 6(3), 414-25.
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  Normal and adenomatous colonic tissues from children with Gardner's syndrome were compared to analogous tissues from adults bearing adenomatous polyps using mucin histochemical and lectin-binding techniques. Adenomatous tissue from children exhibited general morphological similarity to its adult homologue, but showed less dysplasia. Its goblet cells stained weaker for mucins and the lectins Dolichos biflorus agglutinin (DBA) and peanut agglutinin (PNA). This suggested underglycosylation of side chains of mucins in these childhood adenomas. The weak DBA and relatively intense sulfomucin staining in these adenomas suggested that they arose from deep crypt cells. Adult adenomas shared certain histochemical properties with carcinomas, namely, increased affinity for periodic acid-Schiff (PAS) and focally for PNA. There is evidence based on the effects of saponification and sialidase treatments that the weak initial PAS reaction in normal and adenomatous colonic goblet cells from both age groups results from substituents on sialic acid and, in the case of normal colon from children, on other monosaccharides as well. Finally, there was a frequent lack of parellelism between PAS and lectin staining suggesting that different groups within the sugars are responsible for reactivity with those compounds.
• Goodman, P. J., Tangen, C. M., Darke, A. K., Arnold, K. B., Hartline, J., Yee, M., Anderson, K., Caban-Holt, A., Christen, W. G., Cassano, P. A., Lance, P., Klein, E. A., Crowley, J. J., Minasian, L. M., & Meyskens, F. L. (2016). Opportunities and challenges in incorporating ancillary studies into a cancer prevention randomized clinical trial. Trials, 17, 400.
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  The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double-blind, placebo-controlled, prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo). At the time of the trial's development, NIH had invested substantial resources in evaluating the potential benefits of these antioxidants. To capitalize on the knowledge gained from following a large cohort of healthy, aging males on the effects of selenium and/or vitamin E, ancillary studies with other disease endpoints were solicited.
• Jacobs, E. T., Haussler, M. R., Alberts, D. S., Kohler, L. N., Lance, P., Martínez, M. E., Roe, D. J., & Jurutka, P. W. (2016). Association between Circulating Vitamin D Metabolites and Fecal Bile Acid Concentrations. Cancer prevention research (Philadelphia, Pa.), 9(7), 589-97.
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  Although hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in both bile acid metabolism and in the development of colorectal neoplasia. Using a cross-sectional design, we sought to determine whether baseline circulating concentrations of the vitamin D metabolites 25(OH)D and 1,25(OH)2D were associated with baseline fecal bile acid concentrations in a trial of UDCA for the prevention of colorectal adenoma recurrence. We also prospectively evaluated whether vitamin D metabolite concentrations modified the effect of UDCA on adenoma recurrence. After adjustment for age, sex, BMI, physical activity, and calcium intake, adequate concentrations of 25(OH)D (≥30 ng/mL) were statistically significantly associated with reduced odds for high levels of total [OR, 0.61; 95% confidence interval (CI), 0.38-0.97], and primary (OR, 0.61; 95% CI, 0.38-0.96) bile acids, as well as individually with chenodeoxycholic acid (OR, 0.39; 95% CI, 0.24-0.63) and cholic acid (OR, 0.56; 95% CI, 0.36-0.90). No significant associations were observed for 1,25(OH)2D and high versus low fecal bile acid concentrations. In addition, neither 25(OH)D nor 1,25(OH)2D modified the effect of UDCA on colorectal adenoma recurrence. In conclusion, this is the first study to demonstrate an inverse relationship between circulating levels of 25(OH)D and primary fecal bile acid concentrations. These results support prior data demonstrating that vitamin D plays a key role in bile acid metabolism, and suggest a potential mechanism of action for 25(OH)D in colorectal cancer prevention. Cancer Prev Res; 9(7); 589-97. ©2016 AACR.
• Selmin, O. I., Fang, C., Lyon, A. M., Doetschman, T. C., Thompson, P. A., Martinez, J. D., Smith, J. W., Lance, P. M., & Romagnolo, D. F. (2016). Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells. The Journal of nutrition, 146(2), 236-42.
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  The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention.
• Thompson, P. A., Ashbeck, E. L., Roe, D. J., Fales, L., Buckmeier, J., Wang, F., Bhattacharyya, A., Hsu, C. H., Chow, S. H., Ahnen, D. J., Boland, C. R., Heigh, R. I., Fay, D. E., Hamilton, S. R., Jacobs, E. T., Martinez, E. M., Alberts, D. S., & Lance, P. (2016). Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial. Journal of the National Cancer Institute, 108(12).
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  Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis.
• Thompson, P. A., Thompson, P. A., Ashbeck, E. L., Ashbeck, E. L., Roe, D. J., Roe, D. J., Fales, L., Fales, L., Buckmeier, J., Buckmeier, J., Wang, F., Wang, F., Bhattacharyya, A., Bhattacharyya, A., Hsu, C. H., Hsu, C. H., Chow, H. H., Chow, H. H., Ahnen, D. J., , Ahnen, D. J., et al. (2016). Selenium Supplementation for Prevention of Colorectal Adenomas and Risk of Associated Type 2 Diabetes. Journal of the National Cancer Institute, 108(12).
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  Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D).
• Bea, J. W., Jurutka, P. W., Hibler, E. A., Lance, P., Martínez, M. E., Roe, D. J., Sardo Molmenti, C. L., Thompson, P. A., & Jacobs, E. T. (2015). Concentrations of the vitamin D metabolite 1,25(OH)2D and odds of metabolic syndrome and its components. Metabolism: clinical and experimental, 64(3), 447-59.
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  Few epidemiological studies have investigated the association between circulating concentrations of the active vitamin D metabolite 1,25(OH)2D and metabolic syndrome. We sought to determine whether blood levels of 1,25(OH)2D are associated with metabolic syndrome and its individual components, including waist circumference, triglycerides, blood pressure, and glucose, and high-density lipoprotein. We also investigated these associations for the more abundant precursor vitamin D metabolite, 25(OH)D.
• Hibler, E. A., Klimentidis, Y. C., Jurutka, P. W., Kohler, L. N., Lance, P., Roe, D. J., Thompson, P. A., & Jacobs, E. T. (2015). CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence. Nutrition and cancer, 67(7), 1131-41.
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  Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1α,25-hydroxyvitamin D [1,25(OH)2D]. This study examined associations between CYP27B1 and CYP24A1 polymorphisms, circulating 25(OH)D and 1,25(OH)2D concentrations, and colorectal adenoma recurrence in a pooled sample from 2 clinical trials (n = 1,188). Nominal associations were observed between increasing copies of the T allele in CYP24A1 rs927650 and 25(OH)D concentrations (P = 0.02); as well as colorectal adenoma recurrence, with odds ratios (95% confidence intervals) of 1.30 (0.99-1.70) and 1.38 (1.01-1.89) for heterozygotes and minor allele homozygotes, respectively (P = 0.04). In addition, a statistically significant relationship between CYP24A1 rs35051736, a functional polymorphism, and odds for advanced colorectal adenoma recurrence was observed (P < 0.001). Further, nominally statistically significant interactions were observed between rs2296241 and 25(OH)D as well as rs2762939 and 1,25(OH)2D (P(interaction) = 0.10, respectively). Overall, CYP24A1 polymorphisms may influence the development of advanced lesions, and modify the effect of vitamin D metabolites on adenoma recurrence. Further study is necessary to characterize the differences between circulating vitamin D metabolite measurements compared to cellular level activity in relation to cancer risk.
• Hibler, E. A., Molmenti, C. L., Lance, P., Jurutka, P. W., & Jacobs, E. T. (2014). Associations between circulating 1,25(OH)₂D concentration and odds of metachronous colorectal adenoma. Cancer causes & control : CCC, 25(7), 809-17.
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  Cellular-level studies demonstrate that the availability of the secosteroid hormone 1α,25-dihydroxyvitamin D [1,25(OH)2D] to colon cells promotes anti-carcinogenic activities. Although epidemiological data are relatively sparse, suggestive inverse trends have been reported between circulating 1,25(OH)2D concentration and colorectal neoplasia. We therefore sought to evaluate the relationship between circulating 1,25(OH)2D concentrations and odds for metachronous colorectal adenomas among 1,151 participants from a randomized trial of ursodeoxycholic acid for colorectal adenoma prevention. No relationship between 1,25(OH)2D and overall odds for metachronous lesions was observed, with ORs (95% CIs) of 0.80 (0.60-1.07) and 0.81 (0.60-1.10) for participants in the second and third tertiles, respectively, compared with those in the lowest (p-trend = 0.17). However, a statistically significant inverse association was observed between circulating 1,25(OH)2D concentration and odds of proximal metachronous adenoma, with an OR (95% CI) of 0.71 (0.52-0.98) for individuals in the highest tertile of 1,25(OH)2D compared with those in the lowest (p-trend = 0.04). While there was no relationship overall between 1,25(OH)2D and metachronous distal lesions, there was a significantly reduced odds for women, but not men, in the highest 1,25(OH)2D tertile compared with the lowest (OR 0.53; 95% CI 0.27-1.03; p-trend = 0.05; p-interaction = 0.08). The observed differences in associations with proximal and distal adenomas could indicate that delivery and activity of vitamin D metabolites in different anatomic sites in the colorectum varies, particularly by gender. These results identify novel associations between 1,25(OH)2D and metachronous proximal and distal colorectal adenoma, and suggest that future studies are needed to ascertain potential mechanistic differences in 1,25(OH)2D action in the colorectum.
• Molmenti, C. L., Hibler, E. A., Ashbeck, E. L., Thomson, C. A., Garcia, D. O., Roe, D., Harris, R. B., Lance, P., Cisneroz, M., Martinez, M. E., Thompson, P. A., & Jacobs, E. T. (2014). Sedentary behavior is associated with colorectal adenoma recurrence in men. Cancer causes & control : CCC, 25(10), 1387-95.
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  The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between physical activity and colorectal adenoma recurrence.
• Robertson, D. J., Lieberman, D. A., Winawer, S. J., Ahnen, D. J., Baron, J. A., Schatzkin, A., Cross, A. J., Zauber, A. G., Church, T. R., Lance, P., Greenberg, E. R., & Martínez, M. E. (2014). Colorectal cancers soon after colonoscopy: a pooled multicohort analysis. Gut, 63(6), 949-56.
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  Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps.
• Tsikitis, V. L., White, I., Mori, M., Potter, A., Bhattcharyya, A., Hamilton, S. R., Buckmeier, J., Lance, P., & Thompson, P. (2014). Differential expression of microRNA-320a, -145, and -192 along the continuum of normal mucosa to high-grade dysplastic adenomas of the colorectum. American journal of surgery, 207(5), 717-22; discussion 722.
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  MicroRNA (miR)-320a, miR-145, and miR-192 have been shown to play a role in colorectal carcinogenesis and metastasis. We examined if there is a difference in expression during the histologic progression from normal mucosa (NM) to high-grade dysplastic adenomas (HG).
• , C. a., Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N., Baron, J. A., Bombardier, C., Cannon, C., Farkouh, M. E., FitzGerald, G. A., Goss, P., Halls, H., Hawk, E., Hawkey, C., Hennekens, C., Hochberg, M., Holland, L. E., Kearney, P. M., , Laine, L., et al. (2013). Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet (London, England), 382(9894), 769-79.
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  The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials.
• Bartley, A. N., Parikh, N., Hsu, C. H., Roe, D. J., Buckmeier, J. A., Corley, L., Phipps, R. A., Gallick, G., Lance, P., Thompson, P. A., & Hamilton, S. R. (2013). Colorectal adenoma stem-like cell populations: associations with adenoma characteristics and metachronous colorectal neoplasia. Cancer prevention research (Philadelphia, Pa.), 6(11), 1162-70.
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  Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma ("recurrence"), has not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1-labeling indices (ALI) were similar across patient characteristics and in advanced and nonadvanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (P = 0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (P = 0.03). A best-fit algorithm-based cutoff point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem cell target for chemoprevention.
• Jacobs, E. T., Hibler, E. A., Lance, P., Sardo, C. L., & Jurutka, P. W. (2013). Association between circulating concentrations of 25(OH)D and colorectal adenoma: a pooled analysis. International journal of cancer, 133(12), 2980-8.
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  The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross-sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of
• Zhu, M., Zhu, Y., & Lance, P. (2013). TNFα-activated stromal COX-2 signalling promotes proliferative and invasive potential of colon cancer epithelial cells. Cell proliferation, 46(4), 374-81.
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  Up to now it has been unclear whether stromal/epithelial interaction affects progression of colon cancer. This study was designed to examine effects of tumour necrosis factor alpha (TNFα)-activated stromal cyclooxygenase-2 (COX-2) signalling on proliferation and invasiveness of colon cancer epithelial cells.
• Thompson, P., Roe, D. J., Fales, L., Buckmeier, J., Wang, F., Hamilton, S. R., Bhattacharyya, A., Green, S., Hsu, C. H., Chow, H. H., Ahnen, D. J., Boland, C. R., Heigh, R. I., Fay, D. E., Martinez, M. E., Jacobs, E., Ashbeck, E. L., Alberts, D. S., & Lance, P. (2012). Design and baseline characteristics of participants in a phase III randomized trial of celecoxib and selenium for colorectal adenoma prevention. Cancer prevention research (Philadelphia, Pa.), 5(12), 1381-93.
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  COX inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women, ages 40 to 80 years, were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared with placebo, as determined by surveillance colonoscopy conducted three to five years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n = 1,621) was completed in November 2008. A further 200 patients with one or more advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n = 1,824) was completed in January 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; body mass index (BMI) 29.1 ± 5.1; 47% taking low-dose aspirin while on trial; 20% with three or more adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported.
• Wertheim, B. C., Smith, J. W., Fang, C., Alberts, D. S., Lance, P., & Thompson, P. A. (2012). Risk modification of colorectal adenoma by CYP7A1 polymorphisms and the role of bile acid metabolism in carcinogenesis. Cancer prevention research (Philadelphia, Pa.), 5(2), 197-204.
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  Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids, is a postulated gene modifier of colorectal cancer risk and target for the therapeutic bile acid, ursodeoxycholic acid (UDCA). We investigated associations between CYP7A1 polymorphisms and fecal bile acids, colorectal adenoma (CRA), and UDCA efficacy for CRA prevention. Seven tagging, single-nucleotide polymorphisms (SNP) in CYP7A1 were measured in 703 (355 UDCA, 348 placebo) participants of a phase III chemoprevention trial, of which 495 had known baseline fecal bile acid concentrations. In the placebo arm, participants with two minor G(rs8192871) alleles (tag for a low activity promoter polymorphism at -204) had lower odds of high secondary bile acids (OR = 0.26, 95% CI: 0.10-0.69), and CRA at 3 years' follow-up (OR = 0.41, 95% CI: 0.19-0.89), than AA carriers. Haplotype construction from the six polymorphic SNPs showed participants with the third most common haplotype (C(rs10957057)C(rs8192879)G(rs8192877)T(rs11786580)A(rs8192871)G(rs13251096)) had higher odds of high primary bile acids (OR = 2.34, 95% CI: 1.12-4.89) and CRA (OR = 1.89, 95% CI: 1.00-3.57) than those with the most common CTACAG haplotype. Furthermore, three SNPs (rs8192877, rs8192871, and rs13251096) each modified UDCA efficacy for CRA prevention, and CCGTAG-haplotype carriers experienced 71% lower odds of CRA recurrence with UDCA treatment, an effect not present for other haplotypes (test for UDCA-haplotype interaction, P = 0.020). Our findings support CYP7A1 polymorphisms as determinants of fecal bile acids and risk factors for CRA. Furthermore, UDCA efficacy for CRA prevention may be modified by genetic variation in CYP7A1, limiting treatment benefit to a subgroup of the population.
• Zhu, Y., Zhu, M., & Lance, P. (2012). IL1β-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells. Experimental cell research, 318(19), 2520-30.
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  COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1β in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts with or without stimulation of IL-1β, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1β. Further analysis indicated that the major COX-2 product, prostaglandin E(2), directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1β. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1β in the fibroblasts.
• Zhu, Y., Zhu, M., & Lance, P. (2012). Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells. Biochemical and biophysical research communications, 425(3), 607-12.
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  COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulation of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.
• Zhu, Y., Zhu, M., & Lance, P. (2012). iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Experimental cell research, 318(16), 2116-27.
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  COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts.
• Hsu, C. H., Li, Y., Long, Q., Zhao, Q., & Lance, P. (2011). Estimation of recurrence of colorectal adenomas with dependent censoring using weighted logistic regression. PloS one, 6(10), e25141.
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  In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial.
• Jacobs, E., Martinez, M. E., Buckmeier, J., Lance, P., May, M., & Jurutka, P. (2011). Circulating fibroblast growth factor-23 is associated with increased risk for metachronous colorectal adenoma. Journal of carcinogenesis, 10, 3.
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  Fibroblast growth factor-23 (FGF-23) is a phosphaturic peptide and a key component of an endocrine feedback loop along with the hormonal vitamin D metabolite 1,25(OH)(2)D. Vitamin D has been shown to be inversely related to colorectal neoplasia; therefore, we hypothesized that the effect of FGF-23 on vitamin D metabolite concentrations could have implications for the risk of colorectal neoplasia.
• Lance, P., & Thompson, P. A. (2011). Perspective: Chemoprevention of colorectal neoplasia: Translating scientific promise into clinical practice. Journal of carcinogenesis, 10, 11.
• LeRoy, E. C., Moore, J. H., Hu, C., Martínez, M. E., Lance, P., Duggan, D., & Thompson, P. A. (2011). Genes in the insulin and insulin-like growth factor pathway and odds of metachronous colorectal neoplasia. Human genetics, 129(5), 503-12.
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  Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 (IGF1R) and AA genotype for rs1823023 (PIK3R1). In contrast, carriers of any A at rs7166348 (IGF1R), any G for the PIK3R1 variant, and AA for rs10426094 (INSR) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 (IGF1R) with the AA genotype at rs1823023 (PIK3R1) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2-6.5), compared with carriage of GG at rs7166348 (IGF1R). Conversely, any A at rs7166348 (IGFR1), any G allele at rs1823023 (PIK3R1), and the AA genotype at rs10426094 (INSR) conferred the lowest odds (OR 0.22; 95% CI 0.07-0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes (INSR and IGF1R) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.
• Bartley, A. N., Thompson, P. A., Buckmeier, J. A., Kepler, C. Y., Hsu, C. H., Snyder, M. S., Lance, P., Bhattacharyya, A., & Hamilton, S. R. (2010). Expression of gastric pyloric mucin, MUC6, in colorectal serrated polyps. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 23(2), 169-76.
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  Serrated polyps of the colorectal mucosa represent a heterogeneous and controversial taxonomic category with variation in histopathological, molecular, and immunohistochemical characteristics and with an incomplete understanding of pathogenesis. A previous study reported that the expression of gastric pyloric-type mucin, MUC6, characterized sessile serrated adenomas. We therefore evaluated the expression of MUC6 in serrated polyps identified among 2502 participants in a Phase III chemoprevention trial within the Arizona Cancer Center Colorectal Cancer Prevention Trials Program and characterized the associated histopathological features and location. We carried out immunohistochemistry for MUC6 on 146 serrated lesions and 87 conventional tubular adenomas, and assessed the percentage of cells with expression and the grade of staining intensity. In all 92 hyperplastic polyps, 43 sessile serrated adenomas, and 11 traditional serrated adenomas were included. Polyps ranged in size from 1-150 mm. The association of MUC6 staining with serrated polyp category was evaluated using classification and regression tree (CART) analysis and two-sided Fisher's exact test. A total of 53% of sessile serrated adenomas (n=23), 17% of hyperplastic polyps (n=16), and 18% of traditional serrated adenomas (n=2), but none of 87 tubular adenomas, expressed MUC6. Expression was limited to the lower crypts in all serrated polyps. The extent of positive staining ranged from 2-100% of crypt cells and was independent of the histopathological type. MUC6 expression had relatively high specificity for sessile serrated adenoma (82%) but low sensitivity (54%). In CART analysis, proximal location was found to be the best partitioning factor for MUC6, followed by classification as sessile serrated adenoma. We conclude that MUC6 expression is strongly associated with proximal location of serrated polyps, but only has modest utility as a tissue biomarker for sessile serrated adenoma.
• Brevik, A., Joshi, A. D., Corral, R., Onland-Moret, N. C., Siegmund, K. D., Le Marchand, L., Baron, J. A., Martinez, M. E., Haile, R. W., Ahnen, D. J., Sandler, R. S., Lance, P., & Stern, M. C. (2010). Polymorphisms in base excision repair genes as colorectal cancer risk factors and modifiers of the effect of diets high in red meat. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 19(12), 3167-73.
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  A diet high in red meat is an established colorectal cancer (CRC) risk factor. Carcinogens generated during meat cooking have been implicated as causal agents and can induce oxidative DNA damage, which elicits repair by the base excision repair (BER) pathway.
• Friedman, A. C., & Lance, P. (2010). Re: "CMS's landmark decision on CT colonography": misguided and short-sighted: pay me now or pay me later. Journal of the American College of Radiology : JACR, 7(2), 159-60.
• Friedman, A. C., Downing, D., Chino, J., Krupinski, E., Kilian, C., & Lance, P. (2010). Feasibility of remote CT colonography at two rural Native American medical centers. AJR. American journal of roentgenology, 195(5), 1110-7.
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  Fort Defiance Indian Hospital and Tuba City Regional Health Care Center are two rural hospitals with limited availability of optical colonoscopy (OC) and other methods of colorectal cancer screening. Our goals were to determine whether adequate examinations could be obtained with remote supervision after brief onsite instruction and to share lessons learned in our experience with a remote CT colonography (CTC) screening program.
• Ashbeck, E. L., Jacobs, E. T., Martínez, M. E., Gerner, E. W., Lance, P., & Thompson, P. A. (2009). Components of metabolic syndrome and metachronous colorectal neoplasia. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 18(4), 1134-43.
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  The consistent association between obesity and colorectal cancer is thought to be explained by metabolic disturbances common, but not exclusive, to the obese.
• Benuzillo, J. G., Jacobs, E. T., Hoffman, R. M., Heigh, R. I., Lance, P., & Martínez, M. E. (2009). Rural-urban differences in colorectal cancer screening capacity in Arizona. Journal of community health, 34(6), 523-8.
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  Colorectal cancer can be prevented via screening by the detection and removal of colorectal adenomas. Few data exist on screening capacity by rural/urban areas. Therefore, the aims of this work were to evaluate current colorectal cancer endoscopy screening capacity and to estimate potential volume for rural and urban regions in Arizona. Gastroenterologists and colorectal surgeons practicing in Arizona completed a survey (n = 105) that assessed current colonoscopy and sigmoidoscopy screening and estimated future capacity. Resources needed to increase capacity were identified, and differences between rural and urban regions were examined. Responders were more likely to practice in an urban region (89.5%). Physicians reported performing 8,717 endoscopic procedures weekly (8,312 in urban and 405 in rural regions) and the vast majority were colonoscopies (91% in urban and 97% in rural regions). Urban physicians estimated being able to increase their capacity by 35.7% (95% confidence interval 34.7-35.7) whereas rural physicians estimated an increase of 53.1% (95% confidence interval 48.1-58.0). The most commonly cited resource needed to increase capacity was a greater number of physicians in urban regions (52.1%); while the top response in rural areas was appropriate compensation (54.6%). Lastly, 27.3% of rural physicians noted they did not need additional resources to increase their capacity. In conclusion, Arizona has the ability to expand colorectal cancer screening endoscopic capacity; this potential increase was more pronounced in rural as compared to urban regions.
• Jacobs, E. T., Ahnen, D. J., Ashbeck, E. L., Baron, J. A., Greenberg, E. R., Lance, P., Lieberman, D. A., McKeown-Eyssen, G., Schatzkin, A., Thompson, P. A., & Martínez, M. E. (2009). Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study. American journal of epidemiology, 169(6), 657-66.
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  A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.
• Joshi, A. D., Corral, R., Siegmund, K. D., Haile, R. W., Le Marchand, L., Martínez, M. E., Ahnen, D. J., Sandler, R. S., Lance, P., & Stern, M. C. (2009). Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk. Carcinogenesis, 30(3), 472-9.
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  Diets high in red meat have been consistently associated with colorectal cancer (CRC) risk and may result in exposure to carcinogens that cause DNA damage [i.e polycyclic aromatic hydrocarbons, heterocyclic amines (HCAs) and N-nitroso compounds]. Using a family-based study, we investigated whether polymorphisms in the nucleotide excision repair (NER) (ERCC1 3' untranslated region (UTR) G/T, XPD Asp312Asn and Lys751Gln, XPC intron 11 C/A, XPA 5' UTR C/T, XPF Arg415Gln and XPG Asp1104His) and mismatch repair (MLH1 Ile219Val and MSH2 Gly322Asp) pathways modified the association with red meat and poultry intake. We tested for gene-environment interactions using case-only analyses (n = 577) and compared the results using case-unaffected sibling comparisons (n = 307 sibships). Increased risk of CRC was observed for intake of more than or equal to three servings per week of red meat [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.3-2.5)] or high-temperature cooked red meat (OR = 1.6, 95% CI = 1.1-2.2). Intake of red meat heavily brown on the outside or inside increased CRC risk only among subjects who carried the XPD codon 751 Lys/Lys genotype (case-only interaction P = 0.006 and P = 0.001, respectively, for doneness outside or inside) or the XPD codon 312 Asp/Asp genotype (case-only interaction P = 0.090 and P < 0.001, respectively). These interactions were stronger for rectal cancer cases (heterogeneity test P = 0.002 for XPD Asp312Asn and P = 0.03 for XPD Lys751Gln) and remained statistically significant after accounting for multiple testing. Case-unaffected sibling analyses were generally supportive of the case-only results. These findings highlight the possible contribution of diets high in red meat to the formation of lesions that elicit the NER pathway, such as carcinogen-induced bulky adducts.
• Rial, N. S., Lazennec, G., Prasad, A. R., Krouse, R. S., Lance, P., & Gerner, E. W. (2009). Regulation of deoxycholate induction of CXCL8 by the adenomatous polyposis coli gene in colorectal cancer. International journal of cancer, 124(10), 2270-80.
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  Elevated deoxycholic acid (DCA), mutations in the adenomatous polyposis coli (APC) gene and chronic inflammation are associated with increased risk of colorectal cancer. APC status was manipulated to determine whether DCA mediates inflammatory molecules in normal or initiated colonic mucosa. DCA increased steady state mRNA and protein levels of CXCL8 in cells which do not express wild-type APC. Steady-state CXCL8 mRNA and protein were suppressed when cells with conditional expression of wild-type APC were exposed to DCA. Immunostaining did not detect CXCL8 in normal human colonic mucosa. CXCL8 was expressed in adenomatous polyps and adenocarcinomas. CXCL8 expression correlated with nuclear beta-catenin localization in epithelial cells of adenomas, but was associated with endothelial cells and neutrophils in the adenocarcinomas. DCA-mediated CXCL8 promoter-reporter activity was elevated in a mutant APC background. Wild-type APC suppressed this effect. Mutation of activator protein-1 (AP-1) or nuclear factor kappa B (NF-kappaB) sites suppressed the activation of the CXCL8 promoter-reporter by DCA. Chromatin immunoprecipitation revealed that AP-1 and NF-kappaB binding to the 5'-promoter of CXCL8 was induced by DCA. The beta-catenin transcription factor was bound to the 5'-promoter of CXCL8 in the absence or presence of DCA. Phenotypic assays determined that DCA-mediated invasion was blocked by antibody-directed against CXCL8 or wild-type APC. CXCL8 exposure led to matrix metalloproteinase-2 production and increased invasion on laminin-coated filters. These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors.
• Thompson, P. A., Wertheim, B. C., Roe, D. J., Ashbeck, E. L., Jacobs, E. T., Lance, P., Martínez, M. E., & Alberts, D. S. (2009). Gender modifies the effect of ursodeoxycholic acid in a randomized controlled trial in colorectal adenoma patients. Cancer prevention research (Philadelphia, Pa.), 2(12), 1023-30.
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  Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to show efficacy to prevent the development of colorectal adenomas in a large, phase III, randomized, placebo-controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk.
• Bobe, G., Sansbury, L. B., Albert, P. S., Cross, A. J., Kahle, L., Ashby, J., Slattery, M. L., Caan, B., Paskett, E., Iber, F., Kikendall, J. W., Lance, P., Daston, C., Marshall, J. R., Schatzkin, A., & Lanza, E. (2008). Dietary flavonoids and colorectal adenoma recurrence in the Polyp Prevention Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 17(6), 1344-53.
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  Two recent case-control studies suggested that some flavonoid subgroups may play a role in preventing colorectal cancer. Previous prospective cohort studies generally reported no association; however, only a small subset of flavonoids was evaluated and partial flavonoid databases were used. We used the newly constructed U.S. Department of Agriculture flavonoid database to examine the association between consumption of total flavonoids, 6 flavonoid subgroups, and 29 individual flavonoids with adenomatous polyp recurrence in the Polyp Prevention Trial. The Polyp Prevention Trial was a randomized dietary intervention trial, which examined the effectiveness of a low-fat, high-fiber, high-fruit, and high-vegetable diet on adenoma recurrence. Intakes of flavonoids were estimated from a food frequency questionnaire. Multivariate logistic regression models (adjusted for age, body mass index, sex, regular non-steroidal anti-inflammatory use, and dietary fiber intake) were used to estimate odds ratios and 95% confidence intervals for both any and advanced adenoma recurrence within quartiles of energy-adjusted flavonoid intake (baseline, during the trial, and change during the trial). Total flavonoid intake was not associated with any or advanced adenoma recurrence. However, high intake of flavonols, which are at greater concentrations in beans, onions, apples, and tea, was associated with decreased risk of advanced adenoma recurrence (4th versus 1st quartile during the trial; odds ratio, 0.24; 95% confidence interval, 0.11, 0.53; P(trend) = 0.0006). Similar inverse associations were observed to a smaller extent for isoflavonoids, the flavonol kaempferol, and the isoflavonoids genistein and formononetin. Our data suggest that a flavonol-rich diet may decrease the risk of advanced adenoma recurrence.
• Jacobs, E. T., Martínez, M. E., Alberts, D. S., Ashbeck, E. L., Gapstur, S. M., Lance, P., & Thompson, P. A. (2008). Plasma insulin-like growth factor I is inversely associated with colorectal adenoma recurrence: a novel hypothesis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 17(2), 300-5.
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  The insulin-like growth factor I (IGF-I) axis has been proposed to be a significant factor in the development of certain cancers, including colorectal. However, results from epidemiologic studies suggest modest effects on colorectal cancer risk. Using cross-sectional and prospective study designs within the same cohort of men who had at least one adenoma at baseline, we investigated whether plasma IGF-I, IGF-I binding protein 1, and IGF-I binding protein 3 were associated with colorectal adenoma characteristics at baseline and whether their levels were related to odds for adenoma recurrence. Plasma levels of each marker were measured at baseline in 299 male participants in the Wheat Bran Fiber Trial, who were followed prospectively for recurrence of their adenomatous lesions. In cross-sectional analyses, plasma IGF-I was significantly positively associated with the presence of adenomas with any villous features (P = 0.04). In contrast, IGF-I levels were inversely associated with odds of colorectal adenoma recurrence, with adjusted odds ratios (95% confidence interval) of 0.55 (0.29-1.01) and 0.49 (0.26-0.91) for the second and third tertiles of IGF-I, respectively, compared with the first tertile (P(trend) = 0.02). The inverse association was stronger for advanced adenoma recurrence (P(trend) = 0.02) than for nonadvanced recurrence (P(trend) = 0.10). These results suggest that, once an adenoma is removed, higher IGF-I levels reduce the odds of the formation of new lesions in the colorectum.
• Laiyemo, A. O., Murphy, G., Albert, P. S., Sansbury, L. B., Wang, Z., Cross, A. J., Marcus, P. M., Caan, B., Marshall, J. R., Lance, P., Paskett, E. D., Weissfeld, J., Slattery, M. L., Burt, R., Iber, F., Shike, M., Kikendall, J. W., Lanza, E., & Schatzkin, A. (2008). Postpolypectomy colonoscopy surveillance guidelines: predictive accuracy for advanced adenoma at 4 years. Annals of internal medicine, 148(6), 419-26.
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  Lack of confidence in postpolypectomy surveillance guidelines may be a factor in the observed low adherence rates among providers.
• Lance, P. (2008). Chemoprevention for colorectal cancer: some progress but a long way to go. Gastroenterology, 134(1), 341-3.
• Lance, P. (2008). Colorectal cancer screening: confusion reigns. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 17(9), 2205-7.
• Lance, P., & Hamilton, S. R. (2008). Sporadic aberrant crypt foci are not a surrogate endpoint for colorectal adenoma prevention. Cancer prevention research (Philadelphia, Pa.), 1(1), 4-8.
• Meyskens, F. L., McLaren, C. E., Pelot, D., Fujikawa-Brooks, S., Carpenter, P. M., Hawk, E., Kelloff, G., Lawson, M. J., Kidao, J., McCracken, J., Albers, C. G., Ahnen, D. J., Turgeon, D. K., Goldschmid, S., Lance, P., Hagedorn, C. H., Gillen, D. L., & Gerner, E. W. (2008). Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer prevention research (Philadelphia, Pa.), 1(1), 32-8.
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  Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.
• Solomon, S. D., Wittes, J., Finn, P. V., Fowler, R., Viner, J., Bertagnolli, M. M., Arber, N., Levin, B., Meinert, C. L., Martin, B., Pater, J. L., Goss, P. E., Lance, P., Obara, S., Chew, E. Y., Kim, J., Arndt, G., Hawk, E., & , C. T. (2008). Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation, 117(16), 2104-13.
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  Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events.
• Alberts, D. S., Einspahr, J. G., Krouse, R. S., Prasad, A., Ranger-Moore, J., Hamilton, P., Ismail, A., Lance, P., Goldschmid, S., Hess, L. M., Yozwiak, M., Bartels, H. G., & Bartels, P. H. (2007). Karyometry of the colonic mucosa. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 16(12), 2704-16.
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  The study summarizes results of karyometric measurements in epithelial cells of the colorectal mucosa to document evidence of a field effect of preneoplastic development among patients with colorectal adenocarcinoma or adenoma.
• Friedman, A., & Lance, P. (2007). AGA position statement of computed tomographic colonography. Gastroenterology, 132(4), 1632-3; author reply 1633.
• Gerner, E. W., Meyskens, F. L., Goldschmid, S., Lance, P., & Pelot, D. (2007). Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention. Amino acids, 33(2), 189-95.
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  Polyamine metabolic genes are downstream targets of several genes commonly mutated in colon adenomas and cancers. Inhibitors of ornithine decarboxylase, such as difluoromethylornithine (DFMO), and agents that stimulate polyamine acetylation and export, such as non-steroidal anti-inflammatory drugs (NSAIDS), act at least additively to arrest growth in human cell models and suppress intestinal carcinogenesis in mice. These preclinical studies provided the rationale for colon cancer prevention trials in humans. A Phase IIb clinical study comparing the combination of DFMO and the NSAID sulindac versus placebo was conducted. Endpoints were colorectal tissue polyamine and prostaglandin E2 contents and overall toxicity to participants. Participants in the Phase IIb study served as a vanguard for a randomized, placebo-controlled prospective Phase III trial of the combination of DFMO and sulindac with the primary study endpoint the prevention of colon polyps. Seventy percent of participants will have completed the three years of treatment in December 2006.
• Jacobs, E. T., Martínez, M. E., Alberts, D. S., Jiang, R., Lance, P., Lowe, K. A., & Thompson, P. A. (2007). Association between body size and colorectal adenoma recurrence. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 5(8), 982-90.
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  Obesity has been associated with increased risk for colorectal adenoma, although its role as a risk factor after polypectomy for recurrence is unclear. Therefore, we sought to evaluate the effect of anthropometric measures of obesity on adenoma after polypectomy.
• Lanza, E., Yu, B., Murphy, G., Albert, P. S., Caan, B., Marshall, J. R., Lance, P., Paskett, E. D., Weissfeld, J., Slattery, M., Burt, R., Iber, F., Shike, M., Kikendall, J. W., Brewer, B. K., Schatzkin, A., & , P. P. (2007). The polyp prevention trial continued follow-up study: no effect of a low-fat, high-fiber, high-fruit, and -vegetable diet on adenoma recurrence eight years after randomization. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 16(9), 1745-52.
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  The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745-52).
• Martínez, M. E., Jacobs, E. T., Ashbeck, E. L., Sinha, R., Lance, P., Alberts, D. S., & Thompson, P. A. (2007). Meat intake, preparation methods, mutagens and colorectal adenoma recurrence. Carcinogenesis, 28(9), 2019-27.
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  Red meat intake has been shown to be associated with higher risk of colorectal cancer. Though the exact mechanisms responsible for this association remain unknown, several tumorigenic properties of meat have been proposed. One well-supported biologic mechanism is elevated exposure to the genotoxic formation of heterocyclic amines (HCAs), which occur when meat is cooked at high temperatures for a long period of time. We prospectively assessed the relation between type of meat, meat preparation method, doneness, a metric of HCAs and other mutagens and colorectal adenoma recurrence among 869 participants in a chemoprevention trial of ursodeoxycholic acid. Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and associated 95% confidence intervals (CIs). Most meat variables assessed were positively but weakly associated with recurrence of any adenoma. In contrast, recurrence of advanced or multiple adenomas was more strongly associated with a number of the meat exposure variables evaluated. For recurrence of advanced lesions, significant associations were detected among individuals in the highest when compared with the lowest tertile of intake for pan-fried red meat (OR = 1.85; 95% CI = 1.10-3.13) and well/very well done red meat (OR = 1.71; 95% CI = 1.02-2.86). Significant positive associations were shown for recurrence of multiple adenomas and the following variables: processed meat (OR = 1.83; 95% CI = 1.10-3.04), pan-fried red meat (OR = 1.63; 95% CI = 1.01-2.61), well/very well done red meat (OR = 1.68; 95% CI = 1.03-2.74), 2-amino-3,4,8-trimethylimidazo[4,5,-f]quinoxaline (OR = 1.74; 95% CI = 1.07-2.82) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (OR = 1.68; 95% CI = 1.03-2.75). Our results support a meat mutagen exposure hypothesis as a potential mechanism for recurrence of clinically significant adenomatous polyps.
• Lance, P. (2006). The cancer genome and diagnostic blood tests. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 15(11), 2017-8.
• Lanza, E., Hartman, T. J., Albert, P. S., Shields, R., Slattery, M., Caan, B., Paskett, E., Iber, F., Kikendall, J. W., Lance, P., Daston, C., & Schatzkin, A. (2006). High dry bean intake and reduced risk of advanced colorectal adenoma recurrence among participants in the polyp prevention trial. The Journal of nutrition, 136(7), 1896-903.
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  Adequate fruit and vegetable intake was suggested to protect against colorectal cancer and colorectal adenomas; however, several recent prospective studies reported no association. We examined the association between fruits and vegetables and adenomatous polyp recurrence in the Polyp Prevention Trial (PPT). The PPT was a low-fat, high-fiber, high-fruit, and vegetable dietary intervention trial of adenoma recurrence, in which there were no differences in the rate of adenoma recurrence in participants in the intervention and control arms of the trial. In this analysis of the entire PPT trial-based cohort, multiple logistic regression analysis was used to estimate the odds ratio (OR) of advanced and nonadvanced adenoma recurrence within quartiles of baseline and change (baseline minus the mean over 3 y) in fruit and vegetable intake, after adjustment for age, total energyy intake, use of nonsteroidal anti-inflammatory drugs, BMI, and gender. There were no significant associations between nonadvanced adenoma recurrence and overall change in fruit and vegetable consumption; however, those in the highest quartile of change in dry bean intake (greatest increase) compared with those in the lowest had a significantly reduced OR for advanced adenoma recurrence (OR = 0.35; 95% CI, 0.18-0.69; P for trend = 0.001). The median in the highest quartile of change in dry bean intake was 370% higher than the baseline intake. The PPT trial-based cohort provides evidence that dry beans may be inversely associated with advanced adenoma recurrence.
• Alberts, D. S., Martínez, M. E., Hess, L. M., Einspahr, J. G., Green, S. B., Bhattacharyya, A. K., Guillen, J., Krutzsch, M., Batta, A. K., Salen, G., Fales, L., Koonce, K., Parish, D., Clouser, M., Roe, D., Lance, P., & , P. a. (2005). Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. Journal of the National Cancer Institute, 97(11), 846-53.
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  Ursodeoxycholic acid (UDCA) treatment is associated with a reduced incidence of colonic neoplasia in preclinical models and in patients with conditions associated with an increased risk for colon cancer. We conducted a phase III, double-blind placebo-controlled trial of UDCA to evaluate its ability to prevent colorectal adenoma recurrence.
• Alberts, D. S., Potter, J. D., Martinez, M. E., Hess, L. M., Stopeck, A., & Lance, P. (2005). What happened to the coxibs on the way to the cardiologist?. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 14(3), 555-6.
• Gerner, E. W., Ignatenko, N. A., Lance, P., & Hurley, L. H. (2005). A comprehensive strategy to combat colon cancer targeting the adenomatous polyposis coli tumor suppressor gene. Annals of the New York Academy of Sciences, 1059, 97-105.
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  Somatic cells in the majority of colorectal polyps and cancers contain mutations/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. APC is involved in normal intestinal development and acts to influence a variety of cellular processes. Loss of APC function leads to intestinal neoplasia in both mice and humans. APC influences expression of specific genes, including the c-Myc oncogene, which functions as a transcriptional activator. Loss of APC function leads to alterations in c-Myc-regulated genes including ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis. A single nucleotide polymorphism (SNP) in the ODC promoter affecting c-Myc-dependent expression has been associated with risk of colorectal and other cancers. Pharmaceuticals that target structural features of the c-Myc promoter, and suppress expression of c-Myc and other genes regulated by similar promoter elements, are being developed as potential colorectal cancer chemotherapies. Difluoromethylornithine (DFMO), a selective inhibitor of ODC, is under clinical evaluation as a colorectal cancer chemopreventive agent. APC and APC-dependent genes, such as c-Myc and ODC, may be useful as genetic markers of risk and as targets for chemoprevention and therapy for colorectal cancer.
• Nelson, M. A., Goulet, A. C., Jacobs, E. T., & Lance, P. (2005). Studies into the anticancer effects of selenomethionine against human colon cancer. Annals of the New York Academy of Sciences, 1059, 26-32.
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  Colorectal cancer is the third most frequent fatal malignant neoplasm in the United States and is expected to cause significant morbidity and mortality. The recent recall of cyclooxygenase-2 inhibitors from clinical trials highlights the need to develop other agents for cancer chemoprevention trials. Intervention strategies with selenium compounds represent a viable option to reduce colon cancer. Here we discuss epidemiologic studies and ongoing clinical trials with selenium. In addition, we discuss preclinical mechanistic studies that provide insights into the biochemical and molecular bases for the anticancer effects of selenomethionine.
• Pabby, A., Schoen, R. E., Weissfeld, J. L., Burt, R., Kikendall, J. W., Lance, P., Shike, M., Lanza, E., & Schatzkin, A. (2005). Analysis of colorectal cancer occurrence during surveillance colonoscopy in the dietary Polyp Prevention Trial. Gastrointestinal endoscopy, 61(3), 385-91.
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  Interval colorectal cancer (CRC) occasionally is detected in patients who have recently undergone colonoscopy. Systematic evaluation of CRC detected after colonoscopy could identify ways to improve the quality and the outcome of colonoscopy.
• Paskett, E. D., Reeves, K. W., Pineau, B., Albert, P. S., Caan, B., Hasson, M., Iber, F., Kikendall, J. W., Lance, P., Shike, M., Slattery, M. L., Weissfeld, J., Kahle, L., Schatzkin, A., Lanza, E., & , P. P. (2005). The association between cigarette smoking and colorectal polyp recurrence (United States). Cancer causes & control : CCC, 16(9), 1021-33.
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  Although evidence exists linking smoking to precancerous colorectal adenomatous polyps, few studies have examined the association between cigarette smoking and recurrence of colorectal polyps. This association was investigated prospectively with data from the Polyp Prevention Trial.
• Ranger-Moore, J., Frank, D., Lance, P., Alberts, D., Yozwiak, M., Bartels, H. G., Einspahr, J., & Bartels, P. H. (2005). Karyometry in rectal mucosa of patients with previous colorectal adenomas. Analytical and quantitative cytology and histology, 27(3), 134-42.
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  To determine whether karyometric measurements taken in biopsies from histologically normal-appearing rectal mucosa could serve as a biomarker for the risk of recurrence of polyps.
• Mathew, A., Sinha, R., Burt, R., Caan, B., Paskett, E., Iber, F., Kikendall, W., Lance, P., Shike, M., Weissfeld, J., Schatzkin, A., Lanza, E., & , P. P. (2004). Meat intake and the recurrence of colorectal adenomas. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 13(3), 159-64.
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  A large multicenter randomized controlled trial was re-assessed to check whether meat intake and a reduction in its consumption are associated with recurrence of adenomatous polyps of the large bowel, which are precursors of most colorectal malignancies. All subjects (n = 1905; 958 interventions and 947 controls) had one or more histologically confirmed colorectal adenomas removed during a colonoscopy within 6 months before randomization. The subjects were followed-up for approximately 4 years after randomization and a colonoscopy for detecting adenomas was conducted at the 1st and 4th year after randomization. Dietary variables were assessed at baseline (T0) and in conjunction with annual visits at the end of the 1st (T1), 2nd (T2), 3rd (T3) and 4th (T4) years. Odds ratios using logistic regression models for meat variables were estimated based on the average intake at T0, T1, T2, T3 and T4 (prior to the T4 colonoscopy) as well as change (T0-T4) in intake. In the intervention group, the total reduction in median intake of red meat from T0 to T4 was observed by the end of 1st year itself (30 and 31% for men and women, respectively). The analysis provide no evidence to suggest that lower intake or reduction in total and in red meat consumption during a period of 4 years reduces the risk of adenoma recurrence (including multiple or advanced adenoma), whereas the data suggest that high intake of fish is associated with lower risk of adenoma recurrence.
• Tangrea, J. A., Albert, P. S., Lanza, E., Woodson, K., Corle, D., Hasson, M., Burt, R., Caan, B., Paskett, E., Iber, F., Kikendall, J. W., Lance, P., Shike, M., Weissfeld, J., Schatzkin, A., & , P. P. (2003). Non-steroidal anti-inflammatory drug use is associated with reduction in recurrence of advanced and non-advanced colorectal adenomas (United States). Cancer causes & control : CCC, 14(5), 403-11.
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  To prospectively examine the association between non-steroidal anti-inflammatory drugs (NSAIDs) use (including dose and dosage schedule) and the recurrence of colorectal adenomas among individuals who were diagnosed with an adenoma at entry into a clinical trial.
• Zhu, Y., Hua, P., & Lance, P. (2003). Cyclooxygenase-2 expression and prostanoid biogenesis reflect clinical phenotype in human colorectal fibroblast strains. Cancer research, 63(2), 522-6.
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  Up-regulated cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2)synthesis contribute causally to the early stages of colorectal neoplasia and carcinogenesis, yet COX-2 expression is barely detectable in normal and premalignant colorectal epithelium. Rather, COX-2 expression in nonmalignant colonic tissue is probably confined to subepithelial cells, such as fibroblasts. We established a panel of 33 primary subepithelial fibroblast strains from human colonoscopic biopsies of normal colon (group I), normal segments of colons that harbored synchronous advanced neoplasms in remote segments (group II), advanced neoplasms (group III), and segments of active ulcerative colitis (group IV). In group I strains, mean basal and peak PGE2 levels after 24 h of interleukin (IL)-1beta stimulation were 5.4 +/- 1.1 and 32.8 +/- 4.9 ng/mg protein, respectively. Mean IL-1beta-stimulated peak levels in groups II, III, and IV strains were, respectively, 6-, 9-, and 7-fold greater than that in group I (P < 0.001 for each comparison), and inductions of COX-2 mRNA and protein were consistent with these findings. IL-1beta-mediated stimulation of PGE2 was fully blocked in the presence of a nonselective COX inhibitor (indomethacin) or a selective COX-2 inhibitor (NS-398). IL-1beta treatment elicited from group I (normal) and group III (cancer-associated) fibroblasts, respectively, approximately 2- and 3-fold inductions of COX-2 transcriptional activity and approximately 1.4- and 1.7-fold inductions of COX-2 promoter activity. This modestly greater COX-2 transcription rate could not alone account for the dramatically higher levels of COX-2 mRNA and protein and PGE2 in cancer-associated compared with normal fibroblasts. However, incubation of fibroblasts with PGE2 after IL-1beta stimulation prolonged COX-2 mRNA half-life from approximately 1 to 9 h. Our results strengthen the evidence that fibroblasts and other mesenchymal cells are the source of COX-2 expression in normal and premalignant colorectal tissue. Group II fibroblasts from normal segments of colons that harbored synchronous remote advanced neoplasms behaved like group III fibroblasts from advanced neoplasms and not group I fibroblasts from normal colons. We hypothesize that the effects of modestly greater COX-2 transcription in groups II-IV fibroblasts yield corresponding modest increases in PGE2 synthesis whose effects are progressively amplified through robust stabilization of COX-2 mRNA.
• Colbert, L. H., Lanza, E., Ballard-Barbash, R., Slattery, M. L., Tangrea, J. A., Caan, B., Paskett, E. D., Iber, F., Kikendall, W., Lance, P., Shike, M., Schoen, R. E., Daston, C., Schatzkin, A., & , P. P. (2002). Adenomatous polyp recurrence and physical activity in the Polyp Prevention Trial (United States). Cancer causes & control : CCC, 13(5), 445-53.
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  To examine prospectively the association between physical activity and adenomatous polyp recurrence.
• Zhu, Y., Hua, P., Rafiq, S., Waffner, E. J., Duffey, M. E., & Lance, P. (2002). Ca2+- and PKC-dependent stimulation of PGE2 synthesis by deoxycholic acid in human colonic fibroblasts. American journal of physiology. Gastrointestinal and liver physiology, 283(3), G503-10.
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  We investigated prostanoid biogenesis by human colonic fibroblasts (CCD-18Co cells and nine primary fibroblast cultures) exposed to a primary (cholic, CA) or a secondary (deoxycholic, DCA) bile acid. Basal PGE2 levels in CCD-18Co cultures and fibroblast strains initiated from normal and adenocarcinomatous colon, respectively, were 1.7 +/- 0.3, 4.0 +/- 2.0, and 15.0 +/- 4.8 ng/mg protein. Peak levels 24 h after exposure to DCA (300 microM) rose, respectively, seven-, six- and sevenfold, but CA elicited no such responses. Increases in PGE2 synthesis were preceded by sequential increases in PGH synthase-2 mRNA and protein expression and were fully prevented by a nonselective (indomethacin) or a selective (celecoxib) nonsteroidal anti-inflammatory drug. DCA, but not CA, caused abrupt, transient increases in fibroblast intracellular Ca2+ concentration ([Ca2+]i) approximately 1 min after exposure. Increased [Ca2+]i was required for DCA-mediated induction of PGE2 synthesis, and protein kinase C was a further essential component of this signaling pathway. Colonic fibroblasts may be a major target for prostanoid biogenesis induced by fecal bile acids and, potentially, other noxious actions of these agents.
• Lanza, E., Schatzkin, A., Daston, C., Corle, D., Freedman, L., Ballard-Barbash, R., Caan, B., Lance, P., Marshall, J., Iber, F., Shike, M., Weissfeld, J., Slattery, M., Paskett, E., Mateski, D., Albert, P., & , P. S. (2001). Implementation of a 4-y, high-fiber, high-fruit-and-vegetable, low-fat dietary intervention: results of dietary changes in the Polyp Prevention Trial. The American journal of clinical nutrition, 74(3), 387-401.
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  The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber (4.30 g/MJ), high-fruit-and-vegetable (0.84 servings/MJ), low-fat (20% of energy from fat) diet on the recurrence of adenomatous polyps in the large bowel.
• Woodson, K., Lanza, E., Tangrea, J. A., Albert, P. S., Slattery, M., Pinsky, J., Caan, B., Paskett, E., Iber, F., Kikendall, J. W., Lance, P., Shike, M., Weissfeld, J., & Schatzkin, A. (2001). Hormone replacement therapy and colorectal adenoma recurrence among women in the Polyp Prevention Trial. Journal of the National Cancer Institute, 93(23), 1799-805.
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  Epidemiologic studies have suggested that estrogen may protect against the development of colorectal cancers and adenomatous polyps. We conducted a prospective study to evaluate the association between hormone replacement therapy (HRT) and adenoma recurrence among perimenopausal and postmenopausal women participating in the Polyp Prevention Trial, a randomized dietary intervention study of individuals with colorectal adenomas.
• Zhu, Y., Srivatana, U., Ullah, A., Gagneja, H., Berenson, C. S., & Lance, P. (2001). Suppression of a sialyltransferase by antisense DNA reduces invasiveness of human colon cancer cells in vitro. Biochimica et biophysica acta, 1536(2-3), 148-60.
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  Transfer of terminal alpha 2,6-linked sialic acids to N-glycans is catalyzed by beta-galactoside alpha 2,6-sialyltransferase (ST6Gal I). Expression of ST6Gal I and its products is reportedly increased in colon cancers. To investigate directly the functional effects of ST6Gal I expression, human colon cancer (HT29) cells were transfected with specific antisense DNA. ST6Gal I mRNA and protein were virtually undetectable in six strains of transfected HT29 cells. ST6Gal activity was reduced to 14% of control (P
• Burkard, P. G., & Lance, P. (2000). Mucosa-associated lymphoid tissue and other gastrointestinal lymphomas. Current opinion in gastroenterology, 16(2), 107-12.
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  The gastrointestinal tract is the most common site for extranodal lymphomas. The most common, and consequently the most studied, gastrointestinal lymphoma is gastric mucosa-associated lymphoid tissue lymphoma, which is a paradigm for all gastrointestinal lymphomas. Recent advances in oncogenesis, genetics, and immunology have all yielded important discoveries that enhance our understanding of this lymphoma. The implications of these new advances are beginning to translate into changes in therapeutic approach.
• Schatzkin, A., Lanza, E., Corle, D., Lance, P., Iber, F., Caan, B., Shike, M., Weissfeld, J., Burt, R., Cooper, M. R., Kikendall, J. W., & Cahill, J. (2000). Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. The New England journal of medicine, 342(16), 1149-55.
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  We tested the hypothesis that dietary intervention can inhibit the development of recurrent colorectal adenomas, which are precursors of most large-bowel cancers.
• Kim, E. C., Zhu, Y., Andersen, V., Sciaky, D., Cao, H. J., Meekins, H., Smith, T. J., & Lance, P. (1998). Cytokine-mediated PGE2 expression in human colonic fibroblasts. The American journal of physiology, 275(4 Pt 1), C988-94.
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  We investigated prostanoid biogenesis in human colonic fibroblasts (CCD-18Co and 5 primary fibroblast cultures) and epithelial cell lines (NCM460, T84, HT-29, and LS 174T) and the effect of PGE2 on fibroblast morphology. Cytokine-stimulated PGE2 production was measured. PGH synthase-1 and -2 (PGHS-1 and -2) protein and mRNA expression were evaluated. Basal PGE2 levels were low in all cell types (0.15-6.47 ng/mg protein). Treatment for 24 h with interleukin-1beta (IL-1beta; 10 ng/ml) or tumor necrosis factor-alpha (50 ng/ml), respectively, elicited maximal 25- and 6-fold inductions of PGE2 synthesis in CCD-18Co cultures and similar results in primary fibroblast cultures; maximal inductions with IL-1beta in colonic epithelial cell lines were from zero to fivefold. Treatment of CCD-18Co fibroblasts with IL-1beta caused maximal 21- and 53-fold increases, respectively, in PGHS-2 protein and mRNA levels without altering PGHS-1 expression. PGE2 (0.1 micromol/l) elicited a dramatic shape change in selected fibroblasts. Colonic fibroblasts are potentially important as cytokine targets and a source of and target for colonic prostanoids in vivo.
• Li, M., Vemulapalli, R., Ullah, A., Izu, L., Duffey, M. E., & Lance, P. (1998). Downregulation of a human colonic sialyltransferase by a secondary bile acid and a phorbol ester. The American journal of physiology, 274(3 Pt 1), G599-606.
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  Fecal constituents such as bile acids and increased sialylation of membrane glycoproteins by alpha-2,6-sialyltransferase (HST6N-1) may contribute to colorectal tumorigenesis. We hypothesized that bile acids and phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] would upregulate HST6N-1 in colonic cells. However, deoxycholate (DOC) (300 mumol/l), a secondary bile acid, and TPA (20 ng/ml) decreased expression of an approximately 100-kDa glycoprotein bearing alpha-2,6-linked sialic acid in a colon cancer cell line (T84) in vitro. HST6N-1 mRNA levels were reduced approximately 80% by treatment (< or = 24 h) with DOC or TPA but not by cholate, a primary bile acid. Treatment (24 h) with DOC or TPA decreased activity of this enzyme to 30% and 13% of control, respectively. These effects of DOC and TPA were transcriptional and were mediated by Ca2+ and protein kinase C, respectively. Thus DOC and TPA both downregulated, and did not upregulate, alpha-2,6-sialyltransferase expression in vitro, but by different transduction pathways. As colorectal tumors grow, their progressive removal from the fecal milieu that normally downregulates this enzyme may favor invasion and metastasis.
• Schoen, R. E., Corle, D., Cranston, L., Weissfeld, J. L., Lance, P., Burt, R., Iber, F., Shike, M., Kikendall, J. W., Hasson, M., Lewin, K. J., Appelman, H. D., Paskett, E., Selby, J. V., Lanza, E., & Schatzkin, A. (1998). Is colonoscopy needed for the nonadvanced adenoma found on sigmoidoscopy? The Polyp Prevention Trial. Gastroenterology, 115(3), 533-41.
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  The need for colonoscopy when small tubular adenomas with low-grade dysplasia are found on sigmoidoscopy is uncertain. The aim of this study was to examine the prevalence and characteristics of proximal adenomas in patients with distal adenomas.
• Kim, E. C., & Lance, P. (1997). Colorectal polyps and their relationship to cancer. Gastroenterology clinics of North America, 26(1), 1-17.
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  Autosomal dominant, familial forms of colorectal adenocarcinoma are recognized, but more than 90% of cases are sporadic. Most familial and sporadic cases arise through malignant transformation of benign adenomas in a process known as the adenoma-to-carcinoma sequence. Adenomas are classified histologically as tubular, tubulovillous, or villous. As a neoplasm, adenomas all manifest mild, moderate, or severe dysplasia. The majority (> 90%) of adenomas are small (< 1 cm in diameter) and do not progress. Risk factors for carcinomatous progression include the presence of multiple adenomas, size greater than or equal to 1 cm, and villous histology or severe dysplasia in adenomas of any size. The adenoma-to-carcinoma sequence advances through the accumulation of lesions involving multiple genes. It appears that similar molecular genetic mechanisms are involved in familial and sporadic forms of colorectal neoplasia.
• Marshall, J. R., Fay, D., & Lance, P. (1996). Potential costs of flexible sigmoidoscopy-based colorectal cancer screening. Gastroenterology, 111(6), 1411-7.
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  Increasing evidence shows that periodic screening by flexible sigmoidoscopy with appropriate referral of patients with adenomas to colonoscopy could substantially decrease colorectal cancer mortality rates. Estimates of the complete cost of such screening are needed. The aim of this study was to estimate the annual costs of periodic screening of Americans 50 years and older by flexible sigmoidoscopy with referral of subjects with adenomas to colonoscopy.
• Smith, T. J., Piscatelli, J. J., Andersen, V., Wang, H. S., & Lance, P. (1996). n-Butyrate induces plasminogen activator inhibitor type 1 messenger RNA in cultured Hep G2 cells. Hepatology (Baltimore, Md.), 23(4), 866-71.
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  n-Butyrate, a short-chain aliphatic carboxylic acid with pleiotropic actions, is present at high concentrations in the portal circulation and thus may play an important role in the regulation of specific gene expression in the mammalian liver. We report here that n-butyrate can increase substantially the level of plasminogen activator inhibitor type 1 (PAI-1) messenger RNA (mRNA) in Hep G2 cells, up to eightfold above control cultures. Maximal effects occurred at a concentration of 3 mmol/L n-butyrate and with a treatment period of 8 to 12 hours. Increases in PAI-1 mRNA were accompanied by modest increases (twofold) in the encoded protein as assessed by specific enzyme-linked immunosorbent assay and by [35S]methionine incorporation into immunoprecipitable PAI-1 in the culture medium. Nuclear run-on studies showed that the rate of transcription of the PAI-1 gene did not appear altered by treatment with 3 mmol/L n-butyrate for 6 hours. The increases in steady-state PAI-1 mRNA caused by exposure to n-butyrate can be blocked by cycloheximide. Enhanced stability of mature PAI-1 transcript could not be demonstrated in Hep G2 cells treated with the carboxylic acid. We have reported previously that n-butyrate can reduce the level of beta-galactoside alpha 2,6-sialyltransferase expression in Hep G2 cells. That effect was attenuated with inhibitors of protein and RNA synthesis and was mediated at the post-transcriptional level. Thus, n-butyrate can influence the expression of multiple genes in this hepatoblastoma cell through its actions on events that appear to be posttranscriptional. These observations may be relevant to the normal physiology of the mammalian liver because of the high concentrations of n-butyrate and related compounds to which the organ is ordinarily exposed.
• Berenson, C. S., Patterson, M. A., Miqdadi, J. A., & Lance, P. (1995). n-Butyrate mediation of ganglioside expression of human and murine cancer cells demonstrates relative cell specificity. Clinical science (London, England : 1979), 88(4), 491-9.
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  1. n-Butyrate, a short chain fatty acid produced by colonic fermentation, induces differentiation in human neoplastic cell lines, and reduces expression in vitro of a sialyltransferase that glycosylates N-linked glycoproteins in hepatoblastoma cells. Gangliosides are amphipathic, sialylated glycosphingolipids that undergo profound changes in many transformed cells and may protect neoplastic cells from host immune surveillance. Colonic mucosal cells are exposed to luminal short-chain fatty acid concentrations of up to 80 mmol/l, and there is some evidence that short-chain fatty acids may alter ganglioside expression in colon cancer cells. 2. Because of the importance of gangliosides in cancer pathogenesis, we investigated the effects of n-butyrate on ganglioside expression of colonic (human and murine) and non-colonic cancer cells. 3. Three separate colon cancer cell lines (LS174T, T84 and MCA-38), when butyrate treated, demonstrated striking amplification of specific individual gangliosides. However, the total lipid-bound sialic acid content of gangliosides of butyrate-treated LS174T cells diminished. In contrast to earlier reports, n-butyrate did not mediate expression of all gangliosides and specifically did not mediate expression of GM3. This effect persisted even after removal of butyrate. 4. In contrast, exposure of extracolonic cells to butyrate, including cervical cancer (HeLa) and laryngeal cancer (HEp-2) cell lines in this study and hepatoblastoma cells (Hep G2) in our previous work, caused no detectable changes in ganglioside expression. 5. In conclusion, our results indicate a relative tissue specificity of butyrate-mediated alterations in ganglioside expression that is not universal but is limited to specific gangliosides.
• Li, M., Andersen, V., & Lance, P. (1995). Expression and regulation of glycosyltransferases for N-glycosyl oligosaccharides in fresh human surgical and murine tissues and cultured cell lines. Clinical science (London, England : 1979), 89(4), 397-404.
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  1. Mammalian membrane and serum proteins are glycosylated by the addition of heterogeneous N-linked oligosaccharides. It has been widely speculated that oligosaccharide diversity is achieved by corresponding heterogeneity of expression of the glycosyltransferases that are responsible for oligosaccharide synthesis. 2. We surveyed mRNA levels of three sequentially acting glycosyltransferases, N-acetylglucosaminyl-transferase I, beta 1,4-galactosyltransferase and alpha 2,6-sialyltransferase, in 11 human tissues and confirmed the expected variations. 3. The size heterogeneity of alpha 2,6-sialytransferase transcripts reported in rat tissues was evident neither in the human tissue survey nor in a panel of murine RNAs. Tissue distributions of alternative terminal sialyltransferases, alpha 2,6-sialyltransferase and alpha 2,3-sialyltransferase, were distinct. 4. Relative glycosyltransferase mRNA levels in four transformed human cell lines cultured in vitro did not fully reflect levels in the corresponding human tissues. 5. Expression of alpha 2,6-sialyltransferase mRNA was approximately 2.6-fold greater in adenocarcinomatous than in normal human colon, and beta 1,4-galactosyltransferase expression was approximately 1.8-fold greater in normal than in adenocarcinomatous colon. 6. n-Butyrate (0.003-0.005 mol/l), a short-chain fatty acid that is produced by colonic bacterial fermentation, caused approximately 80% inhibition of alpha 2,6-sialyltransferase, approximately 2.5-fold induction of beta 1,4-galactosyltransferase and approximately 6-fold induction of N-acetylglucosaminyltransferase mRNAs in T84 (colonic) cells. The effects on alpha 2,6-sialyltransferase and beta 1,4-galactosyltransferase were near maximal by 6h, but induction of N-acetylglucosaminyltransferase was fully apparent only after exposure for 24 h.
• Piscatelli, J. J., Cohen, S. A., Berenson, C. S., & Lance, P. (1995). Determinants of differential liver-colonizing potential of variants of the MCA-38 murine colon cancer cell line. Clinical & experimental metastasis, 13(2), 141-50.
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  We investigated factors that might contribute to the differing liver tumor colonizing potentials of MCA-38 colonic cancer cell line variants injected into the ileocolic veins of C57Bl/6J mice. Non-colonizing (MCA-38 CD) cells were sensitive to lysis by hepatic natural killer (NK) cells in vitro (51Cr-release assay) and cells with high liver-colonizing potential (MCA-38 LD) were resistant. Following abrogation of NK activity by treatment with anti-asialoGM1, liver-colonizing ability to LD cells but not CD cells was enhanced. MCA-38 CD cells were, however, capable of initial liver colonization after ileocolic vein injection. Differing patterns of membrane sialylation may have contributed to the contrasting hepatic tumorigenicities of LD and CD cells; beta-galactoside alpha 2,6-sialyltransferase mRNA levels and activity were approximately four-fold higher in LD than CD cells and qualitative and quantitative differences existed between their ganglioside profiles. In the MCA-38 model outlined, tumor cell susceptibility or resistance to NK lysis was a relatively unimportant determinant of liver-colonizing potential.
• Vemulapalli, R., & Lance, P. (1994). Cancer surveillance in ulcerative colitis: more of the same or progress?. Gastroenterology, 107(4), 1196-9.
• Lance, P. (1993). Fecal occult blood tests: what's new?. Gastroenterology, 104(6), 1852-5.
• Shah, S., Lance, P., Smith, T. J., Berenson, C. S., Cohen, S. A., Horvath, P. J., Lau, J. T., & Baumann, H. (1992). n-butyrate reduces the expression of beta-galactoside alpha 2,6-sialyltransferase in Hep G2 cells. The Journal of biological chemistry, 267(15), 10652-8.
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  n-Butyrate, a short chain fatty acid that is produced by colonic bacterial fermentation, is detectable in portal blood and induces differentiation in various human neoplastic cell lines. Earlier reports indicated approximately 20-fold induction in vitro by n-butyrate of the sialyltransferase that catalyzes terminal glycosylation of GM3 ganglioside in HeLa and colon cancer cells. We previously isolated a 1.3-kilobase cDNA for a human beta-galactoside alpha 2,6-sialyltransferase, for which N-linked glycoproteins are the acceptors. We report here that treatment of Hep G2 cells with 5 mM n-butyrate for 24 h reduced beta-galactoside alpha 2,6-sialyltransferase mRNA levels by approximately 90%. Reductions in mRNA level were followed by approximately 75 and approximately 90% reductions, respectively, in specific beta-galactoside alpha 2,6-sialyltransferase enzyme activity after treatment for 24 and 36 h with 5 mM n-butyrate. However, in contrast with earlier reports of enhanced ganglioside synthesis in response to n-butyrate treatment, incubation of Hep G2 cells with n-butyrate did not alter the ganglioside pattern as assessed by thin layer chromatography of lipids extracted from treated cells. Nuclear run-on reactions indicated that the rate of transcription of beta-galactoside, alpha 2,6-sialyltransferase was not altered by treatment with 5 mM n-butyrate for 24 h, but the effects of this treatment on cytoplasmic levels of beta-galactoside alpha 2,6-sialyltransferase mRNA were largely negated by co-treatment with actinomycin D or cycloheximide. Therefore, our results show that n-butyrate reduces expression of mature beta-galactoside alpha 2,6-sialyltransferase mRNA by post-transcriptional mechanisms.
• Tzung, S. P., Mahl, T. C., Lance, P., Andersen, V., & Cohen, S. A. (1992). Interferon-alpha prevents endotoxin-induced mortality in mice. European journal of immunology, 22(12), 3097-101.
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  Endotoxins, the lipopolysaccharide (LPS) moieties on the bacterial cell wall, cause many of the pathological features of Gram-negative septicemia. Tumor necrosis factor (TNF), primarily a product of monocyte/macrophages, has been shown to mediate many of the pathophysiological effects of endotoxin. Kupffer cells, the largest macrophage population in the body, release TNF when stimulated by LPS in vitro. A recombinant human hybrid interferon-alpha A/D (rIFN-alpha) markedly inhibited this LPS-elicited TNF production by Kupffer cells. The effects of rIFN-alpha were further tested in C57BL/6 mice receiving a lethal dose (400 micrograms/mouse) of LPS. All LPS-treated mice died within 2 days. Pretreatment with rIFN-alpha 1 h before LPS challenge improved the survival at 3 days to 22% (5/23, p < 0.04). In contrast, rIFN-alpha was more effective when administered 20 min after LPS injection, increasing the survival rate to 81% (13/16, p < 0.0001). TNF mRNA expression in the liver and spleen 50 min after LPS challenge, and plasma TNF 1.5 h after LPS were also reduced by either pretreatment or post-treatment with rIFN-alpha. Subsequently, experiments were carried out to test the efficacy of delayed rIFN-alpha treatment. A significant protective effect was still apparent when rIFN-alpha was administered 6, 10 and even 14 h (81%, 62% and 28% survival, respectively) after LPS challenge when serum TNF levels had already returned to near baseline. These experimental results suggest that rIFN-alpha might have a therapeutic potential for the prevention and treatment of the deleterious effects associated with endotoxemia besides mechanisms initially blocking TNF production.
• Fay, D. E., Poplausky, M., Gruber, M., & Lance, P. (1991). Long-term enteral feeding: a retrospective comparison of delivery via percutaneous endoscopic gastrostomy and nasoenteric tubes. The American journal of gastroenterology, 86(11), 1604-9.
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  The use of percutaneous endoscopic gastrostomy (PEG) tubes for enteral feeding is widespread, although their superiority to other feeding devices, such as nasoenteric tubes (NET), has not been substantiated. We retrospectively compared clinical outcomes in patients who received enteral feeding via PEG (n = 80) or NET (n = 29) from 1984 to 1988. Mean follow-up was 192 days in the PEG group and 141 days in the NET group. Changes in nutritional and performance status were similar in both groups. Aspiration pneumonia occurred within 14 days of tube placement in 6% and 24% (p = 0.01) of the PEG and NET patients, respectively. With the exception of tube replacement, cumulative rates of minor and major complications (including aspiration pneumonia) were similar in both groups during follow-up. None of the clinical variables that were assessed correlated with the development of aspiration pneumonia. Mortality was similar in both groups. These results suggest that, for long-term enteral feeding, PEG offers no substantial advantages over NET with respect to patient nutrition, performance, or survival. The reasons for the observed difference in short-term aspiration pneumonia rates are unknown, and must be investigated prospectively.
• Gruber, M., Fay, D., Pudhorodsky, T., & Lance, P. (1991). Palatability of colonic lavage solution is improved by the addition of artificially sweetened flavored drink mixes. Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates, 14(3), 135-7.
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  A frequent complaint of patients asked to drink polyethylene glycol (PEG) colonic lavage solution is the salty flavor. This often results in failure to ingest the entire 4 liters of the solution and compromises bowel cleansing. The purpose of this study was to determine systematically whether the addition of a flavored drink mix sweetened with aspartame to the PEG lavage solution would improve palatability without significantly altering the osmolality of the solution. Eighty-seven (87) staff volunteers participated in a taste test of PEG lavage solutions containing varying amounts of commercially available drink mixes. The solution containing two packages of lemon-flavored KoolAid drink mix sweetened with aspartame was significantly more palatable than the others (p less than 0.005), while osmolality remained within the range specified by the manufacturer of Colyte.
• Lance, P., & Lev, R. (1991). Colonic oligosaccharide structures deduced from lectin-binding studies before and after desialylation. Human pathology, 22(4), 307-12.
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  Dolichos biflorus agglutinin (DBA) binds N-acetylgalactosamine (GalNAc), and peanut agglutinin (PNA) binds Gal beta(1-3)GalNAc residues (Gal = galactose). We used these lectins with neuraminidase to probe colonic oligosaccharides. Tissues included normal epithelium, adenocarcinomas (T) with contiguous transitional (TM) and normal mucosae (RM), and adenomatous polyps. Except for DBA binding in carcinomas, neuraminidase digestion increased DBA and PNA binding in all epithelia. In untreated specimens, reciprocal gradients for binding by DBA (T less than TM and TM less than RM) and PNA (T greater than TM and T greater than RM) were seen. After neuraminidase, all gradients were abolished except for T less than TM and T less than RM with DBA. We conclude that (1) qualitative as well as quantitative differences may exist between the mucins of benign and neoplastic colonic epithelium, (2) the NeuAc-GalNAc dimer is a widely prevalent terminal oligosaccharide in benign epithelium at all stages of differentiation (NeuAc = sialic acid), and (3) in contrast with evidence from recent biochemical studies, the Gal beta(1-3)GalNAc dimer is a common masked oligosaccharide in benign epithelium.
• Tzung, S. P., Gaines, K. C., Lance, P., Ehrke, M. J., & Cohen, S. A. (1990). Suppression of hepatic lymphokine-activated killer cell induction by murine Kupffer cells and hepatocytes. Hepatology (Baltimore, Md.), 12(4 Pt 1), 644-52.
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  Murine lymphokine-activated-killer cell activity was readily induced by culturing spleen cells with 10 U/ml of interleukin-2 for 4 days. In contrast, very little activity was generated under the same culture conditions when nonparenchymal liver cells were used as the responding cells. It was concluded that Kupffer cells produced prostaglandin and interferon alpha/beta, which suppressed lymphokine-activated-killer induction because (a) induction of lymphokine-activated-killer activity from nonparenchymal liver cells was observed in the presence of indomethacin and anti-interferon alpha/beta antibody; (b) when adherent nonparenchymal liver cells, primarily Kupffer cells, were removed, lymphokine-activated-killer activity could be obtained with interleukin-2 alone; (c) coculture of Kupffer cells with nonadherent nonparenchymal liver cells in a two-chambered system inhibited lymphokine-activated killer cell induction in a dose-dependent manner; (d) exogenous prostaglandin E2 and interferon alpha/beta added at the start of culture inhibited interleukin-2-induced cytotoxicity and proliferation, whereas the other major prostaglandin species in the liver, prostaglandin D2, had little effect. These findings are distinctive with Kupffer cells because splenic macrophages did not exert such inhibition in parallel experiments. Moreover, the supernatant collected from the 24-hr culture of nonparenchymal liver cells contained greater than 20-fold more prostaglandin E2 and interferon alpha/beta than that from culture of spleen cells. In subsequent in vivo experiments, when interleukin-2 was given intraperitoneally to mice, the combination of indomethacin and anti-interferon alpha/beta antibody significantly enhanced lymphokine-activated-killer activity recovered from the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
• Lance, P., Lau, K. M., & Lau, J. T. (1989). Isolation and characterization of a partial cDNA for a human sialyltransferase. Biochemical and biophysical research communications, 164(1), 225-32.
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  A probe generated from the coding sequence of the rat hepatic beta-galactoside alpha 2,6-sialyltransferase was used to screen a human cDNA library constructed of human submaxillary gland mRNA lambda gt-11. We report the isolation and characterization of a human cDNA, HSM-ST1, that is putatively the human homolog of the beta-galactoside alpha 2,6-sialyltransferase. The largest human clone contains a 1.3 kb cDNA insert and is predicted to encompass 75% of the coding sequence as well as a small portion of the 3' untranslated region. Comparative analysis of this insert with the rat hepatic alpha 2,6-sialyltransferase sequence indicates 79% nucleotide similarity between the two sequences in the predicted coding region. On the amino acid level, the degree of conservation is 86%. Substantial sequence similarity is observed in the 3'-untranslated region between the rat and human sequences as well. S1 nuclease analysis was performed to demonstrate the expression of HSM-ST1 transcripts in the human hepatoma cell line, HepG2, and in the human colonic adenocarcinoma cell lines, LS174T.
• Lance, P., Wastell, C., & Schiller, K. F. (1986). A controlled trial of cimetidine for the treatment of nonulcer dyspepsia. Journal of clinical gastroenterology, 8(4), 414-8.
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  Sixty patients with nonulcer dyspepsia took cimetidine 1 g daily or a placebo for 5 weeks in a double-blind trial. Thirty-four men and 26 women with normal double-contrast barium meals were included. Five percent had the endoscopic appearances of duodenitis. Symptoms improved during treatment in 62% of those taking cimetidine and in 54% of the placebo group (NS, p = 0.5). We suggest that significant duodenitis is uncommon in the absence of active or quiescent duodenal ulcer disease. From this study there is no evidence that cimetidine benefits those patients with normal double-contrast barium meals and no duodenitis endoscopically who nonetheless have symptoms similar to those of peptic ulcer disease.
• Lance, P., Gibson-Glubb, S., Gazzard, J. A., & Gazzard, B. G. (1985). Chronic dyspepsia pain in general practice--its causes and diagnosis. Postgraduate medical journal, 61(715), 411-3.
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  One hundred consecutive patients who had consulted their general practitioner because of upper abdominal pain related to eating, were investigated after initial interviews by the general practitioner, a medical registrar and the same consultant physician. Thirty seven had active upper gastrointestinal or biliary tract diseases, including 29 with peptic ulcers. The general practitioner and consultant correctly distinguished between organic and non-organic dyspepsia (NOD) in 51 and 65 cases respectively. Although the sensitivity of the general practitioner diagnosis of organic disease was high (95%), the specificity (23%) and predictive value (42%) were low. There were fewer organic diagnoses amongst the patients under the age of 30 (P less than 0.05) and those with symptoms for less than 3 months (P less than 0.01). No patient under 30 with symptoms for less than 3 months had organic dyspepsia. We suggest that if dyspeptic patients over the age of 30 and those under 30 with symptoms for longer than 3 months are investigated, about one-third will be found to have organic diseases.
• Lev, R., Lance, P., & Camara, P. (1985). Histochemical and morphologic studies of mucosa bordering rectosigmoid carcinomas: comparisons with normal, diseased, and malignant colonic epithelium. Human pathology, 16(2), 151-61.
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  Surgically obtained rectosigmoid mucosa ("transitional" mucosa, TM) adjacent to eight primary carcinomas was compared with diseased mucosa (DM) from eight patients without primary carcinoma and mucosa from two normal control subjects by mucin histochemical and morphologic techniques. No differences were found between TM and DM that might have suggested premalignant changes unique to TM. An excess of sialidase-susceptible sialomucins was found in both TM and DM, as was loss of the sulfomucin-sialomucin gradient usually found between normal crypts and surface cells. Increased sialic acid in TM and DM may represent a nonspecific response to injury or inflammation and has been found in other epithelia under similar circumstances. Sialidase also induced substantial reduction of periodic acid-Schiff (PAS) staining, probably due to loss of sialic acid since no other sugars were released during sialidase digestion, as determined by thin-layer chromatography analysis of post-digestion supernatants. Carcinomas generally showed more staining with PAS than with basic dyes; PAS staining was minimally reduced by diastase and sialidase but markedly reduced by phenylhydrazine interposition, suggesting that some type of neutral glycoprotein was responsible. Finally, it was found that overreliance on the high-iron diamine-Alcian blue technique as a single procedure is unwise; this procedure should be accompanied by the use of singly applied dyes, especially high-iron diamine, together with other enzymatic and staining procedures.
• Boland, C. R., Lance, P., Levin, B., Riddell, R. H., & Kim, Y. S. (1984). Abnormal goblet cell glycoconjugates in rectal biopsies associated with an increased risk of neoplasia in patients with ulcerative colitis: early results of a prospective study. Gut, 25(12), 1364-71.
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  A group of 18 patients with stable ulcerative colitis involving the entire colon for at least eight years was subjected to a biopsy of normal appearing rectal mucosa and followed prospectively over four years for the development of either dysplasia or cancer. Goblet cell glycoconjugate structure was examined in the rectal biopsies using fluorescein conjugated lectins. At the beginning of the study, 13 of the 18 patients had abnormalities of goblet cell mucin or cytoplasmic glycoconjugates in the rectal biopsies. Dysplasia subsequently developed in six and carcinoma in one of these patients. Among the five patients with normal lectin binding studies in the initial rectal biopsies, colonic dysplasia has subsequently developed in one. The abnormalities seen in the rectal goblet cells resembled in part those previously seen in immature and neoplastic colonic cells. The dysplastic tissues all contained the form of mucin which has been found in other neoplastic colonic tissues. This preliminary report after four years of prospective study suggests that abnormalities of glycoconjugate structure may be associated with, and may precede, neoplastic events in the setting of chronic ulcerative colitis.
• Lance, P., & Gazzard, B. G. (1983). Controlled trial of cimetidine for symptomatic treatment of duodenal ulcers. British medical journal (Clinical research ed.), 286(6369), 937-8.
• Lance, P., & Gazzard, B. G. (1983). Ulcerative enteritis and liver disease in a patient with coeliac disease. Gut, 24(5), 433-7.
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  We report a fatal case of adult coeliac disease complicated by ulcerative enteritis and chronic liver disease. Macroscopically the liver was characterised by multiple, small depressions over the whole surface. The portal tracts were infiltrated by mononuclear cells and also scattered, large atypical cells of uncertain origin. Neither feature has been reported previously.
• Lance, P., Bevan, P. G., Hoult, J. G., & Paton, A. (1977). Liver biopsy in "difficult" jaundice. British medical journal, 2(6081), 236.
• Lewis, K. O., Nicholson, G., Lance, P., & Paton, A. (1977). Aminopyrine breath test in alcoholic liver disease and in patients on enzyme-inducing drugs. Journal of clinical pathology, 30(11), 1040-3.
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  The 14C-aminopyrine breath test was used to measure liver function in 14 normal subjects, 16 patients with alcoholic cirrhosis, 14 alcoholics without cirrhosis, and 29 patients taking a variety of drugs. The normal value for the breath test was 8.6 +/- 1.5%, whereas it was significantly lower (5.1 +/- 3.8%) in patients with alcoholic cirrhosis. Higher than normal values were found in some alcoholic patients without cirrhosis and in patients receiving enzyme-inducing drugs, such as phenobarbitone. There was a significant correlation between serum gamma-glutamyltransferase and breath test in these groups. Some patients with alcoholic cirrhosis may also be capable of enzyme induction.

Poster Presentations

• Jacobs, E. T., Alberts, D., Neugut, A., Lance, M. P., Ho, G., Hibler, E., Thomson, C. A., Yang, J., Molmenti, C. L., Molmenti, C. L., Yang, J., Thomson, C. A., Hibler, E., Ho, G., Lance, M. P., Neugut, A., Alberts, D., & Jacobs, E. T. (2017, Fall). Abstract: Risk factors of colorectal adenoma recurrence among individuals under 50 years of age compared to those 50 years of age and older.. American Society of Clinical Oncology. Washington DC.