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1.  Randomized Controlled Trial of Acitretin Versus Placebo in Patients at High Risk for Basal Cell or Squamous Cell Carcinoma of the Skin (North Central Cancer Treatment Group Study 969251) 
Cancer  2011;118(8):2128-2137.
Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post-transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors’ knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high risk for NMSC.
The study was designed as a prospective, randomized, double-blind, placebo-controlled clinical trial. To test the possible skin cancer-preventing effect of a 2-year treatment with acitretin, 70 nontransplantation patients aged ≥18 years who had a history of ≥2 NMSCs within 5 years of trial onset were randomized to receive either placebo or acitretin 25 mg orally 5 days per week. The primary outcome measure was the rate of new NMSC development.
Seventy patients were randomized to receive either acitretin alone (N = 35) or placebo (N = 35). During the 2-year treatment period, the patients who received acitretin did not have a statistically significant reduction in the rate of new primary NMSCs (odds ratio, 0.41; 95% confidence interval, 0.15–1.13; 54% vs 74%; P = .13). However, using the incidence of new NMSC, the time to new NMSC, and total NMSC counts, an umbrella test indicated a significant trend that favored the use of acitretin (chi-square statistic, 3.94; P = .047). The patients who received acitretin reported significantly more mucositis and skin toxicities compared with the patients who received placebo.
Although there was not a statistically significant benefit observed with the use of acitretin, this may have been the result of low statistical power.
PMCID: PMC3365547  PMID: 21882176
acitretin; chemoprevention; basal cell carcinoma; squamous cell carcinoma; clinical trials
2.  Accuracy of urea breath test in Helicobacter pylori infection: Meta-analysis 
AIM: To quantitatively summarize and appraise the available evidence of urea breath test (UBT) use to diagnose Helicobacter pylori (H. pylori) infection in patients with dyspepsia and provide pooled diagnostic accuracy measures.
METHODS: We searched MEDLINE, EMBASE, Cochrane library and other databases for studies addressing the value of UBT in the diagnosis of H. pylori infection. We included cross-sectional studies that evaluated the diagnostic accuracy of UBT in adult patients with dyspeptic symptoms. Risk of bias was assessed using QUADAS (Quality Assessment of Diagnostic Accuracy Studies)-2 tool. Diagnostic accuracy measures were pooled using the random-effects model. Subgroup analysis was conducted by UBT type (13C vs 14C) and by measurement technique (Infrared spectrometry vs Isotope Ratio Mass Spectrometry).
RESULTS: Out of 1380 studies identified, only 23 met the eligibility criteria. Fourteen studies (61%) evaluated 13C UBT and 9 studies (39%) evaluated 14C UBT. There was significant variation in the type of reference standard tests used across studies.Pooled sensitivity was 0.96 (95%CI: 0.95-0.97) andpooled specificity was 0.93 (95%CI: 0.91-0.94). Likelihood ratio for a positive test was 12 and for a negative test was 0.05 with an area under thecurve of 0.985. Meta-analyses were associated with a significant statistical heterogeneity that remained unexplained after subgroup analysis. The included studies had a moderate risk of bias.
CONCLUSION: UBT has high diagnostic accuracy for detecting H. pylori infection in patients with dyspepsia. The reliability of diagnostic meta-analytic estimates however is limited by significant heterogeneity.
PMCID: PMC4306177  PMID: 25632206
Helicobacter pylori; Dyspepsia; Breath tests; Urea/analysis; Diagnosis; Sensitivity; Specificity; Gastritis; Positive predictive value; Negative predictive value
3.  Associations Between Colorectal Cancer Molecular Markers and Pathways With Clinicopathologic Features in Older Women 
Gastroenterology  2013;145(2):348-356.e2.
Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women’s Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times.
We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest.
Patients’ mean age (P = .03) and tumors’ anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07–2.89, compared with the traditional pathway).
We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.
PMCID: PMC3772766  PMID: 23665275
Molecular Epidemiology; Colon Cancer; Prognostic Factor; Integrated Pathways
4.  Patient and Tumor Characteristics and BRAF and KRAS Mutations in Colon Cancer, NCCTG/Alliance N0147 
KRAS and BRAF V600E mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them.
Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided.
KRAS (35%) and BRAF V600E (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF V600E mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF V600E mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR.
Specific patient and tumor characteristics are associated with KRAS and BRAF V600E mutations.
PMCID: PMC4110470  PMID: 24925349
5.  Associations Between Cigarette Smoking Status and Colon Cancer Prognosis Among Participants in North Central Cancer Treatment Group Phase III Trial N0147 
Journal of Clinical Oncology  2013;31(16):2016-2023.
By using data from North Central Cancer Treatment Group Phase III Trial N0147, a randomized adjuvant trial of patients with stage III colon cancer, we assessed the relationship between smoking and cancer outcomes, disease-free survival (DFS), and time to recurrence (TTR), accounting for heterogeneity by patient and tumor characteristics.
Patients and Methods
Before random assignment to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or FOLFOX plus cetuximab, 1,968 participants completed a questionnaire on smoking history and other risk factors. Cox models assessed the association between smoking history and the primary trial outcome of DFS (ie, time to recurrence or death), as well as TTR, adjusting for other clinical and patient factors. The median follow-up was 3.5 years among patients who did not experience events.
Compared with never-smokers, ever smokers experienced significantly shorter DFS (3-year DFS proportion: 70% v 74%; hazard ratio [HR], 1.21; 95% CI, 1.02 to 1.42). This association persisted after multivariate adjustment (HR, 1.23; 95% CI, 1.02 to 1.49). There was significant interaction in this association by BRAF mutation status (P = .03): smoking was associated with shorter DFS in patients with BRAF wild-type (HR, 1.36; 95% CI, 1.11 to 1.66) but not BRAF mutated (HR, 0.80; 95% CI, 0.50 to 1.29) colon cancer. Smoking was more strongly associated with poorer DFS in those with KRAS mutated versus KRAS wild-type colon cancer (HR, 1.50 [95% CI, 1.12 to 2.00] v HR, 1.09 [95% CI, 0.85 to 1.39]), although interaction by KRAS mutation status was not statistically significant (P = .07). Associations were comparable in analyses of TTR.
Overall, smoking was significantly associated with shorter DFS and TTR in patients with colon cancer. These adverse relationships were most evident in patients with BRAF wild-type or KRAS mutated colon cancer.
PMCID: PMC3661936  PMID: 23547084
6.  Young-Onset Colorectal Cancer in Patients With No Known Genetic Predisposition 
Medicine  2008;87(5):259-263.
Early recognition of colorectal cancer (CRC) in young patients without known genetic predisposition is a challenge, and clinicopathologic features at time of presentation are not well described. We conducted the current study to review these features in a large population of patients with young-onset CRC (initial diagnosis at age ≤50 yr without established risk factors).
We reviewed the records of all patients aged 50 years or younger diagnosed with a primary CRC at our institution between 1976 and 2002. Patients with inflammatory bowel disease, polyposis syndromes, or a known genetic predisposition for CRC were excluded. Data regarding clinical and pathologic features at time of initial presentation were abstracted by trained personnel.
We identified 1025 patients, 585 male. Mean age at presentation was 42.4 years (standard deviation 6.4). Eight hundred eighty-six (86%) patients were symptomatic at time of diagnosis. Clinical features in symptomatic patients included rectal bleeding (51%), change in bowel habits (18%), abdominal pain (32%), weight loss (13%), nausea/vomiting (7%), melena (2%), and other (26%). Evaluation of asymptomatic patients was pursued with findings of anemia (14%), positive fecal occult blood test (7%), abdominal mass (2%), mass on digital rectal exam (2%), and other (80%). Site of primary tumor was colonic in 51% and rectal in 49%. Synchronous malignant lesions were noted in 1%. Mucinous and signet cell histology was seen in 11% and 2%, respectively. Tumor grade distribution was grade 1 (2%), grade 2 (54%), grade 3 (34%), and grade 4 (7%). The stage distribution was stage I (13%), stage II (21%), stage III (32%), and stage IV (34%).
To our knowledge, the current study is the largest cohort of young-onset CRC patients with no known genetic predisposition for disease. Most patients were symptomatic, had left-colon or rectal cancers and presented with more advanced stage disease. Our findings should promote increased awareness and the aggressive pursuit of symptoms in otherwise young, low-risk patients, as these symptoms may represent an underlying colorectal malignancy.
PMCID: PMC4437192  PMID: 18794708
7.  Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention 
Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).
At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index.
Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92).
Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.
PMCID: PMC3566344  PMID: 23261228
lung cancer; chemoprevention; phase II clinical trial; sulindac; NSAIDs
8.  Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression 
EBioMedicine  2015;2(5):447-455.
Aspirin intake reduces the risk of colorectal cancer (CRC), but the molecular underpinnings remain elusive. Epidermal growth factor receptor (EGFR), which is overexpressed in about 80% of CRC cases, is implicated in the etiology of CRC. Here, we investigated whether aspirin can prevent CRC by normalizing EGFR expression.
Immunohistochemistry staining was performed on paraffin-embedded tissue sections from normal colon mucosa, adenomatous polyps from FAP patients who were classified as regular aspirin users or nonusers. The interplay between cyclooxygenase-2 (COX-2) and EGFR was studied in primary intestinal epithelial cells isolated from ApcMin mice, immortalized normal human colon epithelial cells (HCECs) as well as murine embryonic fibroblasts (MEFs).
Immunohistochemistry staining results established that EGFR overexpression is an early event in colorectal tumorigenesis, which can be greatly attenuated by regular use of aspirin. Importantly, EGFR and COX-2 were co-overexpressed and co-localized with each other in FAP patients. Further mechanistic studies revealed that COX-2 overexpression triggers the activation of the c-Jun-dependent transcription factor, activator protein-1 (AP-1), which binds to the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation.
Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions.
•CRC progression is accompanied by an elevation in EGFR levels, which can be attenuated by aspirin intake.•The widespread overexpression of EGFR occurs as a consequence of COX-2 activation in FAP patients.•This study revealed a functional association between COX-2 and EGFR expression during colorectal carcinogenesis.
PMCID: PMC4469241  PMID: 26097892
CRC, colorectal cancer; FAP, familial adenomatous polyposis; EGFR, epidermal growth factor receptor; COX-2, cyclooxygenase-2; PGs, prostaglandins; Colorectal cancer; Familial adenomatous polyposis; Epidermal growth factor receptor; Cyclooxygenase-2
9.  Sensitivity of CT Colonography for the Detection of Non-polypoid Adenomas Using Restricted Criteria in the National CT Colonography Trial 
AJR. American journal of roentgenology  2014;203(6):W614-W622.
To determine the prevalence and sensitivity of CT Colonography (CTC) in the detection of non-polypoid adenomas using restricted criteria of height:width ratio of <50% and height elevation of ≤3mm.
In ACRIN 6664, an institutional review board-approved, HIPAA-compliant study, a cohort of 2531 asymptomatic participants underwent CTC and screening colonoscopy. The CTC exams were interpreted by both two-dimensional and three-dimensional techniques. Non-polypoid adenomatous polyps identified by CTC or colonoscopy were retrospectively reviewed to determine which polyps met the restricted criteria. The prevalence of non-polypoid adenomas and prospective sensitivity of CTC were determined. Descriptive statistics are used to report the prevalence, size, and histology. Sensitivities for the non-polypoid (with 95% CIs) and polypoid lesions are compared with a two-sided Z test for two independent binomial proportions.
The retrospective review confirmed 21 non-polypoid adenomas, yielding a prevalence of 0.83% (21/2531 participants). 8 (38.1%) were advanced adenomas, many (50%, 4/8) secondary to large size (≥10mm) only. The overall per polyp sensitivity of CTC (combined 2D and 3D interpretation) for detecting non-polypoid adenomas ≥ 5mm (n=21), ≥ 6mm (n=16) and ≥10mm (n=5) were 0.76, 0.75, and 0.80, respectively, which was not statistically different from the sensitivity of detecting polypoid adenomas (p>0.37).
In this large screening population, non-polypoid adenomas had a very low prevalence (<1%), and advanced pathologic features were uncommon in polyps <10mm in diameter. The majority of non-polypoid adenomas are technically visible at CTC, with prospective sensitivities similar to polypoid adenomas using an interpretation approach combining both two-dimensional and three-dimensional review.
PMCID: PMC4312488  PMID: 25415726
10.  Circulating Prostaglandin Biosynthesis in Colorectal Cancer and Potential Clinical Significance☆☆☆★ 
EBioMedicine  2014;2(2):165-171.
Colorectal cancer (CRC) represents the third leading cause of cancer-related death in the United States. Lack of reliable biomarkers remains a critical issue for early detection of CRC. In this study, we investigated the potential predictive values of circulating prostaglandin (PG) biosynthesis in CRC risk.
Profiles of circulating PG biosynthesis and platelet counts were determined in healthy subjects (n = 16), familial adenomatous polyposis (FAP) patients who were classified as regular aspirin users (n = 14) or nonusers (n = 24), and CRC patients with (n = 18) or without FAP history (n = 20). Immunohistochemistry staining was performed on biopsy samples.
Analysis of circulating PG biosynthesis unexpectedly revealed that CRC progression is accompanied by a pronounced elevation of circulating thromboxane A2 (TXA2) levels. When a circulating TXA2 level of 1000 pg/mL was selected as a practical cutoff point, 95% of CRC patients were successfully identified. Further study suggested that the TXA2 pathway is constitutively activated during colorectal tumorigenesis and required for anchorage-independent growth of colon cancer cells.
This study established the importance of the TXA2 pathway in CRC pathophysiology, and laid the groundwork for introducing a TXA2-targeting strategy to CRC prevention, early detection and management.
•CRC progression is associated with higher circulating TXA2 levels, which merits investigation as a predictor of CRC risk.•TXA2 pathway is constitutively activated during colorectal tumorigenesis.•TXA2 pathway is required for anchorage-independent growth of colon cancer cells.•This study lays the groundwork for introducing a TXA2-targeting strategy to CRC prevention, early detection and management.
PMCID: PMC4347518  PMID: 25750933
CRC, colorectal cancer; FAP, familial adenomatous polyposis; PGs, prostaglandins; TXA2, thromboxane A2; mPGES1, microsomal prostaglandin E synthase-1; TBXAS1, thromboxane A2 synthase 1; TBXA2R, thromboxane A2 receptor; Colorectal cancer; Familial adenomatous polyposis; Thromboxane A2
11.  Cigarette Smoking and Colorectal Cancer Risk by KRAS Mutation Status Among Older Women 
Existing data support a modest association between cigarette smoking and incident colorectal cancer (CRC) overall. In this study, we evaluated associations between cigarette smoking and CRC risk stratified by KRAS mutation status, using data and tissue resources from the Iowa Women’s Health Study (IWHS).
The IWHS is a population-based cohort study of cancer incidence among 41,836 randomly selected Iowa women, ages 55–69 years of age at enrollment (1986). Exposure data, including cigarette smoking, were obtained by self-report at baseline. Incident CRCs (n = 1,233) were ascertained by annual linkage with the Iowa Cancer Registry. Archived tissue specimens from CRC cases recorded through 2002 were recently requested for molecular epidemiology investigations. Tumor KRAS mutation status was determined by direct sequencing of exon 2, with informative results in 507/555 (91%) available CRC cases (342 mutation negative and 165 mutation positive). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between cigarette smoking variables and KRAS-defined CRC subtypes.
Multiple smoking variables were associated with increased risk for KRAS mutation-negative tumors, including age at initiation (P = 0.02), average number of cigarettes per day (P = 0.01), cumulative pack-years (P = 0.05), and induction period (P = 0.04), with the highest point estimate observed for women who smoked ≥ 40 cigarettes per day on average (RR = 2.38; 95% CI = 1.25–4.51; compared with never smokers). Further consideration of CRC subsite suggested that cigarette smoking may be a stronger risk factor for KRAS mutation-negative tumors located in the proximal colon than in the distal colorectum. None of the smoking variables were significantly associated with KRAS mutation-positive CRCs (overall or stratified by anatomic subsite).
Data from this prospective study of older women demonstrate differential associations between cigarette smoking and CRC subtypes defined by KRAS mutation status, and are consistent with the hypothesis that smoking adversely affects the serrated pathway of colorectal carcinogenesis.
PMCID: PMC3588167  PMID: 22349355
12.  Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women 
Gut  2011;61(9):1299-1305.
Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.
To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women’s Health Study of older women.
Exposure data were collected from Iowa Women’s Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.
PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.
In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.
PMCID: PMC3584677  PMID: 22027477
13.  Alcohol Intake and Colorectal Cancer Risk by Molecularly-Defined Subtypes in a Prospective Study of Older Women 
Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly-defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability (MSI-H or MSI-L/MSS), CpG island methylator phenotype (CIMP-positive or CIMP-negative) and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55–69 years at baseline (1986) and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Among alcohol consumers, the median intake (range) was 3.4 (0.9–292.8) g/day. Compared to non-consumers, alcohol intake levels of ≤ 3.4 g/day (RR = 1.00; 95% CI = 0.86–1.15) and > 3.4 g/d (RR = 1.06; 95% CI = 0.91–1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of ≤ 30 g/d and > 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or BRAF-defined CRC subtypes (p > 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly-defined subtypes, among older women.
PMCID: PMC3584678  PMID: 21900595
Colorectal Cancer; Alcohol; Older Women; Cohort Study
14.  Associations Between Intake of Folate and Related Micronutrients with Molecularly Defined Colorectal Cancer Risks in the Iowa Women’s Health Study 
Nutrition and cancer  2012;64(7):899-910.
Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12 and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women’s Health Study (IWHS; 55–69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, while methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models (RR = 0.81; 95% CI = 0.69–0.95; p trend = 0.001 and RR = 0.72; 95% CI = 0.54–0.96; p trend = 0.03 for highest versus lowest quartiles, respectively). None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.
PMCID: PMC3584680  PMID: 23061900
Colorectal Cancer; Alcohol; Older Women; Cohort Study
15.  Postmenopausal Hormone Therapy and Colorectal Cancer Risk in Relation to Somatic KRAS Mutation Status among Older Women 
Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Since colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women (Iowa Women’s Health Study [IWHS]).
The IWHS enrolled 41,836 randomly selected women, ages 55–69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).
PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI = 0.66–1.06; p = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI = 0.58–1.16; p = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI = 0.43–0.96; p = 0.03).
To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status, but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum).
Findings from this prospective cohort study provide novel insights regarding the molecular biology of PMH therapy-related CRC risk reduction.
PMCID: PMC3584684  PMID: 22337533
Postmenopausal hormone therapy; colorectal cancer; cohort study; KRAS
17.  DNA Mismatch Repair Gene Alterations in a Population-Based Sample of Young-Onset Colorectal Cancer Patients 
Background & Aims
Direct germline analysis could be used to screen high-risk patients for DNA mismatch repair gene mutations associated with Lynch Syndrome. To further evaluate this potential strategy, we examined the prevalence of MLH1, MSH2 and MSH6 mutations in a population-based sample of young-onset (age < 50 years) CRC cases.
Young-onset CRC cases were randomly selected from three Colon Cancer Family Registry sites (Cancer Care Ontario, Mayo Clinic, University of Southern California). Extracted DNA from peripheral blood leukocytes was shipped to Myriad Genetic Laboratories (Salt Lake City, UT) for MLH1, MSH2 and MSH6 sequencing, and duplication/deletion analyses for MLH1 and MSH2. Results were reported as: deleterious/suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry testing (IHC) in secondary analyses.
In 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% CI, 2.8%–9.9%), 12 had likely neutral alterations (6.2%; 3.2%–10.5%), 14 had variants of uncertain significance (7.2%; 4.0%–11.8%), 2 had both a likely neutral alteration and a variant of uncertain significance (1.0%; 0.1%–3.7%) and 156 had no alteration detected (80.0%; 73.7%–85.4%). Sensitivity, specificity, positive and negative predictive values for detecting deleterious/suspected deleterious mutations by ACII were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185) and by IHC testing were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18) and 99.3% (136/137).
In this population-based sample of young-onset CRC cases, germline MLH1, MSH2 and/or MSH6 mutations were more prevalent than previously reported for CRC patients overall. Yet, since only about 1 in 20 young-onset CRC cases had confirmed deleterious/suspected deleterious mutations, further comparative effectiveness research is needed to determine the preferred Lynch Syndrome screening strategy for this high-risk group.
PMCID: PMC3058119  PMID: 21056691
Lynch Syndrome screening; mutation prevalence; direct germline analysis; Colon Cancer Family Registry
18.  Population Pharmacokinetic Model for Cancer Chemoprevention With Sulindac in Healthy Subjects 
Journal of clinical pharmacology  2013;53(4):403-412.
Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent.
PMCID: PMC4120995  PMID: 23436338
chemoprevention; exisulind; NONMEM; population pharmacokinetics; sulindac
19.  Phase 0 Clinical Chemoprevention Trial of the AKT Inhibitor SR13668 
SR13668, an orally active AKT pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability.
Patients and Methods
Healthy adult volunteers were randomly assigned to receive a single, 38 mg oral dose of SR13668 in one of five different formulations, with or without food. Based on existing animal data, SR13668 in a PEG400/Labrasol® oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC0-∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size.
Participants (N=20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC0-∞ values were highest in the fed state (range = 122–439 ng/mL × hours) and were statistically significantly different across formulations (p = 0.007), with Solutol® HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2 – 6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation dependent.
Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.
PMCID: PMC3061470  PMID: 21372034
20.  Randomized Phase II Trial of Sulindac, Atorvastatin and Prebiotic Dietary Fiber for Colorectal Cancer Chemoprevention 
Sulindac, atorvastatin or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects age ≥ 40 years, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required ≥ 5 rectal ACF at baseline. Intervention assignments were: (A) atorvastatin 20 mg qd; (B) sulindac 150 mg bid; (C) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (D) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and post-intervention, respectively. The median (standard deviation) for %ΔACF was 5.6 (−69–143%), −18.6 (−83–160%), −3.6 (−88-83%) and −10.0 (−100–117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within arm (p=0.12–0.59) nor between arm (p=0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also appeared to have similar effects on mucosal proliferation and apoptosis (p > 0.05 for each comparison). Data from this multi-center, phase II trial do not provide convincing evidence of CRC risk reduction from six month interventions with atorvastatin, sulindac or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size.
PMCID: PMC3046804  PMID: 21209397
Colorectal cancer; chemoprevention; clinical trial; phase II
21.  Functional and Clinical Significance of Variants Localized to 8q24 in Colon Cancer 
Multiple GWAS have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1178 cases and 1009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal OR=0.82, 95% CI=0.072-0.94, Ptrend=0.0037) and rs6983267 (ordinal OR=1.17, 95% CI=1.03-1.32, Ptrend=0.013). Survival analysis was performed using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (N=380) for structural abnormalities at or near the c-MYC locus using FISH analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by FISH, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several SNPs at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not appear to be associated with survival.
PMCID: PMC4059694  PMID: 19690179
8q; SNP; association; survival; FISH; fragile site; c-MYC
22.  Body Size and Incident Colorectal Cancer: A Prospective Study of Older Women 
Obesity is a controversial risk factor for colorectal cancer (CRC) in older women. We evaluated associations between multiple body size parameters and incident CRC in the prospective, population-based Iowa Women's Health Study (IWHS). IWHS participants, ages 55–69 years, provided data regarding height; weight; weight at ages 50, 40, 30, 18 years; hip circumference; and waist circumference at baseline (1986). Derived variables included body mass index (BMI), waist-to-hip ratio (WHR) and “overweight years” (OWYs; conceptually similar to cigarette pack-years). Incident CRC cases (n=1464) were ascertained from the State Health Registry of Iowa, through 2005. Multivariable Cox regression models were fit to estimate body size-associated CRC risks. Among 36,941 women (619,961 person-years), baseline height, weight, BMI, hip circumference, waist circumference and WHR were all positively associated with incident CRC (p trend ≤ 0.003 for each). Baseline BMI yielded the highest CRC risk estimates (obese III versus normal, RR=1.56; 95% CI=1.10–2.22; p trend < 0.001) and was more closely associated with distal than proximal tumors (p trend < 0.001 vs. 0.06). Conversely, height was more closely associated with proximal than distal tumors (p trend < 0.001 vs. 0.04). Other body size parameters were less predictive of incident CRC. These data strongly support a positive association between increased body size and CRC risk among older women. Further investigation of when increased body size has the greatest effect on CRC risk (i.e., early adulthood versus later adulthood) might also be informative, particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis.
PMCID: PMC3005991  PMID: 20719902
Colorectal Cancer; Body Size; Older Women; Cohort Study
23.  Cigarette Smoking and Colorectal Cancer Risk by Molecularly Defined Subtypes 
Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.
We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women’s Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).
Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation–positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation–positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation–negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27).
In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation–positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.
PMCID: PMC2915616  PMID: 20587792
24.  Noncathartic CT Colonography: Image Quality Assessment and Performance and in a Screening Cohort 
Cathartic bowel preparation is a major barrier for colorectal cancer screening. We examined noncathartic CT colonography (CTC) quality and performance using four similar bowel-tagging regimens in an asymptomatic screening cohort.
This prospective study included 564 asymptomatic subjects who underwent noncathartic CTC without dietary modification but with 21 g of barium with or without iodinated oral contrast material (four regimens). The quality of tagging with oral agents was evaluated. A gastrointestinal radiologist evaluated examinations using primary 2D search supplemented by electronic cleansing (EC) and 3D problem solving. Results were compared with complete colonoscopy findings after bowel purgation and with retrospective unblinded evaluation in 556 of the 564 (99%) subjects.
Of the 556 subjects, 7% (37/556) and 3% (16/556) of patients had 52 and 20 adenomatous polyps ≥ 6 and ≥ 10 mm, respectively. The addition of iodine significantly improved the percentage of labeled stool (p ≤ 0.0002) and specificity (80% vs 89–93%, respectively; p = 0.046). The overall sensitivity of noncathartic CTC for adenomatous polyps ≥ 6 mm was 76% (28/37; 95% CI, 59–88%), which is similar to the sensitivity of the iodinated regimens with most patients (sensitivity: 231 patients, 74% [14/19; 95% CI, 49–91%]; 229 patients, 80% [12/15; 95% CI, 52–96%]). The negative predictive value was 98% (481/490), and the lone cancer was detected (0.2%, 1/556). EC was thought to improve conspicuity of 10 of 21 visible polyps ≥ 10 mm.
In this prospective study of asymptomatic subjects, the per-patient sensitivity of noncathartic CTC for detecting adenomas ≥ 6 mm was approximately 76%. Inclusion of oral iodine contrast material improves examination specificity and the percentage of labeled stool. EC may improve polyp conspicuity.
PMCID: PMC3919488  PMID: 24059367
bowel preparation; colon cancer screening; CT colonography; patient compliance
25.  Prospective evaluation of trans-fatty acid intake and colorectal cancer risk in the Iowa Women’s Health Study 
Concerns regarding the safety of dietary trans-fatty acids (tFAs) have generated recent public interest, scientific discussion and legislative action. Although most widely recognized as a risk factor for cardiovascular disease, associations between tFA intake and incident cancer have also been proposed. With respect to colorectal cancer (CRC), existing observational data remain limited and inconclusive. Therefore, we conducted a prospective evaluation of tFA intake and CRC risk, overall and by anatomic subsite, among participants in the Iowa Women’s Health Study, a population-based cohort of older women (ages 55–69 years at enrollment). Exposure data were collected at baseline using a semi-quantitative food-frequency questionnaire. Incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. CRC risks were estimated using Cox proportional hazards regression models. In total, 35,216 women met our inclusion criteria and 1229 CRC cases (631 proximal, 571 distal, 27 site not specified) were observed through 18 years of follow-up. Adjusting for age and total energy consumption, tFA intake in the fourth versus first quartile was not significantly associated with overall CRC risk (relative risk [RR] = 1.12; 95% confidence interval [CI] = 0.96–1.32). Similarly, risk estimates based on proximal (RR = 1.09; 95% CI = 0.87–1.37) and distal (RR = 1.18; 95% CI = 0.93–1.49) CRC subsites did not differ from unity. Multivariable adjustment yielded slightly attenuated risk estimates, but the observed associations were not meaningfully altered. Given these findings, tFA intake does not appear to be a major CRC risk factor, at least among older women.
PMCID: PMC2575073  PMID: 18767047
Colorectal cancer; trans fatty acids; dietary fat; cohort study

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