Cenk Pusatcioglu

Excess of Proximal Microsatellite-Stable Colorectal Cancer in African Americans from a Multiethnic Study

Purpose: African Americans (AA) have the highest incidence of colorectal cancer compared with other U.S. populations and more proximal colorectal cancers. The objective is to elucidate the basis of these cancer disparities. Experimental design: Of note, 566 AA and 328 non-Hispanic White (NHW) colorectal cancers were ascertained in five Chicago hospitals. Clinical and exposure data were collected. Microsatellite instability (MSI) and BRAF (V600E) and KRAS mutations were tested. Statistical significance of categorical variables was tested by the Fisher exact test or logistic regression and age by the Mann–Whitney U test. Results: Over a 10-year period, the median age at diagnosis significantly decreased for both AAs (68–61; P < 0.01) and NHWs (64.5– 62; P = 0.04); more AA patients were diagnosed before age 50 than NHWs (22% vs. 15%; P = 0.01). AAs had more proximal colorectal cancer than NHWs (49.5% vs. 33.7%; P < 0.01), but overall frequencies of MSI, BRAF and KRAS mutations were not different nor were they different by location in the colon. Proximal colorectal cancers often presented with lymphocytic infiltrate (P < 0.01) and were diagnosed at older ages (P = 0.02). Smoking, drinking, and obesity were less common in this group, but results were not statistically significant. Conclusions: Patients with colorectal cancer have gotten progressively younger. The excess of colorectal cancer in AAs predominantly consists of more proximal, microsatellite stable tumors, commonly presenting lymphocytic infiltrate and less often associated with toxic exposures or a higher BMI. Younger AAs had more distal colorectal cancers than older ones. These data suggest two different mechanisms driving younger age and proximal location of colorectal cancers in AAs. Clin Cancer Res; 20(18); 4962–70. ©2014 AACR.

Subcutaneous Adipose Tissue from Obese and Lean Adults Does Not Release Hepcidin In Vivo

Hepcidin is the main regulator of systemic iron homeostasis and is primarily produced by the liver but is also expressed, at the mRNA-level, in periphery tissues including the subcutaneous and visceral adipose tissue. Obesity is associated with elevated hepcidin concentrations and iron depletion suggesting that the exaggerated fat mass in obesity could contribute significantly to circulating hepcidin levels consequently altering iron homeostasis. The objective of this study was to determine if abdominal subcutaneous adipose tissue (AbScAT) releases hepcidin in vivo and if release is modified by obesity. Arterio-venous differences in concentrations of hepcidin were measured across AbScAT in 9 obese and 9 lean adults. Overall (n = 18), mean plasma hepcidin concentrations were significantly higher in arterialized compared to AbScAT venous samples [mean difference (arterialized-AbScAT venous plasma hepcidin) = 4.9 ± 9.6 ng/mL, P = 0.04]. Net regional release was not calculated because mean venous plasma hepcidin concentrations were lower than mean arterialized concentrations indicating no net release. Significant correlations between AbScAT venous and arterialized plasma hepcidin concentrations with anthropometric variables were not observed. Findings from this vein drainage study suggest there is no net release of hepcidin from the AbScAT depot and thereby no ability to signal systemically, even in obesity.

A comprehensive review of randomized placebo-controlled pharmacological clinical trials in children with functional abdominal pain disorders.

Objectives: Abdominal pain–predominant functional gastrointestinal disorders (AP-FGIDs) are the most common cause of consultation to pediatric gastroenterology; however, no medications have been approved to treat this group of disorders in children. The Food and Drug Administration have published recommendations for clinical trials on AP-FGIDs in adults but not in children. The lack of methodological guidelines and accepted primary endpoints for clinical trials in children hampers the progress of the field, making the approval of new medications difficult. A necessary first step to determine the feasibility of clinical trials in children and provide recommendations on the best design for future trials is to review the methods, ability to recruit, attrition rate, and results of previous clinical trials. We designed a comprehensive review of pharmacological clinical trials in AP-FGIDs in children focused on study design. Methods: Study eligibility was randomized controlled trials (RCTs) evaluating the efficacy of pharmacological interventions compared with that of placebo in children and adolescents with AP-FGIDs. Results: There is no evidence to support the use of most commonly used drugs in children. Only 7 pharmacological RCTs on AP-FGIDs in children were found. Most studies were single center based and had a small sample size. The methods and outcomes were heterogeneous. Primary endpoints varied widely among studies. Many of the RCTs did not show a consistently significant benefit of the drug over placebo in some or all of the outcomes. We found a considerable risk of bias in most studies. None of the studies have considered minimal clinically important differences in their selection of primary endpoints. Conclusions: Few randomized clinical trials have been conducted. Most studies have methodological limitations and small sample size. There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures.

Moving Beyond Diet and Colorectal Cancer

olorectal cancer (CRC) is third in incidence and mor- tality of all cancers worldwide, with rates parallel- ing economic development and a Westernized life- style (1,2). The majority of CRC cases occur sporadically, with environmental influences such as diet, exercise, al- cohol, and smoking viewed as risk factors. CRC is also associated with increasing age, with the majority of CRC cases diagnosed in individuals who are 60 years or older. CRC develops from precancerous lesions (adenomas or polyps) to malignant adenocarcinoma through genetic mutations altering the cell growth cycle (3). It is believed that it takes 10 to 15 years for an adenoma to develop into an adenocarcinoma, thus highlighting the importance of exposure and time for environmental factors. A recent review by the World Cancer Research Fund/American Institute for Cancer Research states that whereas there is convincing evidence that reduced physical activity, in- creased abdominal adiposity, and increased red meat and processed meat intakes increase CRC risk, evidence of the protective effects of fruits and nonstarchy vegetables on CRC risk is limited (4). Because tumor location (left vs right-sided cancers) is influenced by potential different biological pathways that may be responsible for carcino- genesis (5), studying fruit and vegetable (F/V) intake based on cancer subsites remains to be explored. earlier. Total and subgroups for F/V intakes were quan- tified as daily equivalent frequencies and divided into quartiles. Body mass index (BMI) was calculated from self-reported weight and height (as kg/m 2 ) at age 20 years. Individuals were categorized by diabetes and smoking status, physical activity level, and socioeconomic index. Case and control subjects were frequency matched on age and sex. Odds ratios and a test of trends were calculated across quartiles of F/V intakes, adjusting for covariates. In addition, analyses for all CRC cases were done based on tumor site. Differences between case and control subjects were found. Subjects with proximal cases of colon cancer were older and more likely to be female, whereas cases of rectal cancers were more likely to be male compared with con- trol subjects. Control subjects were also more likely to be underweight (at age 20) compared with all case (tumor site) groups. Participants with distal and rectal cancers drank 30 g more alcohol per day than control subjects. Case subjects also lived in lower socioeconomic regions than did control subjects. Multivariate modeling for overall CRC risk demon- strated no association between total F/V intake (together and separate), but when subgroups were analyzed, intake of apples (highest to lowest quartile) and dark-yellow vegetables (second, third quartiles compared to lowest) was significantly associated with a decreased CRC risk. In contrast, intake of fruit juice (highest to lowest quar- tile) was associated with an increased risk of CRC with significance for trend. When multinomial modeling was done to examine the risks by cancer site, the results seemed similar to the overall CRC risk. Intake of F/V was not associated with proximal colon cancer and rectal cancer risk. In addition, similar to the overall CRC models, intake of dark yellow vegetables (Q4 vs Q1, odds ratio (OR) 0.61 95% confi- dence interval (CI): 0.41 to 0.92) and apples (Q4 vs Q1, OR 0.51 95% CI: 0.34 to 0.77) were significant for a protective effect for distal colon cancers, and fruit juice (Q4 vs Q1, OR 1.74 95% CI: 1.24 to 2.45) was associated with an increased risk for rectal cancers. The exceptions in cancer site risks compared with overall CRC risk were that distal colon cancers exhibited a significance for a protective effect (Q4 vs Q1, OR 0.58 95% CI: 0.36 to 0.93) for total F/V intakes, and intake of brassica vegeta- bles was protective for proximal colon cancer risk (Q4 vs Q1, OR 0.62 95% CI: 0.41 to 0.93). These findings are similar to previous findings in meta- analyses in which weak or no associations were reported (4); however, the analysis by cancer site provides new information. Historically, nutritional epidemiology has relied on using the dietary intake model to assess cancer risk without accounting for other factors involved in the carcinogenesis pathway and also often used self-report for anthropometric data. Information on obesity-related

Clinical presentation of acute gastroenteritis in children with functional gastrointestinal disorders

ABSTRACT Visceral hypersensitivity and abnormal coping are common in children with functional abdominal pain disorders (FAPDs). Thus, it would be expected that children with visceral hypersensitivity would report more pain if their gut is acutely inflamed. The aim of the study was to compare clinical symptoms and somatization of children with and without FAPDs at time of an episode of acute gastroenteritis. Seventy children with acute gastroenteritis and their parents completed the Rome III Diagnostic Questionnaire for Pediatric Functional GI Disorders and the Childrens Somatization Inventory. Twenty-one percent of children were diagnosed with an FAPD. Children with FAPDs showed significantly more nongastrointestinal somatic symptoms than children without FAPDs. There were no significant differences in abdominal pain, nausea, vomiting, or school absenteeism between both groups at time of consultation.

Abstract 3597: The Chicago Colorectal Cancer Consortium (CCCC) experience: Understanding colorectal cancer disparities

Colorectal cancer (CRC) affects disproportionally African Americans (AAs) who have a 20% higher incidence and a 40% higher mortality than Caucasians. Very few studies have specifically addressed CRC in AAs. In order to uncover the factors that underlie this disparity we set up the CCCC, a large, robust and well-characterized database and biorepository of CRC patients from the Chicago metropolitan area that is highly enriched with AAs. The project enrolls newly diagnosed CRCs, polyps at different stages, and cancer/polyp-free controls in 5 large hospitals. Extensive clinical, family history, demographic, dietary, toxic exposure data is collected along with tumor and uninvolved mucosa as well as plasma, serum, and paraffin-embedded samples. Tumors are molecularly characterized and germline DNA is used to assess genetic factors implicated in CRC development. The primary goal of the project is to study how genetic and environmental factors as well as their interaction contribute to CRC development and which factors make AAs more prone to develop this cancer. We will also assess specific factors that may contribute to the worse prognosis in AAs. Results: A total of 205 CRCs, (58% AAs), 86 patients with high-risk adenomas, 75 mild-risk adenomas, and 173 controls have been recruited so far. The mean age at diagnosis was 60.2 for AAs and 61.8 for whites (P=0.08), in both cases significantly lower than the mean age reported for the US CRCs in general (68-70). There was a significantly higher number of AA patients younger than age 50 at diagnosis (19.5% vs. 7.1% whites; P=0.043). In AA patients tumors were more often on the right side of the colon (43.3% vs. 22.7%; P=0.02) and more were undifferentiated (19.1% vs. 3.5%; P=0.03). Both groups had a similar number of colonoscopies before cancer diagnosis (60.2% for AAs vs. 68.3% for whites; P=0.11). While there was no significant difference among AA cases and controls regarding high tobacco use (>20 pack/years)(16.9% cases vs. 17.1% controls), more whites with CRC were heavy smokers (45.7% cases vs. 29.7 controls). Less AA patients reported family history of CRC than whites (16.4% vs. 35.2%; P0.02) or family history of polyps (21.7% vs. 44%). Conclusions: In our urban cohort both AA and white patients present CRC significantly earlier than expected. Very important differences are seen between AAs and whites that may have significant implications when considering CRC screening approaches, such as the high percentage of AA patients diagnosed before age 50 or the much higher number of right-sided tumors. Heavy tobacco use seems to associate with CRC in whites but not in AAs. Altogether points towards important biological differences that need to be further assessed. As we are ascertaining toxic and dietary exposure and molecularly characterizing all tumors, eventually we should be able to explain the biological basis of the significant disparity in CRC Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3597. doi:1538-7445.AM2012-3597

Abstract B73: The Chicago Colorectal Cancer Consortium (CCCC), a step forward in understanding colorectal cancer in African Americans

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related death in both sexes in the United States. While the overall CRC incidence rates have declined over the past 10 years, the disparity between African Americans (AAs) and non-Hispanic whites has increased and the incidence in AAs remains higher than in other populations. Very few studies have specifically addressed CRC in AAs, and important studies on CRC almost never include significant numbers of AAs to draw any firm conclusions. Objective: To establish a large, robust and well-characterized database and bio-repository collection of CRC from AA patients and controls strengthening a collaborative working group, the Chicago Colorectal Cancer Consortium (CCCC), which spans 5 of the main hospitals of the Chicago area. We collect clinical, demographic and dietary data; and a biological repository of specimens consisting of tumor and non-tumor genomic DNA, RNA, plasma, serum, and paraffin-embedded samples. Specific Aims: The primary goal of the project is to study how genetic and environmental factors and their interaction result in the development of CRC. We will also study prognosis determinants in the AA population. Results:Recruitment and data collection: So far we have recruited 56 AA and 17 white-non Hispanic adenocarcinoma colorectal patients. We have also recruited 84 AAs and 32 white patients with adenomatous polyps, and 44 AAs and 30 white controls (individuals without polyps or previous history of polyps). From all individuals we have collected demographic/socioeconomic data, clinical data, family history of cancer, medication and toxic substance history, and dietary data using the Block Brief 2000 Food Frequency Questionnaire. Preliminary analyses: To identify potential variables that could influence the cancer disparity between AAs and whites, we performed a preliminary analysis of all these data using a Fisher exact test. A systematic molecular analysis of BRAF and KRAS mutations, microsatellite instability and presence of CpG island methylation phenotype in all CRC tumors is being performed. We are also analyzing protein expression of the mismatch repair genes through immunohistochemistry. We will test for an association between these molecular features and clinical variables. Moreover, 1 year follow-up data is already available and being collected on 23 cases. Therefore, we will soon be able to start investigating the relationship of those molecular features with survival and specific chemotherapy response. Summary: The preliminary analysis has highlighted some significant differences between AA and white CRC patients. In comparison with white patients, a higher proportion of AA patients are less than 50 years at diagnosis, take NSAIDS, and fulfill Bethesda criteria, which is a set of criteria to select out patients to be pre-screened for mismatch repair deficiency and eventually for genetic testing to rule out Lynch syndrome. It has also highlighted that CRC patients have a lower level of education than cancer-free individuals in both ethnicities. This type of sociocultural disparities could potentially be associated with different life styles. In fact, AA CRC cases consumed more carbohydrates than controls reflecting this potential life style difference. Cancer Relevance: Understanding the key molecular features and environmental factors that impact CRC development in the AA population is of paramount importance given the scarce information available. Understanding the role genetic factors will be crucial to help risk stratify patients, recommend screening modalities, and recommend preventive measures. When this information is combined with environmental factors, such as dietary habits, we will be able to offer a comprehensive personalized medicine approach for AA CRC patients. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B73.