Laura K. Bianchi

Fundic gland polyp dysplasia is common in familial adenomatous polyposis.

BACKGROUND & AIMSnFundic gland polyps (FGPs) are common in familial adenomatous polyposis (FAP) but have been considered nonneoplastic. Gastric carcinoma arises from FGPs in FAP presumably from a dysplasia-carcinoma pathway. Our study examined the prevalence of FGPs and FGP dysplasia in FAP and identified endoscopic or demographic features associated with FGPs and dysplasia.nnnMETHODSnDemographic and endoscopic information were obtained prospectively from 75 consecutive subjects undergoing upper-endoscopic surveillance for FAP. Systematic biopsy specimens of FGPs, normal-appearing fundic mucosa, and antral mucosa for Helicobacter pylori were obtained. Multivariable analysis assessed the association of demographic or endoscopic factors with the presence of FGP or FGP dysplasia.nnnRESULTSnFGPs were detected in 88% of subjects and were dysplastic in 41% (38% low grade, 3% high grade). H pylori infection was rare in subjects with vs without FGPs (1.5% vs 33.3%, P = .005). In the multivariable analysis larger FGP size (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.1-14.4), higher stage of duodenal polyposis (OR, 2.3; 95% CI, 1.2-4.5), and antral gastritis (OR, 11.2; 95% CI, 1.2-103.9) were associated with FGP dysplasia. Exposure to acid-suppressive medications was associated with a marked decrease in dysplastic FGPs (OR, 0.14; 95% CI, 0.03-0.64).nnnCONCLUSIONSnThe majority of FAP patients have FGPs and nearly half will have dysplastic FGPs. There is an inverse relationship between H pylori and FGPs. FGP dysplasia is associated with larger polyp size, increased severity of duodenal polyposis, and antral gastritis. Acid-suppressive therapy use appears protective against dysplasia in FGPs.

Esophagogastric Junction Morphology Predicts Susceptibility to Exercise-Induced Reflux

BACKGROUND AND AIM:Although strenuous exercise has been reported to increase gastroesophageal reflux, there are few data exploring the mechanism behind this relationship. The aim of this study was to use vigorous exercise as a provocation for strain-induced reflux and examine the correlation between endoscopically assessed EGJ integrity and exercise-induced reflux.METHODS:Ten controls and 10 GERD patients were studied for a 2-day period using the wireless Bravo™ pH monitoring system. The subjects were randomly assigned to perform 60 min of exercise on day 1 or 2 consuming the same diet on both days. Exercise consisted of 30 min of running and 30 min of 5 resistance exercises. Subjects underwent endoscopy to grade the EGJ “flap valve” and manometry to measure basal LES pressure.RESULTS:Nineteen subjects completed the 2-day study with 100% data capture during exercise. Median acid exposure was increased more than threefold for both controls and GERD patients during exercise when compared to nonexercise periods. In addition, a strong correlation existed between EGJ grade and % time pH < 4 during exercise while there was not a significant correlation between LES pressure and EGJ grade. These findings were present even after exclusion of hiatus hernia patients (flap valve grade 4).CONCLUSIONS:Exercise caused a threefold increase in esophageal acid exposure in both controls and GERD patients. The degree of exercise-induced reflux is strongly correlated with EGJ morphology and this supports the hypothesis that anatomical integrity of the EGJ is of cardinal importance in preventing strain-induced reflux.

Current and past cigarette smoking significantly increase risk for microscopic colitis

Background: Cigarette smoking is an important environmental factor affecting inflammatory bowel disease. The role of smoking has not been rigorously studied in microscopic colitis (MC). The aim of this study was to compare the association of cigarette smoking in individuals with MC compared to a control population without MC. Methods: We reviewed the records of patients with a clinical and histologic diagnosis of collagenous colitis (CC) or lymphocytic colitis (LC). Clinical history, including alcohol and smoking status at the time of diagnosis of MC, were reviewed. In this case–control study, age‐ and gender‐matched patients without diarrhea presenting for outpatient colonoscopy served as the control population. Results: We analyzed a total of 340 patients with MC: 124 with CC and 216 with LC. Overall, any smoking status (former or current) was associated with MC (odds ratio [OR] 2.12, 95% confidence interval [CI]: 1.56–2.88). This risk was more prominent in current smokers (adjusted OR 5.36, 3.81, and 4.37 for CC, LC, and all MC, respectively, 95% CI all greater than 1). The association of smoking was not significantly affected by gender or average alcohol consumption. Conclusions: In our study population, cigarette smoking is a risk factor for the development of both forms of microscopic colitis. There were no significant differences between LC and CC, and current smoking and the development of microscopic colitis affected men and women similarly. We feel that these data are sufficient to discuss the potential risks of tobacco use in patients with microscopic colitis. (Inflamm Bowel Dis 2012)

Nanocytology of rectal colonocytes to assess risk of colon cancer based on field cancerization

Developing a minimally invasive and cost-effective prescreening strategy for colon cancer is critical because of the impossibility of conducting colonoscopy on the entire at-risk population. The concept of field carcinogenesis, in which normal-appearing tissue away from a tumor has molecular and, consequently, nano-architectural abnormalities, offers one attractive approach to identify high-risk patients. In this study, we investigated whether the novel imaging technique partial wave spectroscopic (PWS) microscopy could risk-stratify patients harboring precancerous lesions of the colon, using an optically measured biomarker (L(d)) obtained from microscopically normal but nanoscopically altered cells. Rectal epithelial cells were examined from 146 patients, including 72 control patients, 14 patients with diminutive adenomas, 20 patients with nondiminutive/nonadvanced adenomas, 15 patients with advanced adenomas/high-grade dysplasia, 12 patients with genetic mutation leading to Lynch syndrome, and 13 patients with cancer. We found that the L(d) obtained from rectal colonocytes was well correlated with colon tumorigenicity in our patient cohort and in an independent validation set of 39 additional patients. Therefore, our findings suggest that PWS-measured L(d) is an accurate marker of field carcinogenesis. This approach provides a potential prescreening strategy for risk stratification before colonoscopy.

Nanoscale changes in chromatin organization represent the initial steps of tumorigenesis: a transmission electron microscopy study

BackgroundNuclear alterations are a well-known manifestation of cancer. However, little is known about the early, microscopically-undetectable stages of malignant transformation. Based on the phenomenon of field cancerization, the tissue in the field of a tumor can be used to identify and study the initiating events of carcinogenesis. Morphological changes in nuclear organization have been implicated in the field of colorectal cancer (CRC), and we hypothesize that characterization of chromatin alterations in the early stages of CRC will provide insight into cancer progression, as well as serve as a biomarker for early detection, risk stratification and prevention.MethodsFor this study we used transmission electron microscopy (TEM) images of nuclei harboring pre-neoplastic CRC alterations in two models: a carcinogen-treated animal model of early CRC, and microscopically normal-appearing tissue in the field of human CRC. We quantify the chromatin arrangement using approaches with two levels of complexity: 1) binary, where chromatin is separated into areas of dense heterochromatin and loose euchromatin, and 2) grey-scale, where the statistics of continuous mass-density distribution within the nucleus is quantified by its spatial correlation function.ResultsWe established an increase in heterochromatin content and clump size, as well as a loss of its characteristic peripheral positioning in microscopically normal pre-neoplastic cell nuclei. Additionally, the analysis of chromatin density showed that its spatial distribution is altered from a fractal to a stretched exponential.ConclusionsWe characterize quantitatively and qualitatively the nanoscale structural alterations preceding cancer development, which may allow for the establishment of promising new biomarkers for cancer risk stratification and diagnosis. The findings of this study confirm that ultrastructural changes of chromatin in field carcinogenesis represent early neoplastic events leading to the development of well-documented, microscopically detectable hallmarks of cancer.

Differences in Colon Adenomas and Carcinomas Among Women and Men Potential Clinical Implications

COLORECTAL CANCER REMAINS THE THIRD LEADING cause of cancer deaths among women and men in the United States, underscoring the need for more effective preventive strategies for both sexes. Many promising approaches are based on the adenoma-carcinoma paradigm of colon carcinogenesis. The clinical corollary to this model is that the presence of adenomas represents a robust marker of colon carcinogenesis. This leads to 2 distinct applications for colorectal cancer prevention: target for intervention and risk marker. Indeed, removing adenomas through colonoscopy has been shown to decrease future colorectal cancer occurrence by 75% to 90%. From a screening perspective, the colonoscopic adenoma identification is used clinically to gauge long-term risk and dictate the frequency of future colorectal cancer screening. Most data suggest that the effect of colorectal cancer is approximately equivalent in both sexes. In 2009, an estimated 71 380 women and 75 590 men will develop colorectal cancer. This is consistent with data from 1993-2003 in which women composed 50% of patients in an unselected cohort of 161 172 patients with colorectal cancer from US community cancer centers. Moreover, while estimates of incidence of colorectal cancer has suggested up to a 2-fold male predominance, the more robust lifetime risk estimates for US women and men are comparable (5.1% vs 5.5%, respectively). Taken together, this and other evidence would suggest that colorectal cancer is, by and large, a sex-neutral malignancy. Therefore, it would logically follow that colonic adenomas should also be equivalent in women and men. However, several large-scale studies have indicated that women have a substantially lower adenoma detection rate than men. For instance, in a cross-sectional analysis of 50 148 patients undergoing colonoscopybased screening program, Regula et al demonstrated that, compared with women, men had an adjusted odds ratio for advanced adenomas of 1.73 (95% confidence interval [CI], 1.52-1.98). Additionally, Schoenfeld et al noted that the relative risk (RR) of clinically significant neoplasia (advanced adenomas) in men was 1.91 (95% CI, 1.42-2.56) compared with women. In a recent metaanalysis including 924 932 adults, Nguyen et al reported that the RR of advanced neoplasia in men vs women was 1.83 (95% CI, 1.69-1.97). These findings would imply that adenomas (even those designated as advanced, ie, size 1 cm or high-grade dysplasia or 25% villous features) represent a less reliable marker of colorectal cancer risk in women than in men, and would lead to speculation that colonoscopic identification of adenomas may be less protective of colorectal cancer in women than in men. Although rigorous evidence for this hypothesis is lacking, an administrative database review by Bressler et al noted that women were 41% more likely than men to develop colorectal cancer despite undergoing colonoscopy (4.1% vs 2.9%, P .001). Other supportive evidence centers on the predilection for proximal lesions among women. Baxter et al demonstrated that even though having a colonoscopy was associated with decreased risk of subsequent colorectal cancer by two-thirds in the distal colon, no protective effect was found for lesions in the proximal colon. These studies suggest that the lower prevalence of adenomas in women may translate into possibly less efficacy of colonoscopy. There is biological precedence for the sex-related differential clinical behavior of colonic neoplasia. Randomized controlled studies have demonstrated the chemopreventive abilities of estrogens/progesterones, potentially mediated by the tumor suppressor role of estrogen receptor . Moreover, numerous studies have documented the higher proportion of microsatellite-unstable (MSI-high) lesion in women consonant with their slightly better prognosis. From a risk factor perspective, women appear to have differential sensitivity to the carcinogenic effect of cigarette smoking. From an epidemiological perspective, women develop more proximal colorectal cancer, but lesions generally occur somewhat later in life com-

Rectal mucosal microvascular blood supply increase is associated with colonic neoplasia.

Purpose: Endoscopic examination has proven effective in both detecting and preventing colorectal cancer; however, only about a quarter of eligible patients undergo screening. Even if the compliance rate increased, limited endoscopic capacity and cost would be prohibitive. There is a need for an accurate method to target colonoscopy to those most at risk of harboring colonic neoplasia. Exploiting field carcinogenesis seems to be a promising avenue. Our group recently reported that an early increase in blood supply (EIBS) is a reliable marker of field carcinogenesis in experimental models. We now investigate whether in situ detection of EIBS in the rectum can predict neoplasia elsewhere in the colon. Experimental Design: We developed a novel polarization-gated spectroscopy fiber-optic probe that allows depth-selective interrogation of microvascular blood content. Using the probe, we examined the blood content in vivo from the rectal mucosa of 216 patients undergoing screening colonoscopy. Results: Microvascular blood content was increased by ∼50% in the endoscopically normal rectal mucosa of patients harboring advanced adenomas when compared with neoplasia-free patients irrespective of lesion location. Demographic factors and nonneoplastic lesions did not confound this observation. Logistic regression using mucosal oxyhemoglobin concentration and patient age resulted in a sensitivity of 83%, a specificity of 82%, and an area under the receiver operating characteristic curve of 0.88 for the detection of advanced adenomas. Conclusions: Increased microvascular blood supply in the normal rectal mucosa is associated with the presence of clinically significant neoplasia elsewhere in the colon, supporting the development of rectal EIBS as a colon cancer risk-stratification tool.

Decreased Colorectal Cancer and Adenoma Risk in Patients with Microscopic Colitis

IntroductionMicroscopic colitis is currently considered to harbor no increased risk for colorectal cancer, based on a few small studies with limited long-term follow-up. Our aim was to identify patients with microscopic colitis, and to compare long-term rates of colorectal cancer or adenoma to a control group of patients without microscopic colitis.MethodsWe reviewed the records of patients diagnosed with microscopic colitis, as identified by a hospital-based pathology database from January 2000 to August 2008. Clinical factors, including history of adenoma or adenocarcinoma, and all colonoscopy findings, were recorded. Age and gender-matched patients without microscopic colitis served as the control in a 1:1 fashion.ResultsA total of 647 patients (153 male: 494 female) were identified with microscopic colitis (MC). Any history of colorectal cancer was detected in 1.92, 1.81, and 4.17% of patients with collagenous colitis (CC), lymphocytic colitis (LC), and controls, respectively (Pxa0=xa00.095, Pxa0=xa00.040, Pxa0=xa00.015 for CC, LC, and all MC, respectively, comparing to controls). Overall, covariate-adjusted risk (odds ratio) of any history of colorectal cancer and colorectal adenoma in MC patients was 0.34 (95% confidence interval [CI] 0.16–0.73, Pxa0=xa00.006) and 0.52 (95% CI 0.50–0.76, Pxa0<xa00.0001), respectively. The mean duration of follow-up was 4.63xa0years, with 147/647 (22.7%) of patients with clinical follow-upxa0>7xa0years.ConclusionsIn this case–control study involving a large retrospective cohort, microscopic colitis is negatively associated with the risk for colorectal cancer and adenoma. Further studies are required to determine a temporal relationship between microscopic colitis and the future development of colorectal neoplasia.

Spatially resolved optical and ultrastructural properties of colorectal and pancreatic field carcinogenesis observed by inverse spectroscopic optical coherence tomography.

Abstract. Field carcinogenesis is the initial stage of cancer progression. Understanding field carcinogenesis is valuable for both cancer biology and clinical medicine. Here, we used inverse spectroscopic optical coherence tomography to study colorectal cancer (CRC) and pancreatic cancer (PC) field carcinogenesis. Depth-resolved optical and ultrastructural properties of the mucosa were quantified from histologically normal rectal biopsies from patients with and without colon adenomas (n=85) as well as from histologically normal peri-ampullary duodenal biopsies from patients with and without PC (n=22). Changes in the epithelium and stroma in CRC field carcinogenesis were separately quantified. In both compartments, optical and ultra-structural alterations were consistent. Optical alterations included lower backscattering (μb) and reduced scattering (μs′) coefficients and higher anisotropy factor g. Ultrastructurally pronounced alterations were observed at length scales up to ∼450u2009u2009nm, with the shape of the mass density correlation function having a higher shape factor D, thus implying a shift to larger length scales. Similar alterations were found in the PC field carcinogenesis despite the difference in genetic pathways and etiologies. We further verified that the chromatin clumping in epithelial cells and collagen cross-linking caused D to increase in vitro and could be among the mechanisms responsible for the observed changes in epithelium and stroma, respectively.

Ultrastructural alterations in field carcinogenesis measured by enhanced backscattering spectroscopy

Abstract. Optical characterization of biological tissue in field carcinogenesis offers a method with which to study the mechanisms behind early cancer development and the potential to perform clinical diagnosis. Previously, low-coherence enhanced backscattering spectroscopy (LEBS) has demonstrated the ability to discriminate between normal and diseased organs based on measurements of histologically normal-appearing tissue in the field of colorectal (CRC) and pancreatic (PC) cancers. Here, we implement the more comprehensive enhanced backscattering (EBS) spectroscopy to better understand the structural and optical changes which lead to the previous findings. EBS provides high-resolution measurement of the spatial reflectance profile P(rs) between 30 microns and 2.7 mm, where information about nanoscale mass density fluctuations in the mucosa can be quantified. A demonstration of the length-scales at which P(rs) is optimally altered in CRC and PC field carcinogenesis is given and subsequently these changes are related to the tissue’s structural composition. Three main conclusions are made. First, the most significant changes in P(rs) occur at short length-scales corresponding to the superficial mucosal layer. Second, these changes are predominantly attributable to a reduction in the presence of subdiffractional structures. Third, similar trends are seen for both cancer types, suggesting a common progression of structural alterations in each.