Thomas A Ullman

Penn State Hershey Medical Center and Penn State College of Medicine, Hershey, Pennsylvania, United States

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Publications (85)642.1 Total impact

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    ABSTRACT: Inflammation during inflammatory bowel disease may alter nutrient availability to adherent mucosal bacteria and impact their metabolic function. Microbial metabolites may regulate intestinal CD4 T-cell homeostasis. We investigated the relationship between inflammation and microbial function by inferred metagenomics of the mucosal microbiota from colonic pinch biopsies of patients with inflammatory bowel disease. Paired pinch biopsy samples of known inflammation states were analyzed from ulcerative colitis (UC) (23), Crohn's disease (CD) (21), and control (24) subjects by 16S ribosomal sequencing, histopathologic assessment, and flow cytometry. PICRUSt was used to generate metagenomic data and derive relative Kyoto Encyclopedia of Genes and Genomes Pathway abundance information. Leukocytes were isolated from paired biopsy samples and analyzed by multicolor flow cytometry. Active inflammation was defined by neutrophil infiltration into the epithelium. Carriage of metabolic pathways in the mucosal microbiota was relatively stable among patients with inflammatory bowel disease, despite large variations in individual bacterial community structures. However, microbial function was significantly altered in inflamed tissue of UC patients, with a reduction in carbohydrate and nucleotide metabolism in favor of increased lipid and amino acid metabolism. These differences were not observed in samples from CD patients. In CD, microbial lipid, carbohydrate, and amino acid metabolism tightly correlated with the frequency of CD4Foxp3 Tregs, whereas in UC, these pathways correlated with the frequency of CD4IL-22 (TH22) cells. Metabolic pathways of the mucosal microbiota in CD do not vary as much as UC with inflammation state, indicating a more systemic perturbation of host-bacteria interactions in CD compared with more localized dysfunction in UC.
    Inflammatory Bowel Diseases 02/2014; · 5.12 Impact Factor
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    ABSTRACT: Giant inflammatory polyposis (GIP), characterized by mass-like agglomerations of inflammatory polyps, is a rare complication of inflammatory bowel disease (IBD). We reviewed a series of cases of GIP to determine its diagnostic impact on the clinical and pathologic distinction between ulcerative colitis (UC) and colonic Crohn's disease (CD). All colons with GIP resected over a 13-year period were identified prospectively and the corresponding clinical and pathologic records were reviewed. Twelve cases of GIP were identified, accounting for 0.8% of colectomies for IBD during the same time interval. Preoperatively, 6 (50%) patients were diagnosed with UC, 2 (17%) with CD and 4 (33%) with indeterminate colitis (IC). Postoperatively, 6 of the diagnoses (50%) were revised based on strict histopathologic criteria: all 4 diagnoses of IC to UC, one diagnosis of CD to UC, and one diagnosis of UC to CD, for a total of 10 diagnoses of UC (83%) and two of CD (17%). Significantly, 7 of 10 cases with postoperative diagnoses of UC (70%) had Crohn's-like transmural inflammation exclusively within the polyposis segments attributed to fecal entrapment and stasis and accounting for the Crohn's-like clinical complications in these cases. This case series of GIP, the largest reported from a single center, highlights the high rate of Crohn's-like clinical and pathological manifestations of GIP and their potential to confound the accurate classification of patients with IBD. A diagnosis of UC should not be amended to CD based on the findings of the polyposis segment alone.
    Journal of Crohn s and Colitis 12/2013; · 3.39 Impact Factor
  • Gut 07/2013; · 10.73 Impact Factor
  • Fernando S Velayos, Thomas A Ullman
    Gastroenterology 05/2013; · 12.82 Impact Factor
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    ABSTRACT: T helper type (Th17) cytokines such as interleukin (IL)-17A and IL-22 are important in maintaining mucosal barrier function and may be important in the pathogenesis of inflammatory bowel diseases (IBDs). Here, we analyzed cells from the colon of IBD patients and show that Crohn's disease (CD) patients had significantly elevated numbers of IL-17+, CD4+ cells compared with healthy controls and ulcerative colitis (UC) patients, but these numbers did not vary based on the inflammatory status of the mucosa. By contrast, UC patients had significantly reduced numbers of IL-22+ cells in actively inflamed tissues compared with both normal tissue and healthy controls. There was a selective increase in mono-IL-17-producing cells from the mucosa of UC patients with active inflammation together with increased expression of transforming growth factor (TGF)-β and c-Maf. Increasing concentrations of TGF-β in lamina propria mononuclear cell cultures significantly depleted Th22 cells, whereas anti-TGF-β antibodies increased IL-22 production. When mucosal microbiota was examined, depletion of Th22 cells in actively inflamed tissue was associated with reduced populations of Clostridiales and increased populations of Proteobacteria. These results suggest that increased TGF-β during active inflammation in UC may lead to the loss of Th22 cells in the human intestinal mucosa.Mucosal Immunology advance online publication 22 May 2013; doi:10.1038/mi.2013.31.
    Mucosal Immunology 05/2013; · 7.54 Impact Factor
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    ABSTRACT: BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk for venous thromboembolism (VTE) compared to the general population. Practice guidelines recommend pharmacologic prophylaxis for IBD inpatients. AIM: Our aim was to determine the rates of pharmacologic VTE prophylaxis in ulcerative colitis (UC) inpatients at a tertiary referral center. We also assessed potential predictors of pharmacologic prophylaxis. METHODS: We conducted a retrospective cohort study of 377 UC patients between January 1st, 2007 and December 31st, 2011. The medical record of each patient was examined to determine whether pharmacologic VTE prophylaxis was ordered and administered. We conducted multiple logistic regression to determine predictors of pharmacologic prophylaxis. RESULTS: The overall VTE pharmacologic prophylaxis rate was 67.6%. The rate of patients admitted to the medical service was 57.4% compared to 93.5% for those admitted to surgery. In medical patients who received pharmacologic VTE prophylaxis, 34.0% of ordered doses were not given compared to 17.4% of doses in surgical patients (P<0.001). In the multiple logistic regression analysis, having an additional VTE risk factor (OR 2.46, 95% CI 1.41-4.30), extensive colitis (OR 2.26, 95% CI 1.32-3.87) or being admitted to a surgical service (OR 12.03, 95% CI 5.29-27.38) was associated with VTE pharmacologic prophylaxis. CONCLUSIONS: A substantial proportion of medical patients admitted with UC were not ordered for VTE pharmacologic prophylaxis despite current guidelines. Even in patients who were ordered for pharmacologic prophylaxis, one third of doses were not given. Inappropriate prophylaxis may lead to unnecessary morbidity and mortality.
    Journal of Crohn s and Colitis 05/2013; · 3.39 Impact Factor
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    ABSTRACT: BACKGROUND:: In ulcerative colitis, total proctocolectomy is the treatment of choice for patients with colonic dysplasia or cancer because of the high risk for metachronous neoplasia. It is unknown whether patients with Crohn's disease and colon cancer or dysplasia have a similar risk. METHODS:: We retrospectively reviewed the charts of 75 patients treated at our center from 2001 to 2011 with Crohn's disease and colon cancer who underwent segmental resection or subtotal colectomy (STC). We then identified the presence or absence of subsequent colon cancer or dysplasia in these patients during the follow-up (0-19 years). RESULTS:: Of the 64 patients with colon cancer, 25 had at least 1 metachronous cancer (39%). The mean time to a new cancer was 6.8 years. Eighty-five percent of patients (21/25) were undergoing annual screening colonoscopy. Of the 11 patients with dysplasia, 5 (46%) had a new dysplasia. Mean time to a new dysplastic lesion was 5.0 years. Nineteen of the 47 patients (40%) who had a segmental resection for colon cancer developed metachronous cancer and 6/17 patients (35%) with a STC had metachronous cancer. Two of the 4 patients (50%) with STC for dysplasia (50%) had a new dysplasia and 3/7 patients (43%) with segmental resection had a new dysplasia. There was no significant difference (P = 0.61) between recurrence rates in patients with segmental resection versus STC. CONCLUSIONS:: The high rate of metachronous colon cancer after surgical resection suggests that total proctocolectomy should be considered. Larger studies are required to determine if the same is true for dysplasia.
    Inflammatory Bowel Diseases 05/2013; · 5.12 Impact Factor
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    ABSTRACT: INTRODUCTION:: Variation in adherence to management guidelines for inflammatory bowel disease (IBD) suggests variable quality of care. Quality indicators (QIs) can be developed to measure the structure, processes, and outcomes of health care delivery. The RAND/UCLA appropriateness method was used to develop a set of process and outcome QIs to define quality of care for IBD. METHODS:: Guidelines and position papers for IBD published from 2006 to 2011 were reviewed for potential QIs, which were rated by a multidisciplinary panel. Potential process and outcome QIs were discussed at 3 moderated in-person meetings, with pre-meeting and post-meeting confidential electronic voting. Panelists rated the validity and feasibility of QIs on a 1 through 9 scale; disagreement was assessed using a validated index. QIs rated above 8 were selected for the final set. RESULTS:: More than 500 potential process QIs were extracted from guidelines. Following ratings and discussion by the first panel, 35 process QIs were selected for literature review. After the second panel, 10 process QIs were included in the final set. Candidate outcome QIs were then derived from physician, nurse, and patient input and ratings, in addition to outcomes associated with candidate process QIs. None of the top QIs exhibited disagreement. CONCLUSIONS:: A set of QIs for IBD was developed with expert interpretation of the literature and multidisciplinary input. Outcome QIs focused largely on remission and quality of life, whereas process QIs were aimed at therapeutic optimization and patient safety. Evaluation of these QIs in clinical practice is needed to assess the correlation of performance on process QIs with performance on outcome QIs.
    Inflammatory Bowel Diseases 02/2013; · 5.12 Impact Factor
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    ABSTRACT: BACKGROUND:: The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. METHODS:: Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. RESULTS:: In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. CONCLUSIONS:: FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.
    Inflammatory Bowel Diseases 01/2013; · 5.12 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: Some women with inflammatory bowel disease (IBD) require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus, via the placenta, and then cleared, or whether structurally different TNF antagonists have different rates of transfer. METHODS: We studied 31 pregnant women with IBD receiving infliximab (IFX, n=11), adalimumab (ADA, n=10), or certolizumab (CZP, n=10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. RESULTS: Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were <2 μg/ml. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. CONCLUSIONS: The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 11/2012; · 5.64 Impact Factor
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    ABSTRACT: : The role of intravenous (IV) cyclosporine in severe Crohn's colitis (CC) is poorly studied. : Our primary aim was to determine the in-hospital colonic resection rate in patients with severe CC who received IV cyclosporine, and the potential predictors of resection among these patients. : An inpatient pharmacy query of all patients who received IV cyclosporine at Mount Sinai Medical Center for 12.5 years after January 1, 1996 was reviewed. Patients with CC or indeterminate colitis favoring Crohn's were included and their medical records were reviewed. Subsequent need for colonic surgery was assessed. A Kaplan-Meier plot with log-rank testing was performed to determine the rate of colonic surgery avoidance. Forward stepwise logistic regression was performed to determine independent predictors of surgery. : Forty-eight patients met our inclusion criteria. Prior thiopurine and anti-tumor necrosis factor (anti-TNF) use was 85% and 69%, respectively. The median follow-up time was 12 months (range, 1 to 60 mo). 12.5% of patients required colonic resection during their admission for IV cyclosporine. Anti-TNF use in the 4 weeks preceding IV cyclosporine was the only predictor of surgery in this setting (P=0.05). The cumulative colonic surgery avoidance rate was 72±13% at 6 months and 59±15% at 12 months. : The use of IV cyclosporine resulted in a low rate of in-hospitalization colonic surgery among CC patients with severe disease, the majority of whom previously failed anti-TNFs and thiopurines.
    Journal of clinical gastroenterology 06/2012; 46(9):764-7. · 2.21 Impact Factor
  • The American Journal of Gastroenterology 06/2012; 107(6):951-2; author reply 952. · 9.21 Impact Factor
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    ABSTRACT: BACKGROUND:: Inflammatory bowel disease (IBD) patients are at an increased risk of thrombosis, particularly when hospitalized. Several clinical practice guidelines now recommend pharmacologic prophylaxis for hospitalized ulcerative colitis and Crohn's disease patients. It is unclear to what extent gastroenterologists are aware of these recommendations and whether they are administering pharmacologic venous thromboembolism (VTE) prophylaxis appropriately. Our aim was to explore current practice of VTE prophylaxis in hospitalized IBD patients in the United States. METHODS:: A survey was mailed electronically to gastroenterologists whose electronic mail address was listed in the American College of Gastroenterology (ACG) database. This survey included clinical vignettes outlining scenarios for consideration of VTE prophylaxis. RESULTS:: A total of 6227 surveys were sent to gastroenterologists nationwide, and 591 physicians chose to participate (response rate 9.5%). Respondents (80.6%) believed that hospitalized IBD patients have a higher risk of VTE than other inpatients. A total of 29.1% were unaware of any recommendations addressing pharmacologic prophylaxis included in ACG IBD guidelines and 34.6% would give pharmacologic VTE prophylaxis to a hospitalized patient with severe ulcerative colitis. Heparin VTE prophylaxis use was associated with gastroenterologists who indicated that their practices comprised more than 50% of patients with IBD (P=0.0001), being a physician at an academic hospital (P=0.0001) and providers having less than 5 years practice experience (P=0.003). CONCLUSIONS:: Despite reasonable awareness of the increased risk of thrombosis in hospitalized IBD patients, many US gastroenterologists may not follow clinical practice guidelines and use pharmacologic VTE prophylaxis.
    Journal of clinical gastroenterology 04/2012; · 2.21 Impact Factor
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    ABSTRACT: Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.
    PLoS Genetics 03/2012; 8(3):e1002559. · 8.52 Impact Factor
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    ABSTRACT: Multiple randomized controlled trials (RCTs) have been conducted to determine therapeutic efficacy of the biological agents for the inflammatory bowel diseases (IBD). However, the external validity of findings from RCTs might be compromised by their stringent selection criteria. We investigated the proportion of patients encountered during routine clinical practice who would qualify for enrollment into a pivotal RCT of biological agents for IBD. We performed a retrospective cohort study of adult patients with moderate-severe IBD who presented to a tertiary referral center. Inclusion and exclusion criteria were extracted from published RCTs of biologics approved by the Food and Drug Administration and applied to the study population. Only 31.1% of 206 patients with IBD (34% with Crohn's disease [CD], 26% with ulcerative colitis) would have been eligible to participate in any of the selected RCTs. Patients would have been excluded because they had stricturing or penetrating CD, took high doses of steroids, had comorbidities or prior exposure to biologics, or received topical therapies. Of the trial-ineligible patients with ulcerative colitis, 23.3% had colectomies, and 31.7% received infliximab, with a 63.2% response rate. Approximately half (49.4%) of the 82 trial-ineligible patients with CD received biological therapies, with lower response rates (60%) than trial-eligible patients (89%; P = .03). Most patients with moderate-severe IBD evaluated in an outpatient practice would not qualify for enrollment in a pivotal RCT of biological reagents; this finding raises important questions about their therapeutic efficacy beyond the clinical trial populations. Additional evaluation of the transparency of RCT design and selection criteria is needed to determine whether trial results can be generalized to the population.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 02/2012; 10(9):1002-7; quiz e78. · 5.64 Impact Factor
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    ABSTRACT: Emerging evidence suggests that the biology of sporadic colorectal neoplasia may differ between the proximal and distal colon. Whether such a difference exists in colitis-associated colorectal neoplasia is unknown. To compare the rate of progression to advanced neoplasia (AN) between proximal and distal dysplasia in patients with ulcerative colitis (UC). Retrospective cohort study. Tertiary medical center. From an institutional database of more than 700 patients with UC who underwent 2 or more surveillance colonoscopies between 1994 and 2006, we identified patients with extensive UC and low-grade dysplasia (LGD). Neoplasia proximal to the splenic flexure was considered proximal. Progression to AN, defined as high-grade dysplasia (HGD) or colorectal cancer (CRC). Among 121 patients with LGD, all 7 who progressed to CRC and 6 of 8 who progressed to HGD had distal LGD initially. Subjects with distal LGD had a significantly shorter time to progression than those with proximal LGD (P = .019); 5-year AN-free survivals for distal and proximal LGD were 75 ± 7% and 95 ± 3%, respectively (hazard ratio [HR] 5.0; 95% CI, 1.1-22.0). Additionally, flat LGD was significantly more likely to progress than raised LGD on univariate testing (HR 3.6; 95% CI, 1.3-10.1). Neither morphology nor sidedness remained significant in multivariable testing, although there was little change in the HRs (HR 2.4; 95% CI, 0.8-7.1 for morphology; HR 3.5; 95% CI, 0.7-16.8 for sidedness) in proportional hazards modeling. Nonrandomized, retrospective trial and low incidence of AN. In patients with long-standing, extensive UC, distal LGD is more common and progresses more rapidly to AN than proximal LGD.
    Gastrointestinal endoscopy 09/2011; 74(5):1087-93. · 6.71 Impact Factor
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    ABSTRACT: In patients with long-standing ulcerative colitis (UC), current dysplasia surveillance guidelines recommend four-quadrant biopsies every 10 cm throughout the colon. However, this may be inefficient if neoplastic lesions are localized in particular segments of the colorectum. The aim was to determine whether a difference exists in the anatomic distribution of dysplasia discovered in UC patients undergoing colonoscopic surveillance. From an institutional database of over 700 patients with UC who underwent two or more surveillance colonoscopies between 1994-2006, we identified all patients with flat (endoscopically invisible) low-grade dysplasia (fLGD) or advanced neoplasia (colorectal cancer [CRC] or high-grade dysplasia [HGD]). Pathology reports were reviewed regarding the anatomic location of all dysplastic lesions. Fisher's exact test was used to compare the frequencies of neoplasia among the different colonic segments. We identified 103 patients who progressed to any neoplasia (fLGD, HGD, or CRC). These patients underwent a total of 396 colonoscopies. The mean age at first surveillance colonoscopy was 48.6 years, with a mean UC disease duration of 18.2 years; 100% had extensive disease. Fifty-five patients developed advanced neoplasia. The rectosigmoid was found to have a significantly greater number of biopsies positive for advanced neoplasia and for any neoplasia compared to all other colonic segments (P < 0.0007); 71.2% of all advanced neoplasia was in the rectosigmoid. The majority of dysplastic lesions identified in a surveillance program was detected in the rectosigmoid. Endoscopists should consider taking a greater percentage of biopsies in these segments as opposed to more proximal areas.
    Inflammatory Bowel Diseases 07/2011; 18(5):832-7. · 5.12 Impact Factor
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    ABSTRACT: Adherence to medication in inflammatory bowel disease (IBD) improves outcomes. Current practices of screening for adherence to IBD medications are unknown. The goal of this study was to determine current practice and perception of screening for medication adherence among US-based gastroenterologists. A survey was mailed electronically to gastroenterologists whose electronic-mail address was listed in the American College of Gastroenterology database. Physicians who cared for IBD patients were invited to answer. About 6830 surveys were sent to gastroenterologists nationwide, and 395 physicians who cared for IBD patients completed the survey. The true response rate is unknown, as the number of physicians caring for IBD patients in the database is unknown. About 77% (n = 303) of physicians who responded stated they screen for adherence to medication. Of the 77% of physicians who screened for adherence, only 19% (n = 58) use accepted measures of screening for adherence (pill counts, prescription refill rates, or adherence surveys). The remaining 81% used patient interview to screen for adherence, a measure considered least accepted to determine adherence, as it overestimates adherence. The average number of IBD patients observed in 1 week had no statistical significance in predilection for screening (P = 0.82). Private practice physicians (P = 0.05), younger physicians (P = 0.03), and physicians with fewer years of experience (P = 0.02) all were more likely to screen. About 95% of responders thought determining a low adherer to medicine was important because an intervention can increase adherence. The majority of gastroenterologists surveyed recognize that adherence to medication is important and improves outcomes. The majority of physicians in this study are screening for nonadherence in IBD, but are not using accepted measures for adherence detection. If this study truly reflects the majority of physicians nationwide, changing the way physicians screen for adherence, may detect more low adherers to medication.
    Journal of clinical gastroenterology 05/2011; 45(10):878-82. · 2.21 Impact Factor
  • Thomas A Ullman, Steven H Itzkowitz
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    ABSTRACT: Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer (CRC). Chronic inflammation is believed to promote carcinogenesis. The risk for colon cancer increases with the duration and anatomic extent of colitis and presence of other inflammatory disorders (such as primary sclerosing cholangitis), whereas it decreases when patients take drugs to reduce inflammation (such as mesalamine and steroids). The genetic features that lead to sporadic CRC-chromosome instability, microsatellite instability, and DNA hypermethylation-also occur in colitis-associated CRC. Unlike the normal colonic mucosa, cells of the inflamed colonic mucosa have these genetic alterations before there is any histologic evidence of dysplasia or cancer. The reasons for these differences are not known, but oxidative stress is likely to be involved. Reactive oxygen and nitrogen species produced by inflammatory cells can affect regulation of genes that encode factors that prevent carcinogenesis (such as p53, DNA mismatch repair proteins, and DNA base excision-repair proteins), transcription factors (such as nuclear factor-κB), or signaling proteins (such as cyclooxygenases). Administration of agents that cause colitis in healthy rodents or genetically engineered, cancer-prone mice accelerates development of colorectal tumors. Mice genetically prone to inflammatory bowel disease also develop CRC, especially in the presence of bacterial colonization. Individual components of the innate and adaptive immune response have also been implicated in carcinogenesis. These observations offer compelling support for the role of inflammation in colon carcinogenesis.
    Gastroenterology 05/2011; 140(6):1807-16. · 12.82 Impact Factor
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    The American Journal of Gastroenterology 04/2011; 106 Suppl 1:S2-25; quiz S26. · 9.21 Impact Factor

Publication Stats

2k Citations
642.10 Total Impact Points

Institutions

  • 2013
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • Department of Surgery
      Hershey, Pennsylvania, United States
  • 2012–2013
    • University of California, San Francisco
      • Division of Gastroenterology
      San Francisco, CA, United States
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2008–2013
    • Mount Sinai Medical Center
      New York City, New York, United States
    • The University of Chicago Medical Center
      Chicago, Illinois, United States
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 2002–2013
    • Icahn School of Medicine at Mount Sinai
      • Department of Medicine
      Manhattan, New York, United States
  • 2011
    • McMaster University
      • Health Sciences Centre
      Hamilton, Ontario, Canada
    • Tel Aviv Sourasky Medical Center
      Tell Afif, Tel Aviv, Israel
    • University of Newcastle
      • Faculty of Health and Medicine
      Newcastle, New South Wales, Australia
  • 2009
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 2007
    • University of Texas Southwestern Medical Center
      • Medical School
      Dallas, TX, United States