Gastroenterology

Publications in this journal

• Article: Beyond Gene Discovery in Inflammatory Bowel Disease - The emerging role of epigenetics.

  Nicholas T Ventham, Nick A Kennedy, Elaine R Nimmo, Jack Satsangi
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  ABSTRACT: In the past decade, fundamental advances have been made in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD, and discuss epigenetic mechanisms that could affect IBD development and progression.
  Gastroenterology 06/2013;
• Article: Isolation and Phenotypic Characterization of Colorectal Cancer Stem Cells with Organ-Specific Metastatic Potential.

  Wenchao Gao, Lu Chen, Zhenyu Ma, Zunguo Du, Zhonghua Zhao, Zhiqian Hu, Qingquan Li
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  ABSTRACT: BACKGROUND: & Aims: Migrating cancer stem cells (MCSCs) are believed to form metastases. We sought to identify markers of MCSCs from human colorectal carcinomas (CRCs) and determine their roles in organ-specific metastasis. METHODS: To identify colorectal MCSCs that contribute to organ-specific metastasis, we developed a model of liver or lung metastasis using primary tumor cells from CRC patients with liver and lung metastases. Distinct organ-specific metastatic cells were isolated by 6 cycles of selecting for cells that formed liver and lung tumors following subcutaneous injection into mice. Microarray analysis was used to identify markers of the organ-specific MCSCs. We then measured levels of these markers in colorectal carcinoma cell lines and 128 colorectal carcinoma samples. We characterized the functional roles of these markers in organ-specific metastasis. RESULTS: We identified CD110 and CDCP1 as cell surface markers of MCSCs from human colorectal tumors that metastasized to liver and lung. We observed a distinct pattern of CD110 and CDCP1 in a panel of primary colorectal tumor samples and their matched liver or pulmonary metastases, indicating that these proteins might serve as biomarkers of organ-specific metastasis. Functional studies demonstrated that thrombopoietin attracts CD110+ CSCs, and increases their self-renewal to promote formation of liver metastases. CDCP1 promoted adhesion of colorectal cancer cells to the lung endothelium. CONCLUSIONS: We isolated MCSCs from primary human CRCs, and found that the CD110+ and CDCP1+ subpopulations mediate organ-specific metastasis. These findings might be used to aide in selection of patients for post-operative adjuvant therapy.
  Gastroenterology 06/2013;
• Article: Germline Mutations in the Spindle Assembly Checkpoint Genes BUB1 and BUB3 Are Risk Factors for Colorectal Cancer.

  Richarda M de Voer, Ad Geurts van Kessel, Robbert D A Weren, Marjolijn J L Ligtenberg, Dominique Smeets, Lei Fu, Lilian Vreede, Eveline J Kamping, Eugène T P Verwiel, Marc-Manuel Hahn, [......], Liesbeth Spruijt, Ton van Essen, Gunnar Houge, Hans K Schackert, Jian Q Sheng, Hanka Venselaar, Conny M A van Ravenswaaij-Arts, J Han J M van Krieken, Nicoline Hoogerbrugge, Roland P Kuiper
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  ABSTRACT: The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy-an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (≤40) colorectal cancer (CRC); we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides CRC, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of CRC at young age.
  Gastroenterology 06/2013;
• Article: Post-Translational Loss of Renal TRPV5 Calcium Channel Expression, Ca2+ Wasting, and Bone Loss in Experimental Colitis.

  V M Radhakrishnan, R Ramalingam, C B Larmonier, R D Thurston, D Laubitz, M T Midura-Kiela, R-M T McFadden, Makoto Kuro-O, P R Kiela, F K Ghishan
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  ABSTRACT: BACKGROUND: & Aims: Dysregulated Ca2+ homeostasis likely contributes to the etiology of IBD-associated loss of bone mineral density (BMD). Experimental colitis leads to decreased expression of Klotho, a protein which supports renal Ca2+ reabsorption by stabilizing TRPV5 channel on the apical membrane of distal tubule epithelial cells. METHODS: Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4+IL10-/- and CD4+, CD45RBhi T cells. We investigated changes in bone metabolism, renal processing of Ca2+ , and expression of TRPV5. RESULTS: Mice with colitis had normal serum levels of Ca2+ and parathormone. Computed tomography analysis demonstrated decreased density of cortical and trabecular bone, and there was biochemical evidence for reduced bone formation and increased bone resorption. Increased fractional urinary excretion of Ca2+ was accompanied by reduced levels of TRPV5 protein in distal convoluted tubules, with a concomitant increase in TRPV5 sialylation. In mIMCD3 cells transduced with TRPV5 adenovirus, the inflammatory cytokines tumor necrosis factor (TNF), interferon (IFN)γ, and interleukin 1β reduced levels of TRPV5 on the cell surface, leading to its degradation. Cytomix induced interaction between TRPV5 and UBR4, an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. The effects of cytokines on TRPV5 were not observed in cells stably transfected with membrane-bound Klotho; TRPV5 expression was preserved when colitis was induced with TNBS in transgenic mice that overexpress Klotho or in mice with T-cell transfer colitis injected with soluble recombinant Klotho. CONCLUSION: Following induction of colitis in mice via TNBS administration or T-cell transfer, TNF and IFNγ reduce expression and activity of Klotho, which would otherwise protect TRPV5 from hyper-sialylation and cytokine-induced TRPV5 endocytosis, UBR4-dependent ubiquitination, degradation, and urinary wasting of Ca2+.
  Gastroenterology 06/2013;
• Article: Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma.

  Lei Zheng, Jing Xue, Elizabeth M Jaffee, Aida Habtezion
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  ABSTRACT: Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.
  Gastroenterology 06/2013; 144(6):1230-40.
• Article: A historical perspective on clinical advances in pancreatic diseases.

  Anil K Rustgi
  Gastroenterology 06/2013; 144(6):1249-51.
• Article: Genetic risk factors for pancreatic disorders.

  David C Whitcomb
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  ABSTRACT: A combination of genetic, environmental, and metabolic factors contribute to the development and recurrence of acute and chronic pancreatitis; information on all of these is required to manage patients effectively. For example, variants that affect regulation of the protease, serine (PRSS)1-PRSS2, and claudin (CLDN)2 loci, rather than their coding sequences, interact with other genetic and environmental factors to affect disease development. New strategies are needed to use these data and determine their contribution to pathogenesis, because these variants differ from previously studied, rare variants in exons (coding regions) of genes such as PRSS1, SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin (CTR)C, and calcium-sensing receptor (CASR). Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms.
  Gastroenterology 06/2013; 144(6):1292-302.
• Article: Models of acute and chronic pancreatitis.

  Markus M Lerch, Fred S Gorelick
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  ABSTRACT: Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.
  Gastroenterology 06/2013; 144(6):1180-93.
• Article: Clinical management of patients with acute pancreatitis.

  Bechien U Wu, Peter A Banks
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  ABSTRACT: Acute pancreatitis is the leading cause of hospitalization for gastrointestinal disorders in the United States. As rates of hospitalization for acute pancreatitis continue to increase, so does demand for effective management. We review approaches to best manage patients with acute pancreatitis, covering diagnosis, risk and prognostic factors, treatment, and complications, considering recommendations from current practice guidelines.
  Gastroenterology 06/2013; 144(6):1272-81.
• Article: Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B.

  Fabien Zoulim, Souphalone Luangsay, David Durantel
  Gastroenterology 06/2013; 144(7):1342-1344.
• Article: Subcutaneous Golimumab Induces Clinical Response and Remission in Patients with Moderate-To-Severe Ulcerative Colitis.

  William J Sandborn, Brian G Feagan, Colleen Marano, Hongyan Zhang, Richard Strauss, Jewel Johanns, Omoniyi J Adedokun, Cynthia Guzzo, Jean-Frederic Colombel, Walter Reinisch, Peter R Gibson, Judith Collins, Gunnar Järnerot, Toshifumi Hibi, Paul Rutgeerts
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  ABSTRACT: BACKGROUND: & Aims: Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNFα-antagonist naive patients with moderate-to-severe UC despite conventional treatment. METHODS: We integrated double-blind Phase 2 dose-finding and Phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore ≥2; 774 patients in Phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (Phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The Phase 3 primary endpoint was week-6 clinical response. Secondary endpoints included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change. RESULTS: In Phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In Phase 3, rates of clinical response at week 6 were 51.8% and 55.0% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 29.7% among those given placebo (both P<.0001). Rates of clinical remission and mucosal healing, and mean changes in IBDQ scores, were significantly greater in both golimumab groups vs the placebo group (P≤.0005, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200mg group died of surgical complications from an ischiorectal abscess. CONCLUSIONS: Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life, in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number, NCT00487539.
  Gastroenterology 06/2013;
• Article: Control of cell identity in pancreas development and regeneration.

  Ben Z Stanger, Matthias Hebrok
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  ABSTRACT: The endocrine and exocrine cells in the adult pancreas are not static, but can change their differentiation state in response to injury or stress. This concept of cells in flux means that there may be ways to generate certain types of cells (such as insulin-producing β-cells) and prevent formation of others (such as transformed neoplastic cells). We review different aspects of cell identity in the pancreas, discussing how cells achieve their identity during embryonic development and maturation, and how this identity remains plastic, even in the adult pancreas.
  Gastroenterology 06/2013; 144(6):1170-9.
• Article: Biology and clinical applications of pancreatic cancer stem cells.

  Ethan V Abel, Diane M Simeone
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  ABSTRACT: Pancreatic ductal adenocarcinomas comprise a hierarchy of tumor cells that develop around a population of cancer stem cells. The cancer stem cells promote tumor growth and progression through a number of mechanisms, including differentiation into bulk tumor cells, metastasis, alteration of adjacent stromal cells, and evasion of conventional therapies. As with other cancer stem cells, pancreatic cancer stem cells (PCSCs) can be distinguished from bulk tumor cells based on their expression of unique surface markers, abilities to form spheres under nonadherent conditions and tumors in mice, and self-renewal and differentiation capacities. We review the markers used to identify PCSCs, the signaling pathways that regulate PCSC functions, the complex interactions between PCSCs and stromal cells, and approaches to therapeutically target PCSCs and improve treatment of patients with pancreatic cancer.
  Gastroenterology 06/2013; 144(6):1241-8.
• Article: Roles for KRAS in Pancreatic Tumor Development and Progression.

  Marina Pasca di Magliano, Craig D Logsdon
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  ABSTRACT: The Kras gene is mutated to an oncogenic form in most pancreatic tumors. However, early attempts to use this molecule as a specific biomarker of the disease, or inhibit its activity as a cancer therapy, failed. This left a situation in which everyone was aware of the association between this important oncogene and pancreatic cancer, but no one knew what to do about it. Recent findings have changed this picture-many assumptions made about KRAS and its role in pancreatic cancer were found to be incorrect. Several factors have contributed to increased understanding of the activities of KRAS, including creation of genetically engineered mouse models, which have allowed for detailed analyses of pancreatic carcinogenesis in an intact animal with a competent immune system. Cancer genome sequencing projects have increased our understanding of the heterogeneity of individual tumors. We also have a better understanding of which oncogenes are important for tumor maintenance and are therefore called "drivers." We review the advances and limitations of our knowledge about the role of Kras in development of pancreatic cancers and the important areas for future research.
  Gastroenterology 06/2013; 144(6):1220-9.
• Article: Management of chronic pancreatitis.

  Christopher E Forsmark
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  ABSTRACT: Advances in our understanding of chronic pancreatitis have improved our care of patients with this disease. Although our therapies are imperfect and many patients remain symptomatic, appropriate medical care improves the quality of life in these patients. Proper management requires an accurate diagnosis, recognition of the modifiable causes of disease, assessment of symptoms and complications, treatment of these symptoms and complications utilizing a multidisciplinary team, and ongoing monitoring for the effect of therapy and the occurrence of complications.
  Gastroenterology 06/2013; 144(6):1282-1291.e3.
• Article: A starring role for stellate cells in the pancreatic cancer microenvironment.

  Minoti V Apte, Jeremy S Wilson, Aurelia Lugea, Stephen J Pandol
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  ABSTRACT: Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.
  Gastroenterology 06/2013; 144(6):1210-9.
• Article: Pancreatic cystic neoplasms: management and unanswered questions.

  James J Farrell, Carlos Fernández-Del Castillo
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  ABSTRACT: Approximately 10% of persons 70 years old or older are now diagnosed with pancreatic cysts, but it is not clear which ones require additional analysis, interventions, or follow-up. Primary care doctors rely on gastroenterologists for direction because no one wants to miss a diagnosis of pancreatic cancer, but meanwhile there is pressure to limit use of diagnostic tests and limit costs. We review the different cystic neoplasms of the pancreas and diagnostic strategies based on clinical features and imaging data. We discuss surgical and nonsurgical management of the most common cystic neoplasms, based on the recently revised Sendai guidelines. Intraductal papillary mucinous neoplasm (particularly the branch duct variant) is the lesion most frequently identified incidentally. We report what is known about its pathology, its risk of developing into pancreatic ductal adenocarcinoma, the pros and cons of current guidelines for management, and the potential role of endoscopic ultrasound in determining cancer risk. We also review surgical treatment and strategies for surveillance of pancreatic cysts.
  Gastroenterology 06/2013; 144(6):1303-15.
• Article: The epidemiology of pancreatitis and pancreatic cancer.

  Dhiraj Yadav, Albert B Lowenfels
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  ABSTRACT: Acute pancreatitis is one of the most frequent gastrointestinal causes of hospital admission in the United States. Chronic pancreatitis, although lower in incidence, significantly reduces patients' quality of life. Pancreatic cancer is associated with a high mortality rate and is one of the top 5 causes of death from cancer. The burden of pancreatic disorders is expected to increase over time. The risk and etiology of pancreatitis differ with age and sex, and all pancreatic disorders affect the black population more than any other race. Gallstones are the most common cause of acute pancreatitis, and early cholecystectomy eliminates the risk of future attacks. Alcohol continues to be the single most important risk factor for chronic pancreatitis. Smoking is an independent risk factor for acute and chronic pancreatitis, and its effects could synergize with those of alcohol. Significant risk factors for pancreatic cancer include smoking and non-O blood groups. Alcohol abstinence and smoking cessation can alter the progression of pancreatitis and reduce recurrence; smoking cessation is the most effective strategy to reduce the risk of pancreatic cancer.
  Gastroenterology 06/2013; 144(6):1252-61.
• Article: Therapeutic advances in pancreatic cancer.

  Andrew Scott Paulson, Hop S Tran Cao, Margaret A Tempero, Andrew M Lowy
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  ABSTRACT: Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5-10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of "borderline resectable pancreatic cancer"-a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future.
  Gastroenterology 06/2013; 144(6):1316-26.
• Article: Technologies for imaging the normal and diseased pancreas.

  Gregory A Coté, Jeffrey Smith, Stuart Sherman, Kimberly Kelly
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  ABSTRACT: The prognosis is poor for most patients with pancreatic cancer, chronic pancreatitis, or other pancreatic diseases. Advances in pancreatic imaging could help identify these diseases at earlier stages, when they are easier to treat. Radiographic imaging and endoscopic imaging of the pancreas have progressed from the abdominal roentogram and endoscopic retrograde pancreatography to multi-detector computed tomography, magnetic resonance cholangiopancreatography, endoscopic ultrasonography, and pancreatoscopy. These technologies have improved the diagnosis and treatment of benign disease but have not significantly increased our ability to detect early-stage disease or affect outcomes of patients with pancreatic cancer or chronic pancreatitis. Advances in endoscopic imaging and molecular-based radiographic tests could allow physicians to identify pancreatic lesions and their precursors at earlier stages. Furthermore, research studies that include these tools could improve our understanding of disease pathogenesis and identify diagnostic markers and therapeutic targets. We review endoscopic imaging modalities, focusing on new endoscopic and molecular-based radiographic imaging tests that have the potential to substantially improve diagnosis and treatment of pancreatic disease.
  Gastroenterology 06/2013; 144(6):1262-1271.e1.