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Abstract

One of the most common entities encountered in a gastroenterologist's practice is irritable bowel syndrome (IBS), which is characterized by abdominal pain and changes in stool frequency or consistency. In addition to the syndrome's high prevalence, the paucity of effective therapies compounds the difficulty in caring for these patients. One therapeutic strategy that has recently garnered increasing attention is a dietary strategy whose aim is to reduce dietary fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). The reduction of fermentable substrates within the intestine has been hypothesized to result in decreased gas production, which in turn will reduce the amount of intestinal distention and discomfort. In this issue of Gastroenterology, Halmos et al report on a clinical controlled trial performed in Australia that evaluates the impact of a low FODMAP diet on IBS. The study enrolled 30 patients with IBS as determined by the Rome III criteria and 8 healthy controls. The subjects were randomly assigned to either a low (<0.5 g) FODMAP diet or a typical Australian diet for 21 days. This phase was followed by a washout period for 21 days before the patients were switched to the alternative diet for another 21 days. For this study, almost all foods consumed by the patient were provided by the study. The patients were blinded; they could not discriminate between the low FODMAP and typical Australian diet. The outcomes included daily symptoms measured by a visual analog scale, and the characterization of collected stool from days 17 to 21 that were evaluated for frequency, weight, water content, and the King's Stool Chart rating. Compared with the patients' baseline, the low FODMAP diet resulted in gastrointestinal symptom scores that were lower based on the visual analog scale (22.8 mm [range, 16.7–28.8]; P < .001) and greater on the typical Australian diet (44.9 mm [range, 36.6–53.1]; P < .001) (Figure 1). A similar effect was also observed for the effect of the low FODMAP diet on abdominal pain, bloating, and flatulence. With respect to the fecal analysis, only the King's Stool Chart rating showed a significantly lower score in patients restricted to the IBS-diarrhea subtype. No differences in stool outcomes were observed with other IBS subgroups. An accompanying editorial by Magnus Simren provides additional insight into this study. See page 67; editorial on page 10. Recent studies have demonstrated a role for anti-tumor necrosis factor (TNF)-α in the treatment of ulcerative colitis patients with moderate to severe disease. The most common therapies employed are biologics such as infliximab and adalimumab, which have demonstrated therapeutic efficacy compared to placebo. The infliximab antibody's composition of human and murine elements may lead to human neutralizing antibodies that decrease therapeutic efficacy, which prompted the development of fully human monoclonal antibodies against TNF-α. This issue of Gastroenterology contains 2 papers by Sandborn et al that report on the effectiveness of golimumab, a fully human anti–TNF-α monoclonal antibody, for the treatment of moderate to severe ulcerative colitis. The 2 studies were sponsored by Janssen Pharmaceuticals Research & Development, and conducted by the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT). PURSUIT is composed of 217 sites in Eastern Europe, North America, Asia Pacific, South Africa, Western Europe, and Israel. The first paper consists of an integrated phase 2 and phase 3 clinical trial of subcutaneously administered golimumab that determined the dose–response relationship, safety, and efficacy of various regimens for inducing remission. Subjects were first classified as moderate to severe using the Mayo scoring system that incorporates a stool frequency index, rectal bleeding, endoscopic appearance, and the physician's overall assessment. Eligible subjects possessed a history of failing or not tolerating at least one or more therapies that included oral 5-aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine. Subjects who could not be tapered off corticosteroids were also included. Patients were administered either a placebo, or 200/100 mg or 400/200 mg of golimumab at 0 and 2 weeks. The primary end point of the phase 3 trial was the clinical response at 6 weeks, which was higher for the 200/100 mg and 400/200 mg golimumab-treated groups (51.8% and 55.0%, respectively) than for placebo-treated patients (29.7%; P < .0001). The second paper by Sandborn et al evaluated the efficacy of a maintenance regimen of 50 or 100 mg of golimumab every 4 weeks for patients who experienced a successful therapeutic induction in the prior study. The primary end point was successful maintenance of the clinical response for 54 weeks. Both the 50- and 100-mg treatment groups displayed higher rates of maintaining a clinical response (47.1% and 50.6%, respectively) than placebo (31.4%; P = .010 and P < .001, respectively). Antibodies to golimumab developed in 2.9%, of which 67.7% were neutralizing. Adverse effects observed were similar to those described for other anti–TNF-α biologics. Even though all subjects were previously screened for tuberculosis, 4 cases of tuberculosis were observed, and all originated from endemic areas. An in-depth analysis of these studies is provided in an accompanying editorial by Stephen Hanauer (Figure 2). See pages 85 and 96;editorial on page 13. Inflammation-associated development of gastrointestinal cancers, such as hepatocellular carcinoma in the setting of chronic viral infection and Helicobacter pylori-associated gastric cancer, has been characterized by the stepwise accumulation of genetic and epigenetic alterations in multiple tumor-related genes, including activation of proto-oncogenes and inactivation of tumor-suppressor genes. Identification of the genetic alterations that occur in inflamed tissues before tumor development as well as the mechanisms for these inflammation-associated genetic alterations has potentially broad application to cancer prevention, diagnosis, and therapy. In this issue of Gastroenterology, Ikeda et al use whole exome sequencing of tumors and background inflamed liver tissue from patients with chronic infection with hepatitis C virus (HCV) to examine the genetic basis of HCV-associated hepatocarcinogenesis. Of 2 genes that were recurrently mutated in nontumorous cirrhotic livers, LEPR, the leptin receptor gene, was the focus of additional study. Mutations in LEPR were detected in 90% of tumors and 54.5% of nontumorous cirrhotic livers examined. In contrast, no mutations in LEPR were detected in noncirrhotic, HCV-infected liver or normal liver. Mutations involving the immunoglobulin domain of LEPR were demonstrated to lead to downstream signaling changes including reduction or loss of STAT3 phosphorylation, up-regulation of cyclin D1 and E, and enhanced cell proliferation. Enhanced susceptibility to tumorigenesis from LEPR dysfunction was determined in Lepr-deficient (db/db) mice exposed to the carcinogen, thioacetamide, at doses much lower than carcinogenic doses. After 24 weeks of 2 administration, inflammatory activity was more severe in the db/db mice and in 4 of 10 db/db mice, nodules, exhibiting features of hepatocyte hyperplasia, developed, including well-differentiated hepatocellular carcinoma in 2 db/db mice; none of the control mice developed nodules (Figure 3). These findings suggest that dysregulation of leptin signaling has a role in hepatic tumorigenesis, particularly in the setting of HCV-associated chronic inflammation, although the mechanism remains unknown. See page 222. Pancreatic adenocarcinoma remains among the most lethal human cancers. Significant progress in characterizing the disease's evolution used human pathology samples and murine animal models. The current theory for the disease's pathogenesis begins with the development of pancreatic intraepithelial neoplasia (PanIN) in the pancreatic ducts. These lesions often harbor activating mutations in KRAS. As PanINs progressively express pathologic features consistent with progression toward a metastatic phenotype, additional mutations appear. Recent studies in murine models have demonstrated that PanINs may arise from pancreatic acinar, duct, or centroacinar cells. The development of PanINs and subsequent pancreatic adenocarcinoma is greatly accelerated with pancreatitis-associated injury and inflammation. In this issue of Gastroenterology, 2 groups show that PanINs are heterogeneous and populated by tuft cells. The tuft cells appear early in the metaplastic process and may represent tumor-initiating cells, which have also been coined cancer stem cells. In the study by Bailey et al, murine pancreatic cancer models that conditionally express a mutated constitutively activated KRASG12D during pancreatic development or in adult mice were used to generate PanIN lesions. The authors identified a subpopulation of cells in very early lesions that express DCLK1 and acetylated α-tubulin, and morphologically resembled tuft cells (Figure 4). These tuft cells were found to comprise ≤20% of epithelial cells in acinar to ductal metaplastic lesions. DCLK1 expression declined as the lesions progressed to more advanced PanIN lesions and adenocarcinoma. Examination of human PanIN and pancreatic adenocarcinoma tissues also revealed the presence of tuft-like cells that expressed acetylated α-tubulin. The authors demonstrated that DCLK1 and acetylated α-tubulin expressing cells are potentially tumor-initiating because they possess greater clonogenic activity through their ability to form PanIN spheres in a suspension culture system. A second study by DelGiorno in this issue also similarly identified tuft-like cells as an early feature in cancer pathogenesis. The same group recently published work demonstrating the importance of the epidermal growth factor signaling pathway in the early development of pancreatic cancer (Cancer Cell 2012;22:304–317). The authors utilized the LSL-KrasG12D/+;Ptf1aCre/+ murine model of pancreatic cancer and discovered that cells expressing activated EGF receptors also displayed features of tuft cells, which was confirmed with DLCK1+ immunohistochemistry. This study similarly found that tuft cells were most prominent in early lesions of acinar to duct metaplasia, which declined as the lesions progressed toward pancreatic adenocarcinoma. Tuft cells are absent in the normal pancreatic duct, but are present in normal bile ducts. The authors discovered that tuft cells in pancreatic metaplasia express markers found in their biliary counterpart, namely DLCK1, PDX1, and SOX17. When SOX17 expression was induced in the pancreas of transgenic mice, tuft cells appeared along with the development of a stromal response exhibiting inflammation and fibrosis, similar to chronic pancreatitis. When acinar SOX17 expression was induced along with the KRASG12D mutation, extensive PanIN lesions developed. The authors conclude that metaplastic pancreatic ductal lesions represent a transdifferentiation to a biliary phenotype, which is highlighted by the expression of SOX17. Further insights into these studies are provided in an editorial by Maike Sander. See pages 233 and 245;editorial on page 24. Diet as a Therapy for Irritable Bowel Syndrome: Progress at LastGastroenterologyVol. 146Issue 1PreviewPostprandial worsening of symptoms, as well as adverse reactions to one or more foods are common in patients with irritable bowel syndrome (IBS),1 and self-reported food intolerance in IBS is associated with a high symptom burden and reduced quality of life.2 In line with this, approximately two thirds of IBS patients exclude food items from their diet to improve symptoms.3 Despite this, there is no evidence suggesting inadequate nutrient intake in the majority of patients with IBS.4 For patients, identifying the food item/s they do not tolerate is often central when consulting for their symptoms, and in general guidelines for management of IBS, dietary advice is proposed to be of major importance. Full-Text PDF Subcutaneous Golimumab Induces Clinical Response and Remission in Patients With Moderate-to-Severe Ulcerative ColitisGastroenterologyVol. 146Issue 1PreviewLittle is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) −α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF−α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment. Full-Text PDF New Insights Into the Cell Lineage of Pancreatic Ductal Adenocarcinoma: Evidence for Tumor Stem Cells in Premalignant Lesions?GastroenterologyVol. 146Issue 1PreviewPancreatic ductal adenocarcinoma (PDA) is a deadly disease primarily because of its asymptomatic nature early in the disease process. As a result, the diagnosis is usually not established until the tumor has already become invasive. To improve detection and treatment options for PDA, efforts to better understand the early stages of PDA are clearly warranted. Invasive PDA is believed to arise from a spectrum of preneoplastic mucinous lesions, the most common of which are pancreatic intraepithelial neoplasias (PanINs). Full-Text PDF Subcutaneous Golimumab Maintains Clinical Response in Patients With Moderate-to-Severe Ulcerative ColitisGastroenterologyVol. 146Issue 1PreviewSubcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy. Full-Text PDF Still in PursuitGastroenterologyVol. 146Issue 1PreviewThe titles tell it all. Subcutaneous golimumab induces clinical response and (clinical) remission and maintains clinical response in (out) patients with moderate-to-severe ulcerative colitis.1,2 However, this is not the full story. As the authors state, infliximab and adalimumab have been shown to be effective for induction and maintenance (of clinical responses) for patients with moderate-to-severe symptoms and endoscopic evidence of ulcerative colitis despite ongoing therapy with aminosalicylates, corticosteroids, or thiopurines. Full-Text PDF Leptin Receptor Somatic Mutations Are Frequent in HCV-Infected Cirrhotic Liver and Associated With Hepatocellular CarcinomaGastroenterologyVol. 146Issue 1PreviewHepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver. Full-Text PDF DCLK1 Marks a Morphologically Distinct Subpopulation of Cells With Stem Cell Properties in Preinvasive Pancreatic CancerGastroenterologyVol. 146Issue 1PreviewAs in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell–like properties. Full-Text PDF A Diet Low in FODMAPs Reduces Symptoms of Irritable Bowel SyndromeGastroenterologyVol. 146Issue 1PreviewA diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) often is used to manage functional gastrointestinal symptoms in patients with irritable bowel syndrome (IBS), yet there is limited evidence of its efficacy, compared with a normal Western diet. We investigated the effects of a diet low in FODMAPs compared with an Australian diet, in a randomized, controlled, single-blind, cross-over trial of patients with IBS. Full-Text PDF Identification and Manipulation of Biliary Metaplasia in Pancreatic TumorsGastroenterologyVol. 146Issue 1PreviewMetaplasias often have characteristics of developmentally related tissues. Pancreatic metaplastic ducts are usually associated with pancreatitis and pancreatic ductal adenocarcinoma. The tuft cell is a chemosensory cell that responds to signals in the extracellular environment via effector molecules. Commonly found in the biliary tract, tuft cells are absent from normal murine pancreas. Using the aberrant appearance of tuft cells as an indicator, we tested if pancreatic metaplasia represents transdifferentiation to a biliary phenotype and what effect this has on pancreatic tumorigenesis. Full-Text PDF