Therapeutic Advances in Gastroenterology

Publications in this journal

• Article: Irritable bowel syndrome: a multidimensional disorder cannot be understood or treated from a unidimensional perspective.

  Ami D Sperber, Douglas A Drossman
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):387-393.
• Article: Irritable bowel syndrome: how useful is the term and the 'diagnosis'?

  Michael Camilleri
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):381-386.
• Article: Safety and efficacy of fidaxomicin in the treatment of Clostridium difficile-associated diarrhea.

  Yoav Golan, Lauren Epstein
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  ABSTRACT: Clostridium difficile-associated diarrhea (CDAD) is the most common cause of healthcare-associated diarrhea. The current recommended treatment regimens of metronidazole and vancomycin have not changed in nearly 25 years. Fidaxomicin, an exceedingly narrow spectrum macrolide antibiotic, was recently approved for the treatment of CDAD. In phase III clinical trials, fidaxomicin was noninferior to vancomycin in achieving clinical cure of CDAD. Furthermore, fidaxomicin was associated with fewer recurrences of CDAD compared with vancomycin in clinical trials. These results, combined with the ease of administration and a good safety profile, make fidaxomicin an attractive treatment option for treating CDAD.
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):395-402.
• Article: Fecal microbiota transplantation in relapsing Clostridium difficile infection.

  Faith Rohlke, Neil Stollman
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  ABSTRACT: Clostridium difficile infection rates are Climbing in frequency and severity, and the spectrum of susceptible patients is expanding beyond the traditional scope of hospitalized patients receiving antibiotics. Fecal microbiota transplantation is becoming increasingly accepted as an effective and safe intervention in patients with recurrent disease, likely due to the restoration of a disrupted microbiome. Cure rates of > 90% are being consistently reported from multiple centers. Transplantation can be provided through a variety of methodologies, either to the lower proximal, lower distal, or upper gastrointestinal tract. This review summarizes reported results, factors in donor selection, appropriate patient criteria, and the various preparations and mechanisms of fecal microbiota transplant delivery available to clinicians and patients.
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):403-420.
• Article: What is irritable bowel syndrome?

  Peter J Whorwell
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):379-380.
• Article: Single-balloon enteroscopy in managing Peutz Jeghers syndrome polyps.

  Piyush Aggarwal, Veena Kumaravel, Bennie R Upchurch
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):439-441.
• Article: Management of patients with difficult autoimmune hepatitis.

  Richard Parker, Ye Htun Oo, David H Adams
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  ABSTRACT: Autoimmune hepatitis (AIH) is characterized by a T-cell rich infiltrate associated with lobular and interface hepatitis, hypergammaglobulinemia and production of autoantibodies. Genetic risk is linked to the HLA particularly DRB1*0301 and DRB1*0401 alleles in North American and European Caucasian populations. It has recently been suggested that functional deficiencies in CD4(+)CD25(+)CD127(low)FOXP3(+) regulatory T cells contribute to the breakdown of immune tolerance that results in AIH. Most patients respond to immunosuppressive therapy with corticosteroids and can be maintained in remission by low-dose corticosteroid treatment and/or azathioprine. For those who progress to end-stage disease liver transplantation is an effective treatment although it is associated with recurrence. In the future it is likely that biological therapies will allow more targeted therapy designed to switch the balance to immune regulation and thereby restore immune homeostasis. Although treatment for many cases is relatively straightforward and successful problems are encountered in those who fail to respond to standard treatment, are unable to tolerate it or relapse. In such cases alternative therapies should be considered. In addition treatment is complicated in some patients by comorbidity and special care is required during and after pregnancy. We will discuss the current and future therapeutic options for patients with difficult to treat AIH.
  Therapeutic Advances in Gastroenterology 11/2012; 5(6):421-437.
• Article: Therapeutic targeting of the phosphatidylinositol 3-kinase signaling pathway: novel targeted therapies and advances in the treatment of colorectal cancer.

  Ming Yu, William M Grady
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  ABSTRACT: Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the USA, and more effective treatment of CRC is therefore needed. Advances in our understanding of the molecular pathogenesis of this malignancy have led to the development of novel molecule-targeted therapies. Among the most recent classes of targeted therapies being developed are inhibitors targeting the phosphatidylinositol 3-kinase (PI3K) signaling pathway. As one of the most frequently deregulated pathways in several human cancers, including CRC, aberrant PI3K signaling plays an important role in the growth, survival, motility and metabolism of cancer cells. Targeting this pathway therefore has considerable potential to lead to novel and more effective treatments for CRC. Preclinical and early clinical studies have revealed the potential efficacy of drugs that target PI3K signaling for the treatment of CRC. However, a major challenge that remains is to study these agents in phase III clinical trials to see whether these early successes translate into better patient outcomes. In this review we focus on providing an up-to-date assessment of our current understanding of PI3K signaling biology and its deregulation in the molecular pathogenesis of CRC. Advances in available agents and challenges in targeting the PI3K signaling pathway in CRC treatment will be discussed and placed in the context of the currently available therapies for CRC.
  Therapeutic Advances in Gastroenterology 09/2012; 5(5):319-37.
• Article: Management of hepatitis B reactivation in patients receiving cancer chemotherapy.

  Yi-Wen Huang, Raymond T Chung
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  ABSTRACT: Hepatitis B virus (HBV) reactivation is well documented in previously resolved or inactive HBV carriers who receive cancer chemotherapy. The consequences of HBV reactivation range from self-limited conditions to fulminant hepatic failure and death. HBV reactivation also leads to premature termination of chemotherapy or delay in treatment schedules. This review summarizes current knowledge of management of HBV reactivation in patients receiving cancer chemotherapy. HBV surface antigen (HBsAg) testing should be performed in patients who require cancer chemotherapy. Four meta-analyses support lamivudine prophylaxis for HBV reactivation during chemotherapy in HBsAg-positive patients. Randomized controlled trials to compare different HBV antiviral agents are needed to define optimal regimens for the prevention and treatment of HBV reactivation in patients receiving cancer chemotherapy.
  Therapeutic Advances in Gastroenterology 09/2012; 5(5):359-70.
• Article: Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer.

  Alicia F C Okines, David Cunningham
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  ABSTRACT: The human epidermal receptor-2 (HER-2) is amplified in up to 25% of patients with gastroesophageal adenocarcinomas. Although the presence of this amplification does not appear to confer a poor prognosis, it provides a valuable novel therapeutic target for this group of patients. Trastuzumab is a fully humanized monoclonal antibody directed at HER-2 which binds the external domain of the receptor and exerts its action via a combination of antibody-dependent cytotoxicity, reduced shedding of the extracellular domain, inhibition of dimerization and possibly receptor downregulation. The ToGA trial was an international multicentre randomized phase III study which evaluated the addition of trastuzumab to a cisplatin plus fluoropyrimidine chemotherapy doublet in 594 patients with HER-2-positive advanced gastric or oesophagogastric junction adenocarcinoma. The combination of the antibody with chemotherapy significantly improved response rate, median progression-free survival and median overall survival without additional toxicity or adversely affecting quality of life. Accordingly, trastuzumab plus chemotherapy is now a standard first-line treatment option for patients with advanced HER-2-positive gastroesophageal cancer. Unfortunately, many patients with HER-2-positive cancer exhibit primary resistance to trastuzumab and the remainder will acquire resistance to the antibody; therefore, urgent investigation into novel agents which may circumvent resistance mechanisms is warranted. Small molecule inhibitors of HER-2, which commonly also target other members of the HER family of receptors, such as EGFR and HER-3, are currently undergoing evaluation in gastroesophageal cancer as first-line alternatives to trastuzumab and second-line salvage treatments for trastuzumab-resistant disease. Extrapolating the successful use of trastuzumab in the advanced disease setting, clinical trials are underway to assess the role of this antibody in the perioperative and adjuvant settings, where it is hoped that it will have a meaningful impact upon the currently poor survival rates.
  Therapeutic Advances in Gastroenterology 09/2012; 5(5):301-18.
• Article: Pain management in patients with inflammatory bowel disease: insights for the clinician.

  Arvind Iyengar Srinath, Chelsea Walter, Melissa C Newara, Eva M Szigethy
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  ABSTRACT: Abdominal pain is a common symptom in patients with inflammatory bowel disease (IBD) and has a profound negative impact on patients' lives. There are growing data suggesting that pain is variably related to the degree of active inflammation. Given the multifactorial etiologies underlying the pain, the treatment of abdominal pain in the IBD population is best accomplished by individualized plans. This review covers four clinically relevant categories of abdominal pain in patients with IBD, namely, inflammation, surgical complications, bacterial overgrowth, and neurobiological processes and how pain management can be addressed in each of these cases. The role of genetic factors, psychological factors, and psychosocial stress in pain perception and treatment will also be addressed. Lastly, psychosocial, pharmacological, and procedural pain management techniques will be discussed. An extensive review of the existing literature reveals a paucity of data regarding pain management specific to IBD. In addition, there is growing consensus suggesting a spectrum between IBD and irritable bowel syndrome (IBS) symptoms. Thus, this review for adult and pediatric clinicians also incorporates the literature for the treatment of functional abdominal pain and the clinical consensus from IBD and IBS experts on pharmacological, behavioral, and procedural methods to treat abdominal pain in this population.
  Therapeutic Advances in Gastroenterology 09/2012; 5(5):339-57.
• Article: Persistent spontaneous bacterial peritonitis: a common complication in patients with spontaneous bacterial peritonitis and a high score in the model for end-stage liver disease.

  Archita P Desai, Nancy Reau, K Gautham Reddy, Helen S Te, Smruti Mohanty, Rohit Satoskar, Amanda Devoss, Donald Jensen
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  ABSTRACT: Spontaneous bacterial peritonitis (SBP) is associated with a high mortality rate. After antibiotic therapy, improvement in fluid polymorphonuclear (PMN) cell count is expected within 2 days. However, our institution recognized cases unresponsive to standard treatment. To study these recalcitrant cases, we completed a retrospective chart review of patients admitted for SBP to the University of Chicago from 2002 to 2007. SBP was defined by an ascitic PMN cell count ≥250/ml. Of 55 patients with SBP, 15 did not show improvement in fluid PMN cell count to below 250/ml with standard treatment, leading to a prevalence of 27%. The patients with persistent SBP were younger than those with nonpersistent SBP [mean (SD) 51.80 (9.84) compared with 58.13 (8.79); p = 0.0253]. Persistent SBP had a higher serum ascites albumin gradient (SAAG) [median (Q1, Q3) 1.85 (1.50, 2.41) compared with 1.10 (0.60, 1.60)] and a higher score in the model for end-stage liver disease (MELD) [mean (SD) 27.98 (8.09) compared with 22.22 (8.10)] than nonpersistent SBP patients; p = 0.027 and p = 0.023, respectively. In addition, persistent SBP patients were more likely to have a positive ascitic fluid culture than nonpersistent SBP patients [odds ratio (OR) (95% CI) 4.33 (1.21, 15.47); p = 0.024]. Importantly, in-hospital mortality in the persistent SBP group was 40%, compared with 22.5% in the nonpersistent SBP group [OR = 2.30 (0.64, 8.19); p = 0.20]. The risk of persistent SBP is nearly 40% in patients with MELD score >25, SAAG >1.5 or positive ascitic fluid culture. Furthermore, patients who develop persistent SBP tend to experience a higher mortality rate. This study underscores the importance of further examination of this vulnerable population.
  Therapeutic Advances in Gastroenterology 09/2012; 5(5):275-83.
• Article: Management of Barrett's oesophagus and intramucosal oesophageal cancer: a review of recent development.

  Shanmugarajah Rajendra, Prateek Sharma
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  ABSTRACT: Barrett's oesophagus is the most important and recognizable precursor lesion for oesophageal adenocarcinoma, which is the one of the fastest growing cancers in the Western World. The incidence of oesophageal adenocarcinoma has increased 600% in the United States between 1975 and 2001 and is thought to represent a real increase in burden rather than a result of histologic or anatomical misclassification or overdiagnosis. Thus, the cancer risk in Barrett's oesophagus has to be managed and involves prevention (surveillance endoscopy), treating underlying gastroesophageal reflux disease (medically and or surgically) and endoscopic therapy to remove diseased epithelium in appropriate patient subgroups. In the last decade, new developments in imaging and molecular markers as well as an armamentarium of novel and effective endoscopic eradication therapy has become available to the endoscopist to combat this exponential rise in oesophageal adenocarcinoma. Paradoxically, the cancer risk in Barrett's oesophagus gets progressively downgraded which raises fundamental questions about our understanding of the known and unknown risk factors and molecular aberrations that are involved in the Barrett's metaplasia-dysplasia-carcinoma sequence. Future research has to be directed at these areas to fine tune our screening and surveillance programs to identify more accurately the high-risk group of progressors to oesophageal adenocarcinoma who would benefit most from endoscopic therapy.
  Therapeutic Advances in Gastroenterology 09/2012; 5(5):285-99.
• Article: Chronic constipation: new diagnostic and treatment approaches.

  Brian E Lacy, John M Levenick, Michael Crowell
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  ABSTRACT: Chronic constipation is a highly prevalent disorder that affects approximately 15% of the US population. Chronic constipation refers to patients who have had symptoms for more than 6 months. In clinical practice, chronic constipation is often used interchangeably with the term functional constipation. This is best defined using the Rome III criteria, which involves an evaluation of stool frequency in addition to symptoms of straining, feelings of incomplete evacuation, and the need to use manual maneuvers to assist with stool evacuation. Symptoms can be burdensome, leading to a reduction in patients' quality of life. As a national healthcare issue, chronic constipation is also important because it imposes a significant economic impact on the healthcare system. A number of treatment options are currently available, both over-the-counter and by prescription, although not all patients respond to these therapies. This review will focus on new medical treatment options for the management of chronic constipation, and the safety and efficacy of these agents will be reviewed. In addition, the efficacy of new diagnostic tests to evaluate colonic motility and anorectal function are described.
  Therapeutic Advances in Gastroenterology 07/2012; 5(4):233-47.
• Article: Overutilization of proton-pump inhibitors: what the clinician needs to know.

  Joel J Heidelbaugh, Andrea H Kim, Robert Chang, Paul C Walker
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  ABSTRACT: Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.
  Therapeutic Advances in Gastroenterology 07/2012; 5(4):219-32.
• Article: Evaluation of regional and whole gut motility using the wireless motility capsule: relevance in clinical practice.

  Khoa Tran, Rita Brun, Braden Kuo
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  ABSTRACT: The wireless motility capsule (WMC) is an ambulatory noninvasive and nonradioactive diagnostic sensor that continuously samples intraluminal pH, temperature, and pressure as it moves through the gastrointestinal (GI) tract. This review summarizes the data obtained in clinical trials with the WMC and discusses its role in clinical practice. The United States Food and Drug Administration has approved the SmartPill GI monitoring system for the evaluation of gastric emptying time in patients with suspected gastroparesis, the evaluation of colonic transit time in patients with suspected chronic constipation, and for the characterization of pressure profiles from the antrum and duodenum. Clinical studies have shown that WMC-measured GI transit times can distinguish patients with motility abnormalities similarly to conventional testing. However, the WMC offers the advantage of providing a full GI-tract profile, enabling the detection of multiregional GI transit abnormalities in patients with suspected upper or lower GI dysmotility. The WMC also characterizes pressure profiles of the GI tract and impaired pressure profile limits are reported for the antrum and duodenum. In comparison with manometry, interpretations of pressure measurements obtained by the WMC are limited by an inability to detect a peristaltic pressure wave front, and further investigation is required to develop clinical applications. Clinical studies with the WMC indicated that it should be considered for the evaluation of regional and whole gut transit time in patients with suspected upper or lower dysmotility, particularly if there are concerns about multiregional dysmotility.
  Therapeutic Advances in Gastroenterology 07/2012; 5(4):249-60.
• Article: Irritable bowel syndrome and ischemic colitis: evidence supporting the increased use of alosetron.

  Susan Lucak
  Therapeutic Advances in Gastroenterology 07/2012; 5(4):215-8.
• Article: Vasopressin V2-receptor antagonists in patients with cirrhosis, ascites and hyponatremia.

  Shahid Habib, Thomas D Boyer
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  ABSTRACT: Hyponatremia is a common problem in patients with advanced cirrhosis. It develops slowly (paralleling the rate of progression of the liver disease) and usually produces no neurological symptoms, although it may exacerbate hepatic encephalopathy. For patients awaiting liver transplantation a low serum sodium level is a strong predictor of pretransplant mortality, independent of the Model for End-stage Liver Disease score (MELD). The pathogenesis of hyponatremia is related to the hemodynamic changes and secondary neurohormonal adaptations that occur in patients with cirrhosis and ascites. The nonosmotic release of arginine vasopressin is the principle cause of the hyponatremia and vasopressin-receptor antagonists are a new class of drugs recently approved for treatment of cirrhotic hyponatremia. In this article we review the safety and efficacy of V2-receptor antagonists in patients with cirrhosis, ascites and hyponatremia.
  Therapeutic Advances in Gastroenterology 05/2012; 5(3):189-97.
• Article: Boceprevir: a novel nonstructural 3 (NS3) protease inhibitor for the treatment of chronic hepatitis C infection.

  Paul Y Kwo
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  ABSTRACT: Chronic hepatitis C infection is a leading cause of morbidity and mortality worldwide, with hepatitis C related cirrhosis being the most common indication for transplant and a major cause for the increase in hepatocellular carcinoma worldwide. Treatment for hepatitis C has consisted of nonspecific immunomodulatory therapies that stimulate the immune system and inhibit hepatitis C replication. Pegylated (peg-)interferon and ribavirin have been the standard of care with an overall sustained response rate of 40-50% in patients with genotype 1 infection, and 80% in genotype 2 or 3. Recently, direct-acting antiviral agents, including boceprevir, have demonstrated improved sustained response rates in patients with genotype 1 infection when given in combination with interferon and ribavirin. Boceprevir is a structurally novel hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor that has demonstrated robust antiviral activity in HCV replicons. Clinically, in phase II and III trials, boceprevir 800 mg three times daily with peginterferon and ribavirin has led to improved sustained response rates in genotype 1 infection treatment-naive patients, relapsers, partial responders, and null responders. Phase II data have demonstrated that ribavirin is essential for optimal boceprevir response. Moreover, phase II data have suggested that a 4-week peginterferon or ribavirin lead-in strategy may reduce relapse rates and provide crucial on-treatment data for treatment response with boceprevir addition. Side effects of boceprevir when added to peginterferon and ribavirin are similar to peginterferon and ribavirin, though higher rates of anemia have been noted, with an incremental increase in erythropoietin use. The addition of boceprevir represents a major advance in patients with genotype 1 infection who are treatment naïve.
  Therapeutic Advances in Gastroenterology 05/2012; 5(3):179-88.