Therapeutic Advances in Gastroenterology recent issues

Sequential therapy for Helicobacter pylori eradication: the time is now!

Vaira, D., Zullo, A., Hassan, C., Fiorini, G., Vakil, N. — Fri, 06 Nov 2009 02:37:58 PST

Endoscopic resection with ligation using a multi-band mucosectomy system in Barrett's esophagus with high-grade dysplasia and intramucosal carcinoma

Bhat, Y. M., Furth, E. E., Brensinger, C. M., Ginsberg, G. G. — Fri, 06 Nov 2009 02:37:58 PST

Background: Endoscopic therapy for early neoplasia in Barrett’s esophagus (BE) is evolving. Endoscopic resection has an increasing role. We wanted to evaluate the safety and efficacy of multi-band ligation/resection [ER-L] without pre-injection in BE with high-grade dysplasia [HGD] and intramucosal carcinoma [IMCA].

Methods: A cohort of 65 consecutive patients from a single academic medical center, who underwent ER-L as part of endoscopic eradication therapy for BE with HGD/IMCA were studied. ER-L was performed after endoscopic mapping and endoscopic ultrasound (EUS). Subsequently, adjunctive ablative therapies including photodynamic therapy, argon plasma coagulation and radiofrequency ablation were applied to achieve complete eradication of all BE. Thereafter biopsy surveillance was performed per protocol. All patients were prescribed a proton-pump inhibitor. Main outcome measurements: Change in histopathological stage; eradication of BE and HGD/IMCA; adverse events.

Results: The median number of ER-L applications in each session was 4 (range 1-6) and the mean total number of ER-L sessions was 1.5. Compared with prior forceps biopsy, histopathology from the ER-L specimen changed in 24 (37.5%, p =<0.0001). With median follow-up of 15 months (range 8-42), complete and durable BE eradication was achieved with ER-L alone in 36 (60%) and the remainder with adjunctive ablation therapies. There were nine complications (four (6%) acute bleeding, five (7.5%) strictures, zero perforations).

Conclusions: ER-L without submucosal (SM) pre-injection is safe and effective when applied selectively for eradication of BE with HGD/IMCA. There is significant change in pathological stage after ER-L conferring a diagnostic and staging advantage. ER-L may be used adjunctively with ablation therapies.

Review: Second-line rescue therapy of Helicobacter pylori infection

Gisbert, J. P. — Fri, 06 Nov 2009 02:37:58 PST

Helicobacter pylori infection is the main known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. After more than 20 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found. Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a ‘rescue’ treatment depends on which treatment is used initially. If a first-line clarithromycin-based regimen was used, a second-line metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin-based combination would be a third-line ‘rescue’ option. Alternatively, it has recently been suggested that levofloxacin-based ‘rescue’ therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, quadruple regimen may be reserved as a third-line ‘rescue’ option. Finally, rifabutin-based ‘rescue’ therapy constitutes an encouraging empirical fourth-line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several ‘rescue’ therapies are consecutively given. Therefore, the attitude in H. pylori eradication therapy failure, even after two or more unsuccessful attempts, should be to fight and not to surrender.

Review: Advances in the diagnosis and treatment of small bowel lesions with Crohn's disease using double-balloon endoscopy

Sunada, K., Yamamoto, H., Yano, T., Sugano, K. — Fri, 06 Nov 2009 02:37:58 PST

With the recent development of double-balloon endoscopy (DBE) and capsule endoscopy (CE), it has become possible to observe the entire small bowel endoscopically. DBE enables us to make detailed observations and at the same time takes biopsy samples. Single-balloon endoscopy (SBE), which has a balloon only at the tip of the overtube, has also been introduced. Since DBE and SBE are similar in the concept of insertion method, a general term ‘balloon-assisted endoscopy’ (BAE) is used when referring to these methods. Characteristic small bowel lesions observed with BAE in Crohn’s disease are aphthoid ulcers, round ulcers, irregular ulcers and longitudinal ulcers. These ulcers tend to be located on the mesenteric side of the small bowel. Since BAE can determine the location (mesenteric or antimesenteric side) of the ulceration, it is useful in distinguishing Crohn’s disease from other diseases that have ulcers in the small bowel. Strictures are a major clinical problem in the course of Crohn’s disease. Traditionally, surgery was the main choice for small bowel strictures. In some cases, strictures located in distal ileum or proximal jejunum have been dilated using standard enteroscopes. DBE now enables balloon dilatation to be performed endoscopically even in the deep small bowel.

Review: Management of the returning traveler with diarrhea

de Saussure, P. P. H. — Fri, 06 Nov 2009 02:37:58 PST

Traveler’s diarrhea (TD) strikes 20—60% of travelers visiting developing countries. It occurs shortly after the return and can be distinguished into two categories: acute and persistent TD. Acute TD, mostly caused by bacterial and viral pathogens, is usually mild and self-limited, and deserves empirical symptomatic and/or antibiotic therapy in selected cases. Fluoroquinolones are progressively superseded in this indication by azithromycin, a well tolerated macrolide active against most bacteria responsible for TD, including the quinolone-resistant species of Campylobacter jejuni that are now pervasive, especially in Southeast Asia and India. Persistent TD in the returning traveler is much rarer than its acute counterpart and may be associated with three types of causes. Persistent infections, among which Giardia and possibly Entamoeba predominate, account for a significant proportion of cases. Postinfectious processes represent a second cause and comprise temporary lactose malabsorption and postinfectious irritable bowel syndrome, now considered a major cause of persistent TD. Finally, apparently unrelated chronic diseases causing diarrhea are occasionally unmasked by TD and represent a third type of persistent TD, among which the well established case of incident inflammatory bowel disease poses intriguing pathogenesis questions. This review discusses recent advances in the field and provides practical recommendations for the management of TD in adult, immunocompetent returning travelers.

Acknowledgements

Fri, 06 Nov 2009 02:37:58 PST

Review: Endoluminal treatment of Barrett's esophagus: current and future prospects

Smith, M. S., Lightdale, C. J. — Tue, 01 Sep 2009 09:17:49 PDT

Endoluminal treatment of Barrett’s esophagus has become the preferred option for initial intervention for advanced neoplasia without invasive carcinoma. Data from abstracts presented at Digestive Disease Week 2008 provide greater insight into optimal use of existing techniques and an early look at potential next generation therapies. Results from the AIM Dysplasia trial describe a larger study with longer post-treatment surveillance highlighting the efficacy and tolerability of radiofrequency ablation, while early results from liquid nitrogen cryotherapy studies suggest a potential to obtain similar eradication results with very high tolerability. Endoscopic resection, despite its risks, remains a popular option for focal as well as more widespread resection of Barrett’s mucosa. Additional abstracts highlight novel approaches to ablation and resection. Enhanced imaging techniques and molecular marker analysis also appear to improve treatment outcomes. However, time and further studies of combined approaches to diagnosis and eradication are necessary to optimize treatment algorithms.

Review: Improving compliance with Helicobacter pylori eradication therapy: when and how?

O'Connor, J. P. A., Taneike, I., O'Morain, C. — Tue, 01 Sep 2009 09:17:49 PDT

Compliance with therapy is the single most important factor in Helicobacter pylori (H. pylori) eradication. Poorer levels of compliance with therapy are associated with significantly lower levels of eradication. Numerous factors can contribute to achieving good levels of compliance. These include the complexity and duration of treatment. It is also important that the physician is motivated to ensure eradication is confirmed and the patient is sufficiently informed to empower him or her to achieve high levels of compliance. Compliance is also contingent on medication regimes that are simple, safe, tolerable and efficacious. The opportunity to improve compliance exists at every point of contact between the patient and the medical services. Experts and opinion leaders in the field can play a role by ensuring that physicians are educated and motivated enough to encourage and support compliance with H. pylori eradication therapy. Both patients and physicians need to be aware of the importance of the bacterium in causing disease. The importance of the doctor—patient relationship is paramount. Pragmatic strategies that may be of assistance may come in the form of polypills, combined Blister Packs, adjuvant therapies and modified release compounds. Colleagues such as pharmacists and nurse specialists can also play an important role and should be actively engaged. Structured aftercare and follow up offers the best chance for ensuring compliance and subsequent eradication of the H. pylori pathogen.

Review: Portopulmonary hypertension: challenges in diagnosis and management

Troy, P. J., Waxman, A. B. — Tue, 01 Sep 2009 09:17:49 PDT

Portopulmonary hypertension is defined as the combination of pulmonary arterial hypertension with portal hypertension and presents management complications in patients awaiting liver transplantation. The combination of these vascular disorders has a marked impact on mortality. At present the recommendations for management are limited because of the paucity of definitive clinical trials. We have reviewed the available data on prevalence, diagnosis and treatment. It is clearly time to more formally approach the study of this patient population.

Review: Predicting the probable outcome of treatment in HCV patients

Navaneethan, U., Kemmer, N., Neff, G. W. — Tue, 01 Sep 2009 09:17:49 PDT

Hepatitis C virus (HCV) is a major cause of chronic liver disease infecting more than 170 million people worldwide. HCV produces a wide gamut of manifestations varying from mild self-limiting disease to cirrhosis and hepatocellular carcinoma. A variety of viral, environmental and host genetic factors contribute to the clinical spectrum of patients infected with HCV and influence response to interferon (IFN) therapy. Predicting the probable outcome of treatment in patients with HCV infection has always been a challenging task. Treatment of HCV by pegylated interferon (peg-IFN) plus ribavirin eradicates the virus in approximately 60% of patients — HCV genotype 1 (42—51% response rates) and genotypes 2 and 3 (76—84% response rates); however, a significant number of patients do not respond to therapy or relapse following discontinuation of treatment or have significant side effects that preclude further treatment. Accurately predicting the patients who will respond to therapy is becoming increasingly important, both from the point of patient care and also with respect to the healthcare cost as clinicians need to continue treatment in patients who will respond and stop treatment in patients who are unlikely to respond. Viral RNA measurements and genotyping are used to optimize treatment as a low viral load and nongenotype 1 is more likely to be associated with sustained virological response (SVR). Rapid virological response (RVR) defined by undetectable HCV RNA at 4 weeks of treatment is increasingly being recognized as a powerful tool for predicting treatment response. A variety of host factors including single nuclear polymorphisms (SNPs) of IFN response genes, insulin resistance, obesity, ethnicity, human leukocyte antigens and difference in T-cell immune response has been found to modulate the response to antiviral treatment. The presence of severe fibrosis/cirrhosis on pretreatment liver biopsy predicts a poor response to treatment. Recent studies on gene expression profiling and characterization of the liver and serum proteome provide options to accurately predict the outcome of patients infected with HCV in the future. Future studies on the factors that predict treatment response and tailoring treatment based on this is required if we are to conquer this disease.

Review: New and developing therapies for celiac disease

Tennyson, C. A., Lewis, S. K., Green, P. H. R. — Tue, 01 Sep 2009 09:17:49 PDT

The treatment for celiac disease, a removal of gluten in the diet, is safe and effective for the vast majority of patients. There is a large body of evidence that the diagnosis and treatment of those with celiac disease ensures considerable health benefits. Although a gluten-free diet is the principal treatment for celiac disease, it is relatively expensive, inconvenient and difficult to adhere to. For these reasons, there is interest in developing alternative therapies. Emerging research for the treatment of celiac disease has focused on three areas: to decrease gluten exposure, to modify intestinal permeability and to modulate immune activation. Therapies developed thus far consist of enzymes designed to digest gluten and the use of inhibitors of paracellular permeability to decrease the migration of gluten peptides into the lamina propria. Other potential therapeutic maneuvers include the binding of gluten by polymers, the use of tissue transglutaminase (TTG) inhibitors and DQ2 or DQ8 blockers, or modulation of cytokine production. While all represent new and exciting therapies, an ideal therapy should have virtually no side effects similar to a gluten-free diet. A pharmaceutical agent may be used on an intermittent basis, such as following occasional gluten exposure or on a chronic basis to mitigate the effects of potential inadvertent ingestion of gluten.

Review: Altering the gastrointestinal flora in patients with functional bowel disorders: a way ahead?

Simren, M. — Mon, 20 Jul 2009 04:23:42 PDT

Functional gastrointestinal disorders are very common in the Western world, but unfortunately the underlying mechanisms behind these disorders are incompletely understood. Treatment options are limited and the economic consequences for society are profound. Recent data suggest an involvement of bacteria in the pathogenesis of functional gastrointestinal disorders. Probiotics are promising new treatment alternatives, which will be reviewed in this supplement.

Review: Tools for the tract: understanding the functionality of the gastrointestinal tract

Kovatcheva-Datchary, P., Zoetendal, E. G., Venema, K., de Vos, W. M., Smidt, H. — Mon, 20 Jul 2009 04:23:42 PDT

The human gastrointestinal tract comprises a series of complex and dynamic organs ranging from the stomach to the distal colon, which harbor immense microbial assemblages that are known to be vital for human health. Until recently, most of the details concerning our gut microbiota remained obscure. Over the past several years, however, a number of crucial technological and conceptual innovations have been introduced to shed more light on the composition and functionality of human gut microbiota. Recently developed high throughput approaches, including next-generation sequencing technologies and phylogenetic microarrays targeting ribosomal RNA gene sequences, allow for comprehensive analysis of the diversity and dynamics of the gut microbiota composition. Nevertheless, most of the microbes especially in the human large intestine still remain uncultured, and the in situ functions of distinct groups of the gut microbiota are therefore largely unknown, but pivotal to the understanding of their role in human physiology. Apart from functional and metagenomics approaches, stable isotope probing is a promising tool to link the metabolic activity and diversity of microbial communities, including yet uncultured microbes, in a complex environment. Advancements in current stable isotope probing approaches integrated with the application of high-throughput diagnostic microarray-based phylogenetic profiling and metabolic flux analysis should facilitate the understanding of human microbial ecology and will enable the development of innovative strategies to treat or prevent intestinal diseases of as yet unknown etiology.

Review: Do patients with functional gastrointestinal disorders have an altered gut flora?

Quigley, E. M.M. — Mon, 20 Jul 2009 04:23:42 PDT

The description of the de novo development of irritable bowel syndrome (IBS) following an episode of bacterial gastroenteritis (postinfectious IBS) illustrated the potential for a luminal factor (a bacterial pathogen) to cause this common gastrointestinal ailment. As a consequence of these and other observations as well as results of experiments involving animal models, the enteric flora and the immune response that it generates in the host have, somewhat surprisingly, come centre-stage in IBS research with their potential to induce the pathophysiological changes that are associated with IBS. While evidence for immune dysfunction both in the mucosa and systemically continues to accumulate, methodological limitations have hampered a full delineation of the nature of the microbiota in IBS. The latter is eagerly awaited and may yet provide a firm rationale for the use of certain probiotics and antibiotics in IBS, whose benefits have now been described with some consistency.

Review: Effect of probiotics on gastrointestinal function: evidence from animal models

Verdu, E. F., Bercik, P., Collins, S. M. — Mon, 20 Jul 2009 04:23:42 PDT

The digestive tract works through a complex net of integrative functions. At the level of the gut, this integration occurs between the immune, neuromotor and endocrine systems, the intestinal barrier and gut luminal contents. Gastrointestinal function is controlled and coordinated by the central nervous system to ensure effective motility, secretion, absorption and mucosal immunity. Thus, it is clear that the gut keeps a tightly regulated equilibrium between luminal stimuli, epithelium, immunity and neurotransmission in order to maintain homeostasis. It follows that perturbations of any of these systems may lead to gut dysfunction. While we acknowledge that the gut—brain axis is crucial in determining coordinated gut function, in this review we will focus on peripheral mechanisms that influence gastrointestinal physiology and pathophysiology. We will discuss the general hypothesis that the intestinal content is crucial in determining what we consider normal gastrointestinal physiology, and consequently that alteration in luminal content by dietary, antibiotic or probiotic manipulation can result in changes in gut function. This article focuses on lessons learned from animal models of gut dysfunction.

Review: Do probiotics improve symptoms in patients with irritable bowel syndrome?

Whorwell, P. J. — Mon, 20 Jul 2009 04:23:42 PDT

There is increasing evidence that inflammation or a disturbance of the flora within the gut might contribute to the pathogenesis of irritable bowel syndrome (IBS), at least in a proportion of cases. As a consequence it has been speculated that, as some probiotic bacteria have a range of anti-inflammatory and immunomodulatory properties, the administration of such organisms might prove to be beneficial in this condition. It has to be acknowledged that the quality and design of trials of probiotics in IBS has been somewhat variable but the majority have shown benefit, although some bacteria appear to be more effective than others. More recent studies using Bifidobacterium infantis 35624 and Bifidobacterium lactis DN-173-010 have given particularly encouraging results. Issues for the future include determining which organisms are most effective, defining optimal doses, comparing methods of delivery and assessing the role of mixtures or the addition of prebiotics.

The challenge of developing new therapies for irritable bowel syndrome

Azpiroz, F., Whorwell, P. J. — Mon, 29 Jun 2009 03:39:06 PDT

Review: Therapeutic implications of hepatitis C virus resistance to antiviral drugs

Pawlotsky, J.-M. — Mon, 29 Jun 2009 03:39:06 PDT

Treatment of chronic hepatitis C is currently based on a combination of pegylated interferon- and ribavirin. Neither drug exerts direct selective pressure on viral functions, meaning that interferon-/ribavirin treatment failure is not due to selection of interferon-- or ribavirin-resistant viral variants. Several novel antiviral approaches are currently in preclinical or clinical development, and most target viral enzymes and functions, such as hepatitis C virus protease and polymerase. These new drugs all potentially select resistant viral variants both in vitro and in vivo, and resistance is therefore likely to become an important issue in clinical practice.

Review: The treatment of irritable bowel syndrome

Lacy, B. E., Weiser, K., De Lee, R. — Mon, 29 Jun 2009 03:39:06 PDT

Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder routinely encountered by healthcare providers. Although not life-threatening, this chronic disorder reduces patients' quality of life and imposes a significant economic burden to the healthcare system. IBS is no longer considered a diagnosis of exclusion that can only be made after performing a battery of expensive diagnostic tests. Rather, IBS should be confidently diagnosed in the clinic at the time of the first visit using the Rome III criteria and a careful history and physical examination. Treatment options for IBS have increased in number in the past decade and clinicians should not be limited to using only fiber supplements and smooth muscle relaxants. Although all patients with IBS have symptoms of abdominal pain and disordered defecation, treatment needs to be individualized and should focus on the predominant symptom. This paper will review therapeutic options for the treatment of IBS using a tailored approach based on the predominant symptom. Abdominal pain, bloating, constipation and diarrhea are the four main symptoms that can be addressed using a combination of dietary interventions and medications. Treatment options include probiotics, antibiotics, tricyclic antidepressants, selective serotonin reuptake inhibitors and agents that modulate chloride channels and serotonin. Each class of agent will be reviewed using the latest data from the literature.

Review: Tailoring the treatment to the individual in Crohn's disease

Louis, E., Belaiche, J., Reenaers, C. — Mon, 29 Jun 2009 03:39:06 PDT

Crohn's disease is a heterogeneous disease with approximately 30-40% of patients having a simple benign history and the rest having a chronic progressive disease leading to complications, surgeries and potentially socio-professional marginalisation. Recent studies have shown that an early treatment with immunosuppressive treatment and/or anti-tumour necrosis factor agents could change the natural history of the disease and avoid the development of such disabling disease. The therapy should thus be tailored according to the risk of developing such disabling disease. Recent cohort studies have shown that clinical factors such as age at diagnosis, disease extent, disease location and behaviour at diagnosis were predictive for the development of severe or disabling disease and could be used in helping the physician to tailor therapy.

Review: Predicting response to anti-TNF agents for the treatment of Crohn's disease

Siegel, C. A., Melmed, G. Y. — Mon, 29 Jun 2009 03:39:06 PDT

The arrival of anti-tumor necrosis factor (TNF) agents has led to a dramatic improvement in the care of patients with Crohn's disease. Since these medications do not work in everyone, and are associated with rare, but serious side effects, we want to selectively treat patients who have the highest chance of responding. A number of variables have been studied to determine their association with response to anti-TNF agents. Clinical parameters include patient characteristics, smoking status and disease phenotype, and biologic markers include C-reactive protein, serum TNF levels and immune responses to microbial antigens. More recently, research has focused on genetics to identify polymorphisms associated with treatment response. Results from individual studies of these factors have not yet allowed for solid clinical applicability. However, further work in this area along with multivariate clinical prediction modeling may soon allow us to deliver `personalized medicine' by predicting individualized treatment response in patients with Crohn's disease.

Corrigendum

Mon, 29 Jun 2009 03:39:06 PDT