A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED).

OBJECTIVES: In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA). METHODS: This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of -0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response. RESULTS: Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was -0.37 (95% confidence interval (CI): -0.80, 0.06) with P=0.09 in the full analysis set (N=327) and -0.45 (95% CI: -0.88, -0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of -4.4 (95% CI: -7.4, -1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67%; oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP). CONCLUSIONS: We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose-response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.

Elevated expression of ISY1, APOA-1, SYNE1, MTG1, and MMP10 at HCC initiation: HCC specific protein network involving interactions of key regulators of lipid metabolism, EGFR signaling, MAPK, and splicing pathways.

Identification of molecular regulators of hepatocellular carcinoma (HCC) initiation and progression is not well understood. We chemically induced HCC in male Wistar rats by administration of diethyl nitrosamine (DEN) and 2-acetylaminofluorene (2-AFF). Using 2D-electrophoresis and MALDI-TOF-MS/MS analyses, we characterized differentially expressed proteins in liver tissues at early stage of HCC progression. Using RT-PCR analysis, we quantified the mRNA expression of the characterized proteins and validated the transcript expression with tumor tissues of clinically confirmed HCC patients. Using bioinformatic tools, we analyzed a network among the introduced proteins that identified their interacting partners and analyzed the molecular mechanisms associated with signaling pathways during HCC progression. We characterized a protein, namely, pre-mRNA splicing factor 1 homolog (ISY1), which is upregulated at both transcriptome and proteome levels at HCC initiation, progression, and tumor stages. We analyzed the interacting partners of ISY1, namely, APOA-1, SYNE1, MMP10, and MTG1. Real-time PCR analysis confirmed elevated expression of APOA-1 mRNA at HCC initiation, progression, and tumor stages in animals undergoing tumorigenesis. The mRNA expression of the interacting partners was validated with tumor tissues of clinically confirmed liver cancer patients; the analysis revealed significant elevation in expression of transcripts. The transcriptome and proteome analyses complement each other and dysregulation in mRNA and protein expression of these regulators may play critical role in HCC initiation and progression.

Effect of lactase on symptoms and hydrogen breath levels in lactose intolerance: A crossover placebo-controlled study.

BACKGROUND AND AIM: The absence of lactase in the intestinal villi due to mucosal injury or genetic factors causes undigested lactose to reach the colon where it is fermented. Lactose intolerance is diagnosed based on clinical symptoms like bloating, abdominal pain and flatulence, lactose hydrogen breath test (HBT), and lactose tolerance test. No Indian studies are available on the use of lactase supplements. The aim was to study the effect of lactase chewable tablets on clinical symptoms and hydrogen breath excretion in patients with lactose intolerance. METHODS: This was a randomized, double-blind, crossover placebo-controlled trial to study the effect of lactase tablets on symptoms and hydrogen breath levels in adults with lactose intolerance, confirmed by Lactose HBT. Clinical symptom severity was recorded using a visual analog scale, and HBT was performed every 30 min for 180 min. As it was a crossover design, the same patients were tested with both lactase and placebo, acting as their own controls with a washout period of 1 week between visits. RESULTS: Forty-seven patients (mean age 33.6 years; 30 males) with lactose intolerance formed the study group. Clinical symptoms, mean clinical score (P < 0.05), and mean hydrogen breath levels (P < 0.05) were improved when the patients were given lactase. Reduction in cumulative hydrogen breath level over 180 min was 55% when patients received lactase compared to placebo. CONCLUSIONS: Orally supplemented lactase enzyme significantly reduced the clinical symptoms and hydrogen breath excretion in patients with lactose intolerance.

Diet and nutrition in the management of inflammatory bowel disease.

The role of diet and its manipulation in the management of inflammatory bowel disease (IBD) is gradually acquiring central stage. Certain dietary factors have been identified as putative triggers in IBD as some other factors are found to be protective. The dietary manipulation as part of comprehensive IBD care should be done by the clinician in conjunction with a skilled dietitian. Nutritional deficiencies are common in patients with IBD and can have long-term effects on disease course and quality of life in these patients. So, early identification and correction of these deficiencies along with proper nutritional supplementation should be addressed routinely as a part of IBD management. Oral nutritional supplementation is sufficient for most patients, but in some sick patients, tube feeding may be necessary. Diet needs to be individualized based on the nutritional deficiencies and dietary triggers in a specific patient. Multiple specific diets, with elimination of components that trigger inflammation or addition of components that alter gut microbes in a favorable way, are now appearing as a treatment option in IBD, but more evidence is required before their universal recommendation. Though enteral nutrition (EN) (both exclusive enteral nutrition [EEN] and partial enteral nutrition [PEN]) have proven therapeutic role in pediatric IBD, their uses and role are now expanding in adult IBD patients as well.

A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis.

BACKGROUND & AIMS: Oxidative stress has been implicated in the pathophysiology of chronic pancreatitis (CP). We evaluated the effects of antioxidant supplementation on pain relief, oxidative stress, and antioxidant status in patients with CP. METHODS: In a placebo-controlled double blind trial, consecutive patients with CP were randomized to groups that were given placebo or antioxidants for 6 months. The primary outcome measure was pain relief, and secondary outcome measures were analgesic requirements, hospitalization, and markers of oxidative stress (thiobarbituric acid-reactive substances [TBARS]) and antioxidant status (ferric-reducing ability of plasma [FRAP]). RESULTS: Patients (age 30.5+/-10.5 years, 86 male, 35 alcoholic, and 92 with idiopathic CP) were assigned to the placebo (n=56) or antioxidant groups (n=71). After 6 months, the reduction in the number of painful days per month was significantly higher in the antioxidant group compared with the placebo group (7.4+/-6.8 vs 3.2+/-4, respectively; P< .001; 95% CI, 2.07, 6.23). The reduction in the number of analgesic tablets per month was also higher in the antioxidant group (10.5+/-11.8 vs 4.4+/-5.8 respectively; P= .001; 95% CI, 2.65, 9.65). Furthermore, 32% and 13% of patients became pain free in the antioxidant and placebo groups, respectively (P= .009). The reduction in the level of TBARS and increase in FRAP were significantly higher in the antioxidant group compared with the placebo group (TBARS: placebo 1.2+/-2.7 vs antioxidant 3.5+/-3.4 nmol/mL; P= .001; 95% CI 0.96, 3.55; FRAP: placebo -5.6+/-154.9 vs antioxidant 97.8+/-134.9 microMFe(+2) liberated, P= .001, 95% CI 44.98, 161.7). CONCLUSIONS: Antioxidant supplementation was effective in relieving pain and reducing levels of oxidative stress in patients with CP.

The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis.

BACKGROUND & AIMS: Probiotics can maintain ulcerative colitis (UC) in remission effectively, but little is known of their ability to induce remission. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of a high-potency probiotic, VSL#3, for the treatment of mild-to-moderately active UC. METHODS: Adult patients with mild-to-moderate UC were assigned randomly to groups that were given 3.6 x 10(12) CFU VSL#3 (n = 77) or placebo (n = 70), twice daily for 12 weeks. The primary end point was a 50% decrease in the Ulcerative Colitis Disease Activity Index (UCDAI) at 6 weeks. The secondary end points included remission by 12 weeks and reduction in total individual UCDAI parameters from baseline at 12 weeks. Intention-to-treat analysis was performed. RESULTS: At week 6, the percentage of patients with an improvement in UCDAI score that was greater than 50% was significantly higher in the group given VSL#3 (25; 32.5%) than the group given placebo (7; 10%) (P = .001). At week 12, there were 33 patients given VSL#3 (42.9%) who achieved remission, compared with 11 patients given placebo (15.7%) (P < .001). Furthermore, significantly more patients given VSL#3 (40; 51.9%) achieved a decrease in their UCDAI that was greater than 3 points, compared with those given placebo (13; 18.6%) (P < .001). The VSL#3 group had significantly greater decreases in UCDAI scores and individual symptoms at weeks 6 and 12, compared with the placebo group. CONCLUSIONS: VSL#3 is safe and effective in achieving clinical responses and remissions in patients with mild-to-moderately active UC.

Diet and inflammatory bowel disease: The Asian Working Group guidelines.

INTRODUCTION: These Asian Working Group guidelines on diet in inflammatory bowel disease (IBD) present a multidisciplinary focus on clinical nutrition in IBD in Asian countries. METHODOLOGY: The guidelines are based on evidence from existing published literature; however, if objective data were lacking or inconclusive, expert opinion was considered. The conclusions and 38 recommendations have been subject to full peer review and a Delphi process in which uniformly positive responses (agree or strongly agree) were required. RESULTS: Diet has an important role in IBD pathogenesis, and an increase in the incidence of IBD in Asian countries has paralleled changes in the dietary patterns. The present consensus endeavors to address the following topics in relation to IBD: (i) role of diet in the pathogenesis; (ii) diet as a therapy; (iii) malnutrition and nutritional assessment of the patients; (iv) dietary recommendations; (v) nutritional rehabilitation; and (vi) nutrition in special situations like surgery, pregnancy, and lactation. CONCLUSIONS: Available objective data to guide nutritional support and primary nutritional therapy in IBD are presented as 38 recommendations.

Correction to: Diet and inflammatory bowel disease: The Asian Working Group guidelines.

The recommendations 31 which recommend "VSL#3®", refer only to the product used in the cited literature and equivalent products independent from the present product labelings. This product is now known by the generic name "De Simone Formulation".

Pancreatic stellate cells: new target in the treatment of chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by progressive fibrosis, pain and/or loss of exocrine and endocrine functions. Recent in vitro and in vivo experiments have proven objectively the role of activated pancreatic stellate cells (PSC) in fibrogenesis in CP. Molecular mediators shown to regulate the pathogenesis include transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), and pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha. Furthermore, molecular pathways involving mitogen-activated protein kinases (MAPK), phosphatidyl inositol 3-kinase (PI3K), Ras superfamily G proteins, serine threonine protein kinase Raf-1 and peroxisome proliferator activated receptor gamma (PPAR-gamma) have been elucidated. Understanding of the pathogenesis has led to identification of novel molecular targets and development of potential newer therapeutic agents. Those found to retard the progression of experimental CP and fibrosis in animal models include interferon (IFN) beta and IFN-gamma; a Japanese herbal medicine called Saiko-keishi-to (TJ-10); curcumin; PPAR-gamma ligand (troglitazone); antioxidants (vitamin A, vitamin E, DA 9601 and epigallocatechin-3-gallate); a protease inhibitor (camostat mesilate) and hydroxymethylglutaryl-CoA inhibitor (lovastatin). This review summarizes the current literature addressing the role of different pharmacological agents aimed at reducing or preventing inflammation and the consequent fibrogenesis in CP.

Endotherapy for pain in chronic pancreatitis.

Pain is the most distressing symptom of chronic pancreatitis. Although the pathogenesis of pain is still poorly understood, an increase in intraductal pressure may be the dominant factor. The management of pain can involve medical, endoscopic, neurolytic, and surgical therapies. Endotherapy includes pancreatic sphincterotomy, extraction of stones, placement of stent, and dilatation of strictures, sometimes preceded or followed by extracorporeal shock-wave lithotripsy. Several studies have now shown that endotherapy provides partial or complete relief of pancreatic pain in a majority of patients with an acceptable frequency of early and late complications. Endotherapy should now graduate from an experimental form of treatment to a realistic treatment option in patients with chronic or relapsing pain, particularly in the setting of calcific chronic pancreatitis.

Cause and effect relationship of malnutrition with idiopathic chronic pancreatitis: prospective case-control study.

BACKGROUND AND AIM: Patients with chronic pancreatitis are often malnourished. The role of malnutrition in the pathogenesis of chronic pancreatitis is unclear. The aim of the present article was to study prospectively the cause and effect relationship of malnutrition with idiopathic chronic pancreatitis in a case-control study. METHODS: Consecutive patients with chronic pancreatitis underwent anthropometry, nutritional and dietary assessments. For dietary assessment, food frequency questionnaire and 24-hour dietary recall methods were used. Primary outcome measure was cause and effect relationship of malnutrition with idiopathic chronic pancreatitis. RESULTS: Of 201 patients with chronic pancreatitis, 120 had idiopathic chronic pancreatitis (mean age 29.60 years, 74 males) who formed the study group. None of the patients consumed cassava. The nutritional status and dietary intake of the patients before the onset of chronic pancreatitis were comparable with those of controls with 20.6% of patients and 22.5% of controls being malnourished (body mass index [BMI] < 18.5). After the onset of chronic pancreatitis, 56.5% of patients lost weight and significantly more patients became malnourished compared with controls (45.8% vs 22.5%; P < 0.001). The causes of weight loss were diabetes, higher calories from proteins, and pseudocyst. CONCLUSION: Malnutrition was not a cause of idiopathic chronic pancreatitis and weight loss occurred as an effect of chronic pancreatitis. Cassava was not found to be a cause of idiopathic chronic pancreatitis.

OLGA gastritis staging in young adults and country-specific gastric cancer risk.

Geographical differences have been shown in the clinical outcomes of Helicobacter pylori-associated gastritis phenotypes and in gastric cancer risk. This study tested whether the Operative Link on Gastritis Assessment (OLGA) staging correlated with gastric cancer risk in populations from 3 continents. Mapped gastric biopsies were obtained from 316 dyspeptic adults aged less than 41 years from 8 geographic areas that differed in gastric cancer risk. Gastric atrophy was assessed according to internationally validated criteria. Gastritis stage was established according to the OLGA staging system. The most prevalent gastritis stages were 0 to II, which included all subjects entered from Chile, Germany, India, Italy, and Thailand. Gastritis Stages III and IV were limited to the Chinese and Korean populations. Indians had a high prevalence of H pylori infection without high-stage gastritis. In populations at different cancer risk, the gastritis OLGA stage mirrored the gastric cancer incidence. Gastritis staging identifies a subgroup of higher-risk patients.

Is biliary microlithiasis a significant cause of idiopathic recurrent acute pancreatitis? A long-term follow-up study.

BACKGROUND & AIMS: The cause of recurrent acute pancreatitis (RAP) is not known in 10%-30% of patients. The aim of the present study was to determine the cause of idiopathic RAP in a long-term follow-up study. METHODS: All consecutive patients with idiopathic RAP underwent detailed evaluations and investigations to find out the cause. The pancreatitis was considered to be idiopathic when no cause could be found after standard investigations that included serum biochemistry, transabdominal ultrasonography, and computerized tomography scan of the abdomen. The detailed work-up included repeat serum biochemistry and transabdominal ultrasonography, an endoscopic retrograde cholangiopancreatography, duodenal bile microscopy to diagnose biliary microlithiasis, and endoscopic ultrasonography. RESULTS: Seventy-five patients were studied from June 1995 to May 2003. Their mean age was 31.9 years and 80% were male. The mean number of attacks of acute pancreatitis was 4.82 (range, 2-10). The cause of RAP was attributed to biliary microlithiasis in only 10 (13%) of 75 patients. Two additional patients developed gallstones during the follow-up period. Thirty-five (47%) patients developed chronic pancreatitis during the follow-up period. Ten of these 35 patients with chronic pancreatitis had biliary microlithiasis; 8 of these 10 patients had undergone cholecystectomy/endoscopic sphincterotomy yet continued to have recurrent pancreatitis and developed chronic pancreatitis. Miscellaneous causes were found in 10 (13%) patients. No cause was found in the remaining 18 (24%) patients. CONCLUSIONS: Microlithiasis was not a significant cause of idiopathic RAP in our patients. About one half of the patients with RAP developed chronic pancreatitis during the follow-up period.

Management of patients with HBeAg-negative chronic hepatitis B.

Chronic hepatitis B (CHB) is one of the leading causes of morbidity and mortality worldwide. Although various drugs are available for the treatment of CHB, emergence of the hepatitis B e antigen (HBeAg)-negative mutant variant, specifically in Asia, the Middle East and southern Europe, is creating a new challenge as this variant is less responsive to available treatments. HBeAg-negative CHB rapidly progresses to cirrhosis and its related complications. This review discusses the available literature on the approved and under-trial treatment options and their respective efficacies for HBeAg-negative CHB.

Primary intestinal lymphangiectasia as a component of autoimmune polyglandular syndrome type I: a report of 2 cases.

Chronic diarrhea and steatorrhea occur frequently in patients with autoimmune polyglandular syndrome (APS) type I. Intestinal lymphangiectasia has been reported earlier as a cause of steatorrhea in a young girl with APS Type I. We describe 2 patients with APS Type I who were found to have intestinal lymphangiectasia, one of whom had symptomatic protein-losing enteropathy.

Aluminium phosphide-induced esophageal stricture.

We report a 24-year-old woman and a 58-year-old man who developed short-segment esophageal strictures in the upper and mid esophagus two weeks after ingestion of aluminium phosphide tablets. They responded well to endoscopic dilatation.