Clinical outcomes amongst elderly patients with inflammatory bowel disease.

BACKGROUNDS AND AIMS: Inflammatory bowel disease (IBD) affects a growing cohort of elderly patients. Our aim was to compare the quality of care received by elderly patients with IBD with a nonelderly adult IBD population using clinical markers including steroid-free clinical remission. METHOD: Retrospective audit of all consecutive patients attending a specialist IBD centre over a 1-year period aged >60 (elderly cohort [EC]) and 50 consecutive patients aged 30-45 years (control cohort [CC]). A follow-up survey was completed assessing current symptoms and perceptions of care. RESULTS: One hundred thirty-nine patients were evaluated (89 EC, 50 CC). Steroid-free clinical remission was observed less commonly in the EC (58, 64%) compared with the CC (40, 80%) (P < 0.05). Biologics such as infliximab (15% EC vs 36% CC; P < 0.01) and adalimumab (14% EC vs 30% CC; P = 0.02) were used less frequently in the EC, whilst vedolizumab (6% EC vs 6% CC; P = 1) and ustekinumab (3% EC vs 2% CC; P = 1) were used at a similar frequency. Patients in the EC were less likely to have specialist IBD nursing contact (P < 0.01), smoking screening (P < 0.011) or influenza vaccinations (P < 0.006). IBD nurse contact was associated with significantly greater provision of the preventative care measures. CONCLUSION: Elderly patients with IBD were less likely to experience steroid-free clinical remission or be prescribed biologics. Elderly patients were less likely to receive education with respect to preventative medicine. The models of care for the elderly need re-evaluation and greater incorporation with the multidisciplinary IBD team.

Pelvic floor behavioral treatment for fecal incontinence and constipation in quiescent inflammatory bowel disease.

BACKGROUND AND AIM: Refractory bowel symptoms in quiescent inflammatory bowel disease (IBD) are common but evidence for effective management is limited. We aimed to determine whether behavioral treatment, including pelvic floor muscle training, decreases the severity of functional bowel symptoms in patients with quiescent IBD. Secondary aims were to evaluate the treatment effect on quality of life, psychological well-being and pelvic floor muscle function. METHODS: This prospective study included IBD patients in remission with persistent symptoms of fecal incontinence or constipation who received up to six sessions of behavioral treatment at monthly intervals. The primary outcome was patient-rated symptom improvement on a 7-point Likert scale (1 = substantially worse, 7 = substantially better). Secondary outcomes included validated symptom scores, quality-of-life, psychological measures, and transperineal ultrasound assessment of pelvic floor muscle activity. RESULTS: Thirty-four patients (median age 38 years; 24 females; 18 ulcerative colitis, 13 Crohn's disease, 3 ileo-anal pouch) were included. Twenty-one of the 29 (72%) patients who completed treatment, or 21 of all 34 (62%) patients, reported moderate or substantial improvement (patient rating of 6 or 7). Symptom scores (p < .001), IBD-specific quality of life (p = .008) and illness perception scores (p = .003) significantly improved. General quality of life, and anxiety and depression scores, did not change significantly. Transperineal ultrasound pelvic floor measures did not correlate with patient-rating of symptom improvement. CONCLUSION: Significant symptomatic improvement occurred in a majority of patients with quiescent IBD. Behavioral treatment should be considered for patients with quiescent IBD and ongoing functional bowel symptoms of fecal incontinence, fecal urgency, or constipation.

Quantifying early gastric cancer in Australia: What is the opportunity for gastric endoscopic submucosal dissection?

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is the recommended treatment for early gastric cancer (EGC). However, there are challenges in attaining expertise in ESD in countries where the incidence of gastric cancer and proportion diagnosed at an early stage of disease are relatively low. This study aims to establish the proportion of gastric cancer meeting histological criteria for EGC, which may be suitable for ESD, in a Western population. METHODS: Gastric cancers reported to the Victorian Cancer Registry between January 2011 and December 2016 were analyzed. EGC was defined as tumor confined to mucosa (T1a) or submucosa (T1b). Histology reports were analyzed using Japanese and European guidelines to identify potential ESD candidates. Criteria for extended ESD were based on grade of differentiation, tumor depth, lymphovascular and perineural invasion, and ulceration. RESULTS: Twenty percent of 1217 gastric cancers was EGC (237 cases), with detailed histopathology reports suitable for evaluating ESD criteria recorded in 182 cases. Standard and extended ESD criteria were met in 46% (84/182) and 75% (132/182), respectively. Actual treatment of the 237 EGC was endoscopic in 14% (n = 33) and surgery in 86% (n = 204). Endoscopically treated EGCs were more likely to be stage T1a and located in the proximal stomach. CONCLUSIONS: EGCs represented 20% of reported gastric adenocarcinomas with the majority fulfilling criteria for ESD. ESD should be considered in the management algorithm and discussed at tumor board meetings involving interventional endoscopists. To increase utilization of ESD, systems need to be implemented to improve training, accreditation, and access to ESD.

Determinants of long-term function and general well-being in patients with an ileoanal pouch.

BACKGROUND AND AIM: Fecal incontinence and/or evacuation difficulty are common after ileoanal pouch surgery. This study aimed to determine whether the development of these symptoms can be predicted so that preventive measures might be instituted. METHODS: A consecutive series of 46 patients with ulcerative colitis (median age at surgery, 41 years; 50% female) and a functioning pouch for a duration ≥12 months was included. Assessment utilized medical record review and questionnaires on pre- and postoperative bowel function, quality of life, and psychological well-being. Pouch function was assessed by the Colorectal Functional Outcome score (0 = no impairment, 100 = worst impairment). Good pouch function was defined as a score ≤24. RESULTS: Fecal incontinence occurred in 67% preoperatively and 54% postoperatively; evacuation difficulty occurred in 65% and preoperatively and 85% postoperatively. The postoperative median Colorectal Functional Outcome score was 20 (range 2-74), with 44% of patients >24 (poor pouch function). Preoperative nocturnal fecal incontinence (odds ratio [OR] 4.92, 95% confidence interval [CI] 1.2-19.4, P = 0.02) and pouchitis (OR 5.41, 95% CI 1.2-23.7, P = 0.02) were associated with poor pouch function after multivariable regression analysis. Postoperative satisfaction, psychological well-being, and quality of life were significantly better in those with good pouch function, while poor sleep, impaired work, and sexual dysfunction were independently associated with poor pouch function. CONCLUSIONS: Functional bowel symptoms are common before and after pouch surgery and are associated with the impairment of patient-reported outcomes. Preoperative nocturnal fecal incontinence predicts poor pouch function. Therapeutic focus on continence, bowel evacuation, psychological well-being, and quality of life should begin before surgery.

Systematic review: Pelvic floor muscle training for functional bowel symptoms in inflammatory bowel disease.

BACKGROUND AND AIM: Large bowel functional symptoms are common in patients with inflammatory bowel disease (IBD) who are in disease remission. The efficacy of pelvic floor muscle training for symptoms of evacuation difficulty or fecal incontinence is well established in patients without organic bowel disease but is unknown in these patients. This study aimed to systematically evaluate the published evidence in this group of patients. METHODS: A systematic review was conducted of articles evaluating pelvic floor muscle training, with or without biofeedback, to improve bowel function in patients with quiescent IBD, including those with an ileoanal pouch. The outcome of interest was improved bowel function measured by bowel diary, patient report, or validated questionnaire in randomized controlled studies, cohort studies, or case series. RESULTS: Two randomized controlled trials, four retrospective case series, and one prospective study met eligibility criteria. Pelvic floor muscle training for patients with quiescent IBD improved symptoms in 51 of 76 (68%) patients with evacuation difficulty and 20 of 25 (80%) patients with fecal incontinence. Pelvic floor muscle training for patients with an ileoanal pouch, prior to stoma closure, did not appear to reduce the risk or severity of fecal incontinence following stoma closure. Studies were limited by small numbers, study design, methodological quality, and lack of long-term follow-up. CONCLUSION: Pelvic floor muscle training appears to be of therapeutic value in some patients with quiescent IBD and evacuation difficulty or fecal incontinence. The effectiveness of this approach warrants further investigation.

Gut-Directed Pelvic Floor Behavioral Treatment for Fecal Incontinence and Constipation in Patients with Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) often experience functional bowel symptoms despite achieving disease remission. Although behavioral treatment (bowel and pelvic floor muscle retraining) is effective for managing constipation or fecal incontinence in non-IBD patients, there is limited evidence for its efficacy in patients with quiescent inflammatory bowel disease. The aim of this study was to evaluate the outcome of gut-directed behavioral treatment, including pelvic floor muscle training, for symptoms of constipation or fecal incontinence in patients with IBD in disease remission. METHODS: The outcome of consecutive patients with IBD in remission and symptoms of constipation or fecal incontinence was evaluated. Patients referred to a multidisciplinary gastroenterology clinic underwent gut-directed behavioral treatment, including pelvic floor muscle training. The primary outcome was patient-reported rating of change in symptoms on a 7-point Likert scale at the completion of treatment. RESULTS: Forty IBD patients (median age, 35 years; 80% female; 24 Crohn's disease [CD], 12 ulcerative colitis [UC], 4 UC with ileoanal pouch) with ongoing symptoms of constipation (55%) or fecal incontinence (45%), despite drug therapy, were included. The median symptom duration at referral was 2 years. Thirty-five (87%) completed treatment with a median of 2 sessions. Improvement of "6 = much better" or "7 = very much better" was reported by 77% (17/22) with fecal incontinence and 83% (15/18) with constipation. Improvement occurred irrespective of IBD diagnosis, previous perianal fistulae, colorectal surgery, presence of an ileoanal pouch, or past obstetric trauma. CONCLUSIONS: Behavioral treatment effectively improves functional gut symptoms in a large majority of patients who are in IBD disease remission and who have not responded to drug therapy. 10.1093/ibd/izy344_video1 izy344.video1 5968879349001.

Australian recommendations for the management of hepatitis C virus infection: a consensus statement.

Chronic hepatitis C virus (HCV) infection affects 230 000 Australians, who are at risk of progressive liver fibrosis leading to cirrhosis, liver failure and hepatocellular carcinoma. HCV infection is curable, and all Australians living with HCV should be considered for antiviral therapy. Interferon-free regimens involving combinations of sofosbuvir, ledipasvir, daclatasvir and/or ribavirin for 8, 12 or 24 weeks are now listed on the Pharmaceutical Benefits Scheme (PBS) for treating people with genotypes 1-3 HCV. Treatment for genotypes 4-6 HCV involves sofosbuvir plus peginterferon-alfa and ribavirin for 12 weeks. The PBS listing allows these therapies to be prescribed by specialists experienced in treating chronic HCV infection or by general practitioners in consultation with one of these specialists. People with cirrhosis and other special populations (eg, those with decompensated liver disease or renal impairment) should be referred for specialist care. Key issues during pre-treatment assessment include identifying HCV genotype, evaluating for cirrhosis and considering concomitant medications for risk of drug-drug interactions.

Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma.

BACKGROUND & AIMS: The hepatitis B virus (HBV) genome encodes specific sequence elements which promote splicing of viral DNA. It has been previously suggested that spliced HBV (spHBV) variants promote viral replication and protein production, leading to hepatocellular carcinoma (HCC). In this study, we have analysed changes in spHBV over time; providing the first longitudinal analysis of spHBV in relation to the development of HCC. METHODS: Serial serum samples were collected from 165 patients with chronic HBV monoinfection, including 58 patients who later developed HCC. Real-time PCR was used to amplify and quantify wt and sp DNA loads. RESULTS: spHBV was detected in over 80% of patients with chronic HBV infection. Median serum spHBV levels were significantly higher in HCC patients than HCC-free control patients (p<0.001). Univariate analysis revealed a strong correlation between time to HCC diagnosis and spHBV DNA levels (τ=0.203; p=0.016). Asian HBV genotype (p=0.025) and increased viral load (p<0.001) were also significantly associated with increased spHBV DNA levels. Multiple regression analysis revealed time to diagnosis of HCC, Asian HBV genotypes, and viral load to be associated with increased spHBV DNA (model p<0.001; R(2)=0.189). CONCLUSIONS: HBV splicing is a common event during chronic infection and increases prior to diagnosis of HCC. Measurement of HBV splicing may prove a valuable adjunct to be used in the identification of chronically infected patients who are at increased risk of developing HCC.

Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers.

UNLABELLED: Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. CONCLUSION: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker.

Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: a perspective on Asia.

BACKGROUND & AIMS: Data from clinical trials suggest a potential role for on-treatment monitoring of serum HBsAg titres during interferon-alpha (pegIFN) therapy in predicting virological responses. However, baseline HBsAg titres during the natural history of chronic hepatitis B (CHB) have not been well-characterized. We aimed to define the serum HBsAg titres during the different phases of CHB in a cohort of Asian patients infected with either genotype B or C HBV. METHODS: Two-hundred and twenty patients were classified into immune-tolerant (IT), immune-clearance (IC), non/low-replicative (LR) or hepatitis B e antigen negative hepatitis (ENH) phases. Serum HBsAg was quantified using the ARCHITECT platform (Abbott Laboratories, Chicago, USA). Correlation of HBsAg titre with HBV DNA and serum ALT within each phase of infection was performed. RESULTS: Median HBsAg titres were different between each phase of CHB (p=0.001): IT (4.53 log(10)IU/ml), IC (4.03 log(10)IU/ml), LR (2.86 log(10)IU/ml), and ENH (3.35 log(10)IU/ml). HBsAg titres were highest in the IT phase, and lowest in the LR phase. In general, median HBsAg titres were similar between genotypes B and C HBV. Serum HBsAg titres only correlated with HBV viral load in the IC phase. No correlation between the serum HBsAg level and ALT was observed. CONCLUSIONS: This study demonstrated significant differences in median baseline serum HBsAg titres across the different phases of CHB. These results provide further insight into the HBV viral life cycle in the setting of the various phases of CHB. Baseline HBsAg quantification may help refine future treatment algorithms for both immune-modulator therapy and oral nucleos(t)ide analogue therapy.

Antisense inhibitors, ribozymes, and siRNAs.

The current standard of care for the treatment of hepatitis C virus infection, pegylated interferon-alpha and ribavirin, is costly, associated with significant side effects, and effective in only 50% of patients. There is therefore a need for the development of novel antiviral therapies. One such approach involves the application of gene silencing technologies, including antisense oligonucleotides, ribozymes, RNA interference, and aptamers. However, despite great scientific advances over the past decade, and promising in vitro data, several significant challenges continue to limit the translation of this technology to the clinical setting. This review provides a concise update of the current literature.

Prospective study of cardiac troponin I release in patients with upper gastrointestinal bleeding.

BACKGROUND AND AIM: The rate of cardiac injury in upper gastrointestinal hemorrhage is unclear. The aims of this study were to determine prospectively the risk of cardiac troponin I release and associated adverse cardiac events in patients with acute upper gastrointestinal hemorrhage. METHODS: From January to September 2003, we prospectively studied patients with documented hematemesis and melena referred to the gastroenterology unit in a tertiary teaching hospital in Melbourne, Australia. Serial assays for cardiac troponin I were performed at 0, 12 and 24 h. Serial creatine kinase levels and electrocardiographs were also performed. Clinical and biochemical data were collected. The primary endpoint was a troponin level >0.5 microg/L within 24 h of recruitment. Various clinical variables were then compared between the groups of patients with or without troponin rise. RESULTS: A total of 156 patients were included in the study. The mean age was 67 years (range 19-96). There were 104 (67%) male patients. A troponin level of greater than 0.5 microg/L was found in 30/156 (19%); 126 (81%) patients had normal troponin levels. Age greater than 65 years, signs of hemodynamic instability at presentation, a recent history of cardiac disease, cardiovascular compromise following endoscopy, and re-bleeding were associated with troponin release. CONCLUSION: Upper gastrointestinal bleeding is associated with a risk of cardiac injury of up to 19%. Troponin assay could be used to screen for cardiac damage, especially in elderly patients who present with hemodynamic instability.

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection.

UNLABELLED: Hepatitis B virus (HBV)-specific T cells play a key role in clearance of the virus and in the pathogenesis of liver disease. Peripheral blood (n = 25) and liver biopsies (n = 19) were collected from individuals with chronic untreated HBV infection. Whole blood, cultured peripheral blood mononuclear cells (PBMCs), and cultured liver-infiltrating lymphocytes (LILs) were each stimulated with an overlapping peptide library to the whole HBV genome. The expression of T helper 1 (Th1) cytokines [interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 2 (IL-2)] and interleukin 10 (IL-10) was analyzed by intracellular cytokine staining and flow cytometry. In ex vivo whole blood, more lymphocytes produced Th1 cytokines than IL-10. When comparing cultured LILs with cultured PBMCs, we found a significantly higher magnitude of CD8(+) T cells from the liver producing IL-10 (P = 0.044), primarily in hepatitis B e antigen positive (HBeAg(+)) individuals. A positive correlation resulted between the magnitude of HBV-specific TNF-alpha(+) CD4(+) T cells in the liver and the degree of liver inflammation and fibrosis (P = 0.002 and P = 0.006, respectively). CONCLUSION: The differences in cytokine production from HBV-specific T cells in blood and liver may explain the capacity for HBV to persist in the absence of significant hepatic destruction and highlights the balance between cytokine-mediated viral control and liver damage.

Lamivudine resistance in patients with chronic hepatitis B: role of clinical and virological factors.

BACKGROUND: Lamivudine resistance is associated with long-term monotherapy for chronic hepatitis B and can lead to potentially serious clinical consequences. Scant information exists regarding the influence of hepatitis B virus variants in the development of resistance. The present study was designed to identify factors predictive of lamivudine resistance, with a particular focus on the role of precore and basal core promoter variants in the setting of hepatitis B e antigen-negative disease. METHODS: Eighty-five patients, representing four major genotypes, were followed prospectively on lamivudine therapy. Resistance was defined as an increase in viral load, with polymerase gene sequencing confirming a lamivudine resistance mutation. Median follow up was 19 months (6-54 months). The Cox proportional hazards model was used to determine variables independently predicting for the early onset of lamivudine resistance. RESULTS: The rate of lamivudine resistance was 6%, 31% and 51% at 12, 24 and 48 months, respectively. Multivariate analysis identified the precore variant, high baseline alanine aminotransferase (ALT), and persistent viremia (at 6 months) as independent predictors of the early development of lamivudine resistance, with rate ratios of 4.93 (95% confidence interval [CI]: 1.32-18.5), 1.22 (95%CI: 1.08-1.49), and 4.73 (95%CI: 1.49-15.0), respectively (P < 0.05). Female sex predicted early resistance (rate ratio 5.27 [95%CI: 1.23-22.5, P < 0.05]) although numbers were small (n = 12). Genotype did not influence treatment response nor time to onset of resistance. CONCLUSION: Patients with precore variant hepatitis B virus are likely to develop lamivudine resistance early and should be considered for alternate first-line monotherapy. In the future, combination antiviral therapy may limit the development of resistance.

COX-2 inhibition versus gastroprotection with dual COX inhibitors: an evidence-based approach.

Highly selective inhibitors of cyclooxygenase-2 (COX-2i) were introduced to minimize peptic ulcers and their complications caused by dual COX inhibitors (COXi). Co-prescribing a (generally cheap) dual COXi with a gastroprotectant is an alternative strategy, proven to reduce the incidence of NSAID-associated endoscopic ulcers. This review compares the efficacies of these two strategies and makes some estimates of their relative cost-effectiveness. In standard risk patients, endoscopic ulcers are reduced to about the same extent (around 70-80%) by either co-prescribing omeprazole or lansoprazole with a dual COXi or preferring a COX-2i alone. COX-2i reduced ulcer complications by a weighted mean of around 60% in comparative studies with dual COXi. There is little information about the influence of PPI on this endpoint, although one study using H. pylori treatment as a possible surrogate for placebo intervention found 77% protection against recurrent upper gastrointestinal bleeding by co-administered omeprazole. One direct comparison of the two strategies in high-risk patients (recent ulcer bleed) found quite high rates of re-presentation with bleeding ulcer using either strategy, and the differences between them were not significant. Drug costs in four Western countries were compared for each strategy. In one, the costs were similar, but in the others the combination of a cheap dual COXi with omeprazole was usually more expensive than using a COX-2i. The safest strategy in highest risk patients may be to co-prescribe a gastroprotectant with a COX-2i, with resulting higher drug costs but possibly offset by savings in other health costs. The efficacy and cost-benefit of this alternative approach warrants investigation.