A comparison of the acceptance of immunochemical faecal occult blood test and colonoscopy in colorectal cancer screening: a prospective study among Chinese

Aliment Pharmacol Ther 2010; 32: 74–82

Summary

Background Preferences to choose immunochemical faecal occult blood test (FIT) and colonoscopy as colorectal cancer (CRC) screening modalities among asymptomatic Chinese subjects remain unknown. Aim To evaluate the preference of choosing colonoscopy vs. FIT among CRC screening participants. Methods From a community‐based CRC screening programme for asymptomatic Hong Kong Chinese aged 50–70 years, participants attended standardized educational sessions and chose the options of annual FIT for 5 years or direct colonoscopy once. Factors associated with choosing colonoscopy were evaluated by multivariate regression analysis. Results Among 3430 participants [mean age 56.8 years (s.d. 5.0); female 55.1%, male 44.9%], 51.3% chose colonoscopy and 48.7% chose FIT. Older participants (65–70 years) were less likely to choose colonoscopy [adjusted odds ratio (aOR) 0.731, P = 0.041]. Subjects who chose colonoscopy were those disagreed screening would lead to discomfort (aOR 1.356, P < 0.001), had relatives or friends who had CRC (first degree relatives aOR 1.679, P < 0.001; second degree relatives aOR 1.304, P = 0.019; friends or others aOR 1.252, P = 0.026) and those who self‐perceived their health as poor (aOR 1.529, P = 0.025). Conclusions Faecal occult blood test and direct colonoscopy were equally preferable to Chinese. Colonoscopy was preferred among the younger subjects, those with positive family history of CRC and self‐perceived poor health status.     

Identification of colorectal adenomas by a quantitative immunochemical faecal occult blood screening test depends on adenoma characteristics, development threshold used and number of tests performed

Background  Faecal occult blood tests (FOBT) are faulted by low sensitivity for advanced adenomatous polyps (AAP). Quantified, immunochemical, haemoglobin (Hb)-specific immunochemical FOBT (I-FOBT) measurements are now used for colorectal screening.
Aims  To correlate adenoma characteristics to amount of faecal Hb lost and to evaluate sensitivity and specificity for AAP by faecal Hb development threshold used and number of I-FOBTs collected.
Methods  Three daily I-FOBTs were collected and analysed in 1221 patients scheduled for colonoscopy. Faecal Hb was analysed as ngHb/mL of buffer and the highest result related to colonoscopy findings.
Results  In 1204 patients without cancer, colonoscopy identified adenomas in 294, 99 with AAPs. Adenoma patients had elevated faecal Hb increasing with advanced histology, size, pedunculated shape and multiplicity ( P < 0.001 for all). At 50 ngHb/mL threshold, sensitivity and specificity for AAPs were 54.5% (95%CI 44.7, 64.7) and 88.1% (95%CI 86.2, 90.1) for three tests. At higher thresholds, sensitivity decreased, but was significantly higher with more samples collected. Conversely, specificity increased at higher thresholds, but decreased with more samples.
Conclusions  Faecal Hb loss from adenomas is significantly associated with size, number and advanced features. Sensitivity and specificity for AAPs are determined by test threshold chosen and number of samples collected; these determine the number of colonoscopies needed for positive tests.     

Can patients at high risk for significant colorectal neoplasms and having normal quantitative faecal occult blood test postpone elective colonoscopy?

Aliment Pharmacol Ther 31 , 523–533

Summary

Background Common reasons for elective screening and surveillance colonoscopy, at predetermined intervals, are family or personal history of colorectal cancer (CRC) or advanced adenoma (AAP). Quantified, human haemoglobin (Hb)‐specific, immunochemical faecal occult blood tests (I‐FOBT) detect bleeding. Aim To determine I‐FOBT sensitivity for CRC or AAP before elective colonoscopy in patients at high‐risk of cancer or advanced adenoma. Methods Prospective double‐blind study of 1000 ambulatory asymptomatic high‐risk patients (555 family history of CRC, 445 surveillance for past neoplasm), who prepared three I‐FOBTs before elective colonoscopy. I‐FOBTs quantified as ngHb/mL of buffer by OC‐MICRO instrument and results ≥50 ngHb/mL considered positive. Results At colonoscopy, eight patients had CRC, 64 others had AAP. Sensitivity for CRC and/or AAP was the highest, 65.3% (95% CI 54.3, 76.3), when any of the three I‐FOBTs was ≥50 ngHb (15.4%), with specificity of 87.5% (95% CI 86.4, 90.5) identifying all CRCs and 62% of AAPs. Conclusions All cancers or an AAP were detected every third I‐FOBT‐positive colonoscopy (47/154), so colonoscopy was potentially not needed at this time in 84.6% (846 patients). I‐FOBT screening might provide effective supervision of high‐risk patients, delaying unnecessary elective colonoscopies. This favourable evaluation needs confirmation and cost–benefit study by risk‐group.     

Meta‐analysis: reduction in hepatic events following interferon‐alfa therapy of chronic hepatitis B

Aliment Pharmacol Ther 2010; 32: 1059–1068

Summary

Background The long‐term benefit of interferon‐alfa (IFN‐α) treatment in preventing various hepatic complications is not certain. Aim To study the effects of IFN‐α on reducing the risk of developing overall hepatic events (hepatocellular carcinoma, cirrhotic complications and liver‐related mortality) in chronic hepatitis B patients. Methods Randomized controlled trials, case–control studies and cohort studies were retrieved from electronic databases and conference abstracts. Relative risks (RRs) of different hepatic complications among patients treated by IFN‐α vs. no treatment or placebo were studied. Results Eleven studies were identified totalling 975 patients treated by IFN‐α vs. 1147 untreated controls for analysis. Patients were treated by IFN‐α for 1–24 months with a post‐treatment follow‐up of 1–13 years. Treatment by IFN‐α reduced the risk of overall hepatic events (RR 0.55, 95% confident interval or CI 0.43–0.70, P < 0.001) and cirrhotic complications (RR 0.46, 95% CI 0.32–0.67, P < 0.001) by 45% and 54% respectively. Patients who responded to IFN‐α had more profound reduction in overall hepatic events (RR 0.20, 95% CI 0.05–0.87, P = 0.03) and cirrhotic complications (RR 0.19, 95% CI 0.09–0.38, P < 0.001) vs. the untreated controls. Conclusion Interferon‐alfa treatment reduces the risk of hepatic events particularly among responders to treatment.     

Clinical trial: the incidence of NSAID‐associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric‐coated naproxen alone

Aliment Pharmacol Ther 2010; 32: 401–413

Summary

Background Gastroprotective co‐therapy may reduce the risk of nonsteroidal anti‐inflammatory drug (NSAID)‐associated gastric ulcers, but adherence is suboptimal. Aim To compare the incidence of gastric ulcers with PN 400 [enteric‐coated (EC) naproxen 500 mg and immediate‐release esomeprazole 20 mg], or EC naproxen. Methods Two randomized, double‐blind, multicentre studies (PN400‐301, PN400‐302). Patients [stratified by low‐dose aspirin (≤325 mg) use] aged ≥50 years or 18–49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. Results The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low‐dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non‐users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). Conclusions PN 400 significantly reduces the incidence of gastric ulcers, regardless of low‐dose aspirin use, in at‐risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782).     

Effects of a single dose of rabeprazole 20 mg and pantoprazole 40 mg on 24‐h intragastric acidity and oesophageal acid exposure: a randomized study in gastro‐oesophageal reflux disease patients with a history of nocturnal heartburn

Aliment Pharmacol Ther 31 , 991–1000

Summary

Background Nocturnal heartburn is common in patients with gastro‐oesophageal reflux disease (GERD). Aim To compare the effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg on 24‐h intragastric acidity and oesophageal acid exposure (OAE). Methods A total of 52 subjects with GERD and a ≥6‐month history of heartburn were randomized into a blinded, 2 × 2 crossover trial. Subjects’ intragastric pH was monitored in two 48‐h study periods with 6‐ to 13‐day washout between periods. Patients received placebo on day 1, a single dose of rabeprazole 20 mg or pantoprazole 40 mg on day 2, and standardized meals throughout. Results The mean percentage time with intragastric pH >4 was significantly greater with rabeprazole vs. pantoprazole for the 24‐h postdose interval (44.0% vs. 32.8%; P < 0.001). Significant differences were observed in the daytime (51.0% vs. 42.2%; P < 0.001) and nighttime (32.0% vs. 16.9%; P < 0.001). Rabeprazole was also significantly superior in other intragastric pH parameters. There was no statistical difference for OAE between treatments. Conclusions In GERD patients with nocturnal heartburn, rabeprazole 20 mg was significantly more effective than pantoprazole 40 mg in percentage time with intragastric pH >4 during the nighttime, daytime, and 24‐h periods. Differences between treatments in OAE were not demonstrated. This trial is registered with http://clinicaltrials.gov , number NCT00237367.     

Clinical trial: maintenance intermittent therapy with rabeprazole 20 mg in patients with symptomatic gastro‐oesophageal reflux disease – a double‐blind,placebo‐controlled,randomized study

Aliment Pharmacol Ther 31 , 950–960

Summary

Background Optimal long‐term management of symptomatic gastro‐oesophageal reflux disease (sGERD) patients has not been established. Aim To determine the clinical value of maintenance intermittent treatment with rabeprazole 20 mg vs. placebo in patients with sGERD. Methods This multicentre, US study enrolled patients with sGERD (≥3‐month history of GERD symptoms and ≥4 days/week of heartburn during a 2‐week placebo run‐in) without oesophageal erosions. Patients with complete heartburn control after 4 weeks of open‐label rabeprazole 20 mg daily treatment were randomized to 6‐month, double‐blind, maintenance intermittent treatment (7‐ to 14‐day courses when heartburn recurred) with rabeprazole 20 mg or placebo. Results The primary efficacy end point, mean percentage of heartburn‐free days, was significantly greater with rabeprazole vs. placebo: 82.58% and 62.17% (ITT; P < 0.0001) [per protocol 86.74% rabeprazole vs. 74.93% placebo (P < 0.0254)]. Compared with placebo group, the rabeprazole group also experienced a significantly higher percentage of heartburn‐free daytime (84.06% vs. 63.39%; P < 0.0001) and nighttime (95.41% vs. 90.25%; P = 0.0021) periods, had significantly fewer discontinuations because of insufficient heartburn control (6.3% vs. 36.3%; P < 0.0001) and took fewer antacid tablets daily (0.58 vs. 1.16; P = 0.0021). Conclusion Intermittent use of rabeprazole may be an effective maintenance treatment strategy for patients with sGERD and warrants further investigation. This trial was registered with http://clinicaltrials.gov under the number NCT00165841.     

Comparative evaluation of a new bedside faecal occult blood test in a prospective multicentre study

BACKGROUND: Faecal occult blood testing is an established method of colorectal neoplasia screening. Guaiac-based tests are limited by poor patient compliance, low sensitivity, specificity and positive predictive value. Newer immunochemical-based tests, accurate but tedious, require a well-established laboratory set up. There is need for simpler immunochemical tests that can be performed at the out-patient clinic. AIM: To compare the performance characteristics of a new bedside immunological test strip device with a sensitive Guaiac-based and established immunochemical test for detection of faecal occult blood in patients undergoing colonoscopy. METHODS: A total of 389 consecutive patients from four centres who were referred for colonoscopy also provided the stool samples for detection of occult blood without dietary restrictions. Stool tests performed were (i) Guaiac-based, (ii) immunochemical enzyme-linked immunosorbent assay and (iii) bedside immunochemical strip test. RESULTS: At the optimal threshold level, the sensitivity and specificity of the beside immunochemical strip test for detection of significant colorectal neoplasia (adenomas >1.0 cm and carcinomas) were 60% and 95%, respectively. CONCLUSIONS: This bedside immunochemical strip test proved to be a simple, convenient, non-cumbersome and accurate tool with similar performance characteristics for detection of any bleeding lesion including colorectal neoplasia when compared with an established immunochemical faecal occult blood test.     

Quantitative colonoscopic evaluation of relative efficiencies of an immunochemical faecal occult blood test and a sensitive guaiac test for detecting significant colorectal neoplasms

Background  The guaiac faecal occult blood test (G-FOBT), HemoccultSENSA, is sensitive for significant neoplasms [colorectal cancer (CRC), advanced adenomatous polyps (AAP)], but faulted by non-specificity for human haemoglobin (Hb). Quantified, Hb- specific, immunochemical faecal occult blood tests (I-FOBT) are now used.
Aims  To (i) compare I-FOBT and G-FOBT efficacy in identifying significant neoplasms and colonoscopy needs for positive tests and (ii) examine number of I-FOBTs needed and test threshold to use for equivalent or better sensitivity than G-FOBT and fewest colonoscopies for positive tests.
Methods  Three daily G-FOBTs and I-FOBTs were collected and analysed in 330 patients scheduled for colonoscopy.
Results  Colonoscopy found significant neoplasms in 32 patients, 6 CRC, 26 AAP. G-FOBT, sensitivity and specificity were 53.1% (17 neoplasms) and 59.4%, resulting in 8.1 colonoscopies/neoplasm. One I-FOBT having ≥50 ngHb/mL of buffer provided equivalent sensitivity but 94.0% specificity, resulting in 2.1 colonoscopies/neoplasm. By analysing the higher of two I-FOBTs at 50 ngHb/mL threshold, sensitivity increased to 68.8% (22 neoplasms, P  = 0.063), specificity fell to 91.9% ( P  < 0.001), but still required 2.1 colonoscopies/neoplasm.
Conclusions  In this population, quantified I-FOBT had significantly better specificity than G-FOBT for significant neoplasms, reducing the number of colonoscopies needed/neoplasm detected. Results depend on the number of I-FOBTs performed and the chosen development threshold.     

A sensitive guaiac faecal occult blood test is less useful than an immunochemical test for colorectal cancer screening in a Chinese population

BACKGROUND: Colorectal cancer screening by guaiac faecal occult blood test has been shown to reduce the incidence and mortality of colorectal cancer in Western populations. The optimal faecal occult blood test, whether guaiac or immunochemical, for colorectal cancer screening in the Chinese population remains to be defined. AIM: To compare the performance characteristics of a sensitive guaiac-based faecal occult blood test (Hemoccult SENSA) and an immunochemical faecal occult blood test (FlexSure OBT) in a Chinese population referred for colonoscopy. METHODS: One hundred and thirty-five consecutive patients who were referred for colonoscopy and who met the study inclusion criteria took samples for the two faecal occult blood tests simultaneously from three successive stool specimens, with no dietary restrictions. All tests were developed and interpreted by a single experienced technician who was blind to the clinical diagnosis. The sensitivity, specificity and positive predictive value for the detection of colorectal adenomas and cancers were estimated for the two tests. RESULTS: The sensitivity, specificity and positive predictive value for the detection of significant colorectal neoplasia (adenomas > or = 1.0 cm and cancers) were 91%, 70% and 18% for Hemoccult SENSA and 82%, 94% and 47% for FlexSure OBT. The specificity and positive predictive value were significantly higher for FlexSure OBT than for Hemoccult SENSA (P < 0.001 and P = 0.016, respectively). Combining the positive results from both faecal occult blood tests did not improve the accuracy. CONCLUSION: The positive predictive value of the immunochemical faecal occult blood test for the detection of significant colorectal neoplasia was 29% better than that of the sensitive guaiac-based test. This may relate to the Chinese diet and requires further study. The poor specificity of the sensitive guaiac-based test, without dietary restriction, makes it less useful for colorectal cancer screening in a Chinese population.     

MicroRNA‐33a‐5p suppresses colorectal cancer cell growth by inhibiting MTHFD2

Colorectal cancer (CRC) is one of the most common malignancies with high levels of invasiveness, drug resistance and mortality, but the internal mechanisms of CRC are largely unknown. MicroRNAs (miRs) have been reported to be involved in the development of CRC, and numerous studies have demonstrated that the abnormal expression of miR‐33a‐5p might be associated with CRC. However, the function and downstream mechanism of miR‐33a‐5p in colorectal cancer (CRC) remains unclear. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folic acid metabolism, interestingly was confirmed to be one of the target genes of miR‐33a‐5p in the present study. We first confirmed that miR‐33a‐5p in CRC tissues and cell lines were downregulated (P < 0.05), and that the proliferation, clone formation capacities, G1/S progression, and migration capacities of the two CRC cell lines HCT116 cells and HT29 were suppressed by miR‐33a‐5p overexpression in vitro (P < 0.05). Ctrl HCT116 and miR‐33a‐5p‐overexpressing HCT116 were injected into nude mice. In vivo tumour formation was significantly suppressed by miR‐33a‐5p overexpression (P < 0.05) as well as the proliferation marker Ki67 (P < 0.05). Additionally, MTHFD2 protein expression was significantly enhanced in CRC tissues. From bioinformatics predictions and a luciferase report analysis, MTHFD2 was confirmed to be one of the target genes of miR‐33a‐5p. In contrast to the role of miR‐33a‐5p overexpression, MTHFD2 overexpression promoted the proliferation and migration of HCT116 and HT29 cells (P < 0.05), which confirmed that MTHFD2 was a functional target gene of miR‐33a‐5p. In conclusion, miR‐33a‐5p inhibits the growth and migration of CRC by targeting MTHFD2.     

Clinical trial: esomeprazole for moderate‐to‐severe nighttime heartburn and gastro‐oesophageal reflux disease‐related sleep disturbances

Aliment Pharmacol Ther 2010; 32: 182–190

Summary

Background Nighttime heartburn, common among patients with gastro‐oesophageal reflux disease (GERD), is associated with substantial clinical effects. GERD‐related sleep disturbances are underappreciated and undertreated. Aim To evaluate the efficacy of esomeprazole on GERD‐related nighttime heartburn and associated sleep disturbances. Methods In this multicentre, randomized, double‐blind, placebo‐controlled study, patients with moderate‐to‐severe nighttime heartburn and GERD‐related sleep disturbances (endoscopies not required) received esomeprazole 20 mg or placebo each morning for 4 weeks. Heartburn symptoms and GERD‐related sleep disturbances were evaluated using the validated Pittsburgh Sleep Quality Index and validated Work Productivity and Activity Impairment Questionnaire. Results The analysis included 262 patients (esomeprazole, n = 137; placebo, n = 125). Significantly more patients receiving esomeprazole achieved nighttime heartburn relief (primary end point) than those receiving placebo (34.3% vs. 10.4%; P < 0.0001). Secondary end points such as relief of GERD‐related sleep disturbances (P = 0.006), days without GERD‐related sleep disturbances (P = 0.0003) and complete resolution of sleep disturbances (P < 0.0001) favoured esomeprazole over placebo. Sleep quality, work productivity and regular daily activities also improved significantly with esomeprazole vs. placebo. Conclusions Esomeprazole 20 mg is effective for patients with moderate‐to‐severe nighttime heartburn and GERD‐related sleep disturbances, improving heartburn symptoms, sleep quality, work productivity and functionality.

     

Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn's disease and histological findings

Background Faecal calprotectin and lactoferrin increasingly serve as surrogate markers of disease activity in IBD. Data on the correlation of these markers with simple endoscopic score for Crohn’s disease (SES‐CD) and with histological findings are as yet limited. Aim To study the correlation of faecal calprotectin and lactoferrin with SES‐CD and histology. Methods  During 87 consecutive ileocolonoscopies, SES‐CD was calculated and biopsy specimens were obtained from the ileum, colon and rectum. Faecal calprotectin and lactoferrin were measured. Results In ileocolonic or colonic disease, both faecal calprotectin and lactoferrin correlated significantly with colon SES‐CD (P < 0.001) and colon histology (P < 0.001). In patients with normal calprotectin or lactoferrin levels, endoscopic and histology scores were significantly lower than in those with elevated concentrations (P < 0.001). In ileal CD, ileal SES‐CD correlated with histology (P < 0.001), but not with faecal calprotectin (P = 0.161) or lactoferrin (P = 0.448). Conclusion In ileocolonic and colonic disease, endoscopic score SES‐CD and histological findings correlated significantly with faecal calprotectin and lactoferrin. A normal faecal‐marker concentration was a reliable surrogate marker for endoscopically and histologically inactive CD. Ileal endoscopic score and histological findings failed, however, to correlate with faecal markers.     

Role of proteinuria in defining pre‐eclampsia: Clinical outcomes for women and babies

1. The presence of proteinuria is not essential to the diagnosis of pre‐eclampsia under many diagnostic consensus statements. The aim of the present study was to assess maternal and perinatal outcomes after proteinuric pre‐eclampsia compared with other non‐proteinuric disease presentations. 2. An individual patient data review (n = 670) was undertaken for 2003–2006 at a tertiary referral centre in Sydney (NSW, Australia). Women were diagnosed in accordance with the Australasian Society for the Study of Hypertension in Pregnancy Consensus Statement. Data were analysed with the Chi‐squared test, t‐tests and non‐parametric tests. Statistical significance was set at P < 0.05. 3. The proteinuric cohort had higher systolic and diastolic blood pressure recordings than the non‐proteinuric cohort (160/102 and 149/94 mmHg, respectively; P < 0.001), and were also administered magnesium sulphate more frequently (44 vs 22%, respectively; P < 0.001), delivered at earlier gestation (37 vs 38 weeks, respectively; P < 0.001), required operative delivery more frequently (63 vs 48%, respectively; P < 0.001) and received more antihypertensive medications during the antenatal period (72 vs 57%, respectively; P < 0.001). Acute renal failure and acute pulmonary oedema were rare. Four cases of eclampsia all occurred in non‐proteinuric women. The perinatal mortality rate was lower for the offspring of women with proteinuric pre‐eclampsia compared with offspring of non‐proteinuric women (13/1000 and 31/1000, respectively; P = 0.006). 4. The results of the present study indicate that the presence of proteinuria denotes a group of women who have higher antenatal blood pressure, who deliver at earlier gestation and require operative delivery more commonly, although it is not an indicator of other markers of maternal morbidity or perinatal mortality.     

Cost-effectiveness analysis on screening for colorectal neoplasm and management of colorectal cancer in Asia

Background  Faecal occult blood testing (FOBT), flexible sigmoidoscopy (FS) and colonoscopy are recommended for subjects above 50 years of age for screening for colorectal cancer (CRC).
Aim  To evaluate the cost-effectiveness of FOBT, FS and colonoscopy on the basis of disease prevalence, compliance rate and cost of screening procedures in Asian countries.
Methods  A hypothetical population of 100 000 persons aged 50 undergoes either FOBT annually, FS every 5 years or colonoscopy every 10 years until the age of 80 years. Patients with positive FOBT or polyp in FS are offered colonoscopy. Surveillance colonoscopy is repeated every 3 years. The treatment cost of CRC, including surgery and chemotherapy, was evaluated. A Markov model was used to compare the cost-effectiveness of different screening strategies.
Results  Assuming a compliance rate of 90%, colonoscopy, FS and FOBT can reduce CRC incidence by 54.1%, 37.1% and 29.3% respectively. The incremental cost-effectiveness ratio (ICER) for FOBT (US$6222 per life-year saved) is lower than FS (US$8044 per life-year saved) and colonoscopy (US$7211 per life-year saved). When the compliance rate drops to 50% and 30%, FOBT still has the lowest ICER.
Conclusion  FOBT is cost-effective compared to FS or colonoscopy for CRC screening in average-risk individuals aged from 50 to 80 years.     

Clinical trial: impact of prior infliximab therapy on the clinical response to certolizumab pegol maintenance therapy for Crohn’s disease

Aliment Pharmacol Ther 2010; 32: 384–393

Summary

Background Certolizumab pegol (CZP) is an effective therapy for Crohn’s disease refractory to aminosalicylates, corticosteroids and immunosuppressants. In PRECiSE 2, patients were also eligible for enrolment if prior infliximab therapy was terminated due to loss of response. Aim To evaluate prior infliximab therapy on sustained response and remission to CZP for Crohn’s disease. Methods PRECiSE 2 were was analysed for predictors of sustained response and remission. Covariates included prior infliximab therapy, and baseline Crohn’s Disease Activity Index (CDAI). Results Week 26 response (≥100‐point decrease from baseline CDAI) and remission (CDAI ≤ 150) were greater with CZP vs. placebo in patients previously receiving infliximab (response: 44.2% vs. 25.5%, P = 0.018; remission: 32.7% vs. 13.7, P = 0.008) and infliximab‐naïve patients (response: 68.7% vs. 39.6%, P < 0.001; remission: 52.8% vs. 33.3%, P < 0.001). Prior infliximab use was the only independent predictor of week 26 response and remission in both groups [response OR_{CZP vs. placebo} = 3.06 (95% CI: 1.21–7.77); remission OR_{CZP vs. placebo} = 4.22 (95% CI: 1.45–12.28)]. Adverse events were similar for both groups. Conclusions Certolizumab pegol is an effective maintenance therapy in Crohn’s disease regardless of prior infliximab use. Efficacy is higher in patients receiving CZP therapy as a first‐line biologic, but ～50% of infliximab‐experienced patients benefited from second‐line CZP therapy.     

Atorvastatin increases expression of low‐density lipoprotein receptor mRNA in human circulating mononuclear cells

1. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR) inhibitors, or statins, are commonly used to lower plasma cholesterol levels. HMGCR and the low‐density lipoprotein (LDL) receptor (LDLR) are of central importance to cholesterol homeostasis and yet there is a paucity of data on the effect of statins on the regulation of the LDLR and HMGCR in humans. 2. In the present study, we examined the effect of atorvastatin on the expression of HMGCR, LDLR and LDLR‐related protein (LRP) mRNA in circulating mononuclear cells. Twelve human volunteers were treated with atorvastatin, 20 mg/day for 4 weeks. 3. Atorvastatin decreased plasma total and LDL–cholesterol by 29% (P < 0.0001) and 41% (P < 0.001), respectively, and increased LDLR mRNA abundance, in absolute terms, by 35% (P < 0.001) and 31% (P < 0.0001) and 37% (P = 0.01) relative to reference GAPDH and β‐actin mRNA, respectively. In contrast, atorvastatin had no significant effect on LRP or HMGCR mRNA levels. 4. The increase in LDLR mRNA in circulating mononuclear cells agrees with the few human studies conducted, as well as with in vitro and animal studies, whereas the unchanged HMGCR mRNA is consistent with the hepatic specificity of atorvastatin. The present study firmly documents an increase in LDLR mRNA levels in response to statin administration in normal humans.     

Gastritis OLGA‐staging and gastric cancer risk: a twelve‐year clinico‐pathological follow‐up study

Aliment Pharmacol Ther 31 , 1104–1111

Summary

Background Intestinal‐type gastric cancer (GC) still ranks among the high‐incidence, highly lethal malignancies. Atrophic gastritis is the cancerization field in which GC develops. The current histological reporting formats for gastritis do not include any (atrophy‐based) ranking of GC risk. Aim To test the gastritis OLGA‐staging (Operative Link for Gastritis Assessment) in prognosticating neoplastic progression. Methods Ninety‐three Italian patients were followed up for more than 12 years (range: 144–204 months). Clinical examinations, pepsinogen serology, endoscopy and histology (also assessing Helicobacter pylori status) were performed both at enrolment (T1) and at the end of the follow‐up (T2). Results All invasive or intra‐epithelial gastric neoplasia were consistently associated with high‐risk (III/IV) OLGA stages. There was a significant inverse correlation between the mean pepsinogen ratio and the OLGA stage (test for trend; P < 0.001). OLGA‐staging at T1 predicted both the OLGA stage (Kaplan–Maier log‐rank test, P = 0.001) and the neoplasia at T2 (Kaplan–Maier log‐rank test, P = 0.001). Conclusions This long‐term follow‐up study provides the first evidence that gastritis OLGA‐staging conveys relevant information on the clinico‐pathological outcome of gastritis and therefore for patient management. According to OLGA‐staging and H. pylori‐status, gastritis patients could be confidently stratified and managed according to their different cancer risks.     

Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 374–383

Summary

Background Imbalances in gut luminal bacteria may contribute to the pathogenesis of irritable bowel syndrome (IBS). Aim To explore select bacteriological and anti‐inflammatory effects of mesalazine (mesalamine; 5‐aminosalicylic acid or 5ASA) and their relation to potential therapeutic effects in IBS. Methods Prospective pilot study of 12 women with diarrhoea‐predominant IBS. Patients received oral mesalazine (1.5 g b.d.) for 4 weeks followed by a 4‐week washout phase. Molecular profiling of stool bacterial communities and IBS symptoms were assessed before, during and after mesalazine treatment. Colonic mucosal biopsies were assessed for proteolytic activity. Qualitative and quantitative effects of mesalazine on stool microbiota, mucosal proteolytic activity and IBS symptoms were assessed. Results Faecal bacteria decreased by 46% on mesalazine treatment (P = 0.014), but returned to baseline during washout. Firmicutes and Bacteroidetes represented 95% of identified phylotypes, with a trend towards an increase in the proportion of Firmicutes at week 4 in symptomatic responders [median (IQR) 14% (49) increase] compared with nonresponders [median 5% (11) decrease, P = 0.088]. Rectosigmoid mucosal proteolytic activity did not change between baseline and treatment [median 23.2 (17.9) vs. 19.5 (46.7) mU activity/mg tissue, P = 0.433]. Eight of 12 (67%) patients responded favourably to mesalazine based on a global relief questionnaire, with significant decreases in days with discomfort and increases in bowel movement satisfaction. Conclusions Mesalazine treatment is associated with a decrease in faecal bacteria abundance and rebalancing of the major constituents of the microbiota. Further study of the bacteriological and anti‐inflammatory properties of mesalazine in IBS is warranted.     

1,8‐Cineole induces relaxation in rat and guinea‐pig airway smooth muscle

Objectives 1,8‐Cineole is a monoterpene with anti‐inflammatory, vascular and intestinal smooth muscle relaxant activity. We have evaluated the potential bronchodilatatory activity of this compound. Methods 1,8‐Cineole was tested against carbachol, histamine, K⁺ 80 mM and ovalbumin‐induced bronchial contractions in Wistar rat or guinea‐pig tissues. Some of the guinea‐pigs had been previously sensitized with an intramuscular injection of 5% (w/v) ovalbumin/saline solution. Control animals received 0.3 ml saline. In separate experimental groups the response to 1,8‐cineole (1–30 mg/kg), phenoterol (0.05–5 mg/kg) or vehicle (0.3% Tween in saline) was studied. Key findings 1,8‐Cineole decreased, in vivo, rat bronchial resistance with similar efficacy as phenoterol (66.7 ± 3.2% vs 72.1 ± 5.3%). On the other hand, the maximal relaxant response to 1,8‐cineole in carbachol‐precontracted rat tracheas was 85.5 ± 5.7% (IC50 = 408.9 (328–5196) μg/ml) compared with 80.2 ± 4.8% (IC50 = 5.1 (4.3–6.1) μg/ml) with phenoterol. The addition of 1,8‐cineole to guinea‐pig tracheal rings tonically contracted with K⁺ 80 mM induced a concentration‐related relaxation. The maximal relaxation elicited by 1,8‐cineole was 113.6 ± 11.7% (IC50 127.0 (115.9–139.2) μg/ml) compared with 129.7 ± 14.6% (IC50 0.13 (0.12–0.14) μg/ml) achieved after phenoterol administration. In addition, the incubation of tracheal rings with 1,8‐cineole (100, 300 or 1000 μg/ml), 15 min before inducing phasic contractions with K⁺ 80 mM, decreased the maximal amplitude of the contraction by 31.6 ± 4.6, 75.7 ± 2.7 and 92.2 ± 1.5%, respectively. In another set of experiments, neither the maximal response nor the IC50 for the 1,8‐cineole‐induced relaxation were different between normal and ovalbumin‐sensitized tissues. Moreover, the relaxation of bronchial rings contracted after exposure to 1 μg/ml ovalbumin occurred at a faster rate in rings pre‐incubated with 1,8‐cineole when compared with rings pre‐incubated with vehicle only (Tween 0.3%). Therefore, in the first minute after the antigen challenge, the tracheal tissue relaxed after the peak contraction by 6.5, 21.4 (P < 0.05 vs control) and 66.9% (P < 0.05 vs control) in the presence of 100, 300 or 1000 μg/ml 1,8‐cineole, respectively. Conclusions 1,8‐Cineole relaxed rat and guinea‐pig (nonsensitized and ovalbumin‐sensitized) airway smooth muscle by a nonspecific mechanism.