Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Colonic motor abnormalities in slow transit constipation defined by high resolution, fibre-optic manometry.

BACKGROUND: Slow transit constipation (STC) is associated with colonic motor abnormalities. The underlying cause(s) of the abnormalities remain poorly defined. In health, utilizing high resolution fiber-optic manometry, we have described a distal colonic propagating motor pattern with a slow wave frequency of 2-6 cycles per minute (cpm). A high calorie meal caused a rapid and significant increase in this activity, suggesting the intrinsic slow wave activity could be mediated by extrinsic neural input. Utilizing the same protocol our aim was to characterize colonic meal response STC patients. METHODS: A fiber-optic manometry catheter (72 sensors at 1 cm intervals) was colonoscopically placed with the tip clipped at the ascending or transverse colon, in 14 patients with scintigraphically confirmed STC. Manometric recordings were taken, for 2 h pre and post a 700 kCal meal. Data were compared to 12 healthy adults. KEY RESULTS: Prior to and/or after the meal the cyclic propagating motor pattern was identified in 13 of 14 patients. However, the meal, did not increase the cyclic motor pattern (preprandial 7.4 ± 7.6 vs postprandial 8.3 ± 4.5 per/2 h), this is in contrast to the dramatic increase observed in health (8.3 ± 13.3 vs 59.1 ± 89.0 per/2 h; p < 0.001). CONCLUSIONS & INFERENCES: In patients with STC a meal fails to induce the normal increase in the distal colonic cyclic propagating motor patterns. We propose that these data may indicate that the normal extrinsic parasympathetic inputs to the colon are attenuated in these patients.

Quantification of in vivo colonic motor patterns in healthy humans before and after a meal revealed by high-resolution fiber-optic manometry.

BACKGROUND: Until recently, investigations of the normal patterns of motility of the healthy human colon have been limited by the resolution of in vivo recording techniques. METHODS: We have used a new, high-resolution fiber-optic manometry system (72 sensors at 1-cm intervals) to record motor activity from colon in 10 healthy human subjects. KEY RESULTS: In the fasted colon, on the basis of rate and extent of propagation, four types of propagating motor pattern could be identified: (i) cyclic motor patterns (at 2-6/min); (ii) short single motor patterns; (iii) long single motor patterns; and (iv) occasional retrograde, slow motor patterns. For the most part, the cyclic and short single motor patterns propagated in a retrograde direction. Following a 700 kCal meal, a fifth motor pattern appeared; high-amplitude propagating sequences (HAPS) and there was large increase in retrograde cyclic motor patterns (5.6 ± 5.4/2 h vs 34.7 + 19.8/2 h; p < 0.001). The duration and amplitude of individual pressure events were significantly correlated. Discriminant and multivariate analysis of duration, gradient, and amplitude of the pressure events that made up propagating motor patterns distinguished clearly two types of pressure events: those belonging to HAPS and those belonging to all other propagating motor patterns. CONCLUSIONS & INFERENCES: This work provides the first comprehensive description of colonic motor patterns recorded by high-resolution manometry and demonstrates an abundance of retrograde propagating motor patterns. The propagating motor patterns appear to be generated by two independent sources, potentially indicating their neurogenic or myogenic origin.

High resolution colonic manometry--what have we learnt?--A review of the literature 2012.

Despite its size and physiological importance, the human colon is one of the least understood organs of the body. Many disorders arise from suspected abnormalities in colonic contractions, yet, due largely to technical constraints, investigation of human colonic motor function still remains relatively primitive. Most measures of colonic motility focus upon the transit speed (radiology, scintigraphy and, more recently, "smart pills"); however, only colonic manometry can measure pressure/force from multiple regions within the colon in real time (Dinning and Scott (Curr Opin Pharmacol 11:624-629, 2011)). Based upon data from colonic manometry studies, a number of different colonic motor patterns have been distinguished: (1) antegrade high amplitude propagating sequences (contractions), (2) low amplitude propagating sequences, (3) non-propagating contractions, and (4) and rarely episodes of retrograde (oral) propagating pressure waves (Dining and Di Lorenzo (Best Pract Res Clin Gastrolenterol 25(1): 89-101, 2011)). Abnormalities in the characteristics of these motor patterns should help to characterize dysmotility in a patient populations, and in both adults and children colonic motor abnormalities have been identified with manometry studies (Rao et al. Am J Gastroenterol 99(12):2405-2416, (2004), Di Lorenzo et al. Gut. 34(1): 803-807, (1993)). Yet, despite more than two decades of such studies, the clinical utility of colonic manometry remains marginal with no specific manometric biomarkers of colonic dysfunction being established ([Camilleri et al. Neurogastroenterol Motil. 20(12): 1269-1282, 2008). This has been highlighted recently in a colonic manometry study by Singh et al. (2013), in which 41 % of 80 patients, with confirmed slow transit constipation, were reported to have normal motility. While this may suggest that no motor abnormalities exist in a proportion of such patients, the finding may also reflect technical constraints in our ability to detail colonic motility patterns.

Thiopurine metabolite measurement leads to changes in management of inflammatory bowel disease.

BACKGROUND: The thiopurines azathioprine and 6-mercaptopurine are recommended for maintenance of remission in inflammatory bowel disease (IBD). Measurement of concentrations of the metabolites 6-thioguanine nucleotide and 6-methylmercaptopurine helps delineate interindividual variation in metabolism that may underlie variability in efficacy and toxicity. AIMS: We aimed to perform a retrospective observational study to determine the utility of thiopurine metabolite testing following its introduction into South Australia. METHODS: All patients having thiopurine metabolite tests done at Flinders Medical Centre between November 2008 and January 2010 were identified. Case notes of patients with testing done in the context of treatment for IBD were interrogated to determine the reason for testing, clinical context and outcome. RESULTS: One hundred and fifty-one patients were identified with thiopurine metabolite testing for IBD with 157 testing episodes. Eighty (51.0%) had testing done for flare or inefficacy, 18 (11.5%) for adverse effects, 5 (3.2%) for a combination of inefficacy and adverse effects, and 54 (34.4%) for routine or other reasons. Testing was followed by improved outcomes of increased efficacy, reduced toxicity or change to alternative therapy in 55.0% of the inefficacy/flare group, 27.8% of the suspected adverse reaction group, 60.0% of the combination group, and 13.0% of the routine/other group. Allopurinol was used as cotherapy in 16 patients and led to marked improvements in metabolite concentrations. CONCLUSIONS: Thiopurine metabolite testing has quickly become established in South Australia. When used for inefficacy or adverse effects, it often leads to improved outcomes. Prospective studies are needed to determine whether routine testing to guide dosing is of benefit.

Un-promoted issues in inflammatory bowel disease: opportunities to optimize care.

Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gut, which lead to significant morbidity and impaired quality of life (QoL) in sufferers, without generally affecting mortality. Despite CD and UC being chronic, life-long illnesses, most medical management is directed at acute flares of disease. Moreover, with more intensive medical therapy and the development of biological therapy, there is a risk that management will become even more narrowly focused on acute care, and be directed only at those with more severe disease, rather than encompassing all sufferers and addressing important non-acute issues. This imbalance of concentration of medical attention on 'high-end' care is in part driven by the need to perform and publish randomized clinical trials of newer therapies to obtain registration and licensing for these agents, which thus occupy a large proportion of the recent IBD treatment literature. This leads to less attention on relatively 'low-technology' issues including: (i) the psychosocial burden of chronic disease, QoL and specific psychological comorbidities; (ii) comorbidity with functional gastrointestinal disorders (FGIDs); (iii) maintenance therapy, monitoring and compliance; (iv) smoking (with regard to CD); (v) sexuality, fertility, family planning and pregnancy; and (vi) iron deficiency and anaemia. We propose these to be the 'Un-promoted Issues' in IBD and review the importance and treatment of each of these in the current management of IBD.

Clinical trial: the impact of cyclooxygenase inhibitors on gastrointestinal recovery after major surgery - a randomized double blind controlled trial of celecoxib or diclofenac vs. placebo.

BACKGROUND: Ileus occurs after abdominal surgery and may be severe. Inhibition of prostaglandin release reduces post-operative ileus in a rat model. AIM: To determine whether prostaglandin inhibition by cyclooxygenase inhibitors, celecoxib or diclofenac, could enhance gastrointestinal recovery and reduce post-operative ileus in humans. METHODS: Two hundred and ten patients undergoing elective major abdominal surgery were randomized to receive twice daily placebo (n = 67), celecoxib (100 mg, n = 74) or diclofenac (50 mg, n = 69), preoperatively and continuing for up to 7 days. Primary outcomes were hallmarks of gut recovery. Secondary outcomes were paralytic ileus, pain and complications. RESULTS: There was no clinically significant difference between the groups for restoration of bowel function. There was a significant reduction in paralytic ileus in the celecoxib-treated group (n = 1, 1%) compared with diclofenac (n = 7, 10%) and placebo (n = 9, 13%); P = 0.025, RR 0.20, CI 0.01-0.77. Pain scores, analgesia, transfusion requirements and adverse event rates were similar between study groups. CONCLUSIONS: Perioperative low dose celecoxib, but not diclofenac, markedly reduced the development of paralytic ileus following major abdominal surgery, but did not accelerate early recovery of bowel function. This was independent of narcotic use and had no increase in post-operative complications.

Achieving long-term compliance with colonoscopic surveillance guidelines for patients at increased risk of colorectal cancer in Australia.

We have previously demonstrated that we could improve colonoscopic surveillance practice for patients at increased risk of colorectal cancer by the adoption of guidelines, facilitated by a nurse co-ordinator. This study was to determine whether we could sustain this improvement over a longer period (4 years). All colonoscopic surveillance decisions made by the co-ordinated colorectal screening programme of our hospital between 2000 and April 2004 were reviewed. Reasons for variance were recorded, and surveillance decisions made in the last 4 months of the study time were compared with decisions made 4 years previously, both before and after the introduction of the co-ordinated programme. Between 2000 and 2004, 1794 surveillance decisions were made with variance occurring in 100. In the last 4 months of the period of study, 98% of decisions matched guidelines, suggesting that the improvement made following the adoption of the guidelines (45-96% p < 0.05) could be maintained. Reasons for variance from guidelines included a belief that the particular clinical scenario was not covered in the guidelines, disagreement with the guidelines or patient anxiety. Adherence to evidence based medicine guidelines for colonoscopy surveillance can be maintained over time at a high level. A number of clinical scenarios are not covered adequately by the existing guidelines and continue to generate disagreement amongst clinicians.

Interval faecal occult blood testing in a colonoscopy based screening programme detects additional pathology.

BACKGROUND: Colonoscopic based surveillance is recommended for patients at increased risk of colorectal cancer. The appropriate interval between surveillance colonoscopies remains in debate, as is the "miss rate" for colorectal cancer within such screening programmes. AIMS: The main aim of this study was to determine whether a one-off interval faecal occult blood test (FOBT) facilitates the detection of significant neoplasia within a colonoscopic based surveillance programme. Secondary aims were to determine if invitees were interested in participating in interval screening, and to determine whether interval lesions were missed or whether they developed rapidly since the previous colonoscopy PATIENTS: Patients enrolled in a colonoscopic based screening programme due to a personal history of colorectal neoplasia or a significant family history. METHODS: Patients within the screening programme were invited to perform an immunochemical FOBT (Inform). A positive result was followed by colonoscopy; significant neoplasia was defined as colorectal cancer, adenomas either > or =10 mm or with a villous component, high grade dysplasia, or multiplicity (>/=3 adenomas). Participation rates were determined for age, sex, and socioeconomic subgroups. Colonoscopy recall databases were examined to determine the interval between previous colonoscopy and FOBT offer, and correlations between lesion characteristics and interval time were determined. RESULTS: A total of 785 of 1641 patients invited (47.8%) completed an Inform kit. A positive result was recorded for 57 (7.3%). Fifty two of the 57 test positive patients completed colonoscopy; 14 (1.8% of those completing the FOBT) had a significant neoplastic lesion. These consisted of six colorectal cancers and eight significant adenomas. CONCLUSIONS: A one off immunochemical faecal occult blood test within a colonoscopy based surveillance programme had a participation rate of nearly 50% and appeared to detect additional pathology, especially in patients with a past history of colonic neoplasia.

The proximal colonic motor response to rectal mechanical and chemical stimulation.

We aimed to determine whether rectal distension and/or infusion of bile acids stimulates propagating or nonpropagating activity in the unprepared proximal colon in 10 healthy volunteers using a nasocolonic manometric catheter (16 recording sites at 7.5-cm spacing). Sensory thresholds and proximal colonic motor responses were assessed following rectal distension by balloon inflation and rectal instillation of chenodeoxycholic acid. Maximum tolerated balloon volume and the volume that stimulated a desire to defecate were both significantly (P < 0.01) reduced after rectal chenodeoxycholic acid. The frequency of colonic propagating pressure wave sequences decreased significantly in response to initial balloon inflations (P < 0.05), but the frequency doubled after subsequent chenodeoxycholic acid infusion (P < 0.002). Nonpropagating activity decreased after balloon inflation, was not influenced by acid infusion, and demonstrated a further decrease in response to repeat balloon inflation. We concluded that rectal chenodeoxycholic acid in physiological concentrations is a potent stimulus for propagating pressure waves arising in the proximal colon and reduces rectal sensory thresholds. Rectal distension inhibits all colonic motor activity.

Prolonged multi-point recording of colonic manometry in the unprepared human colon: providing insight into potentially relevant pressure wave parameters.

OBJECTIVES: To determine the feasibility of and derive normative data for prolonged, 24-h, multipoint, closely spaced, water perfused manometry of the unprepared human colon. METHODS: In 14 healthy volunteers, 24-h recordings were made using a water perfused, balloon-tipped, 17 lumen catheter which was passed pernasally and positioned so that 16 recording sites spanned the colon at 7.5 cm intervals from cecum to rectum. The area under the pressure curve and propagating pressure wave parameters were quantified for the 16 regions. High amplitude propagating sequences were defined as were rectal motor complexes. RESULTS: Nasocolonic recording was well tolerated and achievable. Propagation sequences, including high amplitude propagating sequences, originated in the cecum (0.32 +/- 0.05/h) more frequently than in other regions and the extent of propagation correlated significantly with proximity of the site of sequence origin to the cecum (p < 0.001). Propagation velocity of propagating sequences was greater than high amplitude propagating sequences (p = 0.0002) and region-dependent, unlike high amplitude propagating sequences (p < 0.01). The frequency of propagating sequences did not increase after the meal, but frequency of high amplitude propagating sequences was increased significantly by the meal (p < 0.01). Rectal motor complexes were seen throughout the colon with no apparent periodicity. CONCLUSIONS: Prolonged, multipoint, perfusion manometry of the unprepared colon provides improved spatial resolution of colonic motor patterns and confirms the diurnal and regional variations in propagating pressure waves detected in the prepared colon. The study demonstrates differences between high amplitude propagating sequences and propagating sequence parameters that may have functional significance; and also, that the rectal motor complex is a ubiquitous pan colonic motor pattern.

Spatial and temporal organization of pressure patterns throughout the unprepared colon during spontaneous defecation.

OBJECTIVE: The aim of this study was to examine colonic motor events associated with spontaneous defecation in the entire unprepared human colon under physiological conditions. METHODS: In 13 healthy volunteers a perfused, balloon-tipped, 17-lumen catheter (outer diameter, 3.5 mm; intersidehole spacing, 7.5 cm) was passed pernasally and positioned in the distal unprepared colon. RESULTS: In the hour before spontaneous defecation, there was an increase in propagating sequence frequency (p = 0.04) and nonpropagating activity when compared to basal conditions (p < 0.0001). During this hour the spatial and temporal relationships among propagating sequences demonstrated a biphasic pattern. Both the early (proximal) and late (distal) colonic phases involved the whole colon and were characterized by respective antegrade and retrograde migration of site-of-origin of arrays of propagating sequences. There was a negative correlation between propagating sequence amplitude and the time interval from propagating sequence to stool expulsion (p = 0.008). CONCLUSIONS: The colonic motor correlate of defecation is the colonic propagating sequence, the frequency and amplitude of which begin to increase as early as 1 h before stool expulsion. During the preexpulsive phase, the spatial and temporal relationship among the sites of origin of individual propagating sequences demonstrate a stereotypic anal followed by orad migration, which raises the possibility of control by long colocolonic pathways.

Relationship between terminal ileal pressure waves and propagating proximal colonic pressure waves.

The relationship between propagating distal ileal and proximal colonic motor patterns has not been systematically examined in humans. Our aim was to define the relationships, if any, between prolonged propagating contractions or discrete clustered contractions and cecal propagating sequences using multiple manometric recording sites spanning the distal ileum and unprepared colon. In 14 healthy volunteers, a 17-lumen-perfused silicon catheter was positioned pernasally such that at least three recording sites lay in the ileum and the remainder in the colon. Intersidehole distance was 7.5 cm. In 271 h of recording, 30% of the terminal ileal propagating events was temporally associated with cecal propagating sequences. Significantly more prolonged propagating contractions (11 of 24, 46%; P = 0.02) were associated with cecal propagating sequences than were associated with ileal discrete clustered contractions (4 of 26, 15%). This trend was more pronounced at night. Of 159 cecal propagating sequences, 15 (9%) were preceded by an ileal propagating event. The remaining 91% was preceded by increased nonpropagating activity commencing 2 min before the cecal propagating sequence (P = 0.0002). We conclude that distal ileal propagating motor patterns are one stimulus for cecal propagating sequences, with the association being stronger for prolonged propagating contractions than for discrete clustered contractions.

Basal pressure patterns and reflexive motor responses in the human ileocolonic junction.

This study aimed to determine whether a sustained high-pressure zone exists at the human ileocolonic junction (ICJ) and whether the motor responses of ICJ are consistent with sphincteric function. In 10 subjects with temporary ileostomies, a high-pressure zone was identified using a manometric pull-through with a mean pressure of 9. 7 +/- 3.2 mmHg and length of 4.8 +/- 1.2 cm. Prolonged recordings using a sleeve sensor confirmed sustained tone in the ICJ and superimposed phasic pressure waves (4-8 counts/min) occupying 35% of fasted state. A meal increased ICJ tone (P = 0.0001) and the proportion of time occupied by phasic activity to 50% (P = 0.013). Terminal ileal propagating pressure wave sequences inhibited ICJ phasic activity, and sequences not extending to the cecum reduced ICJ tone (9.0 +/- 7.2 to 5.6 +/- 6.3 mmHg; P = 0.04). Cecal distension increased ICJ tone (8.9 +/- 4.4 mmHg to 11.7 +/- 4.9 mmHg; P = 0.005). The ICJ response to ileal distension was variable and depended on resting tone at the time of distension. We conclude that the human ICJ has sustained tone with superimposed phasic activity. Tone is augmented by cecal distension or a meal and is inhibited by ileal propagating pressure waves. Response to ileal distension is variable but suggests control by descending excitatory and inhibitory pathways.

A comparison of transnasal and transoral oesophagogastroduodenoscopy.

Transnasal oesophagogastroduodenoscopy (OGD) with a narrow-bore endoscope has been demonstrated to be feasible in unsedated volunteers. The aim of the study was to compare efficacy, safety, patient tolerance and costs between this novel approach to OGD and standard sedated OGD. Sixty day patients were enrolled for either sedated transoral endoscopy with a standard calibre endoscope or for unsedated transnasal endoscopy with a narrow-bore (5.3 mm diameter) endoscope. Visualization was unsatisfactory in one examination in each group. The only complications were minor epistaxis in four of the transnasal group and oxygen desaturation below 90% in two of the sedated transoral group. On a 1 (very uncomfortable) to 5 (very comfortable) visual analogue scale, the mean transnasal group score was 3.09, compared with 3.86 in the transoral group (P = 0.013). In the transnasal group, mean procedure room time was 15 min compared with 20 min in the transoral group (P < 0.0003), and mean recovery room time was 7 min compared with 37 min (P < 0.0001). Consumable and pharmaceutical costs were reduced by 65 and 92%, respectively. This study demonstrates that unsedated transnasal OGD is a safe and effective route for OGD and has acceptable patient tolerance. The safety and decreased recovery times offer major cost savings and the potential for this method of OGD to become an office procedure for the investigation of the upper gastrointestinal tract.

A prospective study of the gastroenterological causes of iron deficiency anaemia in a general hospital.

BACKGROUND: Current practice is to investigate routinely both upper and lower gastrointestinal tracts in patients with unexplained iron deficiency anaemia. AIMS: To determine the efficacy of this approach and whether the use of more stringent biochemical criteria for iron deficiency, symptoms, or a positive immunochemical faecal human haemoglobin (FHH) influenced the findings of the investigations and could help target investigations more efficiently. METHODS: Eighty patients were studied prospectively, 51 who had "definite' iron deficiency anaemia (low ferritin and transferrin saturation) and 29 with "probable' iron deficiency anaemia (either low ferritin or transferrin saturation). Patients underwent a standardised symptom assessment and testing for FHH, upper endoscopy with small bowel biopsy and colonoscopy, and a small bowel series if upper endoscopy and colonoscopy were negative. RESULTS: Lesions potentially causative for iron deficiency anemia were found in 54/80 (60%) of patients. Five patients (7%) had lesions in both upper and lower tracts. Small bowel biopsy was abnormal in one of 80 patients and small bowel series one of 25 patients. Significant lesions in either the upper or lower gastrointestinal tract were found in 14/20 patients with positive FHH and 25/47 with negative FHH. Symptoms, use of non-steroidal anti-inflammatory drugs and classification of patients into "definite' and "probable' iron deficiency did not influence yield of investigations or site of lesions found. CONCLUSIONS: Gastrointestinal lesions are common in patients with unexplained iron deficiency anaemia. Neither symptoms nor presence of FHH predict the presence of site of detectable lesions and neither testing for FHH nor more stringent biochemical criteria for iron deficiency alters clinical decision making. The findings support the routine performance of both upper endoscopy and colonoscopy in the investigation of patients with unexplained iron deficiency anaemia, however routine investigation of the small bowel is of questionable value.

Aortic and coronary embolism of anaplastic small-cell carcinoma of the lung.

A case of macroscopic tumour embolism from an anaplastic small-cell carcinoma of the bronchus to the aortic bifurcation and the left main coronary artery is described. The emboli occluded both vessels and caused sudden death. To our knowledge, this is the first report of coronary embolism by this type of carcinoma. Previous reports of coronary embolism by lung tumours are reviewed briefly.