Results of ambulatory pH monitoring do not reliably predict response to therapy in patients with eosinophilic oesophagitis.

BACKGROUND: The consensus statements for eosinophilic oesophagitis recommend that ambulatory pH monitoring is one means of determining if gastro-oesophageal reflux is the cause of oesophageal eosinophilia and should guide pharmacological therapy. AIM: To evaluate prospectively the accuracy of pH monitoring as a predictor of endoscopic, histological and symptomatic response in patients with oesophageal eosinophilia. METHODS: We conducted a prospective trial in which patients with oesophageal eosinophilic infiltration with ≥15 eos/hpf underwent a 24-h pH study and were placed in one of two treatment arms for 6 weeks based on positive or negative results. Patients with abnormal acid exposure were treated with esomeprazole 40 mg twice daily and others were treated with oral viscous budesonide 1 g twice daily. Response to treatment was assessed by oesophageal histology (<5 eos/hpf) and symptoms. RESULTS: A total of 51 patients were enrolled in the study. The average patient age was 39 years and 31 patients (61%) were male. The average number of eosinophils per hpf, prior to study enrolment was 41.2 (range 15-140, s.d. 27.7). Nineteen (37%) had positive pH studies and 32 (63%) had negative pH studies. Eighteen patients completed treatment with esomeprazole. Only eleven (61%) had histological response and, of these eleven, five (46%) had symptomatic improvement. A total of 28 patients with normal acid exposure completed treatment with budesonide. Only 16 (57%) had histological and 11 (69%) had symptomatic improvement. CONCLUSION: In this prospective trial of pH-guided treatment, neither positive nor negative results of initial pH monitoring accurately predicted response to therapy.

The effects of a weakly acidic meal on gastric buffering and postprandial gastro-oesophageal reflux.

BACKGROUND: Exclusion of the meal during ambulatory pH monitoring presumes that a meal completely buffers gastric acid and reflux of acidic food content cannot be distinguished from gastric acid. However, the ability of a meal to completely buffer gastric acid remains unclear. AIM: To determine the effect of a weakly acid meal on gastric buffering and oesophageal acid exposure. METHODS: Patients undergoing multichannel intraluminal impedance pH studies were given a standard weakly acidic meal (pH = 5.9). Gastric and oesophageal pH was measured during the meal and in 15 min intervals for 2 h postprandially. RESULTS: The study included 30 patients, with pathological acid reflux detected in 18 patients. Complete gastric buffering occurred in seven patients (23%) and was lost in all patients within 75 min of the meal. Oesophageal acid was detected in 33% of patients within 30 min of the meal and 81% of patients during the 2 h postprandial period. Postprandial oesophageal acid exposure was greater in patients with pathological acid reflux (9 ± 2.7% vs. 1.7 ± 0.8% P = 0.05) with a trend towards more incomplete gastric acid buffering and significant differences when measuring weak acid reflux (pH 4-5). Acid reflux rarely occurred in the absence of gastric acid, with gastric acid present in 74 of 79 (94%) fifteen minute postprandial intervals with acid reflux. CONCLUSIONS: The ability of a meal to buffer gastric acid is poor. Early postprandial oesophageal acid reflux occurs in a substantial proportion of patients. Addition of a weakly acidic or pH neutral meal to ambulatory pH monitoring may unmask early postprandial acid reflux and provide data on gastric acid buffering.

Inter-observer agreement for multichannel intraluminal impedance-pH testing.

Twenty-four-hour ambulatory multichannel intraluminal impedance (MII)-pH detects both acid and nonacid reflux (NAR). A computer-based program (Autoscan™, Sandhill Scientific, Highlands Ranch, CO, USA) automates the detection of reflux episodes, increasing the ease of study interpretation. Inter-observer agreement between multiple reviewers and with Autoscan™ for the evaluation of significant NAR with MII-pH has not been studied in the adult population. Twenty MII-pH studies on patients taking a proton pump inhibitor twice daily were randomly selected. Autoscan™ analyzed all studies using the same pre-programmed parameters. Four reviewers interpreted the MII-pH studies, adding or deleting reflux episodes detected by Autoscan™. Positive studies for NAR and total reflux episodes were based on published criteria. Cohen's kappa statistic (κ) evaluated inter-observer agreement between reviewers and Autoscan™ analysis. The average κ for pathologic NAR between reviewers was 0.57 (0.47-0.70), and between reviewers and Autoscan™ was 0.56 (0.4-0.8). When using the total reflux episode number as a marker for pathologic reflux (acid and NAR), the κ score was 0.72 (0.61-0.89) between reviewers, and 0.74 (0.53-0.9) when evaluating total reflux episodes. Two reviewers agreed more often with each other and with Autoscan™ on the number of NAR episodes, while the other two reviewers agreed with each other, but did not agree with either Autoscan™ or the first two reviewers. Inter-observer agreement between reviewers and Autoscan™ for detecting pathologic NAR is moderate, with reviewers either excluding more of the Autoscan™-defined events or excluding fewer events and therefore agreeing with Autoscan™.

Utility of software analysis of esophageal manometry studies in patients with aperistalsis.

Esophageal manometry is the gold standard for the diagnosis of esophageal aperistalsis. There is computer software that analyzes peristalsis on esophageal manometry, but this automated analysis has not been formally evaluated. Our primary aim was to evaluate the software analysis of esophageal aperistalsis by esophageal manometry in patients diagnosed with aperistalsis by an experienced clinician. Esophageal manometry studies from January 2006 to November 2007 were retrospectively reviewed for evidence of aperistalsis by an experienced clinician. All studies demonstrating aperistalsis were selected for further review. The automated analysis performed by our software program for each study was recorded. Agreement between the automated analysis and the clinician was measured by the proportion of agreement on the absence of peristalsis. Eighty-seven of the 962 esophageal manometry studies reviewed demonstrated aperistalsis. The automated analysis reported esophageal body peristalsis with wet swallows in 66 out of 87 patients (75.9%). In these patients, the software analyzed an average of 34.2% of the wet swallows as peristaltic. The agreement between the clinician's review and software analysis of aperistalsis was 24.1%. These data suggest there is poor agreement between the automated analysis of peristalsis and that of an experienced reviewer. Automated analysis cannot be relied upon in the diagnostic evaluation of esophageal aperistalsis as it overestimates the presence of peristalsis and may lead to incorrect diagnoses and management strategies.

One year follow up of a randomized trial comparing Ligasure with open haemorrhoidectomy.

BACKGROUND: Ligasure haemorrhoidectomy is an effective treatment for prolapsing haemorrhoids, however, concerns exist regarding potential damage to the anal sphincters. METHODS: Patients previously included into a randomized trial comparing open and Ligasure haemorrhoidectomy were contacted by postal questionnaire to evaluate their overall satisfaction and continence at 12 months post operatively. RESULTS: Thirteen patients who underwent open and 17 who underwent Ligasure haemorrhoidectomy were evaluated. Three patients from the open group and 2 from the Ligasure group were unhappy with the result (P = 0.37) and minor incontinence was reported in 5 Ligasure and 2 open patients (P = 0.42). CONCLUSION: Patient satisfaction and post operative continence scores at 1 year post operatively are comparable for open and Ligasure haemorrhoidectomy.

FDG-PET for the pre-operative evaluation of colorectal liver metastases.

INTRODUCTION: This study assesses the accuracy of routine whole body fluorodeoxyglucose-positron emission tomography (FDG-PET) in the pre-operative staging of patients with colorectal liver metastases (CLM). METHODS: A prospective study of patients referred for hepatic resection was undertaken. Patients were staged by spiral CT and FDG-PET. The results of these investigations were considered independently. RESULTS: Twenty-eight patients had confirmed CLM. Eleven patients had solitary CLM; 10 of whom were correctly identified by both modalities. In the remaining 17 patients, 10 had multiple CLM and seven had extrahepatic disease. FDG-PET detected all lesions (sensitivity 100%, specificity 91%). CT incorrectly diagnosed solitary CLM in five patients and failed to detect extrahepatic disease in four patients (sensitivity 47%, specificity 91%). FDG-PET resulted in altered management for 12 patients of whom seven avoided inappropriate surgery. CONCLUSION: FDG-PET is more sensitive and specific for pre-operative staging of CLM. FDG-PET confers clinical benefit through altered patient management.

Simultaneous 13C/14C dual isotope breath test measurement of gastric emptying of solid and liquid in normal subjects and patients: comparison with scintigraphy.

BACKGROUND: To develop a simple method for simultaneous solid and liquid gastric emptying assessment using a dual isotope labelled breath test. MATERIAL AND METHODS: 13 patients were given 100 g ground beef labelled with 25 MBq (99m)Tc sulphur colloid and 74 KBq (14)C octanoic acid, and 150 ml 10% glucose drink labelled with 8 MBq (67)Ga citrate and 150 mg (13)C acetate. 10 normal volunteers were given the same test meals but labelled with (14)C and (13)C only. Breath was collected at baseline and regularly for 4 hours. The (14)CO(2) and (13)CO(2) activity was measured with liquid scintillation counting and mass spectroscopy. The times to maximum (14)CO(2) and (13)CO(2), were determined. Comparison was made between times to maximum (14)CO(2) with scintigraphic retention of (99m)Tc at 100 minutes and times to maximum (13)CO(2) with the scintigraphic half-clearance time of (67)Ga. RESULTS: For the solid meal, the times to maximum (14)CO(2) were: 60-120 minutes in the 8 patients with normal gastric emptying of (99m)Tc; 75-145 minutes for the 10 healthy volunteers; 75-180 minutes for the remaining 5 patients with abnormal gastric emptying of (99m)Tc. There was a weak but significant correlation (r = 0.56, p < 0.025) between the time to maximum (14)CO(2) and gastric retention of (99m)Tc at 100 minutes. For the liquid meal, times to maximum (13)CO(2) were: 20-35 minutes for the 4 with normal gastric emptying of (67)Ga; 15-40 minutes for the 10 healthy volunteers; 20-75 minutes for the remaining 9 patients with abnormal gastric emptying of (67)Ga. There was a strong and significant correlation (r = 0.88, p < 0.005) between times to maximum (13)CO(2) and gastric half-clearance time of (67)Ga. CONCLUSIONS: Breath tests utilising test meals labelled with *C isotopes are valid alternatives to scintigraphic studies using (99m)Tc and (67)Ga for the simultaneous assessment of gastric emptying of solids and liquids.

In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography.

BACKGROUND: and aims: Positron emission tomography (PET) using (18)F labelled 2-fluoro-2-deoxy-D-glucose ((18)FDG) is an established imaging tool, although the recent development of a biologically stable thymidine analogue [18F] 3'-deoxy-3-fluorothymidine ((18)FLT) has allowed PET to image cellular proliferation by utilising the salvage pathway of DNA synthesis. In this study, we have compared uptake of (18)FLT and (18)FDG with MIB-1 immunohistochemistry to evaluate the role of PET in quantifying in vivo cellular proliferation in colorectal cancer (CRC). PATIENTS AND METHODS: Patients with resectable, primary, or recurrent CRC were prospectively studied. Thirteen lesions from 10 patients (five males, five females), median age 68 years (range 54-87), were evaluated. Patients underwent (18)FDG and (18)FLT PET scanning. Tracer uptake within lesions was quantified using standardised uptake values (SUVs). Histopathological examination and MIB-1 immunohistochemistry were performed on all lesions, and proliferation quantified by calculating a labelling index (% of MIB-1 positively stained nuclei within 1500 tumour cells). RESULTS: Histology confirmed adenocarcinoma in 12 of 13 lesions; the remaining lesion was reactive. All eight extrahepatic lesions were visualised using both (18)FLT and (18)FDG. Three of the five resected liver metastases were also avid for (18)FLT and showed high proliferation, while the remaining two lesions which demonstrated no uptake of (18)FLT had correspondingly very low proliferation. There was a statistically significant positive correlation (r =0.8, p<0.01) between SUVs of the tumours visualised with (18)FLT and the corresponding MIB-1 labelling indices. No such correlation was demonstrated with (18)FDG avid lesions (r =0.4). CONCLUSIONS: (18)FLT PET correlates with cellular proliferation markers in both primary and metastatic CRC. This technique could provide a mechanism for in vivo grading of malignancy and early prediction of response to adjuvant chemotherapy.

Potential impact of [18F]3'-deoxy-3'-fluorothymidine versus [18F]fluoro-2-deoxy-D-glucose in positron emission tomography for colorectal cancer.

Fluorine-18 labelled fluoro-2-deoxy- d-glucose ((18)FDG) positron emission tomography (PET) imaging demonstrates the increased glucose consumption of malignant cells, but problems with specificity have led to the development of new PET tracers. [(18)F]3'-deoxy-3'-fluorothymidine ((18)FLT) is a new tracer which images cellular proliferation by entering the salvage pathway of DNA synthesis. In this study we compared the cellular uptake of (18)FLT and (18)FDG in patients with colorectal cancer (CRC). Seventeen patients with 50 primary or metastatic CRC lesions were prospectively recruited. Lesions were initially identified using computed tomography. Patients underwent both (18)FDG and (18)FLT scanning. Semi-quantitative analysis of tracer uptake was carried out using standardised uptake values. All the primary tumours ( n=6) were visualised by both tracers, with (18)FDG showing on average twice the uptake of (18)FLT. Similar uptake of both tracers was seen in lung and peritoneal lesions, with (18)FLT imaging five of the six lung lesions and all of the peritoneal lesions. Of the 32 colorectal liver metastases, 11 (34%) were seen as avid for (18)FLT, compared with 31 (97%) for (18)FDG. No correlation was seen between the uptake of the two tracers ( R(2)=0.03). (18)FLT shows a high sensitivity in the detection of extrahepatic disease but poor sensitivity for the imaging of colorectal liver metastases, making it unlikely to have a role as a diagnostic tracer in CRC. We have demonstrated that (18)FDG and (18)FLT image two distinct processes. The prognostic implications of the uptake of (18)FLT need to be assessed in terms of response to chemoradiotherapy and survival.

Randomized clinical trial of Ligasure versus open haemorrhoidectomy.

BACKGROUND: Postoperative pain associated with open haemorrhoidectomy remains problematic. Haemorrhoidectomy performed using bloodless bipolar diathermy--Ligasure--may have advantages over conventional open haemorrhoidectomy in terms of operating time and postoperative pain. METHODS: Thirty-four patients were randomized to undergo Ligasure (18 patients) or diathermy (16) haemorrhoidectomy. The operating time, amount of pain and postoperative analgesic requirement, postoperative complications and overall patient satisfaction were documented. RESULTS: The median duration of operation was shorter in the Ligasure haemorrhoidectomy group (5.1 versus 9.2 min; P < 0.001). There was no statistically significant difference in the postoperative pain score, but the median analgesic requirement was lower in the Ligasure group (850 versus 1600 mg tramadol; P = 0.013). Patient satisfaction was similar in both groups. CONCLUSION: Ligasure haemorrhoidectomy is quick and bloodless and, although as painful as diathermy haemorrhoidectomy, is associated with a reduced analgesic requirement.

Model of opiate dependence in the guinea-pig isolated ileum.

1 Segments of ileum, incubated for 2-24 h at 22 degrees C with normorphine (0.01 - 1.0 muM), in the presence of hexamethonium, contracted when challenged with naloxone (0.03 muM). No response to this dose of naloxone was induced either by incubation in control solution without opiate for 2-24 h or by exposure of the preparation to opiate for 30 min at 37 degrees C.2 When segments were incubated for 24 h, the size of the response to naloxone was directly related both to the normorphine concentration in the incubation fluid (0.01 to 0.1 muM), and to the concentration of naloxone applied (0.03 to 0.1 muM).3 A spontaneous withdrawal contracture was elicited in ilea that had been incubated with normorphine (1.0 muM), when the normorphine-containing bathing fluid was exchanged for one without opiate.4 Normorphine restored to resting level the tension of the withdrawal contracture, whether it had been elicited spontaneously or by naloxone challenge.5 Addition of naloxone (1.0 muM) to normorphine (1.0 muM) in the incubation fluid abolished the withdrawal contracture to subsequent challenge with naloxone.6 Naloxone elicited a contracture from segments incubated for 24 h at 22 degrees C with levorphanol (0.1 muM) but not from those incubated with dextrorphan.7 Application of (+)-naloxone (0.03 muM) to segments previously incubated with normorphine (0.1 muM) did not elicit a contracture.8 The contracture elicited by naloxone in preparations incubated with morphine (10 muM) was associated with a reduction in sensitivity to the acute inhibitory effect of morphine on the electrically-evoked response.9 Addition of hyoscine (0.5 muM) immediately after challenge with naloxone restored the tension of the withdrawal contracture to resting level.10 Tetrodotoxin (3.0 muM) given before challenge, prevented naloxone from eliciting a withdrawal contracture.11 The inclusion of 5-hydroxytryptamine (10 muM) with morphine (10 muM) inhibited the induction of tolerance to morphine.12 These experiments, together with those described earlier, indicate that incubation with opiate induces a dependence in the final cholinergic motor neurones of the myenteric plexus, manifested as a contracture of the longitudinal muscle on removal of opiate or administration of an antagonist. This dependence is associated with tolerance, expressed as a decrease in sensitivity to inhibition by morphine of the electrically-evoked contracture. Tolerance and dependence are induced and withdrawal precipitated through specific and stereospecific opiate receptors.

Clonidine dependence in the guinea-pig isolated ileum.

1 Compared with the response of preparations incubated in solutions without clonidine, a three to four fold increase in the magnitude of the contracture of the longitudinal muscle to challenge with phentolamine (1.0 mum) was induced by incubating the guinea-pig isolated ileum at 22 degrees C for 24 h with clonidine (1.0 mum) in Krebs solution containing hexamethonium (70 mum). Incubation of the ileum with clondine (1.0 mum) for 0.5 h at 37 degrees C did not increase responsiveness to phentolamine.2 The increase in responsiveness to phentolamine was directly related to the clonidine concentration in the incubation fluid over the range 0.01 to 1.0 mum.3 The magnitude of the contracture to phentolamine of ilea incubated with clonidine (1.0 mum) (withdrawal contracture) was directly related to the challenge dose of phentolamine over the range 0.3 to 1.0 mum.4 Yohimbine (1.0 mum) or piperoxane (1.0 mum) elicited a response comparable to that elicited by phentolamine but propranolol (1.0 mum) was inactive.5 Addition of phentolamine (1.0 mum) to clonidine (1.0 mum) in the incubation fluid abolished the increased response of the preparation to subsequent challenge with phentolamine.6 Addition of hyoscine (0.5 mum) immediately after challenge with phentolamine restored the tension of the withdrawal contracture to its resting level.7 Tetrodotoxin (3.0 mum) given before challenge, prevented phentolamine from eliciting a withdrawal contracture.8 Ileal segments incubated with clonidine (1.0 mum) were unresponsive to challenge with naloxone (100 nm); and segments incubated with normorphine (1.0 mum) were unresponsive to phentolamine (1.0 mum), although responsive to naloxone.9 Normorphine (1.0 mum) restored to resting level the tension of the clonidine withdrawal contracture; and clonidine (0.1 mum) restored to resting level the tension of the contracture to naloxone in ileal segments incubated with normorphine.10 These experiments indicate that incubation with clonidine induces, in the final cholinergic motor neurones of the myenteric plexus of the isolated ileum, a dependence the withdrawal from which is expressed as a contracture in response to alpha-adrenoceptor antagonists.11 Although opiate receptors are not involved in clonidine dependence nor alpha-adrenoceptors in opiate dependence, the findings that normorphine suppresses the clonidine withdrawal-contracture and that clonidine suppresses the contracture of opiate-dependent ileum to naloxone, suggest that the withdrawal effect studied in both clonidine and normorphine dependence in this preparation is mediated by release of acetylcholine from the final motor neurone.

Character and meaning of quasi-morphine withdrawal phenomena elicited by methylxanthines.

A quasi-morphine withdrawal syndrome (QMWS) is a pattern of behavior closely resembling the true withdrawal syndrome in the opiate-dependent animal, which can be elicited acutely by a nonopiate drug in an opiate-naive animal. The main criteria proposed for the QMWS, in addition to its resembling the true withdrawal syndrome, are that the effects of opiates and of opiate antagonists on the QMWS should parallel those on true opiate withdrawal. Drugs that wholly or largely fulfill these criteria are 3-isobutyl-1-methylxanthine (IBMX), theophylline, caffeine, ICI 63197, and RO 201724. From the evidence given, it is concluded that these drugs act by inhibiting brain cyclic AMP phosphodiesterase, thus raising the level of cyclic AMP in appropriate neurons. These findings are consistent with the view that the molecular mechanisms of opiate dependence is the hypertrophy of a neuronal cyclic AMP system in compensation for the inhibition by opiate of an adenylate cyclase. Our studies and those of others suggest that: a) very rapid tests for opiate activity and for addictive liability can be devised by use of IBMX; b) opiates may be used clinically to counter poisoning by caffeine or theophylline; and c) a relationship may exist between caffeine consumption and opiate addiction.

Mechanism of quasi-morphine withdrawal behaviour induced by methylxanthines.

Of 7 phosphodiesterase inhibitors tested for ability to induce a quasi-morphine withdrawal syndrome (QMWS) in opiate-naive rats, five were effective in a dose-related way. These, in descending order of potency, were IBMX, ICI-63197, RO-201724, theophylline and caffeine. Their potencies in inducing a QMWS correlated significantly (P less than 0.05) with those in inhibiting low Km cyclic AMP phosphodiesterase of rat brain homogenate. There was no correlation with potencies in inhibiting cyclic GMP phosphodiesterase.