Kevin R. Knowles

Rapid Drink Challenge in high-resolution manometry: an adjunctive test for detection of esophageal motility disorders

The Chicago Classification for diagnosis of esophageal motility disorders by high‐resolution manometry (HRM) is based on single water swallows (SWS). Emerging data suggest that a “Rapid Drink Challenge” (RDC) increases sensitivity for motility disorders. This study establishes normal values and diagnostic thresholds for RDC in clinical practice.

Diagnostic yield of high-resolution manometry with a solid test meal for clinically relevant, symptomatic oesophageal motility disorders: serial diagnostic study

BACKGROUND The use of high-resolution manometry (HRM) to diagnose oesophageal motility disorders is based on ten single water swallows (SWS); however, this approach might not be representative of oesophageal function during the ingestion of normal food. We tested whether inclusion of a standardised solid test meal (STM) to HRM studies increases test sensitivity for major motility disorders. Additionally, we assessed the frequency and cause of patient symptoms during STM. METHODS Consecutive patients who were referred for investigation of oesophageal symptoms were recruited at Nottingham University Hospitals (Nottingham, UK) in the development study and at University Hospital Zürich (Zürich, Switzerland) in the validation study. HRM was done in the upright, seated position with a solid-state assembly. During HRM, patients ingested ten SWS, followed by a standardised 200 g STM. Diagnosis of oesophageal motility disorders was based on the Chicago Classification validated for SWS (CCv3) and with STM (CC-S), respectively. These studies are registered with ClinicalTrials.gov, numbers NCT02407938 and NCT02397616. FINDINGS The development cohort included 750 patients of whom 360 (48%) had dysphagia and 390 (52%) had reflux or other symptoms. The validation cohort consisted of 221 patients, including 98 (44%) with dysphagia and 123 (56%) with reflux symptoms. More patients were diagnosed with a major motility disorder by use of an STM than with SWS in the development set (321 [43%] patients diagnosed via STM vs 163 [22%] via SWS; p<0·0001) and validation set (73 [33%] vs 49 [22%]; p=0·014). The increase was most evident in patients with dysphagia (241 [67%] of 360 patients on STM vs 125 [35%] patients on SWS in the development set, p<0·0001), but was also present in those referred with reflux symptoms (64 [19%] of 329 patients vs 32 [10%] patients in the development set, p=0·00060). Reproduction of symptoms was reported by nine (1%) of 750 patients during SWS and 461 (61%) during STM (p<0·0001). 265 (83%) of 321 patients with major motility disorders and 107 (70%) of 152 patients with minor motility disorders reported symptoms during the STM (p=0·0038), compared with 89 (32%) of 277 patients with normal motility as defined with CC-S (p<0·0001). INTERPRETATION The diagnostic sensitivity of HRM for major motility disorders is increased with use of the STM compared with SWS, especially in patients with dysphagia. Observations made during STM can establish motility disorders as the cause of oesophageal symptoms. FUNDING None.

A tailored surgical approach for gastro-oesophageal reflux disease : the Nottingham experience

OBJECTIVE The objective was to assess the results which can be achieved by tailoring the anti-reflux procedure to the anatomical and functional situation of the patient with gastro-oesophageal reflux disease (GORD). PATIENTS AND METHODS Two hundred and seventy six patients undergoing a primary tailored anti-reflux procedure between 1986 and 1996 were evaluated. An anti-reflux procedure was selected on the basis of the anatomical and functional findings assessed by means of barium video, endoscopy, manometry and prolonged pH monitoring. The operations performed were Nissen fundoplication (77), total fundoplication gastroplasty (TFG; 140) and Belsey Mark IV (BMIV; 59). The unit policy is for life-long follow-up. The symptoms at review were assessed and graded according to previously published criteria (Orringer MB, Skinner DB, Besley HR. Long-term results of the mark IV operation for hiatal hernia and analyses of recurrences and their treatment. J Thorac Cardiovasc Surg 1972;63:25-31). Patients with recurrent symptoms were fully re-investigated. RESULTS Mean hospital stay was 8.2 days (5-32 days). There was one hospital death (0.36%). Mean follow-up was 6.7 years (range, 2.2-13.1 years). Overall excellent or good results were achieved in 247 (89.5%) patients (92.2% in Nissen, 90.7% in TFG and 83.1% in BMIV group, P=0.1). In patients without oesophagitis (n=72), the success rate was 93.1%, while for patients with grade IV oesophagitis (n=89) this was 87.6% (P=0.2). Kaplan-Meier freedom from recurrent or new, operation-induced, symptoms at 10 years was 88.1% (89.5% in Nissen, 87.4% in TFG and 73.8% in BMIV groups, P=0.08). CONCLUSIONS These data suggest that where the appropriate anti-reflux procedure is selected, surgery can achieve satisfactory mid- and long-term success rates across the spectrum of GORD. When oesophageal shortening is evident, or merely suspected, we favour a TFG. In the presence of impaired motility and no evidence of oesophageal shortening, a BMIV is the preferred approach. The Nissen procedure is used for uncomplicated cases.

The Cause of Dysphagia in Eosinophilic Esophagitis: Obstruction to Bolus Passage Not Oesophageal Dysmotility

Introduction Eosinophilic Oesophagitis (EO) presents with dysphagia and chest pain; however the cause of symptoms remains uncertain. Endoscopy reveals fibrotic and inflammatory mucosal disease but rarely tight stenosis. Conventional manometry with water swallows is usually normal; however this may not be clinically relevant as most patients report dysphagia on eating bread and meat but not on drinking liquids. This study applied HRM with water and solid bolus swallows to identify abnormal oesophageal function in EO patients and to associate abnormal pressure events with symptoms. Methods Retrospective case review of 14 consecutive patients (10 male; age 36 (26–65)) on two sites referred for HRM with EO on biopsy of proximal and distal oesophagus. HRM studies in the seated position included 10×5 ml water swallows and 5–10 solid (bread) swallows. 23 healthy volunteers (11 M:12 F, age 20–56) served as control. Association between abnormal pressure events and symptoms was assessed on a per patient and per swallow basis. Results HRM identified oesophageal dysfunction in 3/14 (21%) patients with water swallows and 11/14 (79%) patients with solids (p<0.008). All 11 had increased intrabolus pressure gradient (IBPG) ≥30 mm Hg with solids (maximum at lower oesophageal sphincter (LOS) (n=9), mid-oesophagus (n=1) and upper oesophageal sphincter (n=1)). Per patient: Typical symptoms were reported with IBPG >30 mm Hg by 1 (7%) patient with water and 7 (50%) patients with solids (p=0.039). Conversely, 7/11 (64%) patients with IBPG >30 mm Hg had symptoms (7/7 patients with IBPG >50 mm Hg). Per swallow: There was temporal association between raised IBPG and patient reports of symptoms (p<0.001). Pan-oesophageal pressurisation >30 mm Hg triggered dysphagia; compartmentalised IBP >50 mm Hg between peristalsis and LOS triggered either dysphagia or chest pain. No association was present for any other pressure event. Patients that had received steroids and/or dilation (n=7) had lower IBPG and reported less symptoms than untreated patients (n=7) (both p<0.001); however, if it occurred, the association between IBPG and symptoms remained. One healthy subject had increased frequency of low-amplitude oesophageal spasm; however none had raised OGPG >30 mm Hg with solids and none reported symptoms. Conclusion Patients with EO have normal motility but evidence of structural obstruction to solid bolus passage (usually across the LOS), presumably due to oesophageal stenosis or reduced LOS compliance due to fibrosis and inflammation. In all but one case this was evident only with solid bolus. Raised IBPG was closely associated with patient reports of symptoms and both improved on treatment.

SKIN ALLOGRAFT AND XENOGRAFT RESPONSES IN NMU-TREATED XENOPUS LAEVIS

Publisher Summary A single dose of the chemical carcinogen N-methyl-N-nitrosourea (NMU) in Xenopus laevis destroys the lymphoid cell populations of the liver, spleen, thymus glands and blood, and results in a permanent loss of allograft immune competence. This chapter discusses a study to investigate the ability of NMU-treated X. laevis to reject xenografts from a frog of another genus and from two other Xenopus species more (Xenopus borealis) or less (Xenopus tropioalis) closely related to X. laevis. X. laevis toadlets were given single injections of 14 mg NMU per 100 g body weight. Adult R. pipiens, X. borealis, X. tropioalis, and X. laevis were anesthetised in 1:300 MS222, and their dorsal skin removed and cut into 3 mm squares for insertion into the dorsal graft beds prepared on control and NMU-treated X. laevis toadlets, which were also given autografts. The results indicate that NMU treatment did not lengthen the MST of xenografts from R. pipiens or X. tropioalis, whereas the first-set X. borealis grafts survived for significantly longer on NMU-treated X. Laevis toadlets than on the controls. There was accelerated second-set rejection of all types of xenograft, but no significant differences in MSTs for second-set grafts on treated and control animals.

Su1076 Measurement of Esophago-Gastric Junction Cross-Sectional Area and Distensibility by Endoflip® (Endolumenal Functional Lumen Imaging Probe) for the Diagnosis of Patients With Gastro-Esophageal Reflux Disease (GERD)

Introduction EndoFLIP ® (Crospon, Ireland) is an innovative device designed to assess the cross sectional area (CSA) and distensiblilty of the esophagogastric junction (EGJ) by combined impedance planimetry and pressure measurement. Initial studies have suggested that this probe may distinguish between gastro-oesophageal reflux disease (GERD) patients and healthy volunteers (HV). Aim To assess the diagnostic agreement of EndoFLIP ® measurements with clinical and physiologic GERD diagnosis. Methods 22 healthy volunteers, (HV; female=16, age 21–46, mean body mass index (BMI) 24.3 kg/m 2 ) and 20 patients with GERD symptoms (female=14, age 19–78, mean BMI 33.2 kg/m 2 ) were studied. Patients were older (p ® balloon volume were measured. A Bravo capsule (Given Imaging, Israel) was attached 6 cm above the Z-line and a 48 h wireless esophageal pH recording acquired. The ability of EndoFLIP ® measurements to discriminate (1) patient group and (2) individuals with pathologic acid exposure (>5.6% time Results Complete measurements were acquired except in one patient with early detachment of Bravo capsule. Distensibility could not be measured in one patient and one volunteer with negative endoFLIP® balloon pressures. 7/22 (32%) HVs and 7/19 (37%) of patients had oesophagitis (six patients with hiatus hernia). 3/22 (14%) HVs and 9/19 (47%) patients had pathologic acid exposure (p=0.126). EGJ CSA was higher in healthy volunteers than the patient group, at 20 ml (p=0.018) and 30 ml (p=0.058, Abstract PTU-178 figure 1) endoFLIP® balloon volume. EGJ distensibility was lower in patients than HVs at 20 ml (p=0.001) and 30 ml balloon volume, (p=0.020, Abstract PTU-178 figure 1). EndoFLIP® measurements were similar in participants with and without pathologic acid exposure (median CSA 40 mm 2 vs 34 mm 2 p=1.0 at 20 ml, 98 mm 2 vs 107 mm 2 , p=0.789 at 30 ml) and distensibility at 20 ml (p=0.574) and 30 ml balloon volume (p=0.704). Post-hoc analysis revealed an inverse association between BMI and CSA (R 2 =0.214, p=0.003) and negative association with distensibility (R 2 =0.211, p=0.003). BMI was associated also with a trend to increased acid exposure (p=0.116). Conclusion EndoFLIP® is not useful for GERD diagnosis as EGJ CSA and distensibilty do not distinguish between HVs and GERD patients defined by clinical presentation or pH measurement. This unexpected result may be due to an important interaction of obesity with EndoFLIP® measurements. Competing interests None declared.

The phylogeny of tumour immunity

Abstract The occurrence of malignant neoplasia in lower animals is considered, and it is concluded that tumours occur not only in all vertebrate classes but also in some invertebrates. Thus, malignant cell populations can develop in animals which do not have cellular defence mechanisms involving immunoglobulins. The significance of natural cytotoxicity is discussed, and it is concluded that natural killer cells may not only provide a link between the natural and immunological cellular defence mechanisms during the lives of individual vertebrate animals, but may also offer some indication of how vertebrate cell-mediated immunity may have evolved from pre-existing natural cellular defence mechanisms.

PTU-157 Outcomes Of Oesophageal Dilatation In Achalasia And Post-fundoplication Dysphagia

Introduction Dilatation of the Oesophago-Gastric Junction (OGJ) provides effective symptom relief in 58–95% of patients with achalasia, similar to that achieved by Heller’s myotomy. Dilatation is also used in patients with persistent (>6 months) dysphagia after fundoplication surgery; there is insufficient safety and outcome data of this procedure. Our aim is to compare patient outcome of endoscopic dilatation for both these conditions. Methods We present 18 month experience of referrals to the dysphagia service 2012–2013. All patients underwent a diagnostic gastroscopy with biopsies, excluding inflammation or neoplasia. Patients with achalasia or clinically relevant outlet obstruction post-fundoplication diagnosed by elevated integrated relaxation pressure (>25 mmHg) on high resolution manometry were selected. Dilatation was performed by 30–35mm Rigiflex II Balloon or Savary-Gillard Bougies (max 18mm) under fluoroscopic guidance. Primary outcome was symptom response at 3–6 months post-procedure by clinic or telephone follow-up. Overall symptom response was documented on an analogue scale from 0% >100% (inadequate <40%, satisfactory 40–60%, good 60–80% and excellent >80%). Results 46/71 referrals had either achalasia or dysphagia post fundoplication. 30 (41%) had achalasia, 6 had prior Heller’s myotomy and 7 had prior Botulinum toxin. 16 (22%) patients had OGJ obstruction after fundoplication. 29/30 patients with achalasia underwent pneumatic dilatation, one bougie dilatation. Overall symptom response was inadequate in 5 (16% referred for surgery), satisfactory in 3 (11%) and good-excellent in 22 (73%).14/16 patients with post fundoplication dysphagia had pneumatic balloon dilatation, 2 had bougie dilatation. Overall symptom response was inadequate in 7 (44% referred for surgery), satisfactory in 4 (25%) and good-excellent in 5 (31%). Complications from the both groups include chest pain (n = 2), chest infection (n = 1), reflux symptoms (n = 4 in each group) and minor bleeding. All resolved with conservative treatment. More than half of achalasia and post-fundoplication patients reported “at least satisfactory” outcome 3–6 months after dilatation (84% vs. 56%; p < 0.07 Fisher Exact Test). A good-excellent symptom response was reported more often by achalasia patients (p = 0.010). Conclusion Endoscopic dilatation is safe and effective treatment for patients with dysphagia related to achalasia and also OGJ obstruction post-fundoplication. A good-excellent response was reported less frequently by the post-fundoplication patients; however more than half had at least “satisfactory” symptom relief and, therefore, a trial of endoscopic dilatation can be considered a viable alternative to re-operation. Disclosure of Interest None Declared.

Tu1788 Comparison of Post-Operative Physiology Parameters Between Asymptomatic and Symptomatic Patients After Anti-Reflux Surgery

Background: A TLESR is a major mechanism of acid reflux in healthy subjects and patients with reflux esophagitis and we have noticed that the amplitude of primary peristalsis and EGJ pressure, following a TLESR, is accompanied by a forceful contraction, when compared with before a TLESR. The aim of this study is to investigate whether or not primary peristalsis and EGJ pressure, when accompanied by a forceful contraction and following a TLESR, is a characteristic finding of a TLESR. Methods: 10 healthy subjects underwent esophageal high-resolution manometry with a 21-lumen perfused assembly, which monitored pressure in the pharynx, the upper esophageal sphincter, the esophageal body, LES and the proximal stomach. The EGJ was evaluated using ten side holes, spaced at 1-cm intervals. Recordings were then taken, in the sitting position, for 1 hour after a meal (692 kcal, 33 % fat). A TLESR is defined as previously described. Data were analyzed, using Trace! Software (Dr. G.S Hebbard, The Royal Melbourne Hospital, Australia). The contractile integral (CI) of the distal esophageal segment (D-CI: volume of the domain above 20 mmHg), excluding the EGJ segment, was measured both before and after a TLESR, and the CI of the EGJ (EGJCI) (volume of the domain above 0 mmHg), was measured for 8 seconds after primary peristalsis reached the EGJ, both before and after a TLESR. Results: 56 TLESRs were measured during the study. The D-CI (1603 mmHg s cm (1177-2120), median (interquartile range)) following a TLESR was significantly greater than before a TLESR (484 (323-1079)) and more than a 50% increase of D-CI in 35 (62.5%) of the 56 TLESRs was observed. The EGJCI (790 (465-1009)) following a TLESR was significantly greater than before a TLESR (238 (186-308)) and more than a 50% increase in the EGJ-CI in 48 (85.7%) of the 56 TLESRs was observed. Conclusions: The D-CI and the EGJ-CI following a TLESR, were significantly greater than before a TLESR and this tendency was evident in the EGJ-CI, although it can, at times, be difficult to evaluate a TLESR. If the focus is on a forceful contraction of primary peristalsis or on the EGJ, it may be easier to detect and evaluate a TLESR.

PTU-197 Diagnosis of gastro-esophageal reflux disease (GERD) and prediction of treatment response to proton pump inhibitors (PPI) by prolonged wireless ph monitoring: a prospective assessment: Abstract PTU-197 Figure 1

Introduction Increasing duration of pH studies improves consistency of GERD diagnosis but clinical utility of the method is not established. Aim: (1) to identify measurements from prolonged pH studies that discriminate healthy volunteers (HVs) and GERD patients (2) to compare prediction of PPI response from prolonged and standard measurement. Methods HVs and patients with reflux symptoms entered a prospective trial. Quality of life (RAND-36) and symptom severity (Eraflux) was assessed on and off PPI and after 2 weeks ×2/day PPI. Endoscopy recorded mucosal disease. Wireless pH system (Bravo®, Given Imaging) measured acid reflux and symptoms up to 4 days. Receiver Operating Curve (ROC) assessed prediction of PPI response. For each prediction 80% of patients were randomly selected as training set, remaining 20% constituted test set. This was repeated 200 times producing average ROC with SEs. Area under Curve (AUC) quantified quality of prediction. Results Complete data were available from 25/33 HVs (18F, age 20–56) and 70/108 patients (31F, age 18–77), >320 days in total. Oesophagitis was present in 9 HVs (32%: Grade A) and 26 patients (33%: Grade A=19, B=2, C-D=5). Acid exposure time was elevated (AET >5.6%) in 3 (12%) HVs and 35 (50%) patients. Eraflux off-PPI was >25 (consistent with GERD) in 60/63 patients and fell by mean 7 (95% CI 5 to 10) on PPI, 46% reported positive response (>3 fall). Diagnosis: Endoscopy, AET and reflux-symptom association analysis (Symptom Index (SI)) did not discriminate health/disease; but reflux-associated symptoms/day (nRS/Day) covered different ranges for HV and patients. Logistic regression with bootstrap validation identified that ≥3 RS/day corresponded to ∼50% probability that participant was a patient. PPI response: Clinical parameters and AET did not predict outcome. SI (9.2 vs 30.2, p=0.0023) and nRS/Day (1 vs 2.6, p=0.012) were higher in responders. RAND-36 scores for poor physical role and pain were higher in non-responders (p∼0.1). SI ROC had an AUC of 0.73 (CI 0.51 to 0.92). SI >25 was the optimal cut-off for identifying PPI responders (Abstract PTU-197 figure 1). Prediction quality from 24 h studies was lower (AUC 0.69) and CIs for all parameters were wider with lower CI.Abstract PTU-197 Figure 1 ROC for SI as predictor of PPI response. Error bars show SE. ROC with cross-validation is black line, without cross-validation is grey line (∼10% greater AUC). Conclusion Diagnostic consistency for all parameters increases with study duration. A simple count of nRS/Day best discriminates HVs from patients on pH studies. SI >25 provides single best prediction of PPI response; but quality of predictions was modest in this population with low PPI response. Competing interests None declared.