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Time to surgery after termination of neoadjuvant chemoradiotherapy for esophageal cancer has traditionally been 4–6 weeks. Observational studies have suggested that delay of surgery for up to three months may lead to improved tumor regression and better outcomes. NeoRes II is the first randomized trial to address this in esophageal cancer. No difference in surgical morbidity or mortality between early and delayed surgery was reported in a previous publication from the trial. A multicenter clinical trial with randomized 1:1 allocation of standard time to surgery of 4–6 weeks, or delay of surgery to 10–12 weeks, after termination of chemoradiotherapy. The primary endpoint was complete histological tumor regression in patients with adenocarcinoma. Secondary endpoints included tumor regression grade, tumor free resection margins and overall survival in all patients, and stratified by histological subtype. In total 249 patients were randomized, 204 with adenocarcinoma and 45 with squamous cell carcinoma. There was no significant difference in histological complete response between adenocarcinoma patients allocated to standard time to surgery (20.6%) compared to delayed (25.6%) surgery (P = 0.18). Tumor free resection margin was achieved in 97.4% after standard time to surgery and 97.1% after delayed surgery (P = 1.0). The median follow-up time for survival was 51 months. Delayed time to surgery was associated with a 35% higher overall mortality, hazard ratio 1.35 (95% CI:0.94–1.95), (P = 0.11). No significant difference in complete histological tumor regression or tumor free resection margins comparing standard and delayed time to surgery after chemoradiotherapy was observed. There was a non-significant trend towards inferior overall survival after delayed surgery, suggesting caution in delaying surgery for more than 6 weeks after neoadjuvant chemoradiotherapy.

The Nordic countries have similar health care systems and registries simplifying epidemiological research and the treatment of esophageal cancer is largely centralized. However, differences in treatment traditions can hamper the possibility to assess results and harmonize control arms in joint randomized trials. In setting up a Nordic multi-center randomized trial regarding the use of nasogastric tube (NG-tube) decompression, we aimed to investigate differences in perioperative routines after esophageal resection at Nordic University hospitals. All Nordic University Hospitals with an upper gastrointestinal cancer center (UGC) were contacted regarding a Nordic randomized controlled trial exploring the effects and complications associated with the use of NG-tube after esophagectomy for cancer. Those who chose to join the trial were sent a questionnaire regarding surgical volumes and practices including mean annual number of esophagectomies, surgical method/access, and routine use of pyloric drainage and jejunostomy. In addition, the current standard postoperative use of NG-tube and routine X-ray/CT evaluation, along with postoperative traditions regarding the start of liquid diet was enquired. High volume centers were defined as performing >20 procedures/year. Thirteen of 17 centers with a combined catchment area of 16 million inhabitants and an annual volume of 445 esophagectomies joined the trial network. All, but one center used a total minimally invasive- or hybrid surgical approach but otherwise, the routine use of pyloric drainage and jejunostomy varied widely without being statistically different. All 13 centers reported routine use of NG-tube and 4 employed continuous suction. The NG-tube was removed between 3 and 7 days postoperatively, but also strategies between the centers (suction on NG-tube, start of liquid diet, routine X-ray/CT evaluation) varied without being statistically significant Firm adherence to standardized operations and safety protocols are implemented in Nordic UGCs to reduce the potential consequences of complications. However, the results find the differences in perioperative care after esophagectomy apparent, highlighting the need for high-level evidence regarding these practices. A unified approach may facilitate clinical trial initiatives. There is a paucity of evidence regarding optimal NG-tube use after esophagectomy for cancer and a randomized trial (kiNETiC ISRCTN39935085) investigating this issue is underway.

Prognostic biomarkers for esophageal adenocarcinoma (EAC) remain elusive but may be helpful in treatment planning, as TNM staging often fails to accurately predict survival. Advanced stage patients are treated by peri-operative chemo/radiotherapy; biomarkers associated with survival are thus likely to represent both true prognostic markers as well as markers of response to chemo/radiotherapy. Here we present first-pass genomic findings for a cohort of optimally staged EAC patients treated by surgery alone. DNA was extracted from fresh frozen EAC and matching normal squamous esophageal tissues obtained at esophagectomy from 65 consenting patients who did not receive any neo- or adjuvant chemo- or radiotherapy due to institutional preference at the time of tissue collection. Library preparation and sequencing for a targeted 600 cancer-associated gene panel designed using the Roche/NimbleGen EZ Choice Library NimbleDesign platform were conducted on Illumina-based platforms followed by analysis with an accredited bioinformatics pipeline. The panel design incorporated the entire coding region plus 10 bp of flanking intron of each gene. Mean age 70 yrs; 88% male. All patients underwent an en bloc esophagectomy (mean 35 lymph nodes). TNM (7th ed.) stages were 61% Stage 3, 18% stage 2, 14% stage 1, 6% stage 4. At median 9.5 years follow-up, 20 (31%) patients remained alive. Copy number changes were common, reflecting chromosomal instability. Less than 8% of patients had high tumour mutational burden (>10mut/MB), associated with mutations in DNA repair genes. Commonest somatic mutations included TP53 (HR: 0.43) and LRP1B (HR: 1.7). Pathways implicated included RTK signalling (PIK3CA, EGFR, KRAS), DNA damage (BRCA1, PALB2, MGMT) and histone remodelling (ARID1A, ARID2, KMT2D). Peri-operative treatment means linking genomic changes independent of stage to clinical outcomes is difficult. Neoadjuvant and/or adjuvant treatment is now standard for T2–4 or node positive EAC. This cohort of 65 patients, most of whom had stage 3 disease and all of whom underwent optimal staging with en bloc esophagectomy, represents a unique opportunity to analyze characteristics of EAC without confounding by peri-operative treatment. An EAC-specific DNA sequencing panel approach offers potential for personalized therapy.

Background Accumulating evidence suggests a survival benefit after curative oesophageal cancer surgery in women compared with men. The aim of this study was to explore sex disparities in survival after surgery with curative intent in patients with oesophageal cancer. Methods This was a population-based cohort study, including all patients with oesophageal or gastric cancer who underwent surgery with a curative intent between 2006 and 2017 in Sweden. Female versus male mortality rate ratio (MRR) and excess mortality rate ratio (EMRR) were used as measures of survival. Two different parametric models were designed to account for potential confounders. Patients with gastric cancer were used as a comparison group as no differences in survival between sexes were expected among these patients. Results A total of 1301 patients underwent resection for oesophageal adenocarcinoma and 305 patients for oesophageal squamous cell carcinoma. Women had a lower EMRR (0.76, 95 per cent c.i. 0.58 to 1.01, P = 0.056; 0.52, 95 per cent c.i. 0.32 to 0.84, P = 0.007 respectively) in both histological subtypes. The effect was more profound in early clinical stages, in patients receiving neoadjuvant treatment, and without postoperative complications. No sex-related difference was observed in survival of patients with gastric cancer. Conclusions Women undergoing resection for oesophageal carcinoma have better survival compared with men.

Oesophageal cancer management requires extensive in-hospital care. This cohort study aimed to quantify in-hospital care for esophageal cancer patients in relation to intended treatment and to analyze factors associated with risk of spending a large proportion of survival time in hospital. Methods All patients with oesophageal cancer in three nationwide registers over a ten-year period, were included. In-hospital care during the first year after diagnosis was evaluated and the proportion of survival time spent in hospital, stratified for intended treatment (curative, palliative or best supportive care) calculated. Associations of relevant factors to a greater proportion of survival time in hospital was analyzed by multivariable logistic regression. Results In-hospital care was provided for a median time of 39, 26 and 15 days the first year after diagnosis of oesophageal cancer for curative, palliative and best supportive care groups respectively. Patients receiving curatively intended treatment spent a median of 12% of their survival time in hospital during the first year after diagnosis, while palliative or best supportive care patients spent 19% and 23% respectively. Factors associated with more in-hospital care included higher age, female sex, being unmarried and chronic obstructive pulmonary disease (COPD). Conclusion The burden of in-hospital care during the first year after diagnosis of oesophageal cancer was substantial. Important clinical and socioeconomic factors were identified that predisposed to a greater proportion of survival time spent in hospital.

Accumulating evidence points to a better survival in female patients after a curative oesophageal cancer surgery. However, there is a need for more well-designed and sufficiently powered studies for limitations in previous studies. Better understanding of sex differences in the postoperative survival may be helpful for a sex-specific treatment. Methods This is a population-based cohort study including all patients in Sweden with oesophageal cancer that underwent a curative surgical treatment between 2006 and 2017. Sex difference in postoperative survival was explored with excess mortality rate ratio (EMRR) and absolute difference of excess mortality rate along the whole follow-up time, using flexible parametric model. Age at the time of surgery, Charlson comorbidity index, ASA score, tumor stage, post-operative complications, marital status, education level and hospital volume were considered as covariates in the analysis model. Stratification analysis by clinical stages, perioperative neoadjuvant treatment and post-operative complications was also performed. Results In all, there were 1301 patients resected for oesophageal adenocarcinoma and 305 patients for oesophageal squamous cell carcinoma. For both oesophageal adenocarcinoma and oesophageal squamous cell carcinoma, female patients had a lower excess mortality rate than males (adjusted EMRR: 0.77, 95% CI: 0.58–1.01, P = 0.059; 0.53, 95% CI: 0.33–0.85, P = 0.009, respectively). This sex difference was particularly strong shortly after surgery then gradually decreased over the ensuing years (Figure) and was more profound in the early clinical stages, and in patients receiving neoadjuvant treatment and without post-operative complications. Conclusion Female patients seem to have a better survival shortly after esophagectomy for patients with oesophageal adenocarcinoma and oesophageal squamous cell carcinoma, and the sex difference thereafter weakened. Our results may imply a different response to oesophageal cancer surgery between the sexes, and associated pre- and post-operative treatment, thus a sex-specific strategy may be considered in further work.

Cancer treatment is increasingly tailored to the individual patient. Treatment decisions are based on the evaluation of clinical stage which in turn is based on the result of the diagnostic pre-treatment work-up. The aim of this study was to investigate the accuracy of clinical staging of esophageal and gastric cancer in Sweden and what factors influence the quality of the staging procedure. Methods All patients operated for esophageal or gastric cancer, without neoadjuvant treatment, in Sweden from 2006 to 2018 was extracted from the Swedish national registry for esophageal and gastric cancer. Clinical TNM (cTNM) and pathological TNM (pTNM) was compared. The most common preoperative modalities for staging were endoscopy and CT-scan. Data on sex, age, smoking habits, multidisciplinary cancer conferences (yes/no), time of surgery (categorized in 5-year periods), number of resected lymph nodes and region of surgery were extracted from the registry. Uni- and multivariate logistic regression analyses were made comparing patients with correct cTNM to patients with incorrect cTNM. Results A total of 2500 patients met the inclusion criteria. 1173 patients were excluded because of missing data leaving 1327 patients for analyses. cTNM stage and pTNM stage was identical in 38% of patients. In 35% of patients there was a +/−1 stage difference comparing cTNM to pTNM. For esophageal cancer T-stage was on target in 32% and N-stage in 50% of cases. For gastric cancer the corresponding figures were 35% and 48% respectively. Multivariate regression analyzes showed that operation in the later time periods, a higher number of resected lymph nodes and discussion at multidisciplinary cancer conference improved staging accuracy. Conclusion In this study we found that 73% of patients were staged on target or +/− one stage-level. Operation in the later time periods, a higher number of resected lymph nodes and discussion at multidisciplinary cancer conference improved staging accuracy. This data indicate that treatment decisions should be made in a multidisciplinary setting. We believe that the gradual centralization of surgery and treatment decisions in Sweden during this time-period partly explains the improved accuracy over time.

Background and Aims Major adverse cardiac events (MACE) remain a leading cause of mortality in chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain & extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in fibrosis, inflammation and calcification. In the phase 3 BETonMACE trial, apabetalone treatment was associated with reduction in MACE in the subpopulation with CKD (eGFR < 60 mL/min/1.73m2; HR 0.50 95% CI 0.26,0.96 p=0.04]) implying favorable effects of apabetalone on cellular responses along the kidney-heart axis. This study examines effects of apabetalone on primary human renal mesangial cells (HRMCs) in culture on fibrosis, inflammation, reactive oxygen species (ROS) and calcification pathways that contribute to renal pathology. Method HRMCs from donors without kidney dysfunction were stimulated with TGF-β1 or lipopolysaccharide (LPS) ± 1-25µM apabetalone, 0.15-0.5µM JQ1 or 0.1µM MZ1 (BET inhibitors [BETi] with chemical scaffolds different than apabetalone). Gene expression was measured by real-time PCR and RNA-seq. Smooth muscle actin (α-SMA) was examined by immunofluorescence microscopy, and alkaline phosphatase enzyme activity in a biochemical assay. RNA-seq from TGF-β1 treated HRMC ± BETi was evaluated by Gene Ontology (GO) Enrichment and Ingenuity Pathway Analysis (IPA). Results TGF-β1 is a pro-fibrotic cytokine that activates HRMC to a fibroblast-like state which over-produces extracellular matrix (ECM). Apabetalone dose dependently suppressed TGF-β1 induced gene expression of (a) α-SMA, a marker of fibrotic activation, up to 90% p In GO Enrichment analysis of RNA-seq from TGF-β1 stimulated HRMCs, multiple gene sets associated with ECM were in the top 20 affected by BETi, supporting anti-fibrotic properties. IPA predicted NfkB-RelA and NFkB (complex) were upstream regulators inhibited by apabetalone, indicating suppression of NF-kB mediated inflammation. IPA also predicted apabetalone activated canonical pathways of glucose utilization & tolerance of ROS production, including Oxidative Phosphorylation (z-score 5.7, p0.05 at 5µM) and NRF2-Mediated Oxidative Stress Response (z score 2.3, p Conclusion Apabetalone downregulated responses to TGF-β1 or LPS in HRMCs that promote fibrotic, inflammatory and calcific processes which exacerbate kidney dysfunction. Changes in energy metabolism pathways predicted apabetalone facilitates adaptation to high glucose in the kidney. Together, our results provide mechanistic insight into reductions in MACE in CKD patients receiving apabetalone in the phase 3 BETonMACE trial. The effect of apabetalone on MACE in patients with diabetes and CKD will be further evaluated in the upcoming BETonMACE2 trial.

Background and Aims Patients with type 2 diabetes (T2D) and acute coronary syndrome (ACS) are at high risk for recurrent cardiovascular (CV) events, particularly in the presence of chronic kidney disease (CKD). Apabetalone (APB) is a novel inhibitor of bromodomain and extraterminal (BET) proteins. Its cardiovascular efficacy and safety were evaluated in a phase 3 trial, BETonMACE. Method BETonMACE was a randomized, double-blind, comparison of effects of ABP or placebo (PBO) on major adverse CV events (MACE) defined as CV-death, non-fatal myocardial infarct or stroke, in 2425 pts with T2D and recent ACS. Here we report MACE plus CHF hospitalization in subjects with or without CKD Stage 3. Results Baseline characteristics: median age 62 years, 25.6% female, 87.6% white, 90% high intensity statin use, mean LDL-C 70.3 and HDL-C 33.3 mg/dl, median HbA1c 7.3%, and 11% with CKD Stage 3. Overall in the trial, MACE plus CHF hospitalization occurred in 139 (11.5%) patients with ABP and 173 (14.3%) with PBO (HR 0.78, 95% CI 0.63-0.98). In the subgroup with CKD, MACE plus CHF hospitalization occurred in 16 (12.9%) on APB and 41 (25%) on PBO (HR 0.48, 95% CI 0.26-0.89). In the subgroup without CKD, MACE plus CHF hospitalization occurred in 123 (11.3%) and 132 (12.7%) with APB or PBO, respectively (HR 0.89, 95% CI 0.70-1. Conclusion Patients with T2D, ACS, and Stage 3 CKD have a very high risk of subsequent MACE plus CHF hospitalization. The BET protein inhibitor ABP may reduce this risk.

Background and Aims Elevated serum alkaline phosphatase (ALP) independently predicts major adverse cardiac events (MACE) by contributing to vascular calcification and endothelial dysfunction arising in chronic kidney disease (CKD) and cardiovascular disease (CVD). Apabetalone is an orally active inhibitor of bromodomain and extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in vascular inflammation and calcification. Here we examined apabetalone’s effects on ALP post-hoc in recent clinical trials, then performed mechanistic studies into apabetalone’s impact on tissue non-specific ALP (TNALP) expression in mice and cell culture. Method Serum ALP was determined in CVD patients in phase 2 trials (3 month ASSERT and 6 month SUSTAIN & ASSURE) and in the phase 3 BETonMACE CVD outcomes trial, including subpopulations with CKD (eGFR Results In phase 2 trials, baseline serum ALP independently predicted MACE (hazard ratio [HR] 1.6, 95% CI 1.2-2.2, p=0.001). In the 3 month ASSERT trial, apabetalone dose dependently reduced serum ALP (p Liver-derived TNALP accounts for ≈50% of circulating ALP. In the liver of mice on high fat diet, apabetalone or JQ1 (BET inhibitors with different chemical scaffolds) reduced Alpl mRNA (p55%, p 40%; p Conclusion Apabetalone lowers serum ALP in clinical trials, which is consistent with reduced hepatic production of TNALP - the most abundant ALP isoform. Further, apabetalone downregulates ALPL gene expression in vascular cell types while reducing calcification. Together, BET-dependent epigenetic modulation of ALP by apabetalone can affect several pathogenetic processes, and thereby improve cardiovascular outcomes. This study provides insights to the CVD event reductions observed in the CKD subpopulation in the BETonMACE Phase 3 trial.

Background and Aims Fabry disease (FD) is a rare X-linked recessive genetic disorder caused by mutations in the α-galactosidase A gene. Absence or defects of this lysosomal enzyme lead to globotriaosylceramide (Gb3) accumulation. Gb3 disrupts basic cellular metabolic processes, inducing oxidative stress and promoting inflammation. Systemically, Gb3 accumulation leads to organ damage throughout the body with an increase in renal, cardiac, cerebrovascular and skin complications. Enzyme replacement therapy (ERT) is current standard of care. This therapy may reduce Gb3 deposits but the impact on cardiac and kidney function is unclear based on the limited studies. Further, ERT is less effective in the late phases of FD, partially due to the development of uncontrolled inflammation and fibrosis. Apabetalone is a clinical stage orally administered bromo and extra terminal domain inhibitor (BETi) that has beneficial effects on vascular inflammation and vascular calcification through an epigenetic pathway. Based on its mechanism of action and impact on multiple disease drivers in both preclinical and clinical studies, apabetalone has therapeutic potential to modulate inflammation in FD patients on ERT therapy. Method PBMCs and neutrophils were isolated from fresh blood of FD patients ± ERT therapy using density gradient centrifugation. The baseline immune status of PBMCs was compared in naïve FD patients (without ERT, n=3) and ERT treated patients (n=8) via flow cytometry. PBMCs or neutrophils from ERT patients were treated ex vivo with 5µM or 20µM apabetalone ± LPS stimulation. Expression of key pro-inflammatory mediators was analyzed with real time quantitative PCR. The production of reactive oxygen species (ROS) in neutrophils was assessed by flow cytometry. Results The PBMC inflammatory profile in baseline showed monocytes from ERT patients produced lower amounts of pro-inflammatory mediators (TNFα and IL6) than naïve patients (∼60%, trending p≤0.06 and p≤0.08 respectively). However, surface abundance of CCR2, a chemokine receptor for the MCP1 chemokine that promotes monocyte recruitment to local inflamed tissue during inflammatory process, was ∼2-fold greater on monocytes from ERT subjects than the naïve controls (trending p≤0.06). Gene expression of MCP1 was approximately 5-fold higher in PBMC from ERT patients versus naïve controls (p=0.01). In response to ex vivo LPS stimulation, PBMCs from FD patients on ERT showed a robust induction of pro-inflammatory responses with increases in gene expression of MCP1, IL12B, TNFA and IL6. Ex vivo treatment with apabetalone (5µM) blocked the LPS-induction of MCP1 gene expression (∼90%, p Conclusion Monocytes from FD patients on ERT therapy display an enhanced expression of the CCR2-MCP-1 axis as compared to naïve controls, indicating the potential for immune cell tissue infiltration and local inflammation. Apabetalone counters this increase by preventing MCP1 gene transcription. Apabetalone also reduces PBMC mediated pro-inflammatory gene transcription (TNFA, IL12B, IL6) and neutrophil mediated ROS production in response to LPS stimulation. Therefore, apabetalone treatment may reduce pathological inflammation in FD patients and thus complement ERT to optimize patient outcomes, which will be tested further with warranted clinical studies.

Background: Benchmarking on an international level might lead to improved outcomes at a national level. The aim of this study was to compare treatment and surgical outcome data from the Swedish National Register for Oesophageal and Gastric Cancer (NREV) and the Dutch Upper Gastrointestinal Cancer Audit (DUCA).Methods: All patients with primary oesophageal or gastric cancer who underwent a resection and were registered in NREV or DUCA between 2012 and 2014 were included. Differences in 30-day mortality were analysed using case mix-adjusted multivariable logistic regression.Results: In total, 4439 patients underwent oesophagectomy (2509 patients) or gastrectomy (1930 patients). Estimated resection rates were comparable. Swedish patients were older but had less advanced disease and less co-morbidity than Dutch patients. Neoadjuvant treatment rates were lower in Sweden than in the Netherlands, both for patients who underwent oesophagectomy (68·6 versus 90·0 per cent respectively; P < 0·001) and for those having gastrectomy (38·3 versus 56·6 per cent; P < 0·001). In Sweden, transthoracic oesophagectomy was performed in 94·7 per cent of patients, whereas in the Netherlands, a transhiatal approach was undertaken in 35·8 per cent. Higher annual procedural volumes per hospital were observed in the Netherlands. Adjusted 30-day and/or in-hospital mortality after gastrectomy was statistically significantly lower in Sweden than in the Netherlands (odds ratio 0·53, 95 per cent c.i. 0·29 to 0·95).Conclusion: For oesophageal and gastric cancer, there are differences in patient, tumour and treatment characteristics between Sweden and the Netherlands. Postoperative mortality in patients with gastric cancer was lower in Sweden. (Less)

Background Anastomotic leakage (AL) after oesophageal surgery is a serious complication, leading to increased postoperative mortality. Early detection and treatment is essential. The aim of this study was to investigate if inflammatory serum parameters in the early postoperative course after oesophageal cancer surgery, could predict development of an AL. Methods All patients in Sweden with AL after thoraco-abdominal surgery for oesophageal or gastroesophageal junction cancer from 2006–01-01 to 2017–01-31 were collected from the Swedish National Registry for esophageal and gastric cancer (NREV). Two matched controls for each AL-patient were also selected from the registry. Pre-, per- and postoperative variables were collected from NREV. The following parameters were collected from patient charts: number of days from surgery to AL, diagnostic modality, method of treatment, serum levels of C-reactive protein (CRP), White blood cell count (WBC) and serum-Albumin taken on postoperative day 1 to 7 (POD1–7). Thoracic- and cervical anastomosis were analysed separately. Perioperative data and inflammatory markers were compared between controls and AL-patients. Receiver Operating Characteristic (ROC) curves was constructed to identify optimal cut-off values and a multivariate analysis was performed to identify independent risk factors. Results A total of 155 patients with AL and 307 controls (n = 462) were analysed. In patients with thoracic anastomosis median levels of CRP and WBC were significantly different on POD 2–7 and on POD 4–7 comparing AL-patients to controls. In patients with cervical anastomosis there was a significant difference in WBC levels on POD 1–7. ROC-curve analysis identified CRP on POD3 (cut-off 221) and POD4 (cut-off 203) as the best candidates for predicting AL in patients with a thoracic anastomosis, displaying an area under curve of 0.754 (Sensitivity 59%, Specificity 83%) and 0.731 (Sensitivity: 57%, Specificity 82%). Conclusion In this nation-wide register study we found that a model combining S-CRP levels on POD 3 and POD 4 after a thoraco-abdominal esophagectomy, could identify patients with increased risk of anastomotic leakage several days before it was diagnosed. However, since the sensitivity of this test is relatively low for predicting AL, it must be assessed in a larger clinical context. Disclosure All authors have declared no conflicts of interest.

Forty patients with a mean age of 45 (range 22–65) years were operated on between 1982 and 1985 for gastro-oesophageal reflux disease with a short floppy 360° fundoplication. The results of the operation were determined by endoscopy, oesophageal manometry, ambulatory 24-h pH recording and symptom evaluation 6 months and 5 years after operation. These results were compared with findings in healthy controls. The median pressure in the lower oesophageal high-pressure zone was 13·3 (interquartile range (i.q.r.) 11·3–21·3) mmHg after 5 years, which did not differ significantly from the value at 6 months' follow-up or from that in controls. It was, however, significantly higher than the preoperative pressure. The median intra-abdominal length of the high-pressure zone was 1·7(i.q.r. 1·3–2·3) cm after 5 years, significantly less than at 6 months but equal to control length. Measurement of the proportion of total time at pH < 4 at 5 years (median 0·2 (i.q.r. 0·0–0·6) per cent) and 6 months after operation revealed a significant reduction in acid reflux compared with preoperative values and normal controls. There was no significant difference in acid exposure between the two postoperative investigations. Endoscopy showed that 27 patients had no oesophagitis, three had erythema and three persistent Barrett's oesophagus 5 years after operation. Normal belching was possible in 22 patients and 18 experienced increased flatulence 5 years after fundoplication. An independent gastroenterologist found that the result was excellent in 16 patients, good in 16 and fair in four; two patients had a poor overall outcome of the operation. It is concluded that a 360° fundoplication provides good long-term control of reflux and that slight symptoms of overcompetence are common among patients operated on without affecting the overall result.