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A letter to the editor is presented in response to the article about the trial of minimally invasive versus open oesophagectomy in an issue.

Introduction: Surgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK. This can be performed as an open oesophagectomy (OO), a laparoscopically assisted oesophagectomy (LAO) or a totally minimally invasive oesophagectomy (TMIO). All three are performed in the National Health Service, with LAO and OO the most common. However, there is limited evidence about which surgical approach is best for patients in terms of survival and postoperative health-related quality of life., Methods and Analysis: We will undertake a UK multicentre randomised controlled trial to compare LAO with OO in adult patients with oesophageal cancer. The primary outcome is patient-reported physical function at 3 and 6 weeks postoperatively and 3 months after randomisation. Secondary outcomes include: postoperative complications, survival, disease recurrence, other measures of quality of life, spirometry, success of patient blinding and quality assurance measures. A cost-effectiveness analysis will be performed comparing LAO with OO. We will embed a randomised substudy to evaluate the safety and evolution of the TMIO procedure and a qualitative recruitment intervention to optimise patient recruitment. We will analyse the primary outcome using a multi-level regression model. Patients will be monitored for up to 3 years after their surgery., Ethics and Dissemination: This study received ethical approval from the South-West Franchay Research Ethics Committee. We will submit the results for publication in a peer-reviewed journal., Trial Registration Number: ISRCTN10386621., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Localised oesophageal cancer can be curatively treated with surgery (oesophagectomy) but the procedure is complex with a risk of complications, negative effects on quality of life and a recovery period of 6-9 months. Minimal-access surgery may accelerate recovery., Objectives: The ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) study aimed to establish the feasibility of, and methodology for, a definitive trial comparing minimally invasive and open surgery for oesophagectomy. Objectives were to quantify the number of eligible patients in a pilot trial; develop surgical manuals as the basis for quality assurance; standardise pathological processing; establish a method to blind patients to their allocation in the first week post surgery; identify measures of postsurgical outcome of importance to patients and clinicians; and establish the main cost differences between the surgical approaches., Design: Pilot parallel three-arm randomised controlled trial nested within feasibility work., Setting: Two UK NHS departments of upper gastrointestinal surgery., Participants: Patients aged ≥ 18 years with histopathological evidence of oesophageal or oesophagogastric junctional adenocarcinoma, squamous cell cancer or high-grade dysplasia, referred for oesophagectomy or oesophagectomy following neoadjuvant chemo(radio)therapy., Interventions: Oesophagectomy, with patients randomised to open surgery, a hybrid open chest and minimally invasive abdomen or totally minimally invasive access., Main Outcome Measure: The primary outcome measure for the pilot trial was the number of patients recruited per month, with the main trial considered feasible if at least 2.5 patients per month were recruited., Results: During 21 months of recruitment, 263 patients were assessed for eligibility; of these, 135 (51%) were found to be eligible and 104 (77%) agreed to participate, an average of five patients per month. In total, 41 patients were allocated to open surgery, 43 to the hybrid procedure and 20 to totally minimally invasive surgery. Recruitment is continuing, allowing a seamless transition into the definitive trial. Consequently, the database is unlocked at the time of writing and data presented here are for patients recruited by 31 August 2014. Random allocation achieved a good balance between the arms of the study, which, as a high proportion of patients underwent their allocated surgery (69/79, 87%), ensured a fair comparison between the interventions. Dressing patients with large bandages, covering all possible incisions, was successful in keeping patients blind while pain was assessed during the first week post surgery. Postsurgical length of stay and risk of adverse events were within the typical range for this group of patients, with one death occurring within 30 days among 76 patients. There were good completion rates for the assessment of pain at 6 days post surgery (88%) and of the patient-reported outcomes at 6 weeks post randomisation (74%)., Conclusions: Rapid recruitment to the pilot trial and the successful refinement of methodology indicated the feasibility of a definitive trial comparing different approaches to oesophagectomy. Although we have shown a full trial of open compared with minimally invasive oesophagectomy to be feasible, this is necessarily based on our findings from the two clinical centres that we could include in this small preliminary study., Trial Registration: Current Controlled Trials ISRCTN59036820., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 48. See the NIHR Journals Library website for further project information.

Background: Oesophageal cancer is increasing in incidence worldwide. Minimally invasive techniques have been used to perform oesophagectomy, but concerns regarding these techniques remain. Since its description by Cuschieri in 1992, the use of minimally invasive oesophagectomy (MIO) has increased, but still only used in a minority of resections in the UK in 2009. In particular, there has been reluctance to use minimally invasive (thoracoscopic and laparoscopic) techniques in more advanced cancers for fears regarding the adequacy of the oncological resection. In order to identify any factors that could affect survival, we undertook a retrospective analysis on all patients who underwent surgery in our department over an 8-year period., Methods: A retrospective data analysis was undertaken on all patients who underwent oesophagectomy in a tertiary upper gastrointestinal surgery unit, from 2005 to 2012 inclusive. Data were collected from the departmental database and case note review, with follow-up and survival data to time of data collection. The survival data were analysed using univariate and multivariate Cox proportional hazard regression models to determine which variables affected survival. Variables examined included age, tumour position, tumour stage (T0, 1, 2 vs T3, 4), nodal stage (N0 vs N1), tumour histology, completeness of resection (R0 vs R1), use of neoadjuvant chemotherapy and operative technique (thoracoscopic/laparoscopic (MIO) vs laparoscopic abdomen/open chest (Lap assisted) vs Open., Results: 334 patients underwent oesophagectomy between 2005 and 2012. Male to female ratio was 3.75:1, with a mean age of 64 years (range 36-87). There were 83 open oesophagectomies, 187 laparoscopically assisted oesophagectomies and 64 minimally invasive oesophagectomies. Following univariate regression analysis the following factors were found to be correlated to survival: use of neoadjuvant chemotherapy (Hazard Ratio 2.889, 95 % CI 1.737-4.806), T stage 3 or 4 (3.749, 2.475-5.72), Node positive (5.225, 3.561-7.665), R1 resection (2.182, 1.425-3.341), type of operation (MIO compared to open oesophagectomy) (0.293, 0.158-0.541). There was no significant relationship between age, tumour position or tumour histology and length of survival. When these factors were entered into a multivariate model, the independently significant factors correlated to survival were found to be T stage 3 or 4 (HR 1.969, 1.248-3.105), Node positive (3.833, 2.548-5.766) and type of operation (MIO compared to open) (0.5186, 0.277-0.972)., Conclusion: Multiple small studies have found reduced pulmonary complication rates and duration of hospital stay when using a minimally invasive approach compared to open. Concerns in the literature over long-term outcomes, however, have led to limited utilisation of this method, especially in advanced disease. The data from this large study show significantly better survival following operations performed using minimally invasive techniques compared to open, however, we have not adjusted for some known or unknown confounding factors. International and national RCTs, however, will provide more information in due course.

Resistance to the growth-inhibitory action of retinoic acid (RA), the bioactive derivative of vitamin A, is common in human tumors. One form of RA resistance has been associated with silencing and hypermethylation of the retinoic acid receptor beta2 gene (RARbeta2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RARbeta2 correlates with lack of the RA receptor alpha (RARalpha). Normally, RARalpha regulates RARbeta2 transcription by mediating dynamic changes of RARbeta2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RARalpha (which was achieved by use of a dominant-negative RARalpha, by downregulation of RARalpha by RNA interference, and by use of RARalpha antagonists) induces an exacerbation of the repressed chromatin status of RARbeta2 and leads to RARbeta2 transcriptional silencing. Further, we demonstrate that RARbeta2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RARbeta2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RARbeta2 through RARalpha leads to RARbeta2 reactivation. This report provides proof of principle that RARbeta2 silencing and RA resistance are consequent to an impaired integration of RA signal at RARbeta2 chromatin.

The reason why patients with isolated supine reflux do not reflux in the upright position and patients with isolated upright reflux do not reflux in the supine position is unknown. Our objective was to determine the characteristics of the crura, lower esophageal sphincter, crura-sphincter dynamics, and esophageal body on manometry, endoscopy, and X-ray in patients with isolated upright and isolated supine reflux. Eighty consecutive patients with isolated upright reflux were compared with 82 consecutive patients with isolated supine reflux. Manometrically there was no difference in lower esophageal sphincter characteristics and esophageal contractions between the two groups. The prevalence of a hiatal hernia on manometry was similar between upright and supine refluxers (88% vs 88%). Upright refluxers had shorter hiatal hernias [median (interquartile range) 1.1 (0.65-1.8) vs 1.2 (1-2.3), P < 0.046)]. The median crural pressure, crura-sphincter pressure gradient, and crura-sphincter pressure ratio in upright refluxers was 14.96 (9.5-21.27), 3.28 (1.7-12.2), and 1.33 (0.87-2.8) mm Hg, respectively. These values were significantly higher (P < 0.001) in supine refluxers at 21.43 (16.6-29.9), 10.66 (4.3-19.7), and 2.1 (1.3-4.2) mm Hg, respectively. We conclude that the significantly higher crural pressure in patients with supine reflux acts as a mechanical ring and as a physiologic protector against the unfolding of the sphincter in the postprandial and upright periods. Higher crura-sphincter pressure gradient and larger-size hiatal hernias in patients with supine reflux results in pressurization of the hernia sac and subsequent reflux when these patients are in a supine position.

Hypothesis: Obesity impairs the antireflux function of a structurally intact barrier., Design: Retrospective analysis of body mass index in patients with normal esophageal manometric findings but with symptomatic and objectively confirmed gastroesophageal reflux., Setting: Specialist esophageal center., Patients: Patients symptomatic and diagnostic for gastroesophageal reflux, referred between October 1, 1998, and June 30, 2000. Exclusion criteria were a defective barrier, motility disorders, or previous surgery., Main Outcome Measures: Reflux was defined and quantified using the DeMeester score, and body mass index was calculated., Results: There was a strong correlation between body mass index and severity of gastroesophageal reflux. Patients who were overweight had significantly higher distal esophageal acid exposure. No significant difference in manometric findings was demonstrated between patients with normal weight and those who were overweight., Conclusion: The barrier to gastroesophageal reflux is rendered insufficient in patients who are overweight.