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Background Whether Peroral Endoscopic Myotomy (POEM) can be proposed as a second-line treatment in patients with achalasia remains to be confirmed in real-life series. Objective This study aimed to compare the efficacy, feasibility and safety of POEM between treatment-naïve patients and patients who had prior endoscopic or surgical therapies for achalasia. Methods All consecutive patients who underwent a POEM procedure for achalasia in our centre from June 2015 to September 2018 were included in this retrospective study. They were classified into treatment-naïve patients (POEM1) and patients who had at least one previous endoscopic and/or surgical treatment for achalasia (POEM2). Results A total of 105 patients were included, 52 in the POEM1 group and 53 in the POEM2 group. Clinical success (defined as an Eckardt score ≤ 3) at 6 months was observed in 93% of POEM1 patients and 84% of POEM2 patients (p = 0.18). Technical success rate was not significantly different between the two groups (100% vs 96%, respectively; p = 0.50). No significant difference was noted in terms of adverse event rate (19% vs 19%, respectively; p = 1.00). Post-procedure pain occurred in 12% of treatment-naive and 9% of non-naïve patients (p = 0.76). The median length of hospital stay was 3 days in both groups (p = 0.17). Symptomatic gastroesophageal reflux occurred in 25% of POEM1 patients and 16% of POEM2 patients (p = 0.24). Conclusion Efficacy, feasibility and safety of POEM are not different between treatment-naïve and non-naïve patients. POEM is a valuable second-line approach in patients with persistent symptoms of achalasia after surgical or endoscopic treatments.

Refereed/Peer-reviewed

Background: Foreign bodies in the upper aerodigestive tract represent an uncommon cause of visits to emergency departments. In the majority of cases, foreign bodies do not go beyond the pharynx. They cause dyspnoea or pneumonia if they reach the tracheobronchial tree. If ingested, they will pass spontaneously through the gastrointestinal canal in the majority of cases. Nevertheless, especially in the case of sharp-pointed or large objects, the foreign bodies can stop in the oesophagus. In case of dysphagia, stinging sensation and/or odynophagia occurring after eating a meal, a foreign body in the upper aerodigestive tract should be suspected. If not clinically visible, imaging is required. Case presentation: A 72-year-old woman presented to the Emergency Department with pharyngodynia, odynophagia, stinging, dysphagia, and sialorrhea for 12 hours. Her symptoms started after eating a meal involving meat. The patient underwent a standard two-projection radiogram of the neck. The antero-posterior projection radiogram was unremarkable. The lateral projection radiogram showed 16 millimetres in maximum length radiopaque foreign body within the cervical oesophagus. The patient underwent transoral flexible oesophagoscopy under general anaesthesia, which resulted in successful removal of the foreign body (bony fragment). Her symptoms improved rapidly after the procedure, and the patient was discharged after 48 hours in good health. Conclusion: A foreign body in the cervical oesophagus may lead to visceral perforation. Once suspected, every effort should be made to identify and remove the foreign body to avoid potentially catastrophic consequences. In some cases, imaging could be necessary to detect the foreign body.

Objective Tegaserod is a 5-hydroxytryptamine type 4 (5-HT4) receptor agonist, formerly used in treating constipation predominant irritable bowel syndrome, which desensitizes 5-HT4 receptors in rat oesophagus and colon in vitro. Desensitization of 5-HT4 receptors is regulated by G-protein coupled receptor kinases. This study was designed to assess the effect of 5-HT4 receptor activation on the expression of GRK2 and GRK6 in the rat oesophagus and distal colon by acute administration of tegaserod. Results Rats were treated with a single dose of tegaserod (5 mg/kg) and tissue samples of the oesophagus and distal colon were prepared and level of GRK2 and GRK6 protein expression was determined using western blotting. The immunodensity of GRK2 and GRK6 was normalized against the loading control β-actin and compared with control animals. Acute administration of tegaserod for 1, 2, 3, 4, 6, and 8 h did not change significantly the immunodensity of GRK2 or GRK6 in the oesophagus or GRK2 in the distal colon when compared with control animals. This may indicate that the basal level of GRK2 and GRK6 expression is sufficient to regulate the desensitization of 5-HT4 receptors in acute drug treatment.

Eosinophilic oesophagitis (EoE) may lead to severe complications if not promptly recognised.To assess the diagnostic delay in patients with EoE and to explore its risk factors.EoE patients followed-up at eight clinics were included via retrospective chart review. Diagnostic delay was estimated as the time lapse occurring between the appearance of the first likely symptoms indicative of EoE and the final diagnosis. Patient-dependent and physician-dependent diagnostic delays were assessed. Multivariable regression models were computed.261 patients with EoE (mean age 34±14 years; M:F ratio=3:1) were included. The median overall diagnostic delay was 36 months (IQR 12-88), while patient- and physician-dependent diagnostic delays were 18 months (IQR 5-49) and 6 months (IQR 1-24). Patient-dependent delay was greater compared to physician-dependent delay (95% CI 5.1-19.3, p0.001). A previous misdiagnosis was formulated in 109 cases (41.8%; gastro-oesophageal reflux disease in 67 patients, 25.7%). The variables significantly associated with greater overall diagnostic delay were being a non-smoker,1 episode of food impaction, previous endoscopy with no biopsies, regurgitation, and ≥2 assessing physicians. Being single was significantly associated with lower overall and patient-dependent diagnostic delay.EoE is burdened by substantial diagnostic delay, depending on both patient-related and physician-related factors.

We aimed to evaluate the association between three previously defined pro-vegetarian (PVG) food patterns and the cancers of the oesophagus, stomach, and pancreas in a multi case-control study. We analyzed data from a multi-case hospital-based study carried out in two Mediterranean provinces in Spain. A total of 1233 participants were included in the analyses: 778 incident cancer cases, histologically confirmed (199 oesophagus, 414 stomach, and 165 pancreas) and 455 controls. A dietary assessment was performed using a validated food frequency questionnaire (FFQ). Three PVG food patterns (general, healthful, and unhealthful) were estimated using 12 food groups for the general PVG (gPVG), scoring positive plant-based foods and negative animal-based foods, and 18 food groups, for the healthful (hPVG) and unhealthful (uPVG) food patterns. Multinomial logistic regression was used to estimate relative risk ratios (RRR) and confidence intervals (95% CI) for quintiles of adherence to PVG patterns and as a continuous variable. The RRR (95% CI) for the highest vs. the lowest quintile of gPVG were, RRR = 0.37 (0.32, 0.42) for the oesophagus, RRR = 0.34 (0.27, 0.43) for the stomach, and RRR = 0.43 (0.35, 0.52) for pancreas cancer. For the hPVG, the RRR were RRR = 0.72 (0.58, 0.90) for the oesophagus, RRR = 0.42 (0.34, 0.52) for the stomach, and RRR = 0.74 (0.59, 0.92) for pancreas cancer. The uPVG was associated with a higher risk of stomach cancer RRR = 1.76 (1.42, 2.18). Higher adherence to gPVG and hPVG food patterns is associated with a lower risk of oesophageal, stomach, and pancreas cancers, while a higher adherence to a uPVG food pattern is associated with a higher risk of stomach cancer. Funding: This work was supported by the Spanish Ministry of Health (FIS 91/0435, RCESP C03/09), the Generalitat Valenciana (EVES 030/2005, CTGCA/2002/06, G03/136), CIBERESP.

The incidences of many cancers vary substantially across the world, reflecting genetic differences between populations and exposure to environmental carcinogens. This is illustrated by keratinocyte skin cancers and oesophageal squamous cell carcinoma, which both develop from squamous epithelium, yet are remodelled during ageing by very different mutagenic processes and environmental exposures. In this thesis, I investigate the influence of cancer risk factors on the somatic mutations present in normal aged skin and oesophageal epithelium using a range of sequencing methods. I find sun-exposed facial skin from donors of the UK to have a 4-fold increased mutation burden and 10-fold increase in copy number aberrant clones compared to donors of Singapore, a country with a 17-fold lower incidence of keratinocyte skin cancer. The majority of these mutations in the UK are due to ultraviolet radiation (UV) but, in Singapore, age-related signatures predominate. Mutations in TP53 are more strongly selected in epidermis of the UK, whilst those in NOTCH1 and NOTCH2 are preferentially selected in Singapore, reflecting differences in the level of competition within the tissue. A survey of mutations in UK skin across body sites reveals differences in UV signature and selection between sites. In aged oesophageal epithelium from UK donors, I observe an increase in mutations with an alcohol-associated signature with reported alcohol consumption. Furthermore, mutation burden increases with smoking, without a detectable change in the mutational signature, consistent with tobacco smoke increasing oesophageal cancer risk independent of its mutagenic effects. Finally, in donors over the age of 60, mutations in TP53 and FAT1 are more strongly selected, whilst those in NOTCH3 more weakly selected, suggesting changes to levels of competition within the tissue with age. I conclude that the mutational landscapes of normal oesophagus and skin are shaped by age and environmental exposures and that this, in turn, may alter the risk of keratinocyte cancers.

Pseudoachalasia, also known as secondary achalasia, is a rare clinical condition mimicking idiopathic achalasia but unrelated to primary loss of nitrergic innervation. It has mostly been attributed to malignancy infiltrating the oesophageal wall, but several other benign underlying pathologies have been reported. Because of similar manometric appearance, high-resolution manometry (HRM) of the oesophagus alone cannot distinguish between idiopathic achalasia and pseudoachalasia. Misdiagnosis can result in ineffective treatment by dilatation or even more invasive therapy. This is the first case-report of pseudoachalasia secondary to oesophageal deviation resulting from mediastinal shift and left atrial enlargement following prior left lower lobectomy. HRM, the gold standard for the diagnosis of achalasia, confirmed the incomplete relaxation of the lower oesophageal sphincter (LES) in absence of normal oesophageal peristalsis. However, additional workup with CAT scan and cardiac ultrasound identified an anatomical shift by the extrinsic mass effect resulting from the atrial enlargement, but without contrast retention at the LES.

The Garden Dormouse (Eliomys quercinus) and the Edible Dormouse (Glis glis) differ in their omnivorous diet, with the first being more carnivorous and readily consuming small vertebrates and even poisonous invertebrates, while the latter consumes more plant-based foods. These differences could lead to histological differences in their gastrointestinal tract, which we wanted to test. Six animals of each species were caught in nature and fed the same diet for two weeks to diminish the impact of the short-term external factors. Tissue samples were taken of middle oesophagus, glandular stomach, middle small intestines and large intestines. They were stained with H&E for measuring the thickness of layers in oesophagus gastric mucosa and epithelial cell height in the intestines. Alcian blue - PAS stain was used for goblet cell count and type identification in the intestines, differentiating blue (acidic), lilac (neutral) and purple (mixed) cells. Results showed Eliomys quercinus having greater variance in oesophageal layer thicknesses, significantly thicker muscularis mucosae and thinner tunica muscularis in the oesophagus, and thicker gastric mucosa compared to Glis glis. Eliomys quercinus also had a significantly higher total goblet cell count in both intestines and a higher count of each type in the large intestine, although Glis glis had far more mixed and neutral goblet cells in the small intestine. Both showed intriguingly low numbers of neutral goblet cells in the small intestine. These results indicate interesting differences in gastrointestinal histology and goblet cell distribution in comparison with their distinct diets.

Aims Thermal injury to the oesophagus is an important cause of life-threatening complication after ablation for atrial fibrillation (AF). Thermal protection of the oesophageal lumen by infusing cold liquid reduces thermal injury to a limited extent. We tested the ability of a more powerful method of oesophageal temperature control to reduce the incidence of thermal injury. Methods and results A single-centre, prospective, double-blinded randomized trial was used to investigate the ability of the ensoETM device to protect the oesophagus from thermal injury. This device was compared in a 1:1 randomization with a control group of standard practice utilizing a single-point temperature probe. In the protected group, the device maintained the luminal temperature at 4°C during radiofrequency (RF) ablation for AF under general anaesthesia. Endoscopic examination was performed at 7 days post-ablation and oesophageal injury was scored. The patient and the endoscopist were blinded to the randomization. We recruited 188 patients, of whom 120 underwent endoscopy. Thermal injury to the mucosa was significantly more common in the control group than in those receiving oesophageal protection (12/60 vs. 2/60; P = 0.008), with a trend toward reduction in gastroparesis (6/60 vs. 2/60, P = 0.27). There was no difference between groups in the duration of RF or in the force applied (P value range= 0.2–0.9). Procedure duration and fluoroscopy duration were similar (P = 0.97, P = 0.91, respectively). Conclusion Thermal protection of the oesophagus significantly reduces ablation-related thermal injury compared with standard care. This method of oesophageal protection is safe and does not compromise the efficacy or efficiency of the ablation procedure.

Dysphagia has a broad aetiology and so it is essential to identify the precise cause. Cervical cancer metastasis is distinctive in that it usually involves local lymph node invasion; however, approximately 1% of cases have mediastinal involvement, which can cause severe compressive symptoms in rare situations. To highlight an uncommon severe manifestation of cervical cancer relapse, we describe a case of dysphagia in a woman with a history of cervical cancer. After a thorough investigation that included endoscopy, endoscopy with ultrasound, an oesophagogram and fine needle aspiration, we eventually reached the diagnosis of mediastinal metastatic cervical cancer. Following interventions, the patient's condition gradually improved, both clinically and radiographically.Mediastinal lymph node enlargement causing dysphagia can be a presenting sign of a metastatic lesion from treated cervical cancer.A PEG tube is helpful in relieving dysphagia caused by metastatic mediastinal lymph node enlargement and as bridge for nutrition during chemotherapy.The VEGF inhibitor bevacizumab can be used in advanced metastatic cervical cancer.Check-point inhibitors like pembrolizumab can be used in metastatic cervical cancer.

Background To determine the optimal volume of barium for oesophageal localisation on cone-beam CT (CBCT) for locally-advanced non-small cell lung cancers (NSCLC) and quantify the interfraction oesophageal movement relative to tumour. Methods Twenty NSCLC patients with mediastinal and/or hilar disease receiving radical radiotherapy were recruited. The first five patients received 25 ml of barium prior to their planning CT and alternate CBCTs during treatment. Subsequent five patient cohorts, received 15 ml, 10 ml and 5 ml. Six observers contoured the oesophagus on each of the 107 datasets and consensus contours were created. Overall 642 observer contours were generated and interobserver contouring reproducibility was assessed. The kappa statistic, dice coefficient and Hausdorff Distance (HD) were used to compare barium-enhanced CBCTs and non-enhanced CBCTs. Oesophageal displacement was assessed using the HD between consensus contours of barium-enhanced CBCTs and planning CTs. Results Interobserver contouring reproducibility was significantly improved in barium-enhanced CBCTs compared to non-contrast CBCTs with minimal difference between barium dose levels. Only 10 mL produced a significantly higher kappa (0.814, p = 0.008) and dice (0.895, p = 0.001). The poorer the reproducibility without barium, the greater the improvement barium provided. The median interfraction HD between consensus contours was 4 mm, with 95% of the oesophageal displacement within 15 mm. Conclusions 10 mL of barium significantly improves oesophageal localisation on CBCT with minimal image artifact. The oesophagus moves substantially and unpredictably over a course of treatment, requiring close daily monitoring in the context of hypofractionation.

The development of new capsules now allows endoscopic diagnosis in all segments of the gastrointestinal tract and comes with new needs for differentiated preparation regimens. Although the literature is steadily increasing, the results of the conducted trials on preparation are sometimes conflicting. The ingestion of simethicone before gastric and small bowel capsule endoscopy for prevention of air bubbles is established. The value of a lavage before small bowel capsule endoscopy (SBCE) is recommended, although not supported by all studies. Ingestion in the morning before the procedure seems useful for the improvement of mucosa visualization. Lavage after swallowing of the capsule seems to improve image quality, and in some studies also diagnostic yield. Prokinetics has been used with first generation capsules to shorten gastric transit time and increase the rate of complete small bowel visualization. With the massively prolonged battery capacity of the new generation small bowel capsules, prokinetics are only necessary in significantly delayed gastric emptying as documented by a real-time viewer. Lavage is crucial for an effective colon capsule or pan-intestinal capsule endoscopy. Mainly high or low volume polyethylene glycol (PEG) is used. Apart from achieving optimal cleanliness, propulsion of the capsule by ingested boosts is required to obtain a complete passage through the colon within the battery lifetime. Boosts with low volume sodium picosulfate (NaP) or diatrizoate (gastrografin) seem most effective, but potentially have more side effects than PEG. Future research is needed for more patient friendly but effective preparations, especially for colon capsule and pan-intestinal capsule endoscopy.

Background.Currently, scleroderma is a rather rare disease, including among children. Despite the growing interest of investigators in this pathology, the problem of diagnosing oesophageal affection in various forms of systemic sclerosis remains under-investigated since endoscopic data does not provide a complete picture of the oesophageal function. Currently, mano-impedancemetry (MIP) is the leading method in Europe for determining the oesophageal function, including in children with scleroderma; in the Russian Federation, it is used only in adults. Proper and timely evaluation of the oesophageal motility state will allow not only to expand our understanding of the disease pathogenesis but also to determine the efficacy of the initiated therapy and to give practice suggestions in terms of treatment tactics in the early stages of the disease.Our aim wasto determine the possibilities of mano-impedancemetry for diagnosing oesophageal affection in juvenile scleroderma.Patients and Methods.The study included children with juvenile scleroderma taken to the department of rheumatology and dermatology from June to August 2016. To identify oesophageal function disorders, all patients underwent high-resolution manometry in combination with impedancemetry.Results.A decrease in the distal oesophageal contraction amplitude in more than 30% of “wet” swallows was found in 2 of 7 children with juvenile systemic scleroderma and in one of 6 children with juvenile focal scleroderma. All 13 patients had peristaltic waves in the distal oesophagus with an amplitude of Conclusion.Despite the clinical and laboratory methods for diagnosing scleroderma, the data of oesophageal mano-impedancemetry is an important criterion, primarily for the differential diagnosis of systemic and focal scleroderma, and assists in the early initiation of therapy for oesophageal motility disorders.Marina Ju. Stepanyan, Ekaterina I. Alexeeva, Elena V. Komarova confirmed the absence of a reportable conflict of interest.Ekaterina I. Alexeeva — receiving research grants from Pfizer, Roche, Centocor, Novartis.Nikolay N. Murashkin — receiving research funding from pharmaceutical companies Jansen, Eli Lilly. Receiving fees for scientific advice from Galderma, Pierre Fabre, Bayer, Astellas, Libriderm.

Epithelial tissues are the most rapidly dividing tissues in the body, holding a natural ability for renewal and regeneration. This ability is crucial for survival as epithelia are essential to provide the ultimate barrier against the external environment, protecting the underlying tissues. Tissue stem and progenitor cells are responsible for self-renewal and repair during homeostasis and following injury. Upon wounding, epithelial tissues undergo different phases of haemostasis, inflammation, proliferation and remodelling, often resulting in fibrosis and scarring. In this review, we explore the phenotypic differences between the skin, the oesophagus and the oral mucosa. We discuss the plasticity of these epithelial stem cells and contribution of different fibroblast subpopulations for tissue regeneration and wound healing. While these epithelial tissues share global mechanisms of stem cell behaviour for tissue renewal and regeneration, the oral mucosa is known for its outstanding healing potential with minimal scarring. We aim to provide an updated review of recent studies that combined cell therapy with bioengineering exporting the unique scarless properties of the oral mucosa to improve skin and oesophageal wound healing and to reduce fibrotic tissue formation. These advances open new avenues toward the ultimate goal of achieving scarless wound healing.

Aims Extra-atrial injury can cause complications after catheter ablation for atrial fibrillation (AF). Pulsed field ablation (PFA) has generated preclinical data suggesting that it selectively targets the myocardium. We sought to characterize extra-atrial injuries after pulmonary vein isolation (PVI) between PFA and thermal ablation methods. Methods and results Cardiac magnetic resonance (CMR) imaging was performed before, acutely (, Graphical Abstract

Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.

Altres ajuts: These guidelines have been developed and funded within the United European Gastroenterology. Achalasia is a primary motor disorder of the oesophagus characterised by absence of peristalsis and insufficient lower oesophageal sphincter relaxation. With new advances and developments in achalasia management, there is an increasing demand for comprehensive evidence-based guidelines to assist clinicians in achalasia patient care. Guidelines were established by a working group of representatives from United European Gastroenterology, European Society of Neurogastroenterology and Motility, European Society of Gastrointestinal and Abdominal Radiology, and the European Association of Endoscopic Surgery in accordance with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A systematic review of the literature was performed and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Recommendations were voted upon using a nominal group technique. These guidelines focus on the definition of achalasia, treatment aims, diagnostic tests, medical, endoscopic and surgical therapy, management of treatment failure, follow-up and oesophageal cancer risk. These multidisciplinary guidelines provide a comprehensive evidence-based framework with recommendations on the diagnosis, treatment and follow-up of adult achalasia patients.

Simple Summary Transcription factor NRF2 controls expression of antioxidant and detoxification genes. Normally, the activity of NRF2 is tightly controlled in the cell, and is continuously adjusted to ensure that cells are protected against endogenous chemicals and environmental agents that perturb the intracellular antioxidant/pro-oxidant balance (i.e., redox) that must be maintained for them to grow and survive in an appropriate manner. This tight control of NRF2 is achieved by a repressor protein called KEAP1 that perpetually targets NRF2 protein for degradation under normal conditions, but is unable to do so when challenged with oxidants or thiol-reactive chemicals. In the context of cancer, it is well known that drugs that stimulate short-term and reversible activation of NRF2 can provide protection for a limited period against exposure to chemicals that cause cancer. However, it is also becoming widely recognised that permanent hyper-activation of NRF2 resulting from somatic mutations in the gene that encodes NRF2, or in genes associated with its degradation, is frequently observed in certain cancers and associated with poor outcome. In this article, we provide a critical overview of the literature describing the seemingly ambiguous contributions that NRF2 makes to the development of cancer. In particular, we describe the range of genetic and other mechanisms that are responsible for the upregulation of NRF2 in tumours, and highlight shortcomings in our knowledge of how frequently this occurs in different types of cancer. Moreover, we discuss how upregulation of NRF2 might aid the growth and survival of tumours, whether NRF2 upregulation in particular types of cancer is associated with mutations in specific oncogenes, and at what stage of cancer development this is likely to occur. Lastly, we discuss therapeutic strategies that have been proposed that selectively target tumours in which NRF2 is permanently activated with a view to overcoming NRF2-associated drug resistance. Abstract NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.

Many patients with hiatal hernias (HH) are asymptomatic; however, symptoms may include heartburn, regurgitation, dysphagia, nausea, or vague epigastric pain depending on the hernia type and severity. The ideal technique and timing of repair remains controversial. This report describes short-term outcomes and readmissions of patients undergoing HH repair at our institution. All patients who underwent HH repair from January 2012 through April 2017 were reviewed. Patients undergoing concomitant bariatric surgery were excluded. 239 patients were identified and 128 were included. Eighty-eight were female (69%) and 40 were male (31%) with a mean age of 59 years (range 20–91 years) and a mean BMI of 29.2 kg/m2 (17–42). Worsening GERD was the most common presenting symptom in 79 (61.7%) patients. Eighty-four laparoscopic cases (65.6%) and 44 robotic assisted (34.4%) procedures were performed. Mesh was used in 59 operations (3 polytetrafluoroethylene; 56 biologic). All hiatal hernia types (I-IV) were collected. Majority were initial operations (89%). Techniques included: Toupet fundoplication in 68 cases (63.0%), Nissen fundoplication in 36 (33.3%), Dor fundoplication in 4 (3.7%), concomitant Collis gastroplasty in 4 (3.1%), and primary suture repair in 20 (15.6%). Outcomes between robotic and laparoscopic procedures were compared. Length of stay was reported as median and interquartile range for laparoscopic and robotic: 1.0 day (1.0–3.0) and 2.0 days (1.0–2.5); p = 0.483. Thirty-day readmission occurred in 9 patients, 7 (8.3%) laparoscopic and 2 (4.6%) robotic; p = 0.718. Two 30-day reoperations occurred, both laparoscopic; p = 0.545. Total of 16 complications occurred; 18.6% had a complication with the use of mesh compared to 8.7% without the use of mesh, p = 0.063. There were no conversion to open modality and no mortalities were reported. Hiatal hernia repair can be performed safely with a low incidence of complications.

ObjectiveBarrett’s oesophagus (BE) is a known precursor to oesophageal adenocarcinoma (OAC) but current clinical data have not been consolidated to address whether BE is the origin of all incident OAC, which would reinforce evidence for BE screening efforts. We aimed to answer whether all expected prevalent BE, diagnosed and undiagnosed, could account for all incident OACs in the US cancer registry data.DesignWe used a multiscale computational model of OAC that includes the evolutionary process from normal oesophagus through BE in individuals from the US population. The model was previously calibrated to fit Surveillance, Epidemiology and End Results cancer incidence curves. Here, we also utilised age-specific and sex-specific US census data for numbers at-risk. The primary outcome for model validation was the expected number of OAC cases for a given calendar year. Secondary outcomes included the comparisons of resulting model-predicted prevalence of BE and BE-to-OAC progression to the observed prevalence and progression rates.ResultsThe model estimated the total number of OAC cases from BE in 2010 was 9970 (95% CI: 9140 to 11 980), which recapitulates nearly all OAC cases from population data. The model simultaneously predicted 8%–9% BE prevalence in high-risk males age 45–55, and 0.1%–0.2% non-dysplastic BE-to-OAC annual progression in males, consistent with clinical studies.ConclusionThere are likely few additional OAC cases arising in the US population outside those expected from individuals with BE. Effective screening of high-risk patients could capture the majority of population destined for OAC progression and potentially decrease mortality through early detection and curative removal of small (pre)cancers during surveillance.

Background Neoadjuvant therapy plus oesophagectomy has been accepted as the standard treatment for patients with potentially curable locally advanced oesophageal cancer. No completed randomized controlled trial (RCT) has directly compared neoadjuvant chemotherapy and neoadjuvant chemoradiation in patients with oesophageal squamous cell carcinoma (ESCC). The aim of the current RCT is to investigate the impact of neoadjuvant chemotherapy plus surgery and neoadjuvant chemoradiotherapy plus surgery on overall survival for patients with resectable locally advanced ESCC. Methods This open label, single-centre, phase III RCT randomized patients (cT2-T4aN + M0 and cT3-4aN0M0) in a 1:1 fashion to receive either the CROSS regimen (paclitaxel 50 mg/m2; carboplatin (area under the curve = 2), q1w, 5 cycles; and concurrent radiotherapy, 41.4 Gy/23 F, over 5 weeks) or neoadjuvant chemotherapy (paclitaxel 175 mg/m2; and cisplatin 75 mg/m2, q21d, 2 cycles). Assuming a 12% 5-year overall survival difference in favour of the CROSS regimen, 80% power with a two-sided alpha level of 0.05 and a 5% dropout each year for an estimated 3 years enrolment, the power calculation requires 456 patients to be recruited (228 in each group). The primary endpoint is 5-year overall survival, with a minimum 5-year follow-up. The secondary endpoints include 5-year disease-free survival, toxicity, pathological complete response rate, postoperative complications, postoperative mortality and quality of life. A biobank of pre-treatment and resected tumour tissue will be built for translational research in the future. Discussion This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies. Trial registration NCT04138212, date of registration: October 24, 2019.

Contains fulltext : 220129pub.pdf (Publisher’s version ) (Open Access) BACKGROUND: Despite modern imaging modalities, staging of clinically staged T2N0M0 (cT2N0M0) oesophageal cancer is suboptimal, often leading to overtreatment. Endoscopic resection - the first-line therapy for early localised tumours - could be used to improve staging and to attain predictors of nodal upstaging enabling more stage-guided treatment decisions. OBJECTIVE: A systematic literature review and a meta-analysis were conducted to assess the prevalence and the pathological risk factors of lymph node metastases in cT2N0M0 oesophageal cancer. METHODS: Databases of PUBMED, EMBASE and Cochrane were searched for literature. The primary outcome was lymph node metastases determined after primary surgical resection. RESULTS: Nine studies with a total of 1650 cT2N0M0 patients were included. The prevalence of lymph node metastases was 43% (95% confidence interval: 35-50%) with heterogeneity being high across studies (I(2) = 0.86, p

Introduction Achalasia is a primary motor disorder of the oesophagus characterised by absence of peristalsis and insufficient lower oesophageal sphincter relaxation. With new advances and developments in achalasia management, there is an increasing demand for comprehensive evidence-based guidelines to assist clinicians in achalasia patient care. Methods Guidelines were established by a working group of representatives from United European Gastroenterology, European Society of Neurogastroenterology and Motility, European Society of Gastrointestinal and Abdominal Radiology, and the European Association of Endoscopic Surgery in accordance with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A systematic review of the literature was performed and the certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Recommendations were voted upon using a nominal group technique. Results These guidelines focus on the definition of achalasia, treatment aims, diagnostic tests, medical, endoscopic and surgical therapy, management of treatment failure, follow-up and oesophageal cancer risk. Conclusion These multidisciplinary guidelines provide a comprehensive evidence-based framework with recommendations on the diagnosis, treatment and follow-up of adult achalasia patients.

The use of biologics targeted to the human epidermal growth factor receptor 2 (HER2) protein is the latest addition to the armamentarium used to fight advanced gastric or gastro-oesophageal junction adenocarcinoma. The decision to treat with the biologic trastuzumab is completely dependent on HER2 testing of tumour tissue. In 2017, the College of American Pathologists, American Society for Clinical Pathology and the American Society of Clinical Oncology jointly published guidelines for HER2 testing and clinical decision making in gastro-oesophageal adenocarcinoma. The Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee has issued the following document as a commentary of these guidelines and, in parallel, to provide guidance on HER2 testing in National Health Service pathology departments within the UK. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such HER2 testing.

Objectives: This study aimed to find the optimal radiotherapy VMAT plans, that achieved high conformity and homogeneity to the planned target volume (PTV), and minimize the dose to nearby organs at risk including the non-PTV lung, heart and oesophagus for patients with centrally located non-small Cell Lung Cancer. Methods: A total of 18 patients who were treated for stage III centrally located non-small Cell Lung Cancer were selected retrospectively for this study. Identical CT datasets, 4D CT and structure dataset were used for radiotherapy planning based on single-planar VMAT (SP-VMAT), dual-planar VMAT (DP-VMAT) and Hybrid VMAT (H-VMAT). For SP-VMAT, one full arc and two half arcs were created on single-plane with couch at 0°. For DP-VMAT, one full arc was created with couch at 0°, and two half arcs with couch rotation of 330° or 30°. For H-VMAT, anterior-posterior opposing fixed beam and two half arcs were planned at couch at 0°. Dose constraints were adhered to the RTOG0617. Dose volumetric parameters were collected for statistical analysis. Results: There were no significant differences for the PTV, HI, CI between the SP-VMAT, DP-VMAT and H-VMAT. For the non-PTV lungs, Dmean, V20, V10, V5, D1500 and D1000 were significantly lower (2.05 Gy, 6.47%, 15.89%, 11.66% 4.17 Gy and 5.47 Gy respectively) in H-VMAT than that of SP-VMAT (all p < 0.001). For the oesophagus, Dmax, Dmean, V30 and V18.8 of H-VMAT were 0.08 Gy, 1.73 Gy, 5.54% and 7.17% lower than that of the SP-VMAT plan. For the heart, Dmean, V34, V28, V20 and V10 of DP-VMAT were lower than that of SP-VMAT by 1.45 Gy, 0.65%, 1.74%, 4.8% and 7.11% respectively. Conclusion: The proposed H-VMAT showed more favourable plan quality than the SP-VMAT for centrally located stage III NSCLC, in particular for non-PTV lungs and the oesophagus. It will benefit patients, especially those who planned for immunotherapy (Durvalumab) after standard chemo-irradiation. The proposed DP-VMAT plan showed significant dose reduction to the heart when compared to the H-VMAT plan.

A 57-year-old Hispanic man with diabetes presented with dyspnoea. He had a positive SARS-CoV-2 PCR. He was intubated for severe hypoxia and treated with intermittent pressors, methylprednisolone and supportive care. He was extubated on hospital day (HD) 9 and discharged to a skilled nursing facility (SNF) on HD 18. Approximately 1 month later, he presented with melena. Endoscopy revealed two large 1.5–2 cm wide-based distal oesophageal ulcers without active bleeding. Histology showed ulcerated squamous mucosa with extensive necrosis extending to the muscularis propria and coccoid bacterial colonies with rare fungal forms suggestive of Candida. He was treated with fluconazole and pantoprazole and was discharged to a SNF. Approximately 3 weeks later, he was readmitted for complications. Repeat endoscopy demonstrated improvement and histology revealed chronic inflammation with reactive epithelial changes. Incidentally, SARS-CoV-2 PCR was positive during this visit without any respiratory symptoms.

Dysphagia is a common symptom that is important to recognise and appropriately manage, given that causes include life threatening oesophageal neoplasia, oropharyngeal dysfunction, the risk of aspiration, as well as chronic disabling gastroesophageal reflux (GORD). The predominant causes of dysphagia varies between cohorts depending on the interplay between genetic predisposition and environmental risk factors, and is changing with time. Currently in white Caucasian societies adopting a western lifestyle, obesity is common and thus associated gastroesophageal reflux disease is increasingly diagnosed. Similarly, food allergies are increasing in the west, and eosinophilic oesophagitis is increasingly found as a cause. Other regions where cigarette smoking is still prevalent, or where access to medical care and antisecretory agents such as proton pump inhibitors are less available, benign oesophageal peptic strictures, Barrett’s oesophagus, adeno- as well as squamous cell carcinoma are endemic. The evaluation should consider the severity of symptoms, as well as the pre-test probability of a given condition. In young white Caucasian males who are atopic or describe heartburn, eosinophilic esophagitis and gastroesophageal reflux disease will predominate and a proton pump inhibitor could be commenced prior to further investigation. Upper gastrointestinal endoscopy remains a valid first line investigation for patients with suspected oesophageal dysphagia. Barium swallow is particularly useful for oropharyngeal dysphagia, and oesophageal manometry mandatory to diagnose motility disorders.

Background: Denture restores aesthesis and function of missing teeth. Accidentally swallowed denture is an otorhinolaryngology emergency. The types of denture base and oesophageal anatomy infuluence the site of impaction. Objective: To review site of denture impaction and factors associated with site of impaction. To correlate site and duration of denture impaction before removal with associated sequelae. Method: A retrospective study of 27 patients managed in Otorhinolaryngology Department of University College Hospital Ibadan, Nigeria for oesophageal partial denture impaction, between August 2006 and September 2016. The demographic and clinical data of the patients were extracted from the hospital records, and statistical tables were used to illustrate the data. Results: A total of 27 patients; 14(51.9%) males and 13(48.1%) females, (M: F, 1.1:1) were studied. The age ranged from 24 to 77 years (mean age 49.0 ± 14.2years). Dentures were worn for 3 to 30 years (mean 3.8 ± 2.3years) without follow-up visit to dentist and 85.2% were upper dentures. All patients had history of accidental ingestion of denture, and the mean site of impaction was 18.2 ± 3.2cm from upper incisor, typically at upper cervical oesophagus in elderly patients and in lower oesophagus in females. There was no association between site of denture impaction, duration of denture impaction and operative findings. Conclusion: Advanced age and female gender are associated with site of denture impaction. Late hospital presentation significantly promotes sequelae associated with management of impacted dentures. It is recommended that fundamental changes in denture designs, education on regular follow-ups and avoidance of ill-fitting dentures would reduce the prevalence of denture impaction.

Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In the normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behaviour. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental dataset showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.

Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behaviour. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental data set showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.

ObjectiveTo establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO).DesignIn this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs).ResultsIn the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI –3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI –1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI –4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI –5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI –8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI –9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively.ConclusionOur findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms.Trial registration numberNCT02388724.

Abstract The foundations of ancient rational medicine were laid by Hippocrates, but the credit for rethinking medicine as a comprehensive system of protoscientific knowledge belongs to Galen. Before him, medicine had no unified system of thought on the basic principles of the structure of living things, and no systemic approach to clinical practice, based on the apodictic method. In this article, I examine Galen's teachings on the digestive system (one of the key aspects of his system) in terms of the "commensurability" of the ideas of ancient medicine and modern science. An analysis of the information in Galen's works indicates that his system of theory and practice is substantially commensurable with the principles of modern medicine: many aspects of modern theory and practice represent a development of Galen's ideas. A comparative analysis of Galen's reconstructed views and those found in modern medicine calls for the use of tools from philosophy and the history of science to enable a correct interpretation of the historical medical texts. Such fundamental concepts include "type of rationality" and "scientific worldview". This research is based on extant texts by Galen, primarily his two treatises On the Natural Faculties and On the Usefulness of the Parts of the Body, which may be regarded as fundamental to reconstructing Galen's views on physiology and anatomy. Galen constructs a comprehensive system rather than simply listing individual facts he knows. The treatises in question underline the comprehensive and systemic nature of the great Roman physician's arguments, which were to a large extent supported by experiment.

INTRODUCTION Oesophageal Cancer is usually associated with late presentation and poor prognosis. Unfortunately, advanced disease at presentation is seen in around 70% oesophageal cancer patients with limited curative option. The main objective of treatment remains palliation. Different treatment modalities were tried in locally advanced oesophageal cancer, but the median survival remains less than 10 months. [1-3] A combination of these modalities in advanced cases has marginally improved the results. Radiotherapy can be external beam (EBRT) alone, intraluminal brachytherapy (ILBT) alone or combination of both and nowadays IMRT/IGRT with different fractionation schedules have some promising results and needs further exploration through large clinical studies. MATERIAL AND METHODS We evaluated the efficacy and safety of EBRT followed by ILBT in locally advanced unresectable cases of carcinoma oesophagus and compared it with EBRT alone arm with boost. All the patients were administered three cycles of three weekly neoadjuvant chemotherapy (NACT) with TPF and further received a total target radiation absorbed dose of 40 Gy/20 fractions/4 weeks. All patients were divided in two arms of 30- each. In arm-1, patients received 3 sessions of ILBT boost of 5 Gy each, a week apart. In this arm, ILBT boost was given using state of the art MicroSelectron HDR brachytherapy machine with Iridium192 source. In arm-2, patients received EBRT boost of 20 Gy/10 fractions (Cobalt-60 Teletherapy machine) by three field isocentric technique using Simulix HP Simulator. After completion of treatment, response was evaluated every month, in terms of local control, symptomatic relief like dysphagia, odynophagia, etc. All the patients were followed up regularly for five years. RESULTS Complete response at completion of treatment was 37% vs. 23% in arm-1 & arm-2 respectively although the results were statistically insignificant. There was marked difference in relief of dysphagia and odynophagia at the end of 1-year of completion of treatment and its proving the fact that brachytherapy has been widely performed for the palliation of dysphagia. At 5-year follow-up, 6-patients (20%) were having no evidence of disease (NED) in arm-1 while only 2-patients (6%) were disease-free in arm-2. CONCLUSION The overall prognosis in patients with locally advanced oesophageal cancer is generally very poor, with a mean survival of 2- 10 months. HDR brachytherapy was found to contribute good palliation in a significant number of patients with inoperable oesophageal cancer. In some patients, total remission was achieved lasting more than six months.

Oesophageal malignancies are not an uncommon disease entity in this part of India. It is observed in both the sexes. Patients present with progressive dysphagia for solids. The duration of symptoms varies from 6 months to 2 years. Among the various aetiological factors, smoking, alcohol intake, spicy hot food intake, industrial pollution and achalasia cardia are a few worth mentioning. AIM OF THE STUDY To evaluate the differences in the predisposing factors causing squamous cell carcinoma and adenocarcinoma of oesophagus in this part of India. MATERIALS AND METHODS The study is conducted in the Department of Surgery at Government Medical College Hospital, Kozhikode; Kerala. One hundred patients attending the Department with history of Dysphagia were included after thorough history taking, clinical and endoscopic examination and found to have malignant growths in the oesophagus which was confirmed by biopsy and histopathological examination. Various aetiological factors were elicited and analysed in both the histological varieties of malignancy of oesophagus. OBSERVATIONS AND RESULTS Significant number of patients with history of paan chewing presented with histological picture of squamous cell carcinoma as compared to patients who had adenocarcinoma. Gastroesophageal reflux disease was more commonly associated with adenocarcinoma. Out of 37 patients with adenocarcinoma, 31 patients had history of gastroesophageal reflux disease (83.8%). 6 patients had no history of gastroesophageal reflux disease (16.2%) within histology. Consumption of hot drinks, tea and coffee more than 10 per day has been analysed. 52 were consuming, 48 were not consuming, P value 0.179 non-significant. CONCLUSIONS Squamous cell carcinoma is more prevalent as compared to adenocarcinoma in present study. The main factor that has emerged is lifestyle, dietary habit, smoking and alcohol, and environmental factor. Consumption of alcohol and smoking is known risk factors in carcinoma oesophagus, but present study shows no significance as more number of females are present in this study. Females rarely consume alcohol in this part of the country, but among alcoholics/smokers, majority have squamous cell carcinoma which is significant. Habit of paan chewing is more common among females.

Klagt ein Patient uber Schluckbeschwerden ist die Ursache zwar haufig, aber nicht immer im Osophagus oder dessen nervaler Steuerung zu finden. Auch extraosophageale Storungen sind zu bedenken. Die Kenntnis pragnanter Symptome hilft, den Blick auf diese Ursachen zu lenken, und die falligen Untersuchungen sind weder belastend noch aufwendig.

ObjectiveTo clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC.DesignA systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model.ResultsSixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, I2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias (HR 2.11, 95% CI 1.35 to 3.31, I2=0%).ConclusionsPatients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage.

Here we describe an atypical presentation of progressive dysphagia in a 72-year-old man leading to frequent regurgitations over the course of 30 years. Investigations revealed a foreign body ring surrounding the proximal stomach and dilation of the oesophagus proximal to the gastro-oesophageal junction. An Angelchik device was extracted; however, the patient’s rapid deterioration prior to surgery, in addition to his severely dysfunctional oesophagus, required placement of a jejunostomy feeding tube. Device removal was complicated by prior abdominal surgery, necessitating a thoracic approach. This case offers guidance on the management of patients with Angelchik prostheses who develop similar complications, while drawing attention to the importance and difficulties of early, definitive diagnosis in oesophageal pathology such as achalasia and gastro-oesophageal reflux disease.

One of the major upper gastrointestinal (UGI) complications that affect approximately 1 in 10 Australians is gastro-oesophageal reflux disease (GORD). GORD is when stomach acid frequently passes back up into the oesophagus and damages the oesophageal wall. Research has shown that frequent exposure of acid can increase the risk of adenocarcinoma in the oesophagus, where in Western populations the incidence is increasing. The survival rate for patients with oesophageal adenocarcinoma is low. This thesis proposed to develop a device with the potential to treat GORD and in turn reduce the risk of adenocarcinoma formation. The proposed device is made up of two main components, an anti-reflux valve and a novel device attachment system that uses LED light activation to adhere to tissue. Various tests were conducted such as tensile test, SEM imaging, pressure tests and cell cultures. These tests were performed to determine the device’s potential. The results showed that after 10 minutes of LED light activation the adhesive lap shear strength on porcine tissue was 7.50 kPa. The device showed it could support cell attachment and proliferation. Various valve designs were investigated, with the best valve able to prevent pressure up to 6 kPa, close to the natural pressure exerted by the lower oesophageal sphincter. Deployment of the device in porcine oesophagus using a standard medical endoscope was promising, but further optimisation is required. The significance of this research showed that a light activated adhesive system was possible using standard LED lighting, achieving strengths superior to fibrin glue while being safe and capable of tissue integration. The other key outcome was silicone anti-reflux valves were made from 3D-printed moulds capable of replicating the resistance of natural oesophagus. The final device shows promise and with future development could become a new treatment option for long-term sufferers of GORD. One of the major upper gastrointestinal (UGI) complications that affect approximately 1 in 10 Australians is gastro-oesophageal reflux disease (GORD). GORD is when stomach acid frequently passes back up into the oesophagus and damages the oesophageal wall. Research has shown that frequent exposure of acid can increase the risk of adenocarcinoma in the oesophagus, where in Western populations the incidence is increasing. The survival rate for patients with oesophageal adenocarcinoma is low. This thesis proposed to develop a device with the potential to treat GORD and in turn reduce the risk of adenocarcinoma formation. The proposed device is made up of two main components, an anti-reflux valve and a novel device attachment system that uses LED light activation to adhere to tissue. Various tests were conducted such as tensile test, SEM imaging, pressure tests and cell cultures. These tests were performed to determine the device’s potential. The results showed that after 10 minutes of LED light activation the adhesive lap shear strength on porcine tissue was 7.50 kPa. The device showed it could support cell attachment and proliferation. Various valve designs were investigated, with the best valve able to prevent pressure up to 6 kPa, close to the natural pressure exerted bOne of the major upper gastrointestinal (UGI) complications that affect approximately 1 in 10 Australians is gastro-oesophageal reflux disease (GORD). GORD is when stomach acid frequently passes back up into the oesophagus and damages the oesophageal wall. Research has shown that frequent exposure of acid can increase the risk of adenocarcinoma in the oesophagus, where in Western populations the incidence is increasing. The survival rate for patients with oesophageal adenocarcinoma is low. This thesis proposed to develop a device with the potential to treat GORD and in turn reduce the risk of adenocarcinoma formation. The proposed device is made up of two main components, an anti-reflux valve and a novel device attachment system that uses LED light activation to adhere to tissue. Various tests were conducted such as tensile test, SEM imaging, pressure tests and cell cultures. These tests were performed to determine the device’s potential. The results showed that after 10 minutes of LED light activation the adhesive lap shear strength on porcine tissue was 7.50 kPa. The device showed it could support cell attachment and proliferation. Various valve designs were investigated, with the best valve able to prevent pressure up to 6 kPa, close to the natural pressure exerted by the lower oesophageal sphincter. Deployment of the device in porcine oesophagus using a standard medical endoscope was promising, but further optimisation is required. The significance of this research showed that a light activated adhesive system was possible using standard LED lighting, achieving strengths superior to fibrin glue while being safe and capable of tissue integration. The other key outcome was silicone anti-reflux valves were made from 3D-printed moulds capable of replicating the resistance of natural oesophagus. The final device shows promise and with future development could become a new treatment option for long-term sufferers of GORD. y the lower oesophageal sphincter. Deployment of the device in porcine oesophagus using a standard medical endoscope was promising, but further optimisation is required. The significance of this research showed that a light activated adhesive system was possible using standard LED lighting, achieving strengths superior to fibrin glue while being safe and capable of tissue integration. The other key outcome was silicone anti-reflux valves were made from 3D-printed moulds capable of replicating the resistance of natural oesophagus. The final device shows promise and with future development could become a new treatment option for long-term sufferers of GORD.

AIM To test the feasibility and performance of a novel upper gastrointestinal (GI) capsule endoscope using a nurse-led protocol. METHODS We conducted a prospective cohort analysis of patients who declined gastroscopy (oesophagogastroduodenoscopy, OGD) but who consented to upper GI capsule endoscopy. Patients swallowed the upper GI capsule following ingestion of 1 liter of water (containing simethicone). A series of positional changes were used to exploit the effects of water flow and move the upper GI capsule from one gravity-dependent area to another using a nurse-led protocol. Capsule transit time, video reading time, mucosal visualisation, pathology detection and patient tolerance was evaluated. RESULTS Fifty patients were included in the study. The mean capsule transit times in the oesophagus and stomach were 28 s and 68 min respectively. Visualisation of the following major anatomical landmarks was achieved (graded 1-5: Poor to excellent): Oesophagus, 4.8 (± 0.5); gastro-oesophageal junction (GOJ), 4.8 (± 0.8); cardia, 4.8 (± 0.8); fundus, 3.8 (± 1.2); body, 4.5 (± 1); antrum, 4.5 (± 1); pylorus, 4.7 (± 0.8); duodenal bulb, 4.7 (± 0.7); second part of the duodenum (D2), 4.7 (± 1). The upper GI capsule reached D2 in 64% of patients. The mean video reading time was 48 min with standard playback mode and 20 min using Quickview (P = 0.0001). No pathology was missed using Quickview. Procedural tolerance was excellent. No complications were seen with the upper GI capsule. CONCLUSION The upper GI capsule achieved excellent views of the upper GI tract. Future studies should compare the diagnostic accuracy between upper GI capsule and OGD.

The work presented in this thesis concerns novel diagnostic and therapeutic strategies in the management of dysphagia disorders associated with reduced upper (UOS) or lower (LOS) oesophageal sphincter distensibility caused by two different pathophysiological processes. Dysphagia due to pharyngo-oesophageal junction (POJ) stricture at the level of UOS is a common long-term complication following treatment for head and neck cancer (HNC). High-level evidence is lacking in both the diagnosis and treatment of this iatrogenic problem. The aims of this thesis were as follows. 1) To evaluate, by a RCT, the efficacy and durability of endoscopic dilatation of the POJ in the treatment of HNC therapies-related dysphagia. 2) To validate functional lumen imaging probe (FLIP), an impedance planimetry based technique in detection of POJ stricture. 3) To evaluate a novel dilatation technique for treatment of POJ stricture in laryngectomees utilising a prototype computer-controlled syringe drive, Fox Tissue Modification Device (FTMD). A non-compliant LOS is also implicated in the pathophysiology of idiopathic oesophageal achalasia but for different reasons. In contrast to the HNC population above, the LOS in achalasia has impaired compliance, not due to fibrosis, rather due to an inhibitory neuropathy. Quantifiable gastro-oesophageal junction (GOJ) distensibility measurement has a logical potential in the management of this disorder. We evaluated the utility of FLIP-measured intra-procedural GOJ distensibility in the management of patients undergoing pneumatic dilatation (PD) for achalasia. The main findings from this work are as follows. 1) Endoscopic dilatation is a safe and effective treatment for HNC therapies-related pharyngeal dysphagia. However, novel strategies are needed to address the high dysphagia relapse rate. 2) FLIP-measured POJ distensibility is an accurate technique for the detection of POJ strictures and it may complement conventional tools in the evaluation of dysphagia. 3) We confirmed the feasibility of POJ stricture dilatation using the FTMD. The preliminary safety and efficacy results are encouraging albeit more data is required before a definitive conclusion can be made. 4) We derived a novel intra-procedural GOJ distensibility index that accurately predicts immediate clinical response to PD in achalasia. This technique provides clinicians with real-time objective outcome data that could inform management decisions.

La microestructura del esofago y el estomago del alcaudon gris fueron examinados mediante microscopia de luz. Los resultados mostraron que las glandulas del esofago eran glandulas mucosas, y que las celulas glandulares de descamacion y la mucina de las glandulas del esofago eran secretadas al lumen. El numero de glandulas en la porcion toracica del esofago fue menor que en la porcion cervical. Las aberturas de las glandulas mostraron una reaccion positiva intensa al PAS y azul de Alcian. Se encontraron dos tipos de glandulas en la lamina propia. Las glandulas tubulares simples se localizaron en la lamina superficial de la lamina propia, mientras que las glandulas tubulares compuestas se hallaron en la lamina de profundidad. El epitelio se encontro revestido por una capa cuticular en la zona intermedia entre el proventriculo y la molleja. La superficie de la molleja presento una cuticula gruesa, demostrada por una matriz horizontal positivo para azul de Alcian y varillas verticales positivas para el PAS.

Highlights • We present a case of oesophageal gastrointestinal stromal tumour (GIST). • GISTs in the oesophagus are rare (5%) and their management is surrounded by debate. • Surgical therapy should aim for complete resection. • Preoperative biopsies are best to be avoided as they might propagate seeding., Introduction Gastrointestinal stromal tumours (GIST) account for only one percent of all gastrointestinal malignancies. Presentation of case A 53 year old lady presented to the gastroenterology clinic with iron deficiency anaemia. Oesophagogastroduodenoscopy (OGD) and computed tomography (CT) demonstrated a non-obstructing 7 cm submucosal oesophageal lesion. An oesophagectomy was performed and subsequent histology sections showed a well-circumscribed spindle cell tumour without any cellular atypia. Immunohistochemistry on the tumour was negative for S100 and positive for smooth muscle actin and desmin. C-kit (CD117) showed focal positivity in some of the tumour cells and the overall features were of a gastro-intestinal stromal tumour (GIST). The patient has been fully compliant with the follow-up arrangements and is disease-free six years after her original operation. Discussion GISTs are mesenchymal tumours of the gastrointestinal (GI) tract that express the KIT protein. The incidence rate for GIST is 15 cases to one million in the USA. GISTs in the oesophagus are rare (5%) and their management is surrounded by some debate. Once the diagnosis has been secured the patient should be evaluated for suitability for surgical resection. Optimal surgical therapy should aim to achieve complete resection, if possible, without injury to the pseudocapsule surrounding the tumour. Meticulous atraumatic surgical technique is necessary and preoperative biopsies are best to be avoided as they might propagate seeding. Conclusions Oesophagectomy with clear resection margins should be the preferred method for surgical treatment combined with the use of novel TKI strategies.

Highlights • Basaloid squamous cell carcinoma of the oesophagus (BSCCE) is a rare entity. • A recurrent lesion was observed after resection of the pulmonary BSCCE metastasis. • Pulmonary metastasis of BSCCE after lung metastasectomy was treated successfully with chemoradiotherapy., Introduction Basaloid squamous cell carcinoma of the oesophagus (BSCCE) is a relatively rare variant of oesophageal malignancy. There are no established treatment strategies for pulmonary metastases of BSCCE. Presentation of case A 72-year-old man underwent oesophagectomy and subsequently received a pathological diagnosis of stage IIIA (T3N1M0) BSCCE according to Union for International Cancer Control. One year and 5 months later, he underwent partial resection of the right lung because of metastasis of the BSCCE. One year and 6 months after the pulmonary resection, recurrence in the right lung was observed. The patient was treated with concurrent chemoradiotherapy using cisplatin and 5-fluorouracil, and the lesion completely disappeared. The patient is doing well without recurrence 5 years after chemoradiotherapy. Discussion In our case, the recurrent lesion in the right lung was observed after the pulmonary resection. It is difficult to determine whether the recurrent lesion is solitary or multiple and whether it is a local or pleural metastasis. Therefore, surgical indication must be decided carefully. Systemic chemotherapy or radiotherapy is useful to treat BSCCE metastasis, however, appropriate, but which agents and their regimens are appropriate is not clear. Concurrent chemotherapy using cisplatin and 5-fluorouracil and radiotherapy for pulmonary BSCCE metastases may provide curative therapy and should be considered. Conclusion This report describes a case of recurrent pulmonary metastasis after pulmonary resection of BSCCE metastasis, successfully treated by concurrent chemotherapy and radiotherapy. Further studies are required to establish the indications and efficacy of these therapeutic approaches.

Introduction Knowledge about oesophageal carcinoids is based primarily on case reports, and therefore information about them is incomplete. Aim To collect information on oesophageal carcinoid tumours in a systematic review study. Material and methods Databases including PubMed, Scopus, and Web of Science were searched for the characteristics of oesophageal carcinoid tumour. Studies included original articles, case series, or case reports, reporting at least one of the characteristics of benign carcinoid tumour or carcinoid tumour. Results Out of 670 studies searched, after evaluation and excluding non-relevant studies, 14 studies were included and analysed in the systematic review. These studies included 19 patients with carcinoid tumour of whom 57.9% were males with a mean age of 55.5 years. Dysphagia and weight loss were the most prevalent symptoms and signs in the patients. Lower oesophagus was the most prevalent site of tumour. Conclusions This meta-analysis showed that the mean age at diagnosis of oesophageal carcinoid was around 55 years, with 1.4 times greater prevalence among males, and located mainly in the distal oesophagus. The mean tumour size was 2.4 cm. The main symptoms and signs of this disease were dysphagia, weight loss, and reflux. The tumour behaviour was mainly non-aggressive except for cases associated with adenocarcinoma.

Ethanol is neither genotoxic nor mutagenic. Its first metabolite acetaldehyde, however, is a powerful local carcinogen. Point mutation in ALDH2 gene proves the causal relationship between acetaldehyde and upper digestive tract cancer in humans. Salivary acetaldehyde concentration and exposure time are the two major and quantifiable factors regulating the degree of local acetaldehyde exposure in the ideal target organ, oropharynx. Instant microbial acetaldehyde formation from alcohol represents >70% of total ethanol associated acetaldehyde exposure in the mouth. In the oropharynx and achlorhydric stomach acetaldehyde is not metabolized to safe products, instead in the presence of alcohol it accumulates in saliva and gastric juice in mutagenic concentrations. A common denominator in alcohol, tobacco and food associated upper digestive tract carcinogenesis is acetaldehyde. Epidemiological studies on upper GI tract cancer are biased, since they miss information on acetaldehyde exposure derived from alcohol and acetaldehyde present in 'non-alcoholic' beverages and food. (C) 2017 Published by Elsevier Ltd.

Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members related to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family and are encoded by ten genes in the human. They are secreted at high levels by placental syncytiotrophoblast into maternal blood during pregnancy, and are implicated in immunoregulation, thromboregulation, and angiogenesis. To determine whether PSGs are expressed in tumors, we characterized 16 novel monoclonal antibodies to human PSG1 and used two that do not cross-react with CEACAMs to study PSG expression in tumors and in the gastrointestinal (GI) tract using tissue arrays and immunohistochemistry. Staining was frequently observed in primary squamous cell carcinomas and colonic adenocarcinomas and was correlated with the degree of tumor differentiation, being largely absent from metastatic samples. Staining was also observed in normal oesophageal and colonic epithelium. PSG expression in the human and mouse GI tract was confirmed using quantitative RT-PCR. However, mRNA expression was several orders of magnitude lower in the GI tract compared to placenta. Our results identify a non-placental site of PSG expression in the gut and associated tumors, with implications for determining whether PSGs have a role in tumor progression, and utility as tumor biomarkers.

Objective Barrett’s oesophagus is a premalignant condition that occurs in the context of gastro-oesophageal reflux. However, most Barrett’s cases are undiagnosed because of reliance on endoscopy. We have developed a non-endoscopic tool: the Cytosponge, which when combined with trefoil factor 3 immunohistochemistry, can diagnose Barrett’s oesophagus. We investigated whether a quantitative methylation test that is not reliant on histopathological analysis could be used to diagnose Barrett’s oesophagus. Design Differentially methylated genes between Barrett’s and normal squamous oesophageal biopsies were identified from whole methylome data and confirmed using MethyLight PCR in biopsy samples of squamous oesophagus, gastric cardia and Barrett’s oesophagus. Selected genes were then tested on Cytosponge BEST2 trial samples comprising a pilot cohort (n=20 cases, n=10 controls) and a validation cohort (n=149 cases, n=129 controls). Results Eighteen genes were differentially methylated in patients with Barrett’soesophagus compared with squamous controls. Hypermethylation of TFPI2, TWIST1, ZNF345 and ZNF569 was confirmed in Barrett’s biopsies compared with biopsies from squamous oesophagus and gastric cardia (p