Patient-reported outcomes after oesophagectomy in the multicentre LASER study.

BACKGROUND: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. METHODS: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. RESULTS: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. CONCLUSION: A long-term symptom burden is common after oesophageal cancer surgery.

European guidelines on achalasia: United European Gastroenterology and European Society of Neurogastroenterology and Motility recommendations.

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 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 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.

Incidence and risk factors for esophageal cancer following achalasia treatment: national population-based case-control study.

The objective of this study is to identify the incidence of and risk factors associated with the development of esophageal cancer in treated achalasia patients in a national cohort. Patients with esophageal achalasia diagnosed and receiving a treatment between 2002 and 2012 were identified in England. Patient and treatment factors were compared between individuals who developed esophageal cancer and those that did not using univariate and multivariate analyses. A total of 7487 patients receiving an interventional treatment for esophageal achalasia were included and 101 patients (1.3%) developed esophageal cancer. The incidence of esophageal cancer was 205 cases per 100,000 patient years at risk. Patients who developed esophageal cancer were older and more commonly primarily treated with pneumatic dilation (82.2% vs. 60.3%; P < 0.001). In the esophageal cancer group, there was an increase in the number of patients requiring reinterventions (47.5% vs. 38.0%; P = 0.041) and the average total number of reinterventions per patient (1.2 vs. 0.8; P = 0.026). Multivariate analysis suggested associations between increased reintervention following both surgical myotomy (HR = 5.1; 95%CI 1.12-23.16) and pneumatic dilation (HR = 1.48; 95%CI 0.95-2.29), and esophageal cancer risk. Increasing patient age and reintervention following primary achalasia treatment are important potential risk factors for the development of esophageal cancer. Treated achalasia patients with symptom recurrence should be carefully evaluated for potential development of esophageal cancer prior to considering reintervention, and increased vigilance may help diagnose esophageal cancer in these individuals at an early stage.

The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

The 2018 ISDE achalasia guidelines

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

The influence of hospital volume upon clinical management and outcomes of esophageal achalasia: an English national population-based cohort study.

Management of achalasia is potentially complex. Previous studies have identified equivalence between pneumatic dilatation and surgical cardiomyotomy in terms of clinical outcomes. However, previous research has not investigated whether a management strategies and outcomes are different in high-volume achalasia centers. This national population-based cohort study aimed to identify the treatment modalities utilized in centers, which regularly manage achalasia and those which manage it infrequently. This study also assessed rates of re-intervention and complications to establish if a volume-outcome relationship exists for the management of achalasia in England. In this study, the Hospitals Episode Statistics database was used to identify all patients treated for achalasia in England from 2002 to 2012. Primary treatment was defined as surgical cardiomyotomy, sequential pneumatic dilatation, or botulinum toxin therapy. Primary outcome measure was reintervention. Centers were divided into regular achalasia centers (≥5.7 cases per annum) and infrequent achalasia centers (<5.7 cases per annum), and were analyzed according to tertiary cancer center status. In total, there were 7,487 patients treated for achalasia. Out of 1,947 cases (26%) were treated in regular achalasia centers, with 5,540 (74%) treated in infrequent centers. In binary logistic regression modeling regular centers treated a similar proportion of patients with primary surgical cardiomyotomy (OR: 1.11 (95% CI 0.98-1.27)) and had similar rates of re-intervention to infrequent achalasia centers (HR: 1.03 (0.94-1.12)). RA-CUSUM analysis demonstrated no relationship between total hospital volume and reintervention rates. Tertiary cancer centers treated more achalasia patients with primary surgical cardiomyotomy (OR: 1.51 (95% CI 1.31-1.73)) but there was no significant difference in reintervention rates (OR: 1.05 (95% CI 0.95-1.16)). In conclusion, this analysis failed to demonstrate a volume-outcome relationship in the management of achalasia in England. This study highlights that achalasia is treated infrequently by the majority of centers.

INPP4B overexpression and c-KIT downregulation in human achalasia.

BACKGROUND: Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS: Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS: Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.

Population-based cohort study of surgical myotomy and pneumatic dilatation as primary interventions for oesophageal achalasia.

BACKGROUND: The aim of this national population-based cohort study was to compare rates of reintervention after surgical myotomy versus sequential pneumatic dilatation for the primary management of oesophageal achalasia. METHODS: Patients with oesophageal achalasia diagnosed between 2002 and 2012, and without an intervention in the preceding 5 years were identified from the Hospital Episode Statistics database. Patients were divided into two groups based on the primary treatment, and propensity score matching was used to compensate for differences in baseline characteristics. RESULTS: Some 14 705 patients were diagnosed with oesophageal achalasia, of whom 7487 (50·9 per cent) received interventional treatment: 1742 (23·3 per cent) surgical myotomy, 4534 (60·6 per cent) pneumatic dilatation and 1211 (16·2 per cent) endoscopic botulinum toxin injection. As age increased, the proportion of patients receiving myotomy decreased and the proportion undergoing dilatation increased. Patients who underwent surgical myotomy were younger (mean age 44·8 years versus 58·5 years among those who had pneumatic dilatation; P < 0·001), a greater proportion had a Charlson co-morbidity index score of 0 (90·1 versus 87·7 per cent; P = 0·003) and they were more commonly men (55·6 versus 51·8 per cent; P = 0·020). Following propensity score matching, the safety of the two initial treatment approaches was equivalent, with no difference in incidence of oesophageal perforation (1·3 and 1·4 per cent after myotomy and dilatation respectively; P = 0·750). However, dilatation was associated with increased need for reintervention (59·6 versus 13·8 per cent; P < 0·001) and frequency of reinterventions (mean 0·34 versus 0·06 per year; P < 0·001). CONCLUSION: Surgical myotomy was associated with a lower rate of reintervention and could be offered as primary treatment in patients with oesophageal achalasia who are fit for surgery. For those unfit for surgery, pneumatic dilatation may provide symptomatic relief with approximately 60 per cent of patients requiring reintervention.

Economic evaluation of the randomized European Achalasia trial comparing pneumodilation with Laparoscopic Heller myotomy.

BACKGROUND: A recent multicenter randomized trial in achalasia patients has shown that pneumatic dilation resulted in equivalent relief of symptoms compared to laparoscopic Heller myotomy. Additionally, the cost of each treatment should be also taken in consideration. Therefore, the aim of the present study was to perform an economic analysis of the European achalasia trial. METHODS: Patients with newly diagnosed achalasia were enrolled from to 2003 to 2008 in 14 centers in five European countries and were randomly assigned to either pneumatic dilation (PD) or laparoscopic Heller (LHM). The economic analysis was performed in the three centers in three different countries where most patients were enrolled (Amsterdam [NL], Leuven, [B] and Padova [I]) and then applied to all patients included in the study. The total raw costs of the two treatments per patient include the initial costs, the costs of complications, and the costs of retreatments. RESULTS: Two hundred and one patients, 107 (57 males and 50 females, mean age 46 CI: 43-49 years) were randomized to LHM and 94 (59 males and 34 females, mean age 46 CI 43-50 years) to PD. The total cost of PD per patient was quite comparable in the three different centers; €3397 in Padova, €3259 in Amsterdam and €3792 in Leuven. For LHM, the total costs per patient were highest in Amsterdam: €4488 in Padova, €6720 in Amsterdam, and €5856 in Leuven. CONCLUSION: In conclusion, the strategy of treating achalasia starting with PD appears the most economic approach, independent of the health system.

Peroral endoscopic myotomy for the treatment of esophageal achalasia: systematic review and pooled analysis.

Peroral endoscopic myotomy (POEM) is a novel approach to performing esophageal myotomy for the treatment of achalasia. This review aims to assess subjective and objective metrics of achalasia treatment efficacy, perioperative adverse events and the incidence of postoperative gastroesophageal reflux disease in patients treated with POEM. Secondary aims include a pooled analysis comparison of the clinical outcomes and procedural safety of POEM versus laparoscopic Heller's myotomy (LHM). A systematic review of the literature, up to and including January 15, 2015, was conducted for studies reporting POEM outcomes. Studies comparing POEM to LHM were also included for the purpose of pooled analysis. Outcomes from 1122 POEM patients, from 22 studies, are reported in this systematic review. Minor operative adverse events included capno/pneumo-peritoneum (30.6%), capno/pneumo-thorax (11.0%) and subcutaneous emphysema (31.6%). Major operative adverse events included mediastinal leak (0.3%), postoperative bleeding (1.1%) and a single mortality (0.09%). There was an improvement in lower esophageal sphincter pressure and timed barium esophagram column height of 66% and 80% post-POEM, respectively. Symptom improvement was demonstrated with a pre- and post-POEM Eckardt score ± standard deviation of 6.8 ± 1.0 and 1.2 ± 0.6, respectively. Pre- and post-POEM endoscopy showed esophagitis in 0% and 19% of patients, respectively. The median (interquartile range) points scored for study quality was 15 (14-16) out of total of 32. Pooled analysis of three comparative studies between LHM and POEM showed similar results for adverse events, perforation rate, operative time and a nonsignificant trend toward a reduced length of hospital stay in the POEM group. In conclusion, POEM is a safe and effective treatment for achalasia, showing significant improvements in objective metrics and achalasia-related symptoms. Randomized comparative studies of LHM and POEM are required to determine the most effective treatment modality for achalasia.

Shorter myotomy on the gastric site (≤2.5 cm) provides adequate relief of dysphagia in achalasia patients.

The right length of the myotomy on the gastric side for esophageal achalasia is still a debated issue. We aimed to investigate the final outcome after classic myotomy (CM) as compared with a longer myotomy on the gastric side (LM) in two cohorts of achalasia patients. Forty-four achalasia patients who underwent laparoscopic Heller-Dor were considered; patients with a sigmoid-shaped esophagus were excluded. Symptoms were scored using a detailed questionnaire for dysphagia, regurgitation, and chest pain. Barium swallow, endoscopy, and esophageal manometry were performed before and 6 months after the surgical treatment; 24-hour pH-monitoring was also performed 6 months after the procedure. CM was defined as a gastric myotomy length in the range of 1.5-2.0 cm, while LM was 2.5-3 cm in length. The surgical treatment (CM or LM) was adopted in two consecutive cohorts. Treatment failure was defined as a postoperative symptom score >10th percentile of the preoperative score (i.e. >8). Of the 44 patients representing the study population, 20 had CM and 24 had LM. The patients' demographic and clinical parameters (age, sex, symptom score, duration of symptoms, esophageal diameter, and manometric pattern) were similar in the two groups. The median follow up was 24 months (interquartile range 12-39). One patient in each group was classified as a treatment failure. After the treatment, there was a significant decrease in both groups' symptom score, and resting and residual pressure (P < 0.01), with no statistically significant differences between the two groups in terms of postoperative symptom score, resting and residual pressure, or total and abdominal lower esophageal sphincter length and esophageal diameter. Extending the length of the myotomy on the gastric side does not seem to change the final outcome of the laparoscopic Heller-Dor procedure.

The eminent anatomists who discovered the upper oesophageal sphincter.

OBJECTIVE: To discover the anatomist who first identified the upper oesophageal sphincter. METHOD: The authors searched dozens of antique anatomy textbooks kept in the old section of the 'Vincenzo Pinali' Medical Library of Padua University, looking for descriptions of the upper oesophageal sphincter. RESULTS: The oesophageal sphincter was drawn correctly only in 1601, by Julius Casserius, in the book De vocis auditusque organis historia anatomica… (which translates as 'An Anatomical History on the Organs of Voice and Hearing …'), and was properly described by Antonio Maria Valsalva in 1704 in the book De aure humana tractatus… ('Treatise on the Human Ear …'). CONCLUSION: Anatomists Casserius and Valsalva can be considered the discoverers of the 'oesophageal sphincter'.

Achalasia and esophago-gastric junction outflow obstruction: focus on the subtypes.

BACKGROUND: The choice between pneumatic dilation and surgical myotomy is mainly determined by the preference and expertise of the treating physician. Ideally, however, treatment should be personalized to provide the optimal clinical outcome. The introduction of high resolution manometry has not only improved the specificity to diagnose achalasia, but also identified three different manometric subclasses. PURPOSE: To review, the data suggesting differences in clinical response to treatment depending on the manometric profile.

The Kagoshima consensus on esophageal achalasia.

Esophageal achalasia is a primary esophageal motility disorder characterized by lack of peristalsis and a lower esophageal sphincter that fails to relax appropriately in response to swallowing. This article summarizes the most salient issues in the diagnosis and management of achalasia as discussed in a symposium that took place in Kagoshima, Japan, in September 2010 under the auspices of the International Society for Diseases of the Esophagus.

Programmed cell death 4 nuclear loss and miR-21 or activated Akt overexpression in esophageal squamous cell carcinogenesis.

The programmed cell death 4 (PDCD4) tumor suppressor is down-regulated in several malignancies, and the (subcellular) expression of its protein product is modulated by both oncomiR miR-21 and protein kinase B (Akt). PDCD4 and activated Akt (phosphorylated Akt [pAkt]) expression were assessed immunohistochemically in 53 tissue samples obtained from 25 endoscopic esophageal mucosal resections performed for squamous intraepithelial neoplasia (IEN) or squamous intramucosal carcinoma (IM-SSC). In total, 33 IEN (low-grade = 15; high-grade = 15) and 20 IM-SSC specimens were considered; 50 additional tissue samples of histologically proven normal esophageal mucosa were considered as normal controls. To further validate the results achieved, miR-21 expression (as assessed by quantitative real-time polymerase chain reaction and in situ hybridization) was tested in another series of 15 normal esophageal tissue samples, 15 high-grade IEN, and 15 IM-SCCs. Normal suprabasal squamous epithelial layers consistently featured strong PDCD4 nuclear immunostaining, which was significantly lower (P < 0.001) in IEN (both low-and high-grade) and in IM-SSC. Conversely, pAkt and miR-21 expression was significantly up-regulated in the whole spectrum of preneoplastic/neoplastic lesions considered. PDCD4 down-regulation, as assessed by immunohistochemistry, is a reliable biomarker of early-stage squamous cell esophageal neoplasia, providing additional information in the histological assessment of these lesions.

Diffuse esophageal spasm: the surgical approach.

Diffuse esophageal spasm (DES) is a rare primary motility disorder of unknown cause, that can be found in patients complaining of chest pain and dysphagia and in whom ischemic heart disease and GERD have been excluded. The manometric hallmark of DES is the presence of simultaneous contractions in the distal esophagus alternating with a normal peristalsis. Even at specialized esophageal motility laboratories, DES is considered an uncommon diagnosis. In this review, the authors discuss the clinical and diagnostic aspects of this disease, as well as the possible therapeutic options (medical, endoscopic or surgical therapy). Surgery (esophageal myotomy performed through a thoracotomy or with a thoracoscopic access) seems to have a better outcome than medical or endoscopic treatment, and it is considered "the last resource" in these patients. However, satisfactory results are reported, from highly skilled centers, in only about 70% of treated cases, certainly inferior to those achieved in other esophageal disorders. The role of surgery in this disease requires therefore further study, even if controlled trials are probably difficult to perform, due to the rarity of the disease.