A Method for Increasing the Robustness of Stable Feature Selection for Biomarker Discovery in Molecular Medicine Developed Using Serum Small Extracellular Vesicle Associated miRNAs and the Barrett's Oesophagus Disease Spectrum.

The biomarker development field within molecular medicine remains limited by the methods that are available for building predictive models. We developed an efficient method for conservatively estimating confidence intervals for the cross validation-derived prediction errors of biomarker models. This new method was investigated for its ability to improve the capacity of our previously developed method, StaVarSel, for selecting stable biomarkers. Compared with the standard cross validation method, StaVarSel markedly improved the estimated generalisable predictive capacity of serum miRNA biomarkers for the detection of disease states that are at increased risk of progressing to oesophageal adenocarcinoma. The incorporation of our new method for conservatively estimating confidence intervals into StaVarSel resulted in the selection of less complex models with increased stability and improved or similar predictive capacities. The methods developed in this study have the potential to improve progress from biomarker discovery to biomarker driven translational research.

Clinical pathways and outcomes of patients with Barrett's esophagus in tertiary care settings: a prospective longitudinal cohort study in Australia, 2008-2016.

BACKGROUND: Clinical services for Barrett's esophagus have been rising worldwide including Australia, but little is known of the long-term outcomes of such patients. Retrospective studies using data at baseline are prone to both selection and misclassification bias. We investigated the clinical characteristics and outcomes of Barrett's esophagus patients in a prospective cohort. METHODS: We recruited patients diagnosed with Barrett's esophagus in tertiary settings across Australia between 2008 and 2016. We compared baseline and follow-up epidemiological and clinical data between Barrett's patients with and without dysplasia. We calculated age-adjusted incidence rates and estimated minimally and fully adjusted hazard ratios (HR) to identify those clinical factors related to disease progression. RESULTS: The cohort comprised 268 patients with Barrett's esophagus (median follow-up 5 years). At recruitment, 224 (84%) had no dysplasia, 44 (16%) had low-grade or indefinite dysplasia (LGD/IND). The age-adjusted incidence of esophageal adenocarcinoma (EAC) was 0.5% per year in LGD/IND compared with 0.1% per year in those with no dysplasia. Risk of progression to high-grade dysplasia/EAC was associated with prior LGD/IND (fully adjusted HR 6.55, 95% confidence interval [CI] 1.96-21.8) but not long-segment disease (HR 1.03, 95%CI 0.29-3.58). CONCLUSIONS: These prospective data suggest presence of dysplasia is a stronger predictor of progression to cancer than segment length in patients with Barrett's esophagus.

Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus.

Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett's esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE± low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.

The prognostic value of TP53 mutations in oesophageal adenocarcinoma: a systematic review and meta-analysis.

OBJECTIVE: To 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. DESIGN: A 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. RESULTS: Sixteen 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%). CONCLUSIONS: Patients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage.

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.

CD151 Gene and Protein Expression Provides Independent Prognostic Information for Patients with Adenocarcinoma of the Esophagus and Gastroesophageal Junction Treated by Esophagectomy.

BACKGROUND: Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient's tumor biology and prognosis. METHODS: Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx)-naïve patients with external validation in a separate cohort of 62 CRTx-naïve patients and 169 patients with advanced-stage disease treated with CRTx. RESULTS: As a novel prognostic biomarker after external validation, CD151 showed promise. Patients exhibiting high levels of CD151 (≥median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9 months; p = 0.01). This effect persisted in a multivariable Cox-regression model with adjustment for tumor stage [adjusted hazard ratio (aHR), 0.33; 95 % confidence interval (CI), 0.14-0.78; p = 0.01] and was further corroborated through immunohistochemical analysis (aHR, 0.22; 95 % CI, 0.08-0.59; p = 0.003). This effect was not found in the separate cohort of CRTx-exposed patients. CONCLUSION: Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.

Long-term outcomes of a primary complete endoscopic resection strategy for short-segment Barrett's esophagus with high-grade dysplasia and/or early esophageal adenocarcinoma.

BACKGROUND AND AIMS: Complete endoscopic resection (CER) of Barrett's esophagus (BE) with high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EEA) is a comprehensive and precise staging tool and may produce a sustained treatment response, preventing metachronous disease. There are limited data on long-term clinical outcomes and the sustainability of dysplasia eradication after CER. We aimed to describe long-term outcomes of a primary CER strategy of BE with HGD/EEA. METHODS: Patients with biopsy-proven HGD and EEA in short-segment BE (≤ 3 cm in circumferential length and ≤ 5 cm in maximal length) underwent staged CER by multiband mucosectomy or the cap method. The primary endpoint was remission of HGD or EEA (complete resection of HGD/EEA), dysplasia (complete resection of any dysplasia), and complete resection of intestinal metaplasia. RESULTS: Of 153 patients (126 HGD, 27 EEA; 83.7% male, median age of 66 years) considered suitable for CER, 138 met all inclusion criteria. CER was technically successful in all patients and was established after a median of 2 sessions. Covert synchronous EEA was found in 1 patient. At a mean follow-up of 40.7 months by intention-to-treat analysis, complete remission of HGD/EEA, dysplasia, and intestinal metaplasia was achieved in 98.5%, 89.1%, and 71.0%, respectively. In 47.1% of patients, CER changed the histological grade compared with pretreatment biopsies (28.1% downstaged and 19.0% upstaged). Esophageal dilation was performed in 36.8% in a mean of 2.5 sessions. At the end of follow-up, 96.4% of patients had no or minimal dysphagia and 90.6% of patients found CER an acceptable treatment. CONCLUSIONS: On long-term follow-up, a primary CER strategy was a highly effective, safe, and durable treatment for HGD and EEA. Despite the need for post-CER dilation in one-third of patients, the majority found it an acceptable treatment on long-term follow-up.

High Expression of Cathepsin E in Tissues but Not Blood of Patients with Barrett's Esophagus and Adenocarcinoma.

BACKGROUND: Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia-dysplasia-neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett's esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). METHODS: A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. RESULTS: Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27-1.26, p = 0.17). CONCLUSIONS: CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues.

Early metal stent insertion fails to prevent stricturing after single-stage complete Barrett's excision for high-grade dysplasia and early cancer.

BACKGROUND: Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) can be effectively treated by single-session EMR, resulting in complete Barrett's excision (CBE). CBE provides accurate histology for staging and clinical confirmation of neoplasia eradication but is limited by a high risk of esophageal stricture formation. OBJECTIVE: To evaluate the effectiveness of prophylactic temporary esophageal stenting to prevent post-CBE stricture formation. DESIGN AND SETTING: Single-center, investigator-initiated feasibility study. PATIENTS: Circumferential, short-segment Barrett's esophagus (≤C3≤M5) with HGD or IMC. INTERVENTION: Single-stage CBE and insertion of a fully covered metal esophageal stent at 10 days that was removed at 8 weeks. Patients were followed for a minimum of 2 surveillance endoscopies. MAIN OUTCOME MEASUREMENT: Symptomatic esophageal stricture formation. RESULTS: At the end of the follow-up period, 8 patients (57.1%) required esophageal dilation for symptomatic CBE-related (n = 7) or stent-related (n = 4) strictures. A median of 3 surveillance endoscopies were performed over a median endoscopic follow-up of 17 months (range 4-25 months). Single-stage CBE successfully eliminated Barrett's intestinal metaplasia and neoplasia in 71.4% and 92.9% of patients, respectively. Four patients were admitted to the hospital, and 4 patients had early stent removal because of pain or dysphagia. LIMITATIONS: Single-center feasibility study. CONCLUSIONS: In a prospective study evaluating prophylactic esophageal stent insertion after single-stage CBE, esophageal strictures formed in more than of half the study cohort, and stents were associated with significant morbidity. An alternative method to reduce stricture formation is required. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01554280.).

Australian clinical practice guidelines for the diagnosis and management of Barrett's esophagus and early esophageal adenocarcinoma.

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.

Survival, mortality and morbidity outcomes after oesophagogastric cancer surgery in New South Wales, 2001-2008.

OBJECTIVES: To examine the relationship between hospital volume and patient outcomes for New South Wales hospitals performing oesophagectomy and gastrectomy for oesophagogastric cancer. DESIGN, SETTING AND PATIENTS: A retrospective, population-based cohort study of NSW residents diagnosed with a new case of invasive oesophageal or gastric cancer who underwent oesophagectomy or gastrectomy between 2001 and 2008 in NSW hospitals using linked de-identified data from the NSW Central Cancer Registry, the National Death Index and the NSW Admitted Patient Data Collection. A higher-volume hospital was defined as one performing > 6 relevant procedures per year. MAIN OUTCOME MEASURES: Odds ratios for > 21-day length of stay, 28-day unplanned readmission, 30-day mortality and 90-day mortality, and hazard ratios (HRs) for 5-year absolute and conditional survival. RESULTS: Oesophagectomy (908 patients) and gastrectomy (1621 patients) were undertaken in 42 and 84 hospitals, respectively, between 2001 and 2008. Median annual hospital volume ranged from 2 to 4 for oesophagectomies and ranged from 2 to 3 for gastrectomies. Controlling for known confounders, no associations between hospital volume and > 21-day length of stay and 28-day unplanned readmission were found. Overall 30-day mortality was 4.1% and 4.4% for oesophagectomy and gastrectomy, respectively. Five-year absolute survival was significantly better for patients who underwent oesophagectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.28 [95% CI, 1.10-1.49]; P = 0.002) and for those with localised gastric cancer who underwent gastrectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.83 [95% CI, 1.28-2.61]; P = 0.001). CONCLUSIONS: These data support initial surgery for oesophagogastric cancer in higher-volume hospitals.

A junior doctor led near-peer acute ENT/head and neck surgery workshop for medical students.

Background: Near-peer teaching (NPT) involves teaching by peers who are at a close, but not the same, level of training. This study investigated whether a novel surgical NPT workshop, designed and delivered by junior doctors using simulation models for acute otolaryngology conditions, improved the knowledge and confidence level of senior medical students. Methods: A one-day NPT workshop was held for medical students in their third year of a four-year postgraduate medical degree at the University of Notre Dame, Sydney, Australia. Four acute otolaryngology/head and neck surgery problems that might be encountered by junior doctors and require prompt management were chosen. These were post-operative neck swelling, epistaxis, and tracheostomy management (obstruction and bleeding). Six junior doctors facilitated didactic tutorials and practical skills training using models. Multiple choice question mini-tests and questionnaires were administered before and after the workshop to assess changes in students' knowledge and confidence in assessment, management, and practical skills. Results: The most common reason for participation was to acquire knowledge and practical skills (93.2 %). Mean correct MCQ mini-test knowledge scores increased significantly from 60 % pre-workshop to 83.9 % post-workshop (p < 0.05). Students reported significantly increased confidence in recognition and management of all four conditions. All students favoured including the course in their curriculum and would recommend the course to others. The tutors subjectively reported valuable teaching experience. Conclusion: NPT is an effective method for teaching medical students how to assess and manage acute otolaryngology/ENT surgery conditions that may present as emergencies for junior medical officers on the ward.

Socioeconomic status and the effect of prolonged pandemic confinement on anthropometric and glycaemic outcomes in adults with type 2 diabetes mellitus.

AIM: This systematic review and meta-analysis aimed to investigate the impact of COVID19 lockdown on the anthropometric and glycaemic outcomes of adults with type 2 diabetes mellitus (T2DM) and assess whether socioeconomic status (SES) was relevant to these changes. METHODS: A search of three databases was conducted. Meta-analyses using random effects models were undertaken to combine anthropometric and glycaemic measures pre- and post-confinement. Subgroup analyses according to SES were also conducted. RESULTS: This systematic review of 19 articles demonstrated that prolonged pandemic-related confinement is associated with a deterioration in both anthropometric and glycaemic outcomes among adults with T2DM. Furthermore, SES was found to be relevant to these changes. Specifically, BMI (kg/m2) showed an increase in mean difference of 0.72 (95% CI; 0.13, 1.31; p<0.05) between pre and post lockdown cohorts. High income countries displayed a greater increase in BMI compared to their lower middle-income counterparts. Regarding, fasting blood glucose (FBG), a statistically significant difference was observed in the upper middle-income group (mean difference: 5.10; 95% CI: 2.92, 7.27), and high-income group (mean difference: 6.03; 95% CI: 0.04, 12.02). There were no significant changes to weight, waist circumference, or HbA1C over the lockdown period. CONCLUSION: Our findings suggest adults with T2DM may have received less effective care over the lockdown period, particularly in high income countries. Clinics and care providers may need to adopt more intensive contact and treatment plans in the post lockdown period to prevent lasting impacts on disease progression and metabolic sequelae.

Immune cell-mediated inflammation and the early improvements in glucose metabolism after gastric banding surgery.

AIMS/HYPOTHESIS: The contribution of immune cells to the inflammasome that characterises type 2 diabetes mellitus and obesity is under intense research scrutiny. We hypothesised that early changes in glucose metabolism following gastric banding surgery may relate to systemic inflammation, particularly cell-mediated immunity. METHODS: Obese participants (BMI 43.4 ± 4.9 kg/m(2), n = 15) with diabetes or impaired glucose tolerance (IGT) underwent laparoscopic adjustable gastric banding surgery. Measurements taken before, and at 2 and 12 weeks after surgery included: fasting glucose, glucose levels 2 h after a 75 g oral load, glucose incremental AUC, oral glucose insulin sensitivity index (OGIS), circulating immune cell numbers and activation, and adipokine levels. Subcutaneous and visceral adipose tissue were collected at surgery, and macrophage number and activation measured. RESULTS: There were significant reductions in fasting and 2 h glucose, as well as improved OGIS at 2 and 12 weeks. At 12 weeks, 80% of the diabetic participants reverted to normal glucose tolerance or IGT, and all IGT participants had normalised glucose tolerance. The 12 week fall in fasting glucose was significantly related to baseline lymphocyte and T lymphocyte numbers, and to granulocyte activation, but also to the magnitude of the 12 week reduction in lymphocyte and T lymphocyte numbers and TNF-α levels. In a model that explained 75% of the variance in the change in fasting glucose, the 12 week change in T lymphocytes was independently associated with the 12 week fall in fasting glucose. CONCLUSIONS/INTERPRETATION: Rapid improvements in glucose metabolism after gastric banding surgery are related to reductions in circulating pro-inflammatory immune cells, specifically T lymphocytes. The contribution of immune cell-mediated inflammation to glucose homeostasis in type 2 diabetes and its improvement after bariatric surgery require further investigation.

Use of oral contrast for CT scanning and time to diagnosis and treatment of acute appendicitis.

BACKGROUND: The aim of this study was to investigate whether there is a delay in treatment for patients having pre-operative CT imaging with both intravenous and oral contrast (CTIVO) compared to intravenous contrast alone (CTIV). METHODS: A retrospective review of patients who underwent emergency appendicectomy at a single hospital during a two-year period (1/1/2019-31/12/2020) was performed. Demographic details, imaging timing/modality; biochemical markers; American Society of Anaesthesiologists (ASA) physical status classification, anaesthetic induction time; operative report findings; histopathology, peri-operative complications, admission/discharge times were recorded. The Sunshine Appendicitis Grading System (SAGS) score was used for severity of appendicitis. RESULTS: Pre-operative CT was performed in 294 patients; CTIVO: 159 (54%), CTIV: 135 (46%). Both groups were comparable for age, sex, ASA status and inflammatory markers. The median time from CT request to scanning was longer with CTIVO (CTIVO: 170 min, CTIV: 65 min, P < 0.0001). The median time from CT request to induction of anaesthesia was also longer with CTIVO (CTIVO: 780 minutes, CTIV: 406 min, P < 0.0001). A delay to theatre was not significantly associated with severity of appendicitis (SAGS score). The diagnostic accuracy was not reduced in the CTIV group compared to the CTIVO group. CONCLUSION: CTIVO scans significantly delay CT diagnosis and surgical treatment of appendicitis compared to CTIV. Omitting oral contrast does not result in a reduction in diagnostic accuracy for appendicitis.

How to effectively use and interpret the barium swallow: Current role in esophageal dysphagia.

BACKGROUND: The barium swallow is a commonly performed investigation, though recent decades have seen major advances in other esophageal diagnostic modalities. PURPOSE: The purpose of this review is to clarify the rationale for components of the barium swallow protocol, provide guidance on interpretation of findings, and describe the current role of the barium swallow in the diagnostic paradigm for esophageal dysphagia in relation to other esophageal investigations. The barium swallow protocol, interpretation, and reporting terminology are subjective and non-standardized. Common reporting terminology and an approach to their interpretation are provided. A timed barium swallow (TBS) protocol provides more standardized assessment of esophageal emptying but does not evaluate peristalsis. Barium swallow may have higher sensitivity than endoscopy for detecting subtle strictures. Barium swallow has lower overall accuracy than high-resolution manometry for diagnosing achalasia but can help secure the diagnosis in cases of equivocal manometry. TBS has an established role in objective assessment of therapeutic response in achalasia and helps identify the cause of symptom relapse. Barium swallow has a role in the evaluating manometric esophagogastric junction outflow obstruction, in some cases helping to identify where it represents an achalasia-like syndrome. Barium swallow should be performed in dysphagia following bariatric or anti-reflux surgery, to assess for both structural and functional postsurgical abnormality. Barium swallow remains a useful investigation in esophageal dysphagia, though its role has evolved due to advancements in other diagnostics. Current evidence-based guidance regarding its strengths, weaknesses, and current role are described in this review.

Effectiveness of an Oral Gastrografin Regimen for Complete Distal Intestinal Obstruction Syndrome.

Objectives: To assess the effectiveness of oral Gastrografin treatment and outcomes in adult patients with complete distal intestinal obstruction syndrome (cDIOS). Background: DIOS is an important gastrointestinal complication of cystic fibrosis (CF). Conservative treatment options for cDIOS are largely empirical, and the optimal management remains unclear. Surgery should be reserved for patients who have failed nonoperative treatment or have immediate indications for surgery. Methods: A retrospective single-institution cohort study was undertaken of adults with CF who had undergone lung transplantation and were admitted with an episode of cDIOS between 2004 and 2020. The outcomes of treatment in a high-volume CF transplant center with routine oral Gastrografin-based therapy were assessed. Results: Forty-seven episodes of cDIOS were recorded in 29 (23.3%) of 124 patients who had undergone lung transplantation for CF, and mean age at cDIOS was 30.3 years (SD ±11.2). Mean follow-up post cDIOS was 75.6 months (SD ±45.5). Twelve patients had >1 cDIOS episode. One episode occurred during recovery after transplantation, and 5 patients were readmitted within 30 days posttransplant with cDIOS. A history of previous abdominal surgery was associated with the development of cDIOS (P < 0.001). Oral Gastrografin therapy was used in 95.7% of the episodes, at varying doses. Three patients (7.0%) were resistant to oral Gastrografin treatment, requiring laparotomy. There were no deaths due to DIOS. Conclusions: Oral Gastrografin is effective and safe for the treatment of cDIOS, with low treatment failure rates. It should be considered as a first-line treatment option for patients with CF presenting with complete distal intestinal obstruction.

Structural alterations of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence.

BACKGROUND AND AIM: Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence. METHODS: A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. RESULTS: The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P<0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P<0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P=0.0043). CONCLUSIONS: The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia-dysplasia-adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma.

Reduced number of admissions with acute appendicitis but not severe acute appendicitis at two Sydney hospitals during the first COVID-19 lockdown period.

BACKGROUND: This study investigated whether there was a change in acute appendicitis, appendicectomy admissions or disease severity during the 2020 lockdown period in NSW. METHODS: A retrospective before-and-after study was undertaken of patients admitted to two Sydney hospitals (St. Vincent's and Liverpool Hospitals) who had appendicectomy for presumed acute appendicitis and patients who had confirmed appendicitis but did not undergo surgery. Study periods were the 2020 lockdown period (15 March-15 May 2020), the corresponding period in the previous year, and the 1-month after these periods. Patients were classified as having no, mild or severe appendicitis using operation and histopathological reports. RESULTS: (Thirty-six percent) fewer patients were admitted with acute appendicitis during the lockdown period compared with the previous year with a substantial reduction in normal/mild appendicitis presentations (OR 0.56, 95% CI 0.34-0.93, P = 0.03). There were 46% fewer patients with mild appendicitis during lockdown (56) compared with the previous year (103); numbers of patients with severe appendicitis were very similar (46 vs. 51). There was no increase in number of admissions with severe appendicitis, or in the time from onset of symptoms to admission, in the month following lockdown. CONCLUSION: Compared with the previous year, there were markedly fewer admissions with appendicitis during lockdown, with no evidence of a shift to more cases of severe appendicitis nor delayed presentation in the post-lockdown period. It is plausible that some patients with mild appendicitis may have recovered without hospitalization, supporting the importance of implementing trials on non-surgical management of appendicitis.

Association of clinically significant weight loss with number of patient visits and months of attendance at an Australian multidisciplinary weight management clinic.

Despite the obesity epidemic, there are relatively few multidisciplinary obesity services in Australia, and only limited data on the effectiveness of these services. The aim of this study was to evaluate the effectiveness of a university hospital-based weight management clinic-the 'Healthy Weight Clinic' in supporting patients to achieve clinically significant weight loss (≥5% reduction in body weight), weight maintenance, and changes in body composition. A retrospective review was conducted to determine weight and associated health outcomes in patients who attended an initial consultation in the first 2 years of the clinic-between March 2017 and March 2019. Follow up was at least 1 year for all patients. Patients who underwent bariatric surgery were excluded. Of 213 total patients, 172 patients attended more than one follow-up consultation for lifestyle modification. Mean weight change and percentage total weight change at last follow-up was -6.2 kg (SD 7.4) and - 6.0% (SD 6.9), respectively. For every additional clinic follow-up, there was 21.4% increased odds of achieving clinically significant weight loss, and for every additional month of follow-up, there was 10.1% increased odds of achieving clinically significant weight loss. Twenty percent of patients (34/172) maintained ≥5% of initial body weight loss for at least 1 year. Body composition measurements were also favourable, with significant changes in percentage skeletal muscle mass of +0.8% (SD 1.5) and in percentage fat mass by -1.4% (SD 3.2). Regular support in a structured holistic multidisciplinary obesity service enables patients to achieve clinically meaningful weight loss and improved skeletal muscle mass to body fat ratio, and maintain this loss for at least 1 year. Improved weight loss was associated with more patient visits and longer duration of attendance at the clinic.