Improving esophageal cancer screening across the globe: Translating knowledge into action.

Esophageal cancer (EC) is a pressing global health concern, ranking as the eighth most common cancer and the sixth leading cause for cancer-related deaths worldwide. Esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) are the two major histological types of esophageal cancer associated with distinct risk factors and geographical distributions. Unfortunately, the outcomes for both types of EC remain discouraging, with a five-year survival rate of less than 20% when diagnosed at advanced stages. Advanced endoscopic techniques have the potential to vastly enhance patient outcomes and impede the progression of pre-malignant lesions to cancer. However, low screening rates with endoscopy due to its invasive nature and high cost hinder its effectiveness. Despite extensive research on risk predictors, a significant number of cases still go undiagnosed, highlighting the need for improved screening techniques that can be implemented at the population level. To increase uptake, a shift towards minimally invasive, well-tolerated and cost-effective non-endoscopic technologies is crucial. The implementation of such devices in primary care settings, specifically targeting high-risk populations, can be a promising strategy. With early detection and enrollment in surveillance programs, there is hope for substantial improvement in morbidity and mortality rates through modern minimally invasive endoscopic and surgical techniques.

Rates of Recurrent Intestinal Metaplasia and Dysplasia After Successful Endoscopic Therapy of Barrett's Neoplasia by Endoscopic Mucosal Resection vs Endoscopic Submucosal Dissection and Ablation: A Large North American Multicenter Cohort.

INTRODUCTION: Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. METHODS: Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. RESULTS: A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51-1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56-1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. DISCUSSION: Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Prevalence and Predictors of Barrett's Esophagus After Negative Initial Endoscopy: Analysis From Two National Databases.

BACKGROUND & AIMS: Guidelines suggest a single screening esophagogastroduodenoscopy (EGD) in patients with multiple risk factors for Barrett's esophagus (BE). We aimed to determine BE prevalence and predictors on repeat EGD after a negative initial EGD, using 2 large national databases (GI Quality Improvement Consortium [GIQuIC] and TriNetX). METHODS: Patients who underwent at least 2 EGDs were included and those with BE or esophageal adenocarcinoma detected at initial EGD were excluded. Patient demographics and prevalence of BE on repeat EGD were collected. Multivariate logistic regression was performed to assess for independent risk factors for BE detected on the repeat EGD. RESULTS: In 214,318 and 153,445 patients undergoing at least 2 EGDs over a median follow-up of 28-35 months, the prevalence of BE on repeat EGD was 1.7% in GIQuIC and 3.4% in TriNetX, respectively (26%-45% of baseline BE prevalence). Most (89%) patients had nondysplastic BE. The prevalence of BE remained stable over time (from 1 to >5 years from negative initial EGD) but increased with increasing number of risk factors. BE prevalence in a high-risk population (gastroesophageal reflux disease plus ≥1 risk factor for BE) was 3%-4%. CONCLUSIONS: In this study of >350,000 patients, rates of BE on repeat EGD ranged from 1.7%-3.4%, and were higher in those with multiple risk factors. Most were likely missed at initial evaluation, underscoring the importance of a high-quality initial endoscopic examination. Although routine repeat endoscopic BE screening after a negative initial examination is not recommended, repeat screening may be considered in carefully selected patients with gastroesophageal reflux disease and ≥2 risk factors for BE, potentially using nonendoscopic tools.

Efficacy of Rifaximin in Patients With Abdominal Bloating or Distension: A Systematic Review and Meta-analysis.

BACKGROUND: Abdominal bloating is a common complaint in patients with functional and organic bowel disease. Rifaximin, a nonabsorbable antibiotic, has been tried for the treatment of this disease. We performed a systematic review and meta-analysis to study the efficacy of rifaximin in abdominal bloating and distension in patients with functional gastrointestinal disorders (FGID). METHODS: We accessed 4 databases (MEDLINE, Embase, SCOPUS, and Web of Science) to identify randomized placebo-controlled trials that utilized rifaximin in FGID. We excluded observational studies, those including patients with organic bowel disorders such as inflammatory bowel diseases, or those in which rifaximin was given for other indications, such as hepatic encephalopathy. RESULTS: A total of 1426 articles were available, of which 813 articles were screened after removing duplicates and 34 articles were selected for full-text review. Finally, 10 trials (3326 patients) were included. Rifaximin was administered in doses ranging from 400 to 1650 mg per day for 1 to 2 weeks. Rifaximin therapy led to a higher likelihood of improvement in symptoms of bloating (44.6% vs. 34.6%, RR 1.22, 95% CI 1.11, 1.35; n=2401 patients) without significant heterogeneity. However, daily doses less than 1200 mg/day were similar to placebo ( P =0.09). Bloating was quantified subjectively in 7 studies, and rifaximin led to a greater reduction in bloating scores compared with placebo (standardized mean difference -0.3, 95% CI -0.51, -0.1, P =0.04) but carried significant heterogeneity ( I2 =61.6%, P =0.01). CONCLUSIONS: Rifaximin therapy is associated with an increased likelihood of improvement in bloating and distension, as well as reduces the subjective severity of these symptoms in patients with FGID.

Clinical Outcomes After Endoscopic Management of Low-Risk and High-Risk T1a Esophageal Adenocarcinoma: A Multicenter Study.

INTRODUCTION: Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS: Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS: One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION: Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

B-Lymphoblastic Leukaemia Presenting as Intrahepatic Cholestasis.

Acute cholangitis is a critical medical condition requiring prompt intervention. This case report explores the complexities and uncertainties encountered in clinical decision-making when faced with a patient presenting with symptoms suggestive of acute cholangitis. We emphasise the importance of considering individual circumstances and factors in the diagnostic process. A 38-year-old woman with a history of Crohn's colitis presented with abdominal pain, jaundice and leukocytosis. Initial evaluation raised suspicions of acute cholangitis, but unexpected findings of blast cells in the peripheral smear led to a diagnosis of B-lymphoblastic leukaemia with BCR-ABL1 fusion. Treatment with steroids and chemotherapy resulted in the resolution of liver abnormalities. This case underscores the necessity of comprehensive assessments for obstructive jaundice and highlights the potential diagnostic challenges posed by underlying haematologic malignancies. It also raises awareness about drug-induced liver injury, and emphasises the importance of complete blood counts and differentials in the initial workup. Healthcare providers should be vigilant in considering alternative diagnoses when faced with obstructive jaundice, as misdiagnosis can lead to invasive procedures with potential adverse events. LEARNING POINTS: This case highlights the significance of conducting a thorough initial assessment when a patient presents with symptoms suggestive of liver involvement, such as abdominal pain, jaundice and leukocytosis. In this case, the patient's initial symptoms were initially attributed to potential cholangitis due to her clinical presentation, but a peripheral smear unexpectedly revealed blast cells, leading to a diagnosis of B-lymphoblastic leukaemia.The case demonstrates that haematologic malignancies can manifest with various patterns of hepatic involvement, and their presentation can be diverse. In this instance, obstructive jaundice was caused by leukaemic infiltration of the liver, which is a rare initial presentation of acute lymphoblastic leukaemia (ALL).This demonstrates the diagnostic challenges in identifying rare conditions such as leukaemic infiltration of the liver, emphasising the importance of appropriate investigations and consultation with specialists.

Development of Electronic Health Record-Based Machine Learning Models to Predict Barrett's Esophagus and Esophageal Adenocarcinoma Risk.

INTRODUCTION: Screening for Barrett's esophagus (BE) is suggested in those with risk factors, but remains underutilized. BE/esophageal adenocarcinoma (EAC) risk prediction tools integrating multiple risk factors have been described. However, accuracy remains modest (area under the receiver-operating curve [AUROC] ≤0.7), and clinical implementation has been challenging. We aimed to develop machine learning (ML) BE/EAC risk prediction models from an electronic health record (EHR) database. METHODS: The Clinical Data Analytics Platform, a deidentified EHR database of 6 million Mayo Clinic patients, was used to predict BE and EAC risk. BE and EAC cases and controls were identified using International Classification of Diseases codes and augmented curation (natural language processing) techniques applied to clinical, endoscopy, laboratory, and pathology notes. Cases were propensity score matched to 5 independent randomly selected control groups. An ensemble transformer-based ML model architecture was used to develop predictive models. RESULTS: We identified 8,476 BE cases, 1,539 EAC cases, and 252,276 controls. The BE ML transformer model had an overall sensitivity, specificity, and AUROC of 76%, 76%, and 0.84, respectively. The EAC ML transformer model had an overall sensitivity, specificity, and AUROC of 84%, 70%, and 0.84, respectively. Predictors of BE and EAC included conventional risk factors and additional novel factors, such as coronary artery disease, serum triglycerides, and electrolytes. DISCUSSION: ML models developed on an EHR database can predict incident BE and EAC risk with improved accuracy compared with conventional risk factor-based risk scores. Such a model may enable effective implementation of a minimally invasive screening technology.

Revised Algorithmic Approach to Differentiate Between Nonspecific and Specific Etiologies of Chronic Terminal Ileitis.

INTRODUCTION: Chronic isolated terminal ileitis (TI) may be seen in Crohn's disease (CD) and intestinal tuberculosis (ITB) in addition to other etiologies that may be managed symptomatically. We developed a revised algorithm to distinguish patients with a specific etiology from a nonspecific etiology. METHODS: Patients with chronic isolated TI followed up from 2007 to 2022 were retrospectively reviewed. A specific (ITB or CD) diagnosis was made based on standardized criteria, and other relevant data were collected. Using this cohort, validation of a previously suggested algorithm was conducted. Furthermore, based on the results of a univariate analysis, a multivariate analysis with bootstrap validation was used to develop a revised algorithm. RESULTS: We included 153 patients (mean age 36.9 ± 14.6 years, males-70%, median duration-1.5 years, range: 0-20 years) with chronic isolated TI of whom 109 (71.2%) received a specific diagnosis (CD-69, ITB-40). On multivariate regression and validation statistics with a combination of clinical, laboratory, radiological, and colonoscopic findings, an optimism corrected c-statistic of 0.975 and 0.958 was obtained with and without histopathological findings, respectively. Revised algorithm, based on these, showed sensitivity, specificity, positive and negative predictive values, and overall accuracy of 98.2% (95% CI: 93.5-99.8), 75.0% (95% CI: 59.7-86.8), 90.7% (95% CI: 85.4-94.2), 94.3% (95% CI: 80.5-98.5) and 91.5%(95% CI:85.9-95.4), respectively. This was more sensitive and specific than the previous algorithm (accuracy 83.9%, sensitivity 95.5%, and specificity 54.6%). DISCUSSION: We developed a revised algorithm and a multimodality approach to stratify patients with chronic isolated TI into specific and nonspecific etiologies with an excellent diagnostic accuracy, which could potentially avoid missed diagnosis and unnecessary side effects of treatment.

Serum albumin is the strongest predictor of anti-tumor necrosis factor nonresponse in inflammatory bowel disease in resource-constrained regions lacking therapeutic drug monitoring.

BACKGROUND/AIMS: Evidence on predictors of primary nonresponse (PNR), and secondary loss of response (SLR) to anti-tumor necrosis factor (anti-TNF) agents in inflammatory bowel disease is scarce from Asia. We evaluated clinical/biochemical/molecular markers of PNR/SLR in ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Inflammatory bowel disease patients treated with anti-TNF agents (January 2005-October 2020) were ambispectively included. Data concerning clinical and biochemical predictors was retrieved from a prospectively maintained database. Immunohistochemistry for expression of oncostatin M (OSM), OSM receptor (OSM-R), and interleukin-7 receptor (IL-7R) were done on pre anti-TNF initiation mucosal biopsies. RESULTS: One-hundred eighty-six patients (118 CD, 68 UC: mean age, 34.1±13.7 years; median disease duration at anti-TNF initiation, 60 months; interquartile range, 28-100.5 months) were included. PNR was seen in 17% and 26.5% and SLR in 47% and 28% CD and UC patients, respectively. In CD, predictors of PNR were low albumin (P<0.001), postoperative recurrence (P=0.001) and high IL-7R expression (P<0.027) on univariate; and low albumin alone (hazard ratio [HR], 0.09; 95% confidence interval [CI], 0.03-0.28; P<0.001) on multivariate analysis respectively. Low albumin (HR, 0.31; 95% CI, 0.15-0.62; P=0.001) also predicted SLR. In UC, predictors of PNR were low albumin (P<0.001), and high C-reactive protein (P<0.001), OSM (P<0.04) and OSM-R (P=0.07) stromal expression on univariate; and low albumin alone (HR, 0.11; 95% CI, 0.03-0.39; P=0.001) on multivariate analysis respectively. CONCLUSIONS: Low serum albumin at baseline significantly predicted PNR in UC and PNR/SLR in CD patients. Mucosal markers of PNR were high stromal OSM/OSM-R in UC and high IL-7R in CD patients.

Interferon-gamma release assay has poor diagnostic accuracy in differentiating intestinal tuberculosis from Crohn's disease in tuberculosis endemic areas.

BACKGROUND/AIMS: Intestinal tuberculosis (ITB) and Crohn's disease (CD) frequently present with a diagnostic dilemma because of similar presentation. Interferon-gamma release assay (IGRA) has been used in differentiating ITB from CD, but with sparse reports on its diagnostic accuracy in tuberculosis endemic regions and this study evaluated the same. METHODS: Patients with definitive diagnosis of ITB (n=59) or CD (n=49) who underwent IGRA testing (n=307) were retrospectively included at All India Institute of Medical Sciences, New Delhi (July 2014 to September 2021). CD or ITB was diagnosed as per standard criteria. IGRA was considered positive at >0.35 IU/mL. Relevant data was collected and IGRA results were compared between ITB and CD to determine its accuracy. RESULTS: Among 59 ITB patients (mean age, 32.6±13.1 years; median disease duration, 1 year; male, 59.3%), 24 were positive and 35 tested negative for IGRA. Among 49 CD patients (mean age, 37.8±14.0; median disease duration, 4 years; male, 61.2%), 12 were positive and 37 tested negative for IGRA. Hence, for diagnosing ITB, IGRA showed a sensitivity, specificity, positive and negative predictive values of 40.68%, 75.51%, 66.67%, and 51.39%, respectively. The area under the curve of IGRA for ITB diagnosis was 0.66 (95% confidence interval, 0.55-0.75). In a subset (n=64), tuberculin skin test (TST) showed sensitivity, specificity, positive and negative predictive values of 64.7%, 73.3%, 73.3%, and 64.71%, respectively. IGRA and TST were concordant in 38 (59.4%) patients with κ=0.17. CONCLUSIONS: In a tuberculosis endemic region, IGRA had poor diagnostic accuracy for differentiating ITB from CD, suggesting a limited value of IGRA in this setting.

Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial.

OBJECTIVE: Microbiome and dietary manipulation therapies are being explored for treating ulcerative colitis (UC). We aimed to examine the efficacy of multidonor faecal microbiota transplantation (FMT) and anti-inflammatory diet in inducing remission followed by long-term maintenance with anti-inflammatory diet in patients with mild-moderate UC. DESIGN: This open-labelled randomised controlled trial (RCT) randomised patients with mild-moderate (Simple Clinical Colitis Activity Index (SCCAI) 3-9) endoscopically active UC (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)>1) on stable baseline medications in 1:1 ratio to FMT and anti-inflammatory diet (FMT-AID) versus optimised standard medical therapy (SMT). The FMT-AID arm received seven weekly colonoscopic infusions of freshly prepared FMT from multiple rural donors(weeks 0-6) with anti-inflammatory diet. Baseline medications were optimised in the SMT arm. Clinical responders (decline in SCCAI>3) at 8 weeks in both arms were followed until 48 weeks on baseline medications (with anti-inflammatory diet in the FMT-AID arm). Primary outcome measures were clinical response and deep remission (clinical-SCCAI <2; and endoscopic-UCEIS <1) at 8 weeks, and deep remission and steroid-free clinical remission at 48 weeks. RESULTS: Of the 113 patients screened, 73 were randomised, and 66 were included in (35-FMT-AID; 31-SMT) modified intention-to-treat analysis (age-35.7±11.1 years; male-60.1%; disease duration-48 (IQR 24-84) months; pancolitis-34.8%; SCCAI-6 (IQR 5-7); UCEIS-4 (IQR 3-5)). Baseline characteristics were comparable. FMT-AID was superior to SMT in inducing clinical response (23/35 (65.7%) vs 11/31 (35.5%), p=0.01, OR 3.5 (95% CI 1.3 to 9.6)), remission (21/35 (60%) vs 10/31 (32.3%), p=0.02, OR 3.2 (95% CI 1.1 to 8.7)) and deep remission (12/33 (36.4%) vs 2/23 (8.7%), p=0.03, OR 6.0 (95% CI 1.2 to 30.2)) at 8 weeks. Anti-inflammatory diet was superior to SMT in maintaining deep remission until 48 weeks (6/24 (25%) vs 0/27, p=0.007). CONCLUSION: Multidonor FMT with anti-inflammatory diet effectively induced deep remission in mild-moderate UC which was sustained with anti-inflammatory diet over 1 year. TRIAL REGISTRATION NUMBER: ISRCTN15475780.

Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence.

Environmental pollutants and allergens induce oxidative stress and mitochondrial dysfunction, leading to key features of allergic asthma. Dysregulations in autophagy, mitophagy, and cellular senescence have been associated with environmental pollutant and allergen-induced oxidative stress, mitochondrial dysfunction, secretion of multiple inflammatory proteins, and subsequently development of asthma. Particularly, particulate matter 2.5 (PM2.5) has been reported to induce autophagy in the bronchial epithelial cells through activation of AMP-activated protein kinase (AMPK), drive mitophagy through activating PTEN-induced kinase 1(PINK1)/Parkin pathway, and induce cell cycle arrest and senescence. Intriguingly, allergens, including ovalbumin (OVA), Alternaria alternata, and cockroach allergen, have also been shown to induce autophagy through activation of different signaling pathways. Additionally, mitochondrial dysfunction can induce cell senescence due to excessive ROS production, which affects airway diseases. Although autophagy and senescence share similar properties, recent studies suggest that autophagy can either accelerate the development of senescence or prevent senescence. Thus, in this review, we evaluated the literature regarding the basic cellular processes, including autophagy, mitophagy, and cellular senescence, explored their molecular mechanisms in the regulation of the initiation and downstream signaling. Especially, we highlighted their involvement in environmental pollutant/allergen-induced major phenotypic changes of asthma such as airway inflammation and remodeling and reviewed novel and critical research areas for future studies. Ultimately, understanding the regulatory mechanisms of autophagy, mitophagy, and cellular senescence may allow for the development of new therapeutic targets for asthma.

miR-511-3p protects against cockroach allergen-induced lung inflammation by antagonizing CCL2.

miR-511-3p, encoded by CD206/Mrc1, was demonstrated to reduce allergic inflammation and promote alternative (M2) macrophage polarization. Here, we sought to elucidate the fundamental mechanism by which miR-511-3p attenuates allergic inflammation and promotes macrophage polarization. Compared with WT mice, the allergen-challenged Mrc1-/- mice showed increased airway hyperresponsiveness (AHR) and inflammation. However, this increased AHR and inflammation were significantly attenuated when these mice were pretransduced with adeno-associated virus-miR-511-3p (AAV-miR-511-3p). Gene expression profiling of macrophages identified Ccl2 as one of the major genes that was highly expressed in M2 macrophages but antagonized by miR-511-3p. The interaction between miR-511-3p and Ccl2 was confirmed by in silico analysis and mRNA-miR pulldown assay. Further evidence for the inhibition of Ccl2 by miR-511-3p was given by reduced levels of Ccl2 in supernatants of miR-511-3p-transduced macrophages and in bronchoalveolar lavage fluids of AAV-miR-511-3p-infected Mrc1-/- mice. Mechanistically, we demonstrated that Ccl2 promotes M1 macrophage polarization by activating RhoA signaling through Ccr2. The interaction between Ccr2 and RhoA was also supported by coimmunoprecipitation assay. Importantly, inhibition of RhoA signaling suppressed cockroach allergen-induced AHR and lung inflammation. These findings suggest a potentially novel mechanism by which miR-511-3p regulates allergic inflammation and macrophage polarization by targeting Ccl2 and its downstream Ccr2/RhoA axis.