The Utility of Functional Luminal Imaging Probes Measurements to Diagnose Dysmotility and Their Relationship to Impaired Bolus Clearance.

BACKGROUND: Functional luminal imaging probes (FLIP) have been used by multiple centers to assess esophagogastric junction (EGJ) function in patients at risk for esophageal obstruction but its role in diagnosing peristaltic disorders is less well studied. In particular, there are no studies comparing the sensitivity of FLIP to diagnose motility abnormalities and impaired bolus transit by high-resolution esophageal manometry with impedance. METHODS: We prospectively recruited 42 patients undergoing high-resolution esophageal manometry with impedance (HRIM) who also underwent FLIP between 2018 and 2020. HRIM parameters were analyzed using Swallow Gateway software to determine peristaltic and lower esophageal sphincter pressure measurements as well as bolus flow parameters. FLIP tracings were analyzed for the presence of repetitive antegrade contractions (RACs), EGJ distensibility, and associated parameters. RESULTS: Forty-two patients were included (11 controls, 7 achalasia, 16 fundoplication, 8 dysmotility). The mean age of patients was 10.1 ±â€Š0.9 years. There were significant differences in bolus flow parameters across diagnosis with longer bolus presence (BPT) in control patients compared with fundoplication and dysmotility patients. There was a significant correlation between EGJ diameter, EGJ distensibility and bolus flow time (BFT) for solid foods (r2 > 0.518, P < 0.02). The presence of RACs and EGJ relaxation during RACs was associated with a greater BFT and BPT across textures (P < 0.05). Forty-two percentage of patients with absent RACs, however, had clear peristalsis by HRIM. CONCLUSIONS: The presence of RACs and EGJ relaxation by FLIP correlate with improved bolus flow. Patients with an absence of RACs need HRIM to confirm any diagnoses of dysmotility.

Impact of Coronavirus Disease 2019 on the Pediatric Population with Aerodigestive Disease.

OBJECTIVE: To determine the impact of the coronavirus disease 2019 (COVID-19) quarantine on baseline health, medication use, health anxiety, and healthcare use in pediatric patients with aerodigestive disease and to evaluate for associations of commonly prescribed medications with the risk of COVID-19 illness. STUDY DESIGN: Prospective study of patients presenting in person to pediatric neurogastroenterology clinics between July 2020 and March 2021. RESULTS: Of 202 recruited patients, 71.3% were seen in the aerodigestive diseases center and 28.7% in the functional abdominal pain (FAP)/motility clinic. Of all patients, 25.1% reported improved overall health during quarantine; patients with aerodigestive disease (35.3%) reported higher rates of improved overall health compared with patients with FAP/motility disorders (3.6%, P = .0001). Patients with aerodigestive disease had fewer airway symptoms (P < .05) and less medication use during quarantine (inhaled steroids, P < .05 and albuterol, P < .05). Despite objective improvement, there was significant health-related anxiety, with greater anxiety scores reported during and at the end of quarantine (P < .05), with no difference between patient groups (P > .11). Patients continued to access healthcare during quarantine. In total, 28.7% of patients were seen in the emergency department (patients with FAP more than patients with aerodigestive disease, P = .02), and 19.8% were hospitalized. COVID-19 testing was performed in 58.4% of patients and 2.0% (n = 4) of the entire cohort tested positive. CONCLUSIONS: Patients with aerodigestive disease show improvement of airway symptoms and decreased use of medications during the pandemic, despite increased health-related anxiety. Despite complexities of accessing care due to the widespread lockdown, all patient groups continued to access healthcare.

Pharmacogenomics fail to explain proton pump inhibitor refractory esophagitis in pediatric esophageal atresia.

BACKGROUND: Esophagitis is prevalent in patients with esophageal dysmotility despite acid suppression, likely related to poor esophageal clearance. Esophageal atresia (EA) is a classic model of dysmotility where this observation holds true. In adult non-dysmotility populations, failure of esophagitis to respond to proton pump inhibitors (PPI) has been linked to variants in CYP2C19 that influence the activity of the encoded enzyme. It is unknown if CYP2C19 metabolizer phenotype contributes to PPI-refractory, non-allergic esophagitis in EA. METHODS: We performed a cross-sectional study of 314 children with (N = 188) and without (N = 126) EA who were on PPI therapy at the time of endoscopy to evaluate for possible gastroesophageal reflux disease. Patients with eosinophilic esophagitis and/or fundoplication were excluded. Clinical and histology data were collected. Genomic DNA from biopsy samples was genotyped for polymorphisms in CYP2C19. RESULTS: CYP2C19 metabolizer phenotypes were not associated with presence or severity of esophagitis (P = 0.994). In a multivariate logistic regression adjusted for potential confounders, EA was the strongest and only significant predictor of esophagitis (odds ratio 2.72, P = 0.023). Using negative binomial regression, we found that CYP2C19 phenotype was not a significant predictor of eosinophil count in children with PPI-refractory esophagitis. CONCLUSIONS: Patients with EA are significantly more likely to experience PPI-refractory, non-allergic esophagitis than controls regardless of CYP2C19 metabolizer phenotype, suggesting that factors other than CYP2C19 genetics, including dysmotility, are the primary drivers of esophagitis in EA. CYP2C19 genotype failed to predict PPI-refractory, non-allergic esophagitis in both EA and non-EA children.

Risk Factors for Bile Aspiration and its Impact on Clinical Outcomes.

INTRODUCTION: Bile reflux may cause for lung allograft rejection, yet there are no studies that determine (i) the relationship between gastric and lung bile concentrations, (ii) whether bile is present in lungs of nontransplant patients, (iii) the relationship between gastric dysmotility and lung bile, (iv) the impact of reflux therapies on lung bile, and (v) whether lung bile worsens outcomes in nontransplant patients. This study will address these gaps in the literature. METHODS: We prospectively recruited lung transplant (LTX) patients and nontransplant patients with respiratory symptoms (RP) and collected paired gastric and lung samples. Bile concentration and composition of samples was assessed using liquid chromatography-mass spectrometry. Bile results were compared with clinical parameters, including the presence of esophagitis, gastric dysmotility, and/or pathologic gastroesophageal reflux. RESULTS: Seventy patients (48 RP and 22 LTX) were recruited. Overall, 100% of gastric and 98% of bronchoalveolar lavage samples contained bile. The mean gastric bile concentrations in RP and LTX patients were 280 ± 703 nmol/L and 1,004 ± 1721 nmol/L, respectively (P = 0.02). There was no difference in lung bile concentrations between RP (9 ± 30 nmol/L) and LTX (11 ± 15 nmol/L, P = 0.7). Patients with delayed gastric emptying had higher lung bile concentrations (15.5 ± 18.8 nmol/L) than patients with normal gastric emptying (4.8 ± 5.7 nmol/L, P = 0.05) independently of reflux burden. Proton pump inhibitor use increased the proportion of unconjugated gastric bile acids. High lung bile concentrations were associated with an increased risk of hospitalization and longer hospital stays in RP patients (P < 0.05). DISCUSSION: Lung bile is almost universally present in symptomatic patients, and higher concentrations are associated with poorer respiratory outcomes.

The impact of gastrointestinal dysmotility on the aerodigestive microbiome of pediatric lung transplant recipients.

BACKGROUND: Delayed gastric emptying has been associated with increased graft rejection, although the mechanism of this association is not known. This study aims to investigate the interrelationship between delays in gastrointestinal motility and the diversity and composition of gastric, oropharyngeal, and lung microbiomes in pediatric lung transplant recipients. METHODS: We prospectively recruited 23 pediatric lung transplant recipients and 98 pediatric patients with respiratory symptoms undergoing combined endoscopy and bronchoscopy. Gastric, oropharyngeal, and bronchoalveolar lavage samples were collected for 16S sequencing. Gastric samples were also analyzed for bile composition using liquid chromatography. RESULTS: Patients who underwent lung transplantation had significantly reduced alpha diversity in gastric and oropharyngeal sites compared with patients with respiratory symptoms. This reduction in alpha diversity was especially evident in gastric samples in patients with delayed gastric emptying defined as abnormal gastric emptying on nuclear scintigraphy or as an elevation in gastric bile concentration (p ≤ 0.05). Whereas monocolonies were seen in the lungs of patients who underwent transplantation, these were not the same microbes seen in the stomach; the microbial overlap between lung and gastric samples within patients was low, and data indicated high individual variation between lung transplant recipients. Other contributors to reduced alpha diversity included antibiotics in combination with proton pump inhibitors, especially in gastric and oropharyngeal samples. CONCLUSIONS: Lung transplant recipients have reduced microbial diversity in gastric fluid (GF) and oropharynx compared with patients who did not undergo lung transplantation. The decreased alpha diversity in GF may be associated with dysmotility.

Overlapping Symptoms of Gastroesophageal Reflux and Aspiration Highlight the Limitations of Validated Questionnaires.

OBJECTIVES: Infants frequently present with feeding difficulties and respiratory symptoms, which are often attributed to gastroesophageal reflux but may be because of oropharyngeal dysphagia with aspiration. The Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) is a clinical measure of gastroesophageal reflux disease but now there is greater understanding of dysphagia as a reflux mimic. We aimed to determine the degree of overlap between I-GERQ-R and evidence of dysphagia, measured by Pediatric Eating Assessment Tool-10 (Pedi-EAT-10) and videofluoroscopic swallow study (VFSS). METHODS: We performed a prospective study of subjects <18 months old with feeding difficulties. All parents completed Pedi-EAT-10 and I-GERQ-R as a quality initiative to address parental feeding concerns. I-GERQ-R results were compared with Pedi-EAT-10 and, whenever available, results of prior VFSS. Pearson correlation coefficients were calculated to determine the relationship between scores. Groups were compared with 1-way ANOVA and Fisher exact test. ROC analysis was completed to compare scores with VFSS results. RESULTS: One hundred eight subjects with mean age 7.1 ±â€Š0.5 months were included. Pedi-EAT-10 and I-GERQ-R were correlated (r = 0.218, P = 0.023) in all subjects and highly correlated in the 77 subjects who had prior VFSS (r = 0.369, P = 0.001). The blue spell questions on I-GERQ-R had relative risk 1.148 (95% confidence interval [CI] 1.043-1.264, P = 0.142) for predicting aspiration/penetration on VFSS, with 100% specificity. Scores on the question regarding crying during/after feedings were also higher in subjects with abnormal VFSS (1.1 ±â€Š0.15 vs 0.53 ±â€Š0.22, P = 0.04). CONCLUSIONS: I-GERQ-R and the Pedi-EAT-10 are highly correlated. I-GERQ-R results may actually reflect oropharyngeal dysphagia and not just gastroesophageal reflux disease in infants.

A Phase I Dose-Escalation Study of Linsitinib (OSI-906), a Small-Molecule Dual Insulin-Like Growth Factor-1 Receptor/Insulin Receptor Kinase Inhibitor, in Combination with Irinotecan in Patients with Advanced Cancer.

LESSONS LEARNED: The maximum tolerated dose of the combination of linsitinib and irinotecan is linsitinib 450 mg daily on days 1-3 every 7 days and irinotecan 125 mg/m2 days 1 and 8 of a 21-day cycle.The adverse effects associated with the combination are not significantly increased beyond what is expected of each drug as a single agent.Multiple negative trials of insulin-like growth factor-1 receptor inhibitors performed in unselected patient populations led to the early discontinuation of linistinib development and this trial.Earlier integration of assessment of potential predictive biomarkers into clinical trials, as was planned in this study, is vital to the development of targeted therapies in oncology. BACKGROUND: This phase I dose-escalation study was designed to evaluate the safety and tolerability of the combination of irinotecan and insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib in patients with advanced cancer refractory to standard therapy. METHODS: Dose escalation in three specified dose levels was performed according to a standard 3 + 3 design. Dose levels were as follows: (a) linsitinib 400 mg and irinotecan 100 mg/m2, (b) linsitinib 450 mg and irinotecan 100 mg/m2, and (c) linsitinib 450 mg and irinotecan 125 mg/m2. Linisitinib was administered once daily on days 1-3, 8-10, and 15-17, and irinotecan on days 1 and 8. Assessment of a candidate predictive biomarker was planned in all patients, with further evaluation in an expansion cohort of advanced colorectal cancer. RESULTS: A total of 17 patients were treated, with 1 patient in both cohort 2 and 3 experiencing dose-limiting toxicity. Linsitinib 450 mg and irinotecan 125 mg/m2 was the maximum tolerated dose. Sixteen (94%) patients experienced at least one treatment-related adverse event. Neutropenia was the only grade >3 toxicity (4%). No significant hyperglycemia or QT interval prolongation was noted. No objective responses were observed; 47% (n = 8) had stable disease with median duration of 5.25 months. CONCLUSION: Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.