Upright Integrated Relaxation Pressure Facilitates Characterization of Esophagogastric Junction Outflow Obstruction.

BACKGROUND & AIMS: Under the Chicago Classification of esophageal motility disorders, esophagogastric junction outflow obstruction (EGJOO) includes a varied clinical spectrum that results in diagnostic and management difficulties. We aimed to demonstrate that including upright swallows during high-resolution manometry (HRM) helps identify patients with clinically significant EGJOO. METHODS: We performed a retrospective study of consecutive patients diagnosed with EGJOO on HRM from January 2015 through July 2017. HRM studies included 10 supine and 5 upright 5-ml liquid swallows. HRM values, esophagrams, and patient-reported outcomes were evaluated to identify factors associated with objective EGJOO (defined by esophagram) and symptomatic dysphagia (brief esophageal dysphagia questionnaire scores, >10). RESULTS: Of the 1911 patients who had HRM during the study period, 16.2% (310) were diagnosed with EGJOO; 155 patients completed an esophagram and 227 completed the brief esophageal dysphagia questionnaire. Of these patients, 30.3% (47/155) had radiographic evidence of EGJOO and 52.4% (119/227) had symptomatic dysphagia. The median upright integrated relaxation pressure for patients with radiographic evidence of EGJOO or symptomatic dysphagia was higher than for patients without. An upright integrated relaxation pressure >12 mmHg identified patients with radiographic evidence of EGJOO with 97.9% sensitivity and 15.7% specificity; for symptomatic dysphagia these values were 88.2% and 23.1%, respectively. CONCLUSION: An upright integrated relaxation pressure of >12 mmHg identifies patients with clinically significant esophageal outflow obstruction or dysphagia with a high level of sensitivity. This simple manometric maneuver (upright swallows) should be added to the standard manometric protocol.

Esophagogastric Junction Distensibility on Functional Lumen Imaging Probe Topography Predicts Treatment Response in Achalasia-Anatomy Matters!

INTRODUCTION: To compare the utility of the distensibility index (DI) on functional lumen imaging probe (FLIP) topography to other esophagogastric junction (EGJ) metrics in assessing treatment response in achalasia in the context of esophageal anatomy. METHODS: We prospectively evaluated 79 patients (at ages 17-81 years; 47% female patients) with achalasia during follow-up after pneumatic dilation, Heller myotomy, or per-oral endoscopic myotomy with timed barium esophagram, high-resolution impedance manometry, and FLIP. Anatomic deformities were identified based on consensus expert opinion. Patients were classified based on anatomy and EGJ opening to determine the association with radiographic outcome and Eckardt score (ES). RESULTS: Twenty-seven patients (34.1%) had an anatomic deformity-10 pseudodiverticula at myotomy, 7 epiphrenic diverticula, 5 sigmoid, and 5 sinktrap. A 5-minute column area of >5 cm was best associated with an ES of >3, with a sensitivity of 84% (P = 0.0013). Area under the curve for EGJ metrics in association with retention was as follows: DI, 0.90; maximal EGJ diameter, 0.76; integrated relaxation pressure, 0.64; and basal esophagogastric junction pressure, 0.53. Only FLIP metrics were associated with retention given normal anatomy (DI 2.4 vs 5.2 mm/mm Hg and maximal EGJ diameter 13.1 vs 16.6 mm in patients with and without retention, respectively; P values < 0.0001 and 0.002). Using a DI cutoff of <2.8 as abnormal, 40 of 45 patients with retention (P = 0.0001) and 23 of 25 patients with an ES of >3 (P = 0.02) had a low DI and/or anatomic deformity. With normal anatomy, 21 of 22 patients with retention had a low or borderline low DI. DISCUSSION: The FLIP DI is most useful metric for assessing the effect of achalasia treatment on EGJ opening. However, abnormal anatomy is an important mediator of outcome and treatment success will be modulated by anatomic defects that impede bolus emptying.

Postprandial High-Resolution Impedance Manometry Identifies Mechanisms of Nonresponse to Proton Pump Inhibitors.

BACKGROUND & AIMS: Recognition of rumination and supragastric belching is often delayed as symptoms may be mistakenly attributed to gastroesophageal reflux disease. However, distinct from gastroesophageal reflux disease, rumination and supragastric belching are more responsive to behavioral interventions than to acid-suppressive and antireflux therapies. Postprandial high-resolution impedance manometry (PP-HRIM) is an efficient method to identify rumination and belches. We investigated the distribution of postprandial profiles determined by PP-HRIM, and identified patient features associated with postprandial profiles among patients with nonresponse to proton pump inhibitors (PPIs). METHODS: We performed a retrospective analysis of PP-HRIM studies performed on 94 adults (mean age, 50.6 y; 62% female) evaluated for PPI nonresponsiveness at an esophageal referral center, from January 2010 through May 2016. Following a standard esophageal manometry protocol, patients ingested a solid refluxogenic test meal (identified by patients as one that induces symptoms) with postprandial monitoring up to 90 minutes (median, 50 min). Patients were assigned to 1 of 4 postprandial profiles: normal; reflux only (>6 transient lower esophageal sphincter relaxations (TLESRs)/h); supragastric belch (>2 supragastric belches/h), with or without TLESR; or rumination (≥1 rumination episode/h) with or without TLESR and supragastric belching. The primary outcome was postprandial profile. RESULTS: Of the study participants, 24% had a normal postprandial profile, 14% had a reflux-only profile, 42% had a supragastric belch profile, and 20% had a rumination profile. In multinomial regression analysis, the rumination group most frequently presented with regurgitation, the supragastric belch and rumination groups were younger in age, and the reflux-only group had a lower esophagogastric junction contractile integral. The number of weakly acidic reflux events measured by impedance-pH monitoring in patients receiving PPI therapy was significantly associated with frequency of rumination episodes and supragastric belches. CONCLUSIONS: In a retrospective analysis of 94 nonresponders to PPI therapy evaluated by PP-HRIM, we detected an abnormal postprandial pattern in 76% of cases: 42% of these were characterized as supragastric belching, 20% as rumination, and 14% as reflux only. Age, esophagogastric junction contractility, impedance-pH profiles, and symptom presentation differed significantly among groups. PP-HRIM can be used in the clinic to evaluate mechanisms of PPI nonresponse.

Improved Assessment of Bolus Clearance in Patients With Achalasia Using High-Resolution Impedance Manometry.

BACKGROUND & AIMS: Esophageal retention is typically evaluated by timed-barium esophagram in patients treated for achalasia. Esophageal bolus clearance can also be evaluated using high-resolution impedance manometry. We evaluated the associations of conventional and novel high-resolution impedance manometry metrics, esophagram, and patient-reported outcomes (PROs) in achalasia. METHODS: We performed a prospective study of 70 patients with achalasia (age, 20-81 y; 30 women) treated by pneumatic dilation or myotomy who underwent follow-up evaluations from April 2013 through December 2015 (median, 12 mo after treatment; range, 3-183 mo). Patients were assessed using timed-barium esophagrams, high-resolution impedance manometry, and PROs, determined from Eckardt scores (the primary outcome) and the brief esophageal dysphagia questionnaire. Barium column height was measured from esophagrams taken 5 minutes after ingestion of barium (200 mL). Impedance-manometry was analyzed for bolus transit (dichotomized) and with a customized MATLAB program (The MathWorks, Inc, Natick, MA) to calculate the esophageal impedance integral (EII) ratio. RESULTS: Optimal cut points to identify a good PRO (defined as Eckardt score of ≤3) were esophagram barium column height of 3 cm (identified patients with a good PRO with 63% sensitivity and 75% specificity) and an EII ratio of 0.41 (identified patients with a good PRO with 83% sensitivity and 75% specificity). Complete bolus transit identified patients with a good PRO with 28% sensitivity and 75% specificity. Of the 25 patients who met these cut points for both esophagram barium column height and EII ratio, 23 (92%) had a good PRO. Of the 17 patients who met neither cut point, 14 (82%) had a poor PRO (Eckardt score above 3). CONCLUSIONS: In a prospective study of 70 patients with achalasia, we found EII ratio identified patients with good PROs with higher levels of sensitivity (same specificity) than timed-barium esophagram or impedance-manometry bolus transit assessments. The EII ratio should be added to achalasia outcome evaluations that involve high-resolution impedance manometry as an independent measure and to complement timed-barium esophagram.

Psychosocial Distress and Quality of Life Impairment Are Associated With Symptom Severity in PPI Non-Responders With Normal Impedance-pH Profiles.

OBJECTIVES: Up to 50% of patients with reflux symptoms do not manifest a satisfactory symptom response to proton pump inhibitor (PPI) therapy. Our primary aim in this study was to identify factors associated with symptom perception among PPI non-responder phenotypes. METHODS: This prospective observational cohort study was performed from September 2014 to January 2017 at a single academic medical center and included PPI non-responders who underwent 24-h impedance-pH monitoring and completed a questionnaire set measuring patient-reported symptom severity, quality of life (QOL), and psychosocial distress. Participants were separated into cohorts based on impedance-pH results: on PPI: -acid exposure time (AET)/-symptom-reflux association (SRA), +AET, and -AET/+SRA; off PPI: functional (-AET/-SRA), gastroesophageal reflux disease (GERD) (+AET), and reflux hypersensitivity (RHS) (-AET/+SRA). The primary outcome was abnormal GERD symptom severity defined by GerdQ≥8. RESULTS: One hundred and ninety-two participants were included. Impedance-pH on PPI was performed on 125: 72 (58%) -AET/-SRA, 42 (34%) +AET, and 11 (9%) -AET/+SRA. Among the -AET/-SRA group, younger age, higher dysphagia scores, QOL impairment, and higher brief symptom index were associated with GerdQ≥8. Among the +AET group, higher number of reflux-associated symptoms and lower distal contractile integral was associated with GerdQ≥8. Impedance-pH off PPI was performed on 67 participants: 39 (58%) functional, 16 (24%) GERD, and 12 (18%) RHS. Among the functional group, higher QOL impairment and dysphagia scores were seen with GerdQ≥8. CONCLUSIONS: Perceptions of reflux symptoms are associated with psychosocial distress, reduced QOL, and sensation of dysphagia among PPI non-responders with normal impedance-pH. Among PPI refractory GERD patients, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors.

Evaluation of Esophageal Motility Utilizing the Functional Lumen Imaging Probe.

OBJECTIVES: Esophagogastric junction (EGJ) distensibility and distension-mediated peristalsis can be assessed with the functional lumen imaging probe (FLIP) during a sedated upper endoscopy. We aimed to describe esophageal motility assessment using FLIP topography in patients presenting with dysphagia. METHODS: In all, 145 patients (aged 18-85 years, 54% female) with dysphagia that completed upper endoscopy with a 16-cm FLIP assembly and high-resolution manometry (HRM) were included. HRM was analyzed according to the Chicago Classification of esophageal motility disorders; major esophageal motility disorders were considered "abnormal". FLIP studies were analyzed using a customized program to calculate the EGJ-distensibility index (DI) and generate FLIP topography plots to identify esophageal contractility patterns. FLIP topography was considered "abnormal" if EGJ-DI was <2.8 mm2/mm Hg or contractility pattern demonstrated absent contractility or repetitive, retrograde contractions. RESULTS: HRM was abnormal in 111 (77%) patients: 70 achalasia (19 type I, 39 type II, and 12 type III), 38 EGJ outflow obstruction, and three jackhammer esophagus. FLIP topography was abnormal in 106 (95%) of these patients, including all 70 achalasia patients. HRM was "normal" in 34 (23%) patients: five ineffective esophageal motility and 29 normal motility. In all, 17 (50%) had abnormal FLIP topography including 13 (37%) with abnormal EGJ-DI. CONCLUSIONS: FLIP topography provides a well-tolerated method for esophageal motility assessment (especially to identify achalasia) at the time of upper endoscopy. FLIP topography findings that are discordant with HRM may indicate otherwise undetected abnormalities of esophageal function, thus FLIP provides an alternative and complementary method to HRM for evaluation of non-obstructive dysphagia.

High-Resolution Impedance Manometry Metrics of the Esophagogastric Junction for the Assessment of Treatment Response in Achalasia.

OBJECTIVES: We aimed to evaluate the value of novel high-resolution impedance manometry (HRIM) metrics, bolus flow time (BFT), and esophagogastric junction (EGJ) contractile integral (CI), as well as EGJ pressure (EGJP) and the integrated relaxation pressure (IRP), as indicators of treatment response in achalasia. METHODS: We prospectively evaluated 75 patients (ages 19-81, 32 female) with achalasia during follow-up after pneumatic dilation or myotomy with Eckardt score (ES), timed-barium esophagram (TBE), and HRIM. Receiver-operating characteristic (ROC) curves for good symptomatic outcome (ES≤3) and good radiographic outcome (TBE column height at 5 min<5 cm) were generated for each potential predictor of treatment response (EGJP, IRP, BFT, and EGJ-CI). RESULTS: Follow-up occurred at a median (range) 12 (3-291) months following treatment. A total of 49 patients had good symptomatic outcome and 46 had good radiographic outcome. The area-under-the-curves (AUCs) on the ROC curve for symptomatic outcome were 0.55 (EGJP), 0.62 (IRP), 0.77 (BFT) and 0.56 (EGJ-CI). The AUCs for radiographic outcome were 0.64 (EGJP), 0.48 (IRP), 0.73 (BFT), and 0.65 (EGJ-CI). Optimal cut-points were determined as 11 mm Hg (EGJP), 12 mm Hg (IRP), 0 s (BFT), and 30 mm Hg•cm (EGJ-CI) that provided sensitivities/specificities of 57%/46% (EGJP), 65%/58% (IRP), 78%/77% (BFT), and 53%/62% (EGJ-CI) to predict symptomatic outcome and 57%/66% (EGJP), 57%/41% (IRP), 76%/69% (BFT), and 57%/66% (EGJ-CI) to predict radiographic outcome. CONCLUSIONS: BFT, a novel HRIM metric, provided an improved functional assessment over manometric measures of EGJP, IRP, and EGJ-CI at follow-up after achalasia treatment and may help direct clinical management.

Cardiomyocytes induce macrophage receptor shedding to suppress phagocytosis.

BACKGROUND: Mobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology. OBJECTIVE: To determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages. RESULTS: In infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk-/- macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of myocyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site. CONCLUSION: Utilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage-cardiomyocyte cross-talk that contribute to cardiac pathophysiology.

Esophageal hypervigilance is prevalent across gastroesophageal reflux disease presentations.

BACKGROUND: There is a need to identify factors outside of abnormal reflux that contribute to gastroesophageal reflux disease (GERD). Esophageal hypervigilance is a psychological process impacting symptom experience in esophageal disease. However, little is known about the presence of hypervigilance in GERD phenotypes, especially in those with abnormal acid exposure or symptom index scores. The primary aim was to assess differences in self-reported esophageal hypervigilance across different GERD presentations. The secondary aim was to evaluate esophageal hypervigilance as a predictor of symptom severity. METHODS: We conducted retrospective data analyses on a cohort of adult patients with reflux symptoms that underwent 96-hour wireless pH monitoring from 9/2015 to 9/2017. Patients were stratified into groups based on the number of days they exhibited positive acid exposure time (AET; 0 days, 1-2 days, 3+ days), and symptom index scores (SI; 0 days, 1-day, 2+ days). Esophageal hypervigilance and anxiety, and symptom frequency and severity were assessed between groups. KEY RESULTS: A total of 123 AET cases and 116 SI cases were included for analysis. Esophageal hypervigilance and anxiety scores did not significantly differ based on the number of days of positive AET (p = 0.311) or SI (p = 0.118). Symptom severity and perceived symptom frequency differed between groups. Hypervigilance significantly predicted symptom severity, when controlling for symptom-specific anxiety. CONCLUSIONS: Esophageal hypervigilance is persistent across patients with reflux, irrespective of acid burden and symptom index, and significantly predicts symptom severity. Hypervigilance should be considered as an independent factor contributing to esophageal symptom perception.

Diagnostic yield and reliability of post-prandial high-resolution manometry and impedance-ph for detecting rumination and supragastric belching in PPI non-responders.

BACKGROUND: Supragastric belching (SGB) and rumination are behavioral disorders associated with proton pump inhibitor (PPI) non-response and can be diagnosed using multichannel intraluminal impedance-pH (MII-pH) and post-prandial high-resolution impedance manometry (PPHRIM). This pilot study compared diagnostic yield and inter-rater agreement for SGB and rumination using MII-pH and PPHRIM. METHODS: Three esophageal physiologists performed blinded interpretations of MII-pH and PPHRIM in 22 PPI non-responders. Raters selected from 4 diagnostic impressions (normal, GERD, behavioral disorders, GERD+behavioral disorders) without clinical context. Primary outcomes were diagnostic impressions compared against clinical gold standard impression, between raters, and between test modalities. Following a 28-month wash-out period, raters re-interpreted MII-pH with clinical context and under consensus definition of diagnostic criteria. KEY RESULTS: Compared to gold standard, rater accuracy for presence of behavioral disorders ranged from 45 to 77% on MII-pH and 45-59% on PPHRIM. On MII-pH, inter-rater agreement was fair for diagnosis (ĸ0.32, p < 0.01) and suboptimal for presence of behavioral disorders (ĸ0.13, p = 0.14). On PPHRIM, inter-rater agreement was suboptimal for both diagnosis (ĸ0.03, p = 0.34) and presence of a behavioral disorder (ĸ-0.22, p = 0.96). Inter-rater agreement improved in post hoc MII-pH interpretations. Rumination was more frequently identified on PPHRIM (23, 35%) compared to MII-pH (7, 11%). CONCLUSIONS AND INFERENCES: Diagnostic accuracy and inter-rater agreement are higher for MII-pH than PPHRIM, and behavioral disorders are more frequently identified on PPHRIM. Identifying behavioral disorders on MII-pH and PPHRIM has implications for clinical evaluation of PPI non-response; clinical context is essential for accurate study interpretation. Further work is needed to standardize definitions and interpretations.

Study of Association Between Different Coronary Artery Disease Presentations and Its Effect on Short-Term Mortality, Readmission, and Cost in Patients Undergoing Percutaneous Coronary Interventions.

Introduction Atherosclerotic coronary artery disease (CAD) is the major cause of mortality in the USA. CAD requiring percutaneous coronary intervention (PCI) can have a wide spectrum of presentations. We reviewed the cost of admission and PCI at the tertiary care center stratified for different CAD presentation types. Methods We performed a retrospective study of 7,389 patients undergoing coronary angiogram at our facility from 2015 to 2017. Patients were selected from CathPCI registry. Chart review was done for readmission and death data. Cost data were provided by the finance department. Patients going for coronary artery bypass surgery (CABG) were excluded. We split the patients based on their need for PCI. Cost analysis was based on CAD presentation types (No symptoms, atypical symptoms, stable angina, unstable angina, NSTEMI [non-ST segment elevation myocardial infarction], STEMI [ST-segment elevation myocardial infarction]). Adjusted linear regression was run for the outcomes. Primary outcomes were 30-day readmission and death. The secondary outcome was cost of admission. Results The final sample size was 6,403. The mean age was 65.6 years (SD: 12.5; male: 63.8%). 2444 required PCI (38%; p < 0.001). PCI group had lower mean age (62.5 years; SD: 12.3, p<0.001) with lower BMI (30.6 vs 31.1, p=0.015). PCI group had significantly lower odds for 30-day readmission (OR: 0.63; CI: 0.45-0.89; p=0.009) and 30-day mortality (OR:0.60; CI: 0.41-0.89; p = 0.011). A severe presentation increased the odds of getting PCI. Cost of admission was higher in all groups receiving PCI. Conclusions PCI group had better 30-day readmission and mortality rates. PCI increases the cost of admission in all CAD types.

Troponin Levels at Presentation Before Coronary Angiogram and Their Association With Cost, Mortality, and Readmission.

Background and objective In patients undergoing coronary angiogram, the degree of cardiac enzyme elevation at presentation has been thought of as a strong and independent predictor of in-hospital mortality and readmission. Recent studies, however, have suggested a lack of clarity regarding this speculation, particularly with regard to troponin elevations. Additionally, the impact of troponin levels (TnI) at presentations on cost is poorly understood. In this study, we aimed to evaluate the association of Tnl at initial presentation with 30-day all-cause readmission and all-cause mortality as well as admission costs. Methods This study was a retrospective analysis of 7,388 patients who underwent coronary angiogram at our facility from 2015 to 2017. Patients were identified from a local CathPCI Registry® registry, and a subsequent chart review was performed for readmission and mortality data. Cost data were provided by our in-facility finance department. We excluded patients with incomplete records and those who required coronary artery bypass grafting (CABG). After the exclusion of patients deemed ineligible, the final sample size eligible for analysis was 1,163. Patients were divided into two groups based on Tnl at presentation with a cut-off value of 0.04 ng/ml. Adjusted regression and multivariate analysis were used for clinical outcomes. Primary outcomes were 30-day readmission and mortality. The secondary outcome was the admission cost. Results Within our cohort, the average participant age was 64.6 years (SD: 12.7), and the majority of them were male (70.7%). Of these patients, 207 had lower TnI (<0.04 ng/ml), while 956 had higher TnI at presentation. The high TnI (≥0.04 ng/ml) group had a significantly higher number of patients with a family history of coronary artery disease (CAD) (13.8% vs. 7.7%: p=0.017) and those on dialysis (3.2% vs. 0.5%: p=0.028) compared to the low Tnl group. Additionally, we did not find any significant difference in 30-day mortality or readmission between the two groups in our cohort. On average, each patient in the high TnI group spent $936 more for hospital admissions compared to patients in the low Tnl group. However, this difference was not statistically significant. Conclusions Tnl at admission did not reveal a significant impact on 30-day mortality or readmission, which is consistent with the findings of previous studies. A high Tnl at admission increased the cost of admission; however, the difference was not statistically significant in our cohort.

Inorganic polyphosphate as an energy source in tumorigenesis.

Cancer cells have high demands for energy to maintain their exceedingly proliferative growth. However, the mechanism of energy expenditure in cancer is not well understood. We hypothesize that cancer cells might utilize energy-rich inorganic polyphosphate (polyP), as energetic reserve. PolyP is comprised of orthophosphates linked by phosphoanhydride bonds, as in ATP. Here, we show that polyP is highly abundant in several types of cancer cells, including brain tumor-initiating cells (BTICs), i.e., stem-like cells derived from a mouse brain tumor model that we have previously described. The polymer is avidly consumed during starvation of the BTICs. Depletion of ATP by inhibiting glycolysis and mitochondrial ATP-synthase (OXPHOS) further decreases the levels of polyP and alters morphology of the cells. Moreover, enzymatic hydrolysis of the polymer impairs the viability of cancer cells and significantly deprives ATP stores. These results suggest that polyP might be utilized as a source of phosphate energy in cancer. While the role of polyP as an energy source is established for bacteria, this finding is the first demonstration that polyP may play a similar role in the metabolism of cancer cells.