Exercise testing and postoperative complications after minimally invasive lung resection: A cohort study.

Background: Peak oxygen uptake ( V ˙ O 2 ) during cardiospulmonary exercise testing (CPET) is used to stratify postoperative risk following lung cancer resection but peak V ˙ O 2 thresholds to predict post-operative mortality and morbidity were derived mostly from patients who underwent thoracotomy. Objectives: We evaluated whether peak V ˙ O 2 or other CPET-derived variables predict post-operative mortality and cardiopulmonary morbidity after minimally invasive video-assisted thoracoscopic surgery (VATS) for lung cancer resection. Methods: A retrospective analysis of patients who underwent VATS lung resection between 2002 and 2019 and in whom CPET was performed. Logistic regression models were used to determine predictors of postoperative outcomes until 30 days after surgery. The ability of peak V ˙ O 2 to discriminate between patients with and without post-operative complications was evaluated using Receiver operating characteristic (ROC) analysis. Results: Among the 593 patients, postoperative cardiopulmonary complications occurred in 92 (15.5%) individuals, including three deaths. Mean peak V ˙ O 2 was 18.8 ml⋅kg-1⋅min-1, ranging from 7.0 to 36.4 ml⋅kg-1⋅min-1. Best predictors of postoperative morbidity and mortality were peripheral arterial disease, bilobectomy or pneumonectomy (versus sublobar resection), preoperative FEV1, peak V ˙ O 2 , and peak V ˙ E / V ˙ C O 2 . The proportion of patients with peak V ˙ O 2 of < 15 ml⋅kg-1⋅min-1, 15 to < 20 ml⋅kg-1⋅min-1 and ≥ 20 ml⋅kg-1⋅min-1 experiencing at least one postoperative complication was 23.8, 16.3 and 10.4%, respectively. The area under the ROC curve for peak V ˙ O 2 was 0.63 (95% CI: 0.57-0.69). Conclusion: Although lower peak V ˙ O 2 was a predictor of postoperative complications following VATS lung cancer resection, its ability to discriminate patients with or without complications was limited.

Safety of Transesophageal Echocardiography to Guide Structural Cardiac Interventions.

BACKGROUND: Despite the widespread use of transesophageal echocardiography (TEE) to guide structural cardiac interventions, studies evaluating safety in this context are lacking. OBJECTIVES: This study sought to determine the incidence, types of complications, and factors associated with esophageal or gastric lesions following TEE manipulation during structural cardiac interventions. METHODS: This was a prospective study including 50 patients undergoing structural cardiac interventions in which TEE played a central role in guiding the procedure (mitral and tricuspid valve repair, left atrial appendage closure, and paravalvular leak closure). An esophagogastroduodenoscopy (EGD) was performed before and immediately after the procedure to look for new injuries that might have arisen during the course of the intervention. Patients were divided in 2 cohorts according to the type of injury: complex lesions (intramural hematoma, mucosal laceration) and minor lesions (petechiae, ecchymosis). The factors associated with an increased risk of complications were assessed. RESULTS: Post-procedural EGD showed a new injury in 86% (n = 43 of 50) of patients, with complex lesions accounting for 40% (n = 20 of 50) of cases. Patients with complex lesions presented more frequently with an abnormal baseline EGD (70% vs. 37%; p = 0.04) and had a higher incidence of post-procedural dysphagia or odynophagia (40% vs. 10%; p = 0.02). Independent factors associated with an increased risk of complex lesions were a longer procedural time under TEE manipulation (for each 10-min increment in imaging time, odds ratio: 1.27; 95% confidence interval: 1.01 to 1.59) and poor or suboptimal image quality (odds ratio: 4.93; 95% confidence interval: 1.10 to 22.02). CONCLUSIONS: Most patients undergoing structural cardiac interventions showed some form of injury associated with TEE, with longer procedural time and poor or suboptimal image quality determining an increased risk. Imaging experts performing this technique should be aware of the nature of potential complications, to take the necessary precautions to prevent their occurrence and facilitate early diagnosis and treatment.

Esophagogastric junction distensibility measurements during Heller myotomy and POEM for achalasia predict postoperative symptomatic outcomes.

BACKGROUND: The functional lumen imaging probe (FLIP) is a novel diagnostic tool that can be used to measure esophagogastric junction (EGJ) distensibility. In this study, we performed intraoperative FLIP measurements during laparoscopic Heller myotomy (LHM) and peroral esophageal myotomy (POEM) for treatment of achalasia and evaluated the relationship between EGJ distensibility and postoperative symptoms. METHODS: Distensibility index (DI) (defined as the minimum cross-sectional area at the EGJ divided by distensive pressure) was measured with FLIP at two time points during LHM and POEM: (1) at baseline after induction of anesthesia, and (2) after operation completion. RESULTS: Measurements were performed in 20 patients undergoing LHM and 36 undergoing POEM. Both operations resulted in an increase in DI, although this increase was larger with POEM (7 ± 3.1 vs. 5.1 ± 3.4 mm(2)/mmHg, p < .05). The two patients (both LHM) with the smallest increases in DI (1 and 1.6 mm(2)/mmHg) both had persistent symptoms postoperatively and, overall, LHM patients with larger increases in DI had lower postoperative Eckardt scores. In the POEM group, there was no correlation between change in DI and symptoms; however, all POEM patients experienced an increase in DI of >3 mm(2)/mmHg. When all patients were divided into thirds based on final DI, none in the lowest DI group (<6 mm(2)/mmHg) had symptoms suggestive of reflux (i.e., GerdQ score >7), as compared with 20 % in the middle third (6-9 mm(2)/mmHg) and 36 % in the highest third (>9 mm(2)/mmHg). Patients within an "ideal" final DI range (4.5-8.5 mm(2)/mmHg) had optimal symptomatic outcomes (i.e., Eckardt ≤ 1 and GerdQ ≤ 7) in 88 % of cases, compared with 47 % in those with a final DI above or below that range (p < .05). CONCLUSIONS: Intraoperative EGJ distensibility measurements with FLIP were predictive of postoperative symptomatic outcomes. These results provide initial evidence that FLIP has the potential to act as a useful calibration tool during operations for achalasia.

Flow time through esophagogastric junction derived during high-resolution impedance-manometry studies: a novel parameter for assessing esophageal bolus transit.

This study aimed to develop and validate a method to measure bolus flow time (BFT) through the esophagogastric junction (EGJ) using a high-resolution impedance-manometry (HRIM) sleeve. Ten healthy subjects were studied with concurrent HRIM and videofluoroscopy; another 15 controls were studied with HRIM alone. HRIM studies were performed using a 4.2-mm-outer diameter assembly with 36 pressure sensors at 1-cm intervals and 18 impedance segments at 2-cm intervals (Given Imaging, Los Angeles, CA). HRIM and fluoroscopic data from four barium swallows, two in the supine and two in the upright position, were analyzed to create a customized MATLAB program to calculate BFT using a HRIM sleeve comprising three sensors positioned at the crural diaphragm. Bolus transit through the EGJ measured during blinded review of fluoroscopy was almost identical to BFT calculated with the HRIM sleeve, with the nadir impedance deflection point used as the signature of bolus presence. Good correlation existed between videofluoroscopy for measurement of upper sphincter relaxation to beginning of flow [R = 0.97, P < 0.001 (supine) and R = 0.77, P < 0.01 (upright)] and time to end of flow [R = 0.95, P < 0.001 (supine) and R = 0.82, P < 0.01 (upright)]. The medians and interquartile ranges (IQR) of flow time though the EGJ in 15 healthy subjects calculated using the virtual sleeve were 3.5 s (IQR 2.3-3.9 s) in the supine position and 3.2 s (IQR 2.3-3.6 s) in the upright position. BFT is a new metric that provides important information about bolus transit through the EGJ. An assessment of BFT will determine when the EGJ is open and will also provide a useful method to accurately assess trans-EGJ pressure gradients during flow.

An extended proximal esophageal myotomy is necessary to normalize EGJ distensibility during Heller myotomy for achalasia, but not POEM.

BACKGROUND: For laparoscopic Heller myotomy (LHM), the optimal myotomy length proximal to the esophagogastric junction (EGJ) is unknown. In this study, we used a functional lumen imaging probe (FLIP) to measure EGJ distensibility changes resulting from variable proximal myotomy lengths during LHM and peroral esophageal myotomy (POEM). METHODS: Distensibility index (DI) (defined as the minimum cross-sectional area at the EGJ divided by pressure) was measured with FLIP after each operative step. During LHM and POEM, each patient's myotomy was performed in two stages: first, a myotomy ablating only the EGJ complex was created (EGJ-M), extending from 2 cm proximal to the EGJ, to 3 cm distal to it. Next, the myotomy was lengthened 4 cm further cephalad to create an extended proximal myotomy (EP-M). RESULTS: Measurements were performed in 12 patients undergoing LHM and 19 undergoing POEM. LHM resulted in an overall increase in DI (1.6 ± 1 vs. 6.3 ± 3.4 mm(2)/mmHg, p < 0.001). Creation of an EGJ-M resulted in a small increase (1.6-2.3 mm(2)/mmHg, p < 0.01) and extension to an EP-M resulted in a larger increase (2.3-4.9 mm(2)/mmHg, p < 0.001). This effect was consistent, with 11 (92%) patients experiencing a larger increase after EP-M than after EGJ-M. Fundoplication resulted in a decrease in DI and deinsufflation an increase. POEM resulted in an increase in DI (1.3 ± 1 vs. 9.2 ± 3.9 mm(2)/mmHg, p < 0.001). Both creation of the submucosal tunnel and performing an EGJ-M increased DI, whereas lengthening of the myotomy to an EP-M had no additional effect. POEM resulted in a larger overall increase from baseline than LHM (7.9 ± 3.5 vs. 4.7 ± 3.3 mm(2)/mmHg, p < 0.05). CONCLUSIONS: During LHM, an EP-M was necessary to normalize distensibility, whereas during POEM, a myotomy confined to the EGJ complex was sufficient. In this cohort, POEM resulted in a larger overall increase in EGJ distensibility.

Assessing bolus retention in achalasia using high-resolution manometry with impedance: a comparator study with timed barium esophagram.

OBJECTIVES: The aim of this study was to assess whether high-resolution impedance manometry (HRIM) could be used to assess bolus retention similar to the timed barium esophagram (TBE). METHODS: Twenty achalasia patients (10 males, aged 21-79 years) were prospectively evaluated with HRIM and TBE to determine the correlation between barium column height and the impedance bolus height (IBH). The TBE protocol used a 200-ml barium challenge and the HRIM protocol used a 200-ml saline challenge protocol. Both protocols were performed in an upright position and the heights of the barium and impedance columns were measured at 1 and 5 min. Analysis of IBH was performed with a topographic technique and a spatial impedance variation plot. RESULTS: There was no significant difference between the median IBH and barium column at 1 min (IBH: 12.0 cm (interquartile range (IQR), 8.0-18.0); TBE: 12.0 cm (IQR, 7.0-19.0); P=0.90) or at 5 min (IBH: 11.0 cm (IQR, 1.0-17.0); TBE: 9.0 cm (IQR, 4.0-12.0); P=0.47). In addition, the correlation between the two measurements at 1 and 5 min was 0.60 and 0.86, respectively. Using a barium column or impedance height of >5.0 as a definition of bolus retention was associated with 75% concordance at 1 min and 95% concordance at 5 min. CONCLUSIONS: There was excellent agreement between TBE and high-resolution impedance manometry (HRIM) for assessing bolus retention at 5 min. Thus, HRM with impedance may be used as a single test to assess bolus retention and motor function in the management of achalasia.

Lack of correlation between HRM metrics and symptoms during the manometric protocol.

OBJECTIVES: Although esophageal motor disorders are associated with chest pain and dysphagia, minimal data support a direct relationship between abnormal motor function and symptoms. This study investigated whether high-resolution manometry (HRM) metrics correlate with symptoms. METHODS: Consecutive HRM patients without previous surgery were enrolled. HRM studies included 10 supine liquid, 5 upright liquid, 2 upright viscous, and 2 upright solid swallows. All patients evaluated their esophageal symptom for each upright swallow. Symptoms were graded on a 4-point likert score (0, none; 1, mild; 2, moderate; 3, severe). The individual liquid, viscous or solid upright swallow with the maximal symptom score was selected for analysis in each patient. HRM metrics were compared between groups with and without symptoms during the upright liquid protocol and the provocative protocols separately. RESULTS: A total of 269 patients recorded symptoms during the upright liquid swallows and 72 patients had a swallow symptom score of 1 or greater. Of the 269 patients, 116 recorded symptoms during viscous or solid swallows. HRM metrics were similar between swallows with and without associated symptoms in the upright, viscous, and solid swallows. No correlation was noted between HRM metrics and symptom scores among swallow types. CONCLUSIONS: Esophageal symptoms are not related to abnormal motor function defined by HRM during liquid, viscous or solid bolus swallows in the upright position. Other factors beyond circular muscle contraction patterns should be explored as possible causes of symptom generation.

Comparison of esophagogastric junction distensibility changes during POEM and Heller myotomy using intraoperative FLIP.

BACKGROUND: Peroral endoscopic myotomy (POEM) is a novel endoscopic surgical procedure for the treatment of achalasia. The comparative effects of POEM and laparoscopic Heller myotomy (LHM) on esophagogastric junction (EGJ) physiology are unknown. A novel measurement catheter, the functional lumen imaging probe (FLIP), allows for intraoperative evaluation of EGJ compliance by measuring luminal geometry and pressure during volume-controlled distensions. METHODS: Distensibility index (DI) (defined as the minimum cross-sectional area at the EGJ divided by pressure) was measured with FLIP intraoperatively in patients undergoing LHM and POEM. Separate measurements were taken after each operative step. During LHM, measurements were performed after: (1) induction of anesthesia, (2) insufflation of pneumoperitoneum, (3) hiatal dissection and esophageal mobilization, (4) myotomy, (5) partial fundoplication, and (6) deinsufflation. During POEM, they were performed after: (1) induction of anesthesia, (2) submucosal tunnel creation, and (3) myotomy. RESULTS: Eleven LHM and 14 POEM patients underwent intraoperative FLIP. Baseline DI was similar between groups. LHM resulted in an overall increase in mean DI (pre 1.4 vs. post 7.6 mm(2)/mmHg, using a 40-ml distension volume; p < 0.001). Insufflation of pneumoperitoneum and hiatal dissection did not affect DI. Myotomy caused an increase in DI. Partial fundoplication (6 Toupet, 5 Dor) caused a decrease in DI, and deinsufflation caused an increase in DI. POEM also resulted in an overall increase in mean DI (pre 1.4 vs. post 7.9 mm(2)/mmHg; p < 0.001). Measured individually, both submucosal tunnel creation and myotomy caused increases in DI. When overall changes were compared, there were no differences in the amount of DI increase between LHM and POEM. CONCLUSIONS: POEM and LHM result in a similar improvement in EGJ distensibility intraoperatively. Further study is needed to correlate intraoperative FLIP measurements with postoperative symptomatic and physiologic outcomes.

Esophageal distensibility as a measure of disease severity in patients with eosinophilic esophagitis.

BACKGROUND & AIMS: The aim of this study was to assess whether measurements of esophageal distensibility, made by high-resolution impedance planimetry, correlated with important clinical outcomes in patients with eosinophilic esophagitis. METHODS: Seventy patients with eosinophilic esophagitis (50 men; age, 18-68 y) underwent endoscopy with esophageal biopsy collection and high-resolution impedance planimetry using the functional lumen-imaging probe. The patients were followed up prospectively for an average of 9.2 months (range, 3-14 mo), and the risk of food impaction, requirement for dilation, and symptom severity during the follow-up period was determined from medical records. Esophageal distensibility metrics and the severity of mucosal eosinophilia at baseline were compared between patients presenting with and without food impaction and those requiring or not requiring esophageal dilation. Logistic regression and stratification assessments were used to assess the predictive value of esophageal distensibility metrics in assessing risk of food impaction, the need for dilation, and continued symptoms. RESULTS: Patients with prior food impactions had significantly lower distensibility plateau (DP) values than those with solid food dysphagia alone. In addition, patients sustaining food impaction and requiring esophageal dilation during the follow-up period had significantly lower DP values than those who did not. The severity of mucosal eosinophilia did not correlate with risk for food impaction, the requirement for dilation during follow-up evaluation, or DP values. CONCLUSIONS: Reduced esophageal distensibility predicts risk for food impaction and the requirement for esophageal dilation in patients with eosinophilic esophagitis. The severity of mucosal eosinophilia was not predictive of these outcomes and had a poor correlation with esophageal distensibility.

Functional luminal imaging probe topography: an improved method for characterizing esophageal distensibility in eosinophilic esophagitis.

OBJECTIVES: The aims of this study were to develop a new method for analysis and presentation of esophageal distensibility data using high-resolution impedance planimetry recordings during a volume-controlled distention. METHODS: Two control subjects and six patients with eosinophilic esophagitis (EoE) with stricture, narrow caliber or normal endoscopy according to EndoFLIP studies were included for analysis. Median filtering and pulse detection techniques were applied to the pressure signal and a wavelet decomposition technique was applied to the 16 channels of raw esophageal diameter data to reduce vascular artifact, respiratory effect and remove esophageal contraction interference. These data were used to generate a functional luminal imaging probe (FLIP) topography plot that describes regional variation of cross-sectional area (CSA). A previously developed computer program was used to calculate and model the CSA-pressure data to derive the slope of line fitting and distension plateau for each individual subject. The results were compared among the four endoscopic phenotypes. RESULTS: Patients with EoE and normal endoscopy had similar esophageal distensibility parameters to those of normal controls whereas patients with EoE and stricture or narrow caliber had much lower distensibility than patients with EoE and normal endoscopy. The FLIP topography plots provided a global assessment of the esophageal distensibility along the axial plane of measurement that differentiated patients with varying degrees of endoscopic abnormality. CONCLUSIONS: New techniques can be leveraged to improve data analysis and presentation using EndoFLIP assessment of the esophageal body in EoE. These techniques may be helpful in defining clinically relevant phenotypes and guiding treatment strategies and should be helpful in structuring future outcome trials.

Partial recovery of peristalsis after myotomy for achalasia: more the rule than the exception.

IMPORTANCE: Although successful treatment of achalasia depends on alleviating the obstruction at the esophagogastric junction, the postintervention contractile and pressurization pattern may also play a role in outcome. OBJECTIVE: To determine whether myotomy that alleviates the esophagogastric junction outflow obstruction in achalasia might improve peristalsis. DESIGN: Retrospective study from August 1, 2004, through January 30, 2012. SETTING: Two tertiary care hospitals in Chicago and Lyon. PATIENTS: We included 30 patients (18 male; mean age [range], 43 [17-78] years), of whom 8 had type 1 (26.6%), 17 had type 2 (56.7%), and 5 (16.7%) had type 3 achalasia according to the Chicago classification. INTERVENTIONS: Esophageal high-resolution manometry before and after laparoscopic or endoscopic myotomy. MAIN OUTCOMES MEASURE: The integrity of peristalsis, characterized as intact, weak contractions; frequent failed peristalsis; or premature contractions. RESULTS: Although peristaltic fragments were evident only in patients with type 3 achalasia before treatment, intact, weak, or frequent failed peristalsis was encountered in 5 patients with type 1 (63%), 8 with type 2 (47%), and 4 with type 3 (80%) achalasia after myotomy. One patient with type 3 achalasia had distal esophageal spasm after treatment. In patients with a postmyotomy integrated relaxation pressure of less than 15 mm Hg, only 10 (40%) had persistent absent peristalsis. Panesophageal pressurization disappeared after myotomy in 16 of 19 patients. In the 5 patients with postmyotomy integrated relaxation pressure of more than 15 mm Hg, 4 had weak peristalsis and 1 had absent peristalsis. CONCLUSIONS AND RELEVANCE: Reduction or normalization of the esophagogastric junction relaxation pressure achieved by myotomy in achalasia is associated with partial recovery of peristalsis in some patients, suggesting that the disease process progresses from the esophagogastric junction to the esophageal body. Whether the return of peristalsis is predictive of an improved therapeutic outcome requires further study.

A comparison of symptom severity and bolus retention with Chicago classification esophageal pressure topography metrics in patients with achalasia.

BACKGROUND & AIMS: We compared findings from timed barium esophagrams (TBEs) and esophageal pressure topography studies among achalasia subtypes and in relation to symptom severity. METHODS: We analyzed data from 50 patients with achalasia (31 men; age, 20-79 y) who underwent high-resolution manometry (HRM), had TBE after a 200-mL barium swallow, and completed questionnaires that determined Eckardt Scores. Twenty-five patients were not treated, and 25 patients were treated (11 by pneumatic dilation, 14 by myotomy). Nonparametric testing was used to assess differences among groups of treated patients (10 had type 1 achalasia and 15 had type 2 achalasia), and the Pearson correlation was used to assess their relationship. RESULTS: There were no significant differences in TBE measurements between patient groups. Of the 25 patients who received treatment, 10 had a manometric pattern consistent with persistent achalasia after treatment (6 patients with type 1 and 4 patients with type 2 achalasia), whereas 15 appeared to have resolved the achalasia pattern (peristalsis was absent in 8 patients and weak in 7 patients). The height of the barium column at 5 minutes and Eckardt Scores were reduced significantly in patients who had resolved their achalasia pattern, based on HRM. The integrated relaxation pressure and the TBE column height correlated at 5 minutes (r = 0.422; P < .05). CONCLUSIONS: Patients who resolved their achalasia pattern, based on HRM, showed improved emptying based on TBE measurements and improved symptom scores. There was no significant difference between patients with type 1 or type 2 achalasia in TBEs. These findings indicate that normalization of the integrated relaxation pressure on HRM is a clinically relevant objective of treatment for achalasia.

High-resolution manometry correlates of ineffective esophageal motility.

OBJECTIVES: There are currently no criteria for ineffective esophageal motility (IEM) and ineffective swallow (IES) in esophageal pressure topography (EPT). Our aims were to use high-resolution manometry metrics to define IEM within the Chicago Classification and to determine the distal contractile integral (DCI) threshold for IES. METHODS: The EPT of 150 patients with either dysphagia or reflux symptoms were reviewed. Peristaltic function in EPT was defined by the Chicago Classification; the corresponding conventional line tracing (CLT) were reviewed separately. Generalized linear mixed models were used to find thresholds for DCI corresponding to traditionally determined IES and failed swallows. An external validation sample was used to confirm these thresholds. RESULTS: In terms of swallow subtypes, IES in CLT were a mixture of normal, weak, and failed peristalsis in EPT. A DCI of 450 mm Hg-s-cm was determined to be optimal in predicting IES. In the validation sample, the threshold of 450 mm Hg-s-cm showed strong agreement with CLT determination of IES (positive percent agreement 83%, negative percent agreement 90%). The patient diagnostic level agreement between CLT and EPT was good (78.6% positive percent agreement and 63.9% negative percent agreement), with negative agreement increasing to 92.0% if proximal breaks were excluded. CONCLUSIONS: The manometric correlate of IEM in EPT is a mixture of failed swallows and weak swallows with breaks in the middle/distal troughs. A DCI value <450 mm Hg-s-cm can be used to predict IES previously defined in CLT. IEM can be defined by >5 swallows with weak/failed peristalsis or with a DCI <450 mm Hg-s-cm.

Adding a radial dimension to the assessment of esophagogastric junction relaxation: validation studies of the 3D-eSleeve.

High-resolution manometry (HRM) with esophageal pressure topography (EPT) allowed for the establishment of an objective quantitative measurement of esophagogastric junction (EGJ) relaxation, the integrated relaxation pressure (IRP). This study assessed whether or not a novel 3D-HRM assembly could improve on this measurement. Twenty-five normal subjects were studied with both a standard HRM assembly and a novel hybrid assembly (3D-HRM), including a 9.0 cm 3D-HRM segment composed of 96 radially dispersed independent pressure sensors. The standard IRP was computed using each assembly and compared with a novel paradigm, the 3D-IRP, an analysis premised on finding the axial maximum and radial minimum pressure at each sensor ring along the sleeve segment. Fourteen additional subjects underwent barium swallows with 3D-HRM and concurrent videofluoroscopy to compare the electronic sleeve (eSleeve) paradigm (circumferential average) to the 3D eSleeve paradigm (radial minimum) as a predictor of transphincteric flow. The 3D-IRP was significantly less than all other calculations of IRP with the upper limit of normal being 12 mmHg vs. 17 mmHg for the standard IRP. The sensitivity (0.78) and the specificity (0.88) of the 3D-eSleeve were also better than the standard eSleeve (0.55 and 0.85, respectively) for predicting flow permissive time verified fluoroscopically. The 3D-IRP and 3D-eSleeve calculated using the radial pressure minimum lowered the normative range of EGJ relaxation (upper limit of normal 12 mmHg) and yielded intraluminal pressure gradients that better correlated with bolus flow than did analysis paradigms based on circumferentially averaged pressure.

Pressure morphology of the relaxed lower esophageal sphincter: the formation and collapse of the phrenic ampulla.

This study aimed to apply novel high-resolution manometry with eight-sector radial pressure resolution (3D-HRM technology) to resolve the deglutitive pressure morphology at the esophagogastric junction (EGJ) before, during, and after bolus transit. A hybrid HRM assembly, including a 9-cm-long 3D-HRM array, was used to record EGJ pressure morphology in 15 normal subjects. Concurrent videofluoroscopy was used to relate bolus movement to pressure morphology and EGJ anatomy, aided by an endoclip marking the squamocolumnar junction (SCJ). The contractile deceleration point (CDP) marked the time at which luminal clearance slowed to 1.1 cm/s and the location (4 cm proximal to the elevated SCJ) at which peristalsis terminated. The phrenic ampulla spanned from the CDP to the SCJ. The subsequent radial and axial collapse of the ampulla coincided with the reconstitution of the effaced and elongated lower esophageal sphincter (LES). Following ampullary emptying, the stretched LES (maximum length 4.0 cm) progressively collapsed to its baseline length of 1.9 cm (P < 0.001). The phrenic ampulla is a transient structure comprised of the stretched, effaced, and axially displaced LES that serves as a "yield zone" to facilitate bolus transfer to the stomach. During ampullary emptying, the LES circular muscle contracts, and longitudinal muscle shortens while that of the adjacent esophagus reelongates. The likely LES elongation with the formation of the ampulla and shortening to its native length after ampullary emptying suggest that reduction in the resting tone of the longitudinal muscle within the LES segment is a previously unrecognized component of LES relaxation.

Epidermal growth factor and perlecan fragments produced by apoptotic endothelial cells co-ordinately activate ERK1/2-dependent antiapoptotic pathways in mesenchymal stem cells.

Mounting evidence indicates that mesenchymal stem cells (MSC) are pivotal to vascular repair and neointima formation in various forms of vascular disease. Yet, the mechanisms that allow MSC to resist apoptosis at sites where other cell types, such as endothelial cells (EC), are dying are not well defined. In the present work, we demonstrate that apoptotic EC actively release paracrine mediators which, in turn, inhibit apoptosis of MSC. Serum-free medium conditioned by apoptotic EC increases extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and inhibits apoptosis (evaluated by Bcl-xL protein levels and poly (ADP-ribose) polymerase cleavage) of human MSC. A C-terminal fragment of perlecan (LG3) released by apoptotic EC is one of the mediators activating this antiapoptotic response in MSC. LG3 interacts with beta1-integrins, which triggers downstream ERK1/2 activation in MSC, albeit to a lesser degree than medium conditioned by apoptotic EC. Hence, other mediators released by apoptotic EC are probably required for induction of the full antiapoptotic phenotype in MSC. Adopting a comparative proteomic strategy, we identified epidermal growth factor (EGF) as a novel mediator of the paracrine component of the endothelial apoptotic program. LG3 and EGF cooperate in triggering beta1-integrin and EGF receptor-dependent antiapoptotic signals in MSC centering on ERK1/2 activation. The present work, providing novel insights into the mechanisms facilitating the survival of MSC in a hostile environment, identifies EGF and LG3 released by apoptotic EC as central antiapoptotic mediators involved in this paracrine response.

Familial occurrence of thymoma and autoimmune diseases with the constitutional translocation t(14;20)(q24.1;p12.3).

Thymomas are low-grade epithelial cancers of the thymus whose prevalence varies between 0.1/100,000 and 0.4/100,000. Familial occurrence of thymoma is very rare. We studied a family bearing the constitutional chromosome translocation t(14;20)(q24;p12), 3 of whose members had a thymoma. In this family, among 27 patients, 11 had the translocation: 3 had thymoma and 4 others had 5 different autoimmune diseases: type 1 diabetes mellitus, Graves' disease, pernicious anemia, primitive Sjögren disease, and autoimmune pancytopenia. FISH studies allowed us to be more specific about the translocation breakpoints. The 14q24 breakpoint was in intron 5 of RAD51L1, and the 20p12 breakpoint was 100 kb telomeric to BMP2. RAD51L1 is a tumor-suppressor gene belonging to the RAD51 family, already implicated in many tumors (uterine leiomyomas, pseudo-Meigs syndromes, pulmonary chondroid hamartomas) and involved in recombinational repair of DNA double-strand breaks. BMP2 belongs to the TGFbeta superfamily, and the BMP2-BMP4 genes are involved in thymocyte differentiation by blocking progression from CD4-CD8- to CD4+CD8+ while maintaining a sufficient pool of immature precursors. Dysregulation of RAD51L1 and/or BMP2 may explain this familial occurrence of thymomas and autoimmune diseases. Using QRT-PCR, we studied the expression of BMP2 in 20 sporadic thymomas and found various levels of expression that may be associated with autoimmune diseases.