Th2 cytokine signaling through IL-4Rα increases eotaxin-3 secretion and tension in human esophageal smooth muscle.

In esophageal epithelial cells in eosinophilic esophagitis (EoE), Th2 cytokines (IL-4, IL-13) signal through IL-4Rα, activating JAK to increase eotaxin-3 secretion, which draws eosinophils into the mucosa. We explored whether Th2 cytokines also might stimulate eotaxin-3 secretion and increase tension in esophageal smooth muscle (ESM), which might impair esophageal distensibility, and whether those events could be blocked by proton pump inhibitors (PPIs) or agents that disrupt IL-4Rα signaling. We established human ESM cell cultures from organ donors, characterizing Th2 cytokine receptor and P-type ATPase expression by qPCR. We measured Th2 cytokine-stimulated eotaxin-3 secretion by enzyme-linked immunosorbent assay (ELISA) and ESM cell tension by gel contraction assay, before and after treatment with omeprazole, ruxolitinib (JAK inhibitor), or IL-4Rα blocking antibody. CPI-17 (inhibitor of a muscle-relaxing enzyme) effects were studied with CPI-17 knockdown by siRNA or CPI-17 phospho(T38A)-mutant overexpression. ESM cells expressed IL-4Rα and IL-13Rα1 but only minimal H+-K+-ATPase mRNA. Th2 cytokines increased ESM eotaxin-3 secretion and tension, effects blocked by ruxolitinib and IL-4Rα blocking antibody but not consistently blocked by omeprazole. IL-13 increased ESM tension by increasing CPI-17 expression and phosphorylation, effects blocked by CPI-17 knockdown. Blocking IL-4Rα decreased IL-13-stimulated eotaxin-3 secretion, CPI-17 expression, and tension in ESM. Th2 cytokines increase ESM eotaxin-3 secretion and tension via IL-4Rα signaling that activates CPI-17. Omeprazole does not reliably inhibit this process, but IL-4Rα blocking antibody does. This suggests that ESM eosinophilia and impaired esophageal distensibility might persist despite elimination of mucosal eosinophils by PPIs, and IL-4Rα blocking agents might be especially useful in this circumstance.NEW & NOTEWORTHY We have found that Th2 cytokines increase eotaxin-3 secretion and tension in esophageal smooth muscle (ESM) cells via IL-4Rα signaling. Unlike esophageal epithelial cells, ESM cells do not express H+-K+-ATPase, and omeprazole does not inhibit their cytokine-stimulated eotaxin-3 secretion or tension. An IL-4Rα blocking antibody reduces both eotaxin-3 secretion and tension induced by Th2 cytokines in ESM cells, suggesting that an agent such as dupilumab might be preferred for patients with EoE with esophageal muscle involvement.

The broad impact of functional lumen imaging probe panometry in addition to high-resolution manometry in an esophageal clinical practice.

High-resolution manometry (HRM) with the Chicago Classification (CC) is the standard paradigm to define esophageal motility disorders. Functional lumen imaging probe (FLIP) panometry utilizes impedance planimetry to characterize esophageal compliance and secondary peristalsis. The aim of this study was to explore the clinical impact of FLIP panometry in addition to HRM. A retrospective chart review was performed on FLIP panometry cases utilizing the 322N catheter. Cases with prior foregut surgeries or botulinum injection within 6 months of FLIP panometry were excluded. EGJ-diameter and distensibility index (DI) and secondary contraction patterns at increasing balloon volumes were recorded. An EGJ-DI of ≥2.8 mm2/mm Hg at 60 mL was considered as a normal EGJ distensibility. CC diagnosis, Eckhardt score, Brief Esophageal Dysphagia Questionnaire, and clinical outcomes were obtained for each FLIP case. A total of 186 cases were included. Absent contractility and achalasia types 1 and 2 showed predominantly absent secondary contraction patterns, while type 3 had a variety of secondary contractile patterns on FLIP panometry. Among 77 cases with EGJ outflow obstruction (EGJOO), 60% had a low EGJ-DI. Among those with no motility disorder or ineffective esophageal motility on HRM, 27% had a low DI and 47% had sustained contractions on FLIP, raising concern for an esophageal dysmotility process along the achalasia and/or spastic spectrum. FLIP panometry often confirmed findings on HRM in achalasia and absent contractility. FLIP panometry is useful in characterizing EGJOO cases. Spastic features on FLIP panometry may raise concern for a motility disorder on the spastic spectrum not captured by HRM. Further studies are needed on FLIP panometry to determine how to proceed with discrepancy with HRM and explore diagnoses beyond the CC.

A human Barrett's esophagus organoid system reveals epithelial-mesenchymal plasticity induced by acid and bile salts.

The pathogenesis of subsquamous intestinal metaplasia (SSIM), in which glands of Barrett's esophagus (BE) are buried under esophageal squamous epithelium, is unknown. In a rat model of reflux esophagitis, we found that columnar-lined esophagus developed via a wound-healing process involving epithelial-mesenchymal plasticity (EMP) that buried glands under ulcerated squamous epithelium. To explore a role for reflux-induced EMP in BE, we established and characterized human Barrett's organoids and sought evidence of EMP after treatment with acidic bile salts (AB). We optimized media to grow human BE organoids from immortalized human Barrett's cells and from BE biopsies from seven patients, and we characterized histological, morphological, and molecular features of organoid development. Features and markers of EMP were explored following organoid exposure to AB, with and without a collagen I (COL1) matrix to simulate a wound-healing environment. All media successfully initiated organoid growth, but advanced DMEM/F12 (aDMEM) was best at sustaining organoid viability. Using aDMEM, organoids comprising nongoblet and goblet columnar cells that expressed gastric and intestinal cell markers were generated from BE biopsies of all seven patients. After AB treatment, early-stage Barrett's organoids exhibited EMP with loss of membranous E-cadherin and increased protrusive cell migration, events significantly enhanced by COL1. Using human BE biopsies, we have established Barrett's organoids that recapitulate key histological and molecular features of BE to serve as high-fidelity BE models. Our findings suggest that reflux can induce EMP in human BE, potentially enabling Barrett's cells to migrate under adjacent squamous epithelium to form SSIM.NEW & NOTEWORTHY Using Barrett's esophagus (BE) biopsies, we established organoids recapitulating key BE features. During early stages of organoid development, a GERD-like wound environment-induced features of epithelial-mesenchymal plasticity (EMP) in Barrett's progenitor cells, suggesting that reflux-induced EMP can enable Barrett's cells to migrate underneath squamous epithelium to form subsquamous intestinal metaplasia, a condition that may underlie Barrett's cancers that escape detection by endoscopic surveillance, and recurrences of Barrett's metaplasia following endoscopic eradication therapy.

Experience and Technique for Zenker's Diverticulum Per Oral Endoscopic Myotomy: Z-POEM.

OBJECTIVE: With the advent of minimally invasive surgery, incisionless surgery, and third-space endoscopy, the treatment for Zenker's diverticulum has also moved toward less invasive techniques METHODS: New incisionless per oral techniques can be applied for cricopharyngeal myotomy in Zenker's diverticulum. RESULTS: Five patients underwent Zenker's diverticulum per oral endoscopic myotomy (Z-POEM) without complications, minimal discomfort, and narcotic consumption, with complete resolution of their symptoms by history and Eckardt scores. CONCLUSIONS: Z-POEM is performed entirely endoscopically with very little associated pain or complication rates, with short-term follow-up having excellent functional and symptomatic results.

The Pharyngostomy Tube: Indications, Technique, Efficacy, and Safety in Modern Surgical Practice.

BACKGROUND: Long-term nasogastric tubes are uncomfortable and associated with complications such as impairment with speech and swallowing, septum trauma, epistaxis, alar necrosis, and intubation of the trachea among others. Pharyngostomy tubes (PTs) are an alternative for prolonged enteral feeding, transluminal drainage of collections, and gastric decompression in patients with an intestinal obstruction and an inoperable abdomen. PATIENTS AND METHODS: This is a retrospective analysis of patients who had a PT placed at our institution from May 2005 to March 2015. The primary end point of the study was to establish the type and rate of complications and aspiration events related to PT use. RESULTS: During the specified period, a total of 84 PTs were placed. The most common indication for PT placement was enteric decompression in 65 (77.4%), followed by transluminal collection drainage in 12 (14.3%), and enteral access for nutrition in 7 (8.3%) patients. The mean time to tube removal was 17.8 days ± 17.1 (range, 2-119). We encountered 10 (11.2%) complications related to PT placement, including 7 cases of cellulitis, 2 superficial abscesses, and 1 patient with pharyngeal hemorrhage. CONCLUSION: PTs are a relatively simple, safe, and straightforward approach to achieve long-term enteral decompression, access for feeding or transluminal drainage, avoiding the complications associated with prolonged nasogastric tube placement. The complication rate is low and patient satisfaction and compliance appear to be higher than with nasogastric tubes. Modern surgeons should be familiar with the procedure and technique. PTs should be part of every surgeon's armamentarium.

Therapeutic Pneumoperitoneum: Relevant or Obsolete in 2015?

Background Therapeutic pneumoperitoneum (TP) is one alternative to manage pleural space problems. We describe our technique and experience. Materials and Methods Medical records of all patients who underwent TP from January 1, 2007, to January 1, 2015, were reviewed after Institutional Review Board approval. We report indication, preprocedure pulmonary function tests, volume of insufflated air, time to chest tube removal, and complications. We place a red rubber catheter into the peritoneal space through the diaphragm or a small abdominal incision, insufflate with room air, record volume (liters), intraperitoneal pressure (goal 9-10 mm Hg), and monitor vital signs, airway pressures, and urine output. Results We performed TP in 32 patients. Follow-up was available for 31 patients. Indications were prevention of pleural space problems in bilobectomy patients (n = 11), following decortication for empyema (n = 11), prevention of prolonged air leak (n = 3), prevention of postresection space (n = 4), and spontaneous chylothorax (n = 2). TP was done postoperatively in three patients. Median air volume used was 3.5 L (3-6 L). Time to chest tube removal overall was 7.8 days (3-20 days) and to discharge 10.2 days (4-32 days). No patient developed respiratory failure, renal failure, or required evacuation of TP. Conclusion TP is a simple, safe, and effective technique to manage pleural space problems. Proper patient selection and meticulous technique are imperative for the successful clinical application of TP. We believe that TP is an underutilized tool for the management of pleural space problems and merits wider application in thoracic surgical practice.

Ultrasound-Guided Paravertebral Catheter Versus Intercostal Blocks for Postoperative Pain Control in Video-Assisted Thoracoscopic Surgery: A Prospective Randomized Trial.

OBJECTIVE: The use of continuous paravertebral (PV) catheters for management of acute postsurgical pain after video-assisted thoracoscopic surgery (VATS) has not been investigated previously as a randomized controlled trial. The purpose of this study was to compare the efficacy of an ultrasound-guided continuous PV catheter catheter infusion for postoperative pain control with single-shot intercostal blocks (ICB). DESIGN: A prospective, randomized, controlled trial. SETTING: An academic university hospital. PARTICIPANTS: Patients (≥18 years of age) who underwent a VATS procedure. INTERVENTIONS: Patients were randomized into 2 groups. Group 1 received single-shot ICB. Group 2 received an ultrasound-guided PV catheter with a continuous infusion of 0.2% ropivacaine. MEASUREMENTS AND MAIN RESULTS: There were 25 patients in group 1 and 23 patients in group 2. The maximum pain score was significantly lower in the group that received the PV catheter compared with those who received ICB during 24 to 48 hours (3.65 v 6.44, p<0.001). Seventeen patients (74%) who received PV catheters reported satisfaction with a pain control regimen compared to the 11 (44%) who received ICB (p = 0.036). In addition, during 24 to 48 hours after surgery the mean opioid use decreased significantly in the PV catheter group (14.39 v 30.50 mg morphine equivalents, p = 0.046). CONCLUSIONS: Ultrasound-guided continuous PV catheter infusions provided prolonged pain control and superior patient satisfaction compared with single-shot ICB after video-assisted thoracoscopic surgery.

To Sink the Lifted: Selection, Technique, and Result of Laparoscopic Diaphragmatic Plication for Paralysis or Eventration.

Introduction Diaphragmatic eventration is a congenital defect of the muscular portion of a hemidiaphragm that eventually leads to hemidiaphragmatic elevation and dysfunction. The clinical diagnosis of diaphragmatic eventration or diaphragmatic paralysis may be indistinguishable and diaphragmatic plication is the treatment of choice for both conditions. Discussion We review the indications, patient selection, and surgical techniques for diaphragmatic plication. We explain our preferred technique and guide the reader step by step on our approach. Conclusion Minimally invasive diaphragm plication techniques are effective alternatives to open transthoracic plication and result in significant improvement in dyspnea and quality of life in adequately selected patients.

Early real-world experience monitoring circulating tumor DNA in resected early-stage non-small cell lung cancer.

OBJECTIVE: The study objective was to evaluate the impact of monitoring circulating tumor DNA on the detection and management of recurrence in patients with resected early-stage non-small cell lung cancer. METHODS: Between October 2021 and March 2023, postoperative circulating tumor DNA was monitored in patients with non-small cell lung cancer (N = 108). Longitudinal blood samples (n = 378 samples) were collected for prospective circulating tumor DNA analysis at 3-month intervals after curative-intent resection. A tumor-informed assay was used for the detection and quantification of circulating tumor DNA. The primary outcome measure was a circulating tumor DNA-positive result. The secondary outcome measure was changes in practice after a circulating tumor DNA-positive result. RESULTS: The mean age of the patients in this cohort was 68.1 years. Of the 108 patients, 12 (11.1%) were circulating tumor DNA positive at least at 1 timepoint postsurgery, of whom 8 (66.7%) had a clinically evident recurrence and the remaining 4 had limited clinical follow-up. Of the 10 patients with recurrent disease, 8 demonstrated circulating tumor DNA positivity and the remaining 2 patients had brain-only metastases. Postoperative clinical care was altered in 100% (12/12) of circulating tumor DNA-positive patients, with 58.3% (7/12) receiving an early computed tomography scan and 100% (12/12) receiving an early positron emission tomography computed tomography scan as part of their surveillance strategy. Among the patients who received an early positron emission tomography scan, 66.6% (8/12) were positive for malignant features. CONCLUSIONS: Routine monitoring of tumor-informed circulating tumor DNA after curative intent therapy improved patient risk stratification and prognostication.

Spastic secondary contractile patterns identified by FLIP panometry in symptomatic patients with unremarkable high-resolution manometry.

BACKGROUND: Functional lumen imaging probe (FLIP) panometry can show spastic secondary contractile patterns of unclear significance in symptomatic patients who have no esophageal obstructive disorders, and no motility disorders on high-resolution manometry (HRM). METHODS: We retrospectively analyzed non-obstructed, symptomatic patients with HRM findings of no motility disorder or ineffective esophageal motility (IEM) for whom spastic secondary contractile patterns identified by FLIP panometry were used to guide treatment. Symptoms were scored using the Brief Esophageal Dysphagia Questionnaire (BEDQ). KEY RESULTS: We identified ten symptomatic patients treated at our medical center who met inclusion criteria (seven women; mean age 56 years; eight no motility disorder, two IEM). On FLIP panometry, seven had spastic secondary contractions at 60 ml, two at 40 ml, and one at both 40 ml and 60 ml balloon volumes. Eight patients (80%) had improvement in BEDQ scores with therapies that targeted the spastic secondary contractile patterns identified by FLIP (five botulinum toxin injection, two Esoflip dilation, and one Heller myotomy). Interestingly, review of HRM tracings revealed that all patients had a novel HRM finding of mid-vertical pressurization in at least 20% swallows, with seven exhibiting this finding in >50% of swallows. CONCLUSIONS: This case series demonstrates that treatments targeting spastic secondary contractions identified by FLIP panometry can result in symptomatic improvement in patients with no obstructive disorder and no diagnostic motility disorder on HRM. In such patients, we have identified the novel HRM finding of mid-vertical pressurization, which might be the manometric manifestation of spasm limited to the mid-esophagus.

Histologic Study of the Esophagogastric Junction of Organ Donors Reveals Novel Glandular Structures in Normal Esophageal and Gastric Mucosae.

INTRODUCTION: Whether cardiac mucosa at the esophagogastric junction is normal or metaplastic is controversial. Studies attempting to resolve this issue have been limited by the use of superficial pinch biopsies, abnormal esophagi resected typically because of cancer, or autopsy specimens in which tissue autolysis in the stomach obscures histologic findings. METHODS: We performed histologic and immunohistochemical studies of the freshly fixed esophagus and stomach resected from 7 heart-beating, deceased organ donors with no history of esophageal or gastric disease and with minimal or no histologic evidence of esophagitis and gastritis. RESULTS: All subjects had cardiac mucosa, consisting of a mixture of mucous and oxyntic glands with surface foveolar epithelium, at the esophagogastric junction. All also had unique structures we termed compact mucous glands (CMG), which were histologically and immunohistochemically identical to the mucous glands of cardiac mucosa, under esophageal squamous epithelium and, hitherto undescribed, in uninflamed oxyntic mucosa throughout the gastric fundus. DISCUSSION: These findings support cardiac mucosa as a normal anatomic structure and do not support the hypothesis that cardiac mucosa is always metaplastic. However, they do support our novel hypothesis that in the setting of reflux esophagitis, reflux-induced damage to squamous epithelium exposes underlying CMG (which are likely more resistant to acid-peptic damage than squamous epithelium), and proliferation of these CMG as part of a wound-healing process to repair the acid-peptic damage could result in their expansion to the mucosal surface to be recognized as cardiac mucosa of a columnar-lined esophagus.

Lower esophageal sphincter muscle of patients with achalasia exhibits profound mast cell degranulation.

BACKGROUND: Eosinophils and mast cells are key effectors of allergy. When they accumulate in the esophagus, their myoactive, pro-inflammatory, and cytotoxic products potentially could cause achalasia-like motility abnormalities and neuronal degeneration. We hypothesized that there is an allergy-mediated form of achalasia. METHODS: LES muscle samples obtained during Heller myotomy from patients with achalasia or EGJ outflow obstruction (EGJOO) and from organ donor controls were immunostained for tryptase. Eosinophil and mast cell density, and mast cell degranulation were assessed. LES muscle was evaluated by qPCR for genes mediating smooth muscle Ca2+ handling and contraction. KEY RESULTS: There were 13 patients (7 men, median age 59; 10 achalasia, 3 EGJOO) and 7 controls (4 men, median age 42). Eosinophils were infrequent in LES muscle, but mast cells were plentiful. Patients and controls did not differ significantly in LES mast cell density. However, 12 of 13 patients exhibited profound LES mast cell degranulation involving perimysium and myenteric plexus nerves, while only mild degranulation was seen in 2 of 7 controls. Hierarchical clustering analysis of qPCR data revealed two "mototype" LES gene expression patterns, with all type II patients in one mototype, and type I and III patients in the other. CONCLUSIONS & INFERENCES: LES muscle of patients with achalasia or EGJOO exhibits striking mast cell degranulation, and patients with different achalasia manometric phenotypes exhibit different LES patterns of expression for genes mediating Ca2+ handling and muscle contraction. Although these findings are not definitive, they support our hypothesis that achalasia can be allergy-driven.

Laparoscopic resection of an undifferentiated pleomorphic splenic sarcoma.

BACKGROUND: Splenic tumors are rare. Malignant fibrous histiocytoma (MFH) of the spleen is one of the least common primary splenic tumors. Review of the literature shows that a laparoscopic resection has never been tried. METHOD: We discuss the case of a 76-year-old man with a 7-cm MFH in the spleen and present a review of splenic sarcomas. RESULTS: The patient underwent a successful laparoscopic splenectomy; pathology revealed a rare undifferentiated pleomorphic sarcoma of the spleen. A review of the international literature identified 15 additional cases of primary splenic MFH. Survival was rarely longer than 15 months. CONCLUSION: Malignant fibrous histiocytoma of the spleen is an exceedingly rare tumor with a poor prognosis. In experienced hands, laparoscopic splenectomy is a feasible operative choice for primary splenic sarcoma.

Tracheal resection for tracheal stenosis.

Anatomically, patients with refractory tracheal stenosis benefit from tracheal resection, depending on the medical comorbidities or challenging tracheal anatomy, which is often the reason for denial of this option in these patients. We evaluated 15 patients undergoing tracheal resection at our institution from May 2016 through December 2017. Eleven patients had a history of previous tracheostomy, six in place at the time of resection. One had idiopathic stenosis with no known comorbidities. Major comorbidities included chronic obstructive pulmonary disease, non-insulin-dependent diabetes mellitus, hypertension, and cardiovascular disease. One had a left ventricular assist device, and one was a lung transplant recipient. All had primary resection through the cervical approach with a median length of 3.5 cm. Fourteen patients were eventually decannulated. One patient had re-resection 1 year later for recurrent stenosis. Twelve were alive at a median follow-up of 15 months with patent airways. In conclusion, tracheal stenosis patients have significant comorbidities that increase the risks after resection. However, these patients should still be considered for surgery for an improved quality of life and eventual resolution of severe stenosis.

Spontaneous pneumomediastinum secondary to electronic cigarette use.

Vaping, the use of electronic cigarettes, involves different mechanics than conventional combustion cigarettes. Consumers who vape tend to overinhale and then forcefully exhale to eliminate the vapor, which is usually produced in much greater quantity than generated by a regular cigarette. Effectively, they are performing an exaggerated Valsalva maneuver. This can increase their risk for developing potential spontaneous pneumomediastinum. Here we present a case of spontaneous pneumomediastinum secondary to electronic cigarette use.

Left upper lobectomy for a large incidental simple arteriovenous malformation.

We present an incidental finding of a large left upper lobe diffuse pulmonary arteriovenous malformation (PAVM) presenting with cyanosis, exertional shortness of breath, polycythemia, and low peripheral oxygen saturation. PAVMs are mostly diagnosed in symptomatic patients with therapeutic embolization as the first choice of therapy. This young woman had no symptoms but showed signs of hypoxemia, and further investigation revealed a huge central left upper lobe PAVM. A successful upper lobectomy resulted in a quick recovery and immediate return to normal peripheral oxygen saturation levels with no further comorbidity or recurrence during 3 years of current follow-up.

An Expectorated "Stent": An Unexpected Complication of EBUS-TBNA.

Endobronchial ultrasound-guided transbronchial needle aspiration has a low complication rate and is a cost-effective procedure for mediastinal staging and diagnosis when compared with the more invasive mediastinoscopy. There are increasing case reports of unexpected complications including equipment failures with and without significant medical consequences. Knowledge of complications, including those that are rare, is essential for the physician performing this minimally invasive procedure. We report a case of a retained foreign body from the unexpected separation of a distal spring/coil mechanism from the Olympus ViziShot Aspiration needle following early needle deployment within the working channel of the bronchoscope.