Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.

Impact of Change in Sizing Protocol on Outcome of Magnetic Sphincter Augmentation.

OBJECTIVE: To evaluate and compare magnetic sphincter augmentation (MSA) device sizing protocols on postoperative outcomes and dysphagia. SUMMARY BACKGROUND DATA: Among predictors of dysphagia after MSA, device size is the only factor that may be modified. Many centers have adopted protocols to increase device size. However, there is limited data on the impact of MSA device upsizing protocols on the surgical outcomes. METHODS: Patients who underwent MSA were implanted with 2 or 3-beads above the sizing device's pop-off point (POP). Clinical and objective outcomes >1-year after surgery were compared between patients implanted with POP+2-vs-POP+3 sizing protocols. Multiple subgroups were analyzed for benefit from upsizing. Pre- and postoperative characteristics were compared between size patients received, regardless of protocol. RESULTS: A total of 388 patients were implanted under POP+2 and 216 under POP+3. At a mean of 14.2(7.9) months pH normalization was 73.6% and 34.1% required dilation, 15.9% developed persistent dysphagia, and 4.0% required removal. Sizing protocol had no impact on persistent dysphagia ( P =0.908), pH normalization ( P =0.822), or need for dilation ( P =0.210) or removal ( P =0.191). Subgroup analysis found that upsizing reduced dysphagia in patients with <80 percent peristalsis (10.3-vs-31%, P =0.048) or DCI >5000 (0-vs-30.4%, P =0.034). Regardless of sizing protocol, as device size increased there was a stepwise increase in percent male sex ( P <0.0001), BMI>30 ( P <0.0001), and preoperative hiatal hernia>3 cm ( P <0.0001), LA grade C/D esophagitis ( P <0.0001), and DeMeester score ( P <0.0001). Increased size was associated with decreased pH-normalization ( P <0.0001) and need for dilation ( P =0.043) or removal ( P =0.014). CONCLUSIONS: Upsizing from POP+2 to POP+3 does not reduce dysphagia or affect other MSA outcomes; however, patients with poor peristalsis or hypercontractile esophagus do benefit. Regardless of sizing protocol, preoperative clinical characteristics varied among device sizes, suggesting size is not a modifiable factor, but a surrogate for esophageal circumference.

The Impact of Magnetic Sphincter Augmentation (MSA) on Esophagogastric Junction (EGJ) and Esophageal Body Physiology and Manometric Characteristics.

OBJECTIVE: To evaluate the impact of MSA on lower esophageal sphincter (LES) and esophageal body using high resolution impedance manometry. BACKGROUND: MSA is an effective treatment in patients with gastroesophageal reflux disease, but there is limited data on its impact on esophageal functional physiology. METHODS: Patients who underwent MSA were approached 1-year after surgery for objective foregut testing consists of upper endoscopy, esophagram, high resolution impedance manometry, and esophageal pH-monitoring. Postoperative data were then compared to the preoperative measurements. RESULTS: A total of 100 patients were included in this study. At a mean follow up of 14.9(10.1) months, 72% had normalization of esophageal acid exposure. MSA resulted in an increase in mean LES resting pressure [29.3(12.9) vs 25(12.3), P < 0.001]. This was also true for LES overall length [2.9(0.6) vs 2.6(0.6), P = 0.02] and intra-abdominal length [1.2(0.7) vs 0.8(0.8), P < 0.001]. Outflow resistance at the EGJ increased after MSA as demonstrated by elevation in intrabolus pressure (19.6 vs 13.5 mmHg, P < 0.001) and integrated relaxation pressure (13.5 vs 7.2, P < 0.001). MSA was also associated with an increase in distal esophageal body contraction amplitude [103.8(45.4) vs 94.1(39.1), P = 0.015] and distal contractile integral [2647.1(2064.4) vs 2099.7(1656.1), P < 0.001]. The percent peristalsis and incomplete bolus clearance remained unchanged ( P = 0.47 and 0.08, respectively). CONCLUSIONS: MSA results in improvement in the LES manometric characteristics. Although the device results in an increased outflow resistance at the EGJ, the compensatory increase in the force of esophageal contraction will result in unaltered esophageal peristaltic progression and bolus clearance.

The Impact of Ineffective Esophageal Motility on Patients Undergoing Magnetic Sphincter Augmentation.

OBJECTIVE: To evaluate and characterize outcomes of MSA in patients with IEM. SUMMARY BACKGROUND DATA: MSA improves patients with gastroesophageal reflux and normal motility. However, many patients have IEM, which could impact the outcomes of MSA and discourage use. METHODS: An international, multi-institutional case control study of IEM patients undergoing MSA matched to normal patients was performed. Primary outcomes were new onset dysphagia and need for postoperative interventions. RESULTS: A total of 105 IEM patients underwent MSA with matching controls. At 1 year after MSA: GERD-Health Related Quality of Life was similar; DeMeester scores in IEM patients improved to 15.7 and 8.5 in controls ( P = 0.021); and normalization of the DeMeester score for IEM = 61.7% and controls = 73.1% ( P = 0.079).In IEM patients, 10/12 (83%) with preop dysphagia had resolution; 11/66 (17%) had new onset dysphagia and 55/66 (83%) never had dysphagia. Comparatively, in non-IEM patients, 22/24 (92%) had dysphagia resolve; 2/24 (8%) had persistent dysphagia; 7/69 (10%) had new onset dysphagia, and 62/69 (90%) never had dysphagia.Overall, 19 (18%) IEM patients were dilated after MSA, whereas 12 (11%) non-IEM patients underwent dilation ( P = 0.151). Nine (9%) patients in both groups had their device explanted. CONCLUSIONS: Patients with IEM undergoing MSA demonstrate improved quality of life and reduction in acid exposure. Key differences in IEM patients include lower rates of objective GERD resolution, lower resolution of existing dysphagia, higher rates of new onset dysphagia and need for dilation. GERD patients with IEM should be counselled about these possibilities.

Chevalier Jackson: father of endoscopic surgery, and champion of women in medicine, social justice, and public health.

BACKGROUNDS: Chevalier Jackson (1865-1958) was a pioneering force in the medical world, whose extraordinary contributions to surgery and public health have left an indelible impact. He developed the endoscope and perfected the bronchoscope, and his mastery of these tools enabled him to transform the prognosis of foreign body aspiration from 98% mortality to 98% survival. He was also a passionate advocate of public health chairing the national committee on lye legislation, which culminated in the Caustic Poison Act, responsible for poison and antidote labels. Yet Jackson's accomplishments were not limited to these. The aim of this manuscript was to shed light on Chevalier Jackson's lesser-known contributions to surgical science and culture, and to celebrate and honor the life of this remarkable surgeon. METHODS: Digital and physical historical records from the National Library of Medicine, Smithsonian Institution, Heinz History Center in Pittsburgh PA, and Sunrise Mill Museum, Montgomery County PA were reviewed for Chevalier Jackson's scientific, cultural, and social contributions to the field of surgery. RESULTS: Among his lesser-known contributions, Chevalier Jackson was the first to describe erosive esophagitis. He developed the first standardized tracheotomy procedure, still in use today. He was ahead of his time in many ways, pioneering a multidisciplinary approach to medicine, advocating for patient-centered care, and advancing the inclusion of women in the medical profession. CONCLUSION: Chevalier Jackson's legacy extends far beyond the tools and techniques he invented. He was a champion of social justice, a protector of patients, and an inspiration to medical professionals across the globe.

Removal of the magnetic sphincter augmentation device: an assessment of etiology, clinical presentation, and management.

BACKGROUND: Magnetic sphincter augmentation (MSA) erosion, disruption or displacement clearly requires device removal. However, up to 5.5% of patients without anatomical failure require removal for dysphagia or recurrent GERD symptoms. Studies characterizing these patients or their management are limited. We aimed to characterize these patients, compare their outcomes, and determine the necessity for further reflux surgery. METHODS: This is a retrospective review of 777 patients who underwent MSA at our institution between 2013 and 2021. Patients who underwent device removal for persistent dysphagia or recurrent GERD symptoms were included. Demographic, clinical, objective testing, and quality of life data obtained preoperatively, after implantation and following removal were compared between removal for dysphagia and GERD groups. Sub-analyses were performed comparing outcomes with and without an anti-reflux surgery (ARS) at the time of removal. RESULTS: A total of 40 (5.1%) patients underwent device removal, 31 (77.5%) for dysphagia and 9 (22.5%) for GERD. After implantation, dysphagia patients had less heartburn (12.9-vs-77.7%, p = 0.0005) less regurgitation (16.1-vs-55.5%, p = 0.0286), and more pH-normalization (91.7-vs-33.3%, p = 0.0158). Removal without ARS was performed in 5 (55.6%) GERD and 22 (71.0%) dysphagia patients. Removal for dysphagia patients had more complete symptom resolution (63.6-vs-0.0%, p = 0.0159), freedom from PPIs (81.8-vs-0.0%, p = 0.0016) and pH-normalization (77.8-vs-0.0%, p = 0.0455). Patients who underwent removal for dysphagia had comparable symptom resolution (p = 0.6770, freedom from PPI (p = 0.3841) and pH-normalization (p = 0.2534) with or without ARS. Those who refused ARS with removal for GERD had more heartburn (100.0%-vs-25.0%, p = 0.0476), regurgitation (80.0%-vs-0.0%, p = 0.0476) and PPI use (75.0%-vs-0.0%, p = 0.0476). CONCLUSIONS: MSA removal outcomes are dependent on the indication for removal. Removal for dysphagia yields excellent outcomes regardless of anti-reflux surgery. Patients with persistent GERD had worse outcomes on all measures without ARS. We propose a tailored approach to MSA removal-based indication for removal.

Predictors of favorable outcome after pyloroplasty for gastroparesis: should response to pyloric dilation or Botox injection be used as a marker of surgical outcome?

INTRODUCTION: Pyloroplasty and gastric peroral endoscopic myotomy (G-POEM) are effective surgeries for gastroparesis. The primary aim of this study was to evaluate outcomes of pyloroplasty and G-POEM in patients with gastroparesis and determine factors associated with favorable outcome. The secondary aim was to assess the utility of clinical response to preoperative pyloric dilation or botulinum toxin injection (Botox) on surgical outcome, a factor conventionally used as a favorable marker. METHODS: There were 204 patients who underwent pyloroplasty (n = 177) or G-POEM (n = 27) for gastroparesis at our institution from 2014 to 2021. Demographic and clinical parameters were analyzed to assess their impact on surgical outcome. A subgroup of patients who had pyloric dilation or Botox injection were assessed separately. Favorable outcome was defined as patient reported complete resolution of the predominant gastroparesis symptom. RESULTS: Favorable outcome was achieved in 78.4% of patients (pyloroplasty: 79.7% and G-POEM: 70.4%, p = 0.274). Among 61 patients where pre- and postoperative gastric emptying studies (GES) were available, mean 4-hour retention significantly improved from 33.5 to 15.0% (p < 0.001) and 77.0% of patients achieved normalization. Favorable outcome was not significantly impacted by etiology of gastroparesis (p = 0.120), GERD (p = 0.518), or primary gastroparesis symptom (p = 0.244). Age ≥ 40 was a significant predictor of favorable surgical outcome on multivariate analysis [OR: 2.476 (1.224-5.008), p = 0.012]. Among the patients who had preoperative dilation (n = 82) or Botox injection (n = 46), response to these interventions was not a predictor of favorable surgical outcome (p = 0.192 and 0.979, respectively). However, preoperative Botox injection, regardless of response to injection, was associated with favorable surgical outcome [OR: 3.205 (CI 1.105-9.299), p = 0.032]. CONCLUSION: Symptomatic improvement after pyloroplasty or G-POEM is independent of etiology of gastroparesis, GERD, and primary symptom. Response to dilation or Botox are not markers of response to surgery. However, patients who receive Botox are 3.2 times more likely to improve postoperatively.

Need for frequent dilations after magnetic sphincter augmentation: an assessment of associated factors and outcomes.

BACKGROUND: Dysphagia is the most common complaint after magnetic sphincter augmentation (MSA), with nearly one-third of patients requiring at least one dilation following MSA. A subset of patients require frequent dilations, but there is a paucity of data on the characteristics of this population. This study aimed to identify predictors of the need for frequent dilations within the first year after implant and to assess these patients' outcomes. METHODS: This is a retrospective review of prospectively collected data of patients who underwent MSA over an 8-year period. Frequent dilations were defined as 2 or more dilations within 1 year of surgery. Patients completed baseline and 1-year postoperative GERD-HRQL questionnaires and objective physiology testing. Baseline demographic, clinical characteristics, and objective testing data were compared between patients who did and did not require frequent dilations. RESULTS: A total of 697 (62.7% female) patients underwent MSA, with 62 (8.9%) patients requiring frequent dilation. At a mean (SD) of 12.3 (3.4) months follow-up, the frequent dilation group had higher median GERD-HRQL total scores (21.0 vs. 5.0, p < 0.001), PPI use (20.8% vs.10.1%, p = 0.023), dissatisfaction (46.7% vs. 11.6%, p < 0.001), and device removal (25.8% vs. 2.2%, p < 0.001) rates. Acid normalization was comparable (p = 0.997). Independent predictors of frequent dilation included preoperative odynophagia (OR 2.85; p = 0.001), IRP > 15 mmHg (OR 2.88; p = 0.006), and > 30% incomplete bolus clearance (OR 1.94; p = 0.004). At a mean (SD) of 15.7 (10.7) months, 28 (45.1%) patients underwent device removal after frequent dilation. Independent predictors of device removal after frequent dilation within 5 years of surgery were preoperative odynophagia (OR 7.18; p = 0.042), LES resting pressure > 45 mmHg (OR 28.5; p = 0.005), and ≥ 10% failed swallows (OR 23.5; p < 0.001). CONCLUSIONS: The need for frequent dilations after MSA is a marker for poor symptom control, dissatisfaction, and device removal. Patients with preoperative odynophagia, high LES pressures, and poor esophageal motility should be counseled of their risk for these poor outcomes.

The impact of delayed gastric emptying as measured by gastric emptying scintigraphy on the outcome of magnetic sphincter augmentation.

INTRODUCTION: The impact of delayed gastric emptying (DGE) on the outcome of anti-reflux surgery (ARS) is controversial. There is concern that poor gastric emptying diminishes outcomes. Magnetic sphincter augmentation (MSA) may have a comparatively mild impact on gastric physiology, but the relationship between DGE and MSA outcomes is unknown. This study aims to evaluate the relationship between objective DGE and MSA outcomes over time. METHODS: Patients who completed gastric emptying scintigraphy (GES) prior to MSA between 2013 and 2021 were included. DGE was defined as a 4 h retention > 10% or half emptying time > 90 min on GES. Outcomes were compared between DGE and normal gastric emptying (NGE) groups at 6 months, 1 and 2 years. Sub-analysis of patients with severe (> 35%) DGE and correlation analysis between 4-h retention and symptom and acid-normalization were performed. RESULTS: The study population consisted of 26 (19.8%) patients with DGE and 105 with NGE. DGE was associated with more 90-days readmissions (18.5 vs 2.9%, p = 0.009). At 6 months patients with DGE had higher median (IQR) GERD-HRQL total [17.0(10-29) vs 5.5(3-16), p = 0.0013], heartburn [1(1-3) vs 0(0-1), p = 0.0010) and gas-bloat [4(2-5) vs 2(1-3), p = 0.033] scores. Outcomes at 1 and 2 years follow-up were comparable (p > 0.05). From 6 months to 1-year the gas-bloat score decreased from 4(2-5) to 3(1-3), p = 0.041. Total and heartburn scores decreased, but not significantly. Severe DGE (n = 4) patients had lower antiacid medication freedom at 6 months (75 vs 87%, p = 0.014) and 1-year (50 vs 92%, p = 0.046). There were non-significant trends for higher GERD-HRQL scores, dissatisfaction, and removal rates in severe DGE at 6 months and 1-year. There was a weak correlation between 4-h retention and 6-month GERD-HRQL total score [R = 0.253, 95%CI (0.09-0.41), p = 0.039], but not acid-normalization (p > 0.05). CONCLUSION: Outcomes after MSA are diminished early on in patients with mild-to-moderate DGE, but comparable by 1 year and durable at 2 years. Severe DGE outcomes may be suboptimal.

Magnetic sphincter augmentation and high-resolution manometry: impact of biomechanical properties on esophageal motility and clinical significance for selection and outcomes.

Magnetic sphincter augmentation (MSA)was introduced as an alternative to laparoscopic Nissen fundoplication (LNF). This reproducible, outpatient procedure addresses the etiology of gastroesophageal reflux disease by implanting a ring of magnetic beads across the esophagogastric junction (EGJ). MSA is designed to resist effacement of the lower esophageal sphincter (LES) and, similar to LNF, results in restoration of anti-reflux barrier competency by increasing overall length, intraabdominal length and resting pressure of the sphincter. However, the novel use of magnets to augment the physiology of the LES poses unique challenges to the physiology of the EGJ and esophagus. These impacts are best revealed through manometry. The degree of restrictive forces at the EGJ, as measured by intrabolus pressure and integrated relaxation pressure, is higher after MSA compared with LNF. In addition, contrary to the LNF, which retains neurohormonal relaxation capability during deglutition, the magnetic forces remain constant until forcibly opened. Therefore, the burden of overcoming EJG resistance is placed solely on the esophageal body contractile force, as measured by distal contractile integral and distal esophageal amplitude. The main utility of preoperative manometry is in determining whether a patient's esophagus has sufficient contractility or peristaltic reserve to adapt to the challenge of an MSA. Manometric thresholds predictive of MSA outcomes deviate from those used to define named Chicago Classification motility disorders. Therefore, individual preoperative manometric characteristics should be analyzed to aid in risk stratification and patient selection prior to MSA.

Long-term clinical and functional results of magnetic sphincter augmentation.

Magnetic sphincter augmentation (MSA) was introduced in 2007 as an alternative surgical procedure for patients with gastroesophageal reflux disease (GERD). The majority of data since MSA's introduction has focused on short and intermediate-term results, demonstrating safety and high efficacy in terms of reflux symptom control, freedom from proton pump inhibitor use and normalization of distal esophageal acid exposure. However, GERD is a chronic condition that demands a long-term solution. Limited available data from studies reporting outcomes at 5 years or later following MSA demonstrate that the promising short- and mid-term efficacy and safety profile of MSA remains relatively constant in the long term. Compared with Nissen fundoplication, MSA has a much lower rate of gas-bloat and inability to belch at a short-term follow-up, a difference that persists in the long-term. The most common complaint after MSA at a short-term follow-up is dysphagia. However, limited data suggest dysphagia rates largely decrease by 5 years. Dysphagia is the most common indication for dilation and device removal in both early- and long-term studies. However, the overall rates of dilation and removal are similar in short- and long-term reports, suggesting the majority of these procedures are performed in the short-term period after device implantation. The indications and standard practices of MSA have evolved over time. Long-term outcome data currently available are all from patient cohorts who were selected for MSA under early restricted indications and outdated regimens. Therefore, further long-term studies are needed to corroborate the preliminary, yet encouraging long-term results.

CSF-1R inhibitor, pexidartinib, sensitizes esophageal adenocarcinoma to PD-1 immune checkpoint blockade in a rat model.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R), down modulates macrophage-mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors. In this study, we investigated the antitumor activity of pexidartinib alone or in combination with blockade of PD-1 in a de novo EAC rat model. Here, we showed limited toxicity with significant tumor shrinkage in pexidartinib treated animals compared to controls, single agent and in combination with a PD-1 inhibitor, AUNP-12. Suppression of CSF-1/CSF-1R axis resulted in enhanced infiltration of CD3 + CD8 + T cells with reduced M2 macrophage polarization, in the tumor microenvironment (TME). Endpoint tissue gene expression in pexidartinib treated animals demonstrated upregulation of BAX, Cas3, TNFα, IFNγ and IL6 and downregulation of Ki67, IL13, IL10, TGFß and Arg1 (P < 0.05). Additionally, among the pexidartinib treated animals responders compared to nonresponders demonstrated a significant upregulation of pretreatment CSF-1 gene, confirming that tumor-associated macrophage suppression directly translates to clinical benefit. Moreover, a posttreatment serum cytokine assay exhibited similar systemic trends as the gene expression in the TME, depicting increases in proinflammatory cytokines and decreases in anti-inflammatory cytokines. In conclusion, our study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an EAC model, providing the rationale for future clinical strategies.

A blood-based circulating microbial metagenomic panel for early diagnosis and prognosis of oesophageal adenocarcinoma.

BACKGROUND: Emerging evidence indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in oesophageal adenocarcinoma (EAC) patients, particularly as novel non-invasive, early detection, surveillance and prognostic classifiers. METHODS: Metagenome sequencing was performed on 81 serum specimens collected across EAC spectrum, with sequencing reads classified using Bracken and MetaPhlAn3. Followed by the Linear Discriminant Analysis effect size (LEfSe) method to identify microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build classifiers. RESULTS: A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI: 0.78-0.95; P < 0.001) and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 (95% CI: 0.66-0.92; P = 0.006)). CONCLUSION: This study firstly describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC. TRANSLATIONAL RELEVANCE: Accumulating data indicates the clinical relevance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in patients with oesophageal adenocarcinoma (EAC). Herein, we performed metagenome sequencing in serum specimens from EAC patients 81 collected across EAC spectrum and observed a significant loss of alpha and beta diversity, with a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 and this panel, in conjunction with the TNM stage, was a robust predictor of overall survival. This study for the first time describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC.

Measurement of outflow resistance imposed by magnetic sphincter augmentation: defining normal values and clinical implication.

INTRODUCTION: No manometric criteria have been defined to select patients for magnetic sphincter augmentation (MSA). The first step to establish such criteria is to measure the outflow resistance at esophagogastric junction (EGJ) imposed by MSA. This resistance needs to be overcome by the esophageal contraction in order for the esophagus to empty and to avoid postoperative dysphagia. This study was designed to measure the outflow resistance caused by MSA in patients free of postoperative dysphagia. METHODS: Records of the patients who underwent MSA in our institution were reviewed. A group of MSA patients with excellent functional outcome, who were free of clinically significant postoperative dysphagia, were selected. These patients then underwent high-resolution impedance manometry (HRIM) at a target date of 1 year after surgery. The outflow resistance was measured by the esophageal intrabolus pressure (iBP) recorded 2 cm proximal to the lower esophageal sphincter (LES). RESULTS: The study population consisted of 43 patients. HRIM was performed at mean of 20.4 (10.4) months after surgery. The mean (SD) amplitude of the iBP was 13.5 (4.3) before surgery and increased to 19.1 (5.6) after MSA (p < 0.0001). Patients with a smaller size LINX device (≤ 14 beads) had a similar iBP when compared to those with a larger device (> 15 beads) [19.7 (4.5) vs. 18.4 (5.9), p = 0.35]. There was a significant correlation between the iBP and % incomplete bolus clearance [Spearman R: 0.44 (95% CI 0.15-0.66), p = 0.0032]. The 95th percentile value for iBP after MSA was 30.4 mmHg. CONCLUSION: The EGJ outflow resistance measured by iBP is increased after MSA. The upper limit of normal for iBP is 30 mmHg in this cohort of patients who were free of dysphagia after MSA. This degree of resistance needs to be overcome by distal esophageal contraction and will likely be requisite to prevent persistent postoperative dysphagia.

Magnetic sphincter augmentation (MSA) in patients with hiatal hernia: clinical outcome and patterns of recurrence.

INTRODUCTION: Magnetic sphincter augmentation (MSA) is an effective treatment for patients with gastroesophageal reflux disease. In early studies, patients with a hiatal hernia (HH) ≥ 3 cm were excluded from consideration for implantation and initially the FDA considered its use as "precautionary" in this context. This early approach has led to an attitude of hesitance among some surgeons to offer this therapy to patients with HH. This study was designed to evaluate the impact of HH status on the outcome of MSA and to report the rate of HH recurrence after MSA. METHODS AND PROCEDURES: This is a retrospective review of prospectively collected data of patients who underwent MSA between June 2013 and August 2017. Baseline clinical and objective data were collected. Patients were divided into four groups based on HH status: no HH, small HH (< 3 cm), large HH (≥ 3 cm), and paraesophageal hernia (PEH). Patient satisfaction, GERD-HRQL and RSI data, freedom from PPI, need for postoperative dilation, length of hospitalization, 90-day readmission rate, need for device removal, and HH recurrence was compared between groups. RESULTS: There were 350 patients [60% female, mean (SD) age: 53.5 (13.8)] who underwent MSA. There were 65 (18.6%) with no HH, 205 (58.6%) with small HH (< 3 cm), 58 (16.6%) with large HH (≥ 3 cm) and 22 (6.2%) with PEH. At a mean follow-up of 13.6 (10.4) months, the rate of outcome satisfaction was similar between the groups (86%, 87.9%, 92.2% and 93.8%, p = 0.72). This was also true for GERD-HRQL total score clinical improvement (79.1%, 77.8%, 82% and 87.5%, p = 0.77). The rate of postoperative dysphagia (p = 0.33) and freedom from PPIs (p = 0.96) were similar among the four groups. Duration of hospitalization was higher among those with a large HH or PEH, and only PEH patients had a higher 90-day readmission rate (p = 0.0004). There was no difference between the need for dilation among groups (p = 0.13). The need for device removal (5% overall) was similar between the four groups (p = 0.28). HH recurrence was 10% in all groups combined, and only 7 of 240 (2.9%) patients required reoperation; the majority of these patients underwent a minimal dissection approach (no hernia repair) at the index operation. The incidence of recurrent HH increased in direct correlation with the preoperative HH size (0%, 10.1%, 16.6 and 20%, p = 0.032). CONCLUSION: In the largest series of MSA implantation, we demonstrate that the excellent outcomes and high degree of satisfaction after MSA are independent of the presence or size of HH. Despite higher rates of hernia recurrence in large HH and PEH patients, the rates of postoperative endoscopic intervention, and device removal is similar to those with no or small HH. The minimal dissection approach to MSA should be abandoned.

Comparison of surgical payer costs and implication on the healthcare expenses between laparoscopic magnetic sphincter augmentation (MSA) and laparoscopic Nissen fundoplication (LNF) in a large healthcare system.

INTRODUCTION: Magnetic sphincter augmentation (MSA) is a promising antireflux surgical treatment. The cost associated with the device may be perceived as a drawback by payers, which may limit the adoption of this technique. There are limited data regarding the cost of MSA in the management of reflux disease. The aims of the study were to report the clinical outcome and quality of life measures in patients after MSA and to compare the pharmaceutical and procedure payer costs and the disease-related and overall expense of MSA compared to laparoscopic Nissen fundoplication (LNF) from a payer perspective. METHODS AND PROCEDURES: This prospective observational study was performed in conjunction with the region's largest health insurance company. Data were collected on patients who underwent MSA over a 2-year period beginning in September 2015 at the study network hospitals. The LNF comparison group was procured from members' claims data of the payer. Inclusion was predicated by patients having continuous coverage during study period. The total procedural reimbursement and the disease-related and overall medical claims submitted up to 12 months prior to surgery and up to 12 months following surgery were obtained. The payer reimbursement data are presented as allowed cost per member per month (PMPM). These values were then compared between groups. RESULTS: There were 195 patients who underwent MSA and 1131 that had LNF. MSA results in comparable symptom control, PPI elimination rate, and quality of life measures compared to values reported for LNF in the literature. The median (IQR) reimbursement of surgery was $13,522 (13,195-14,439) for those who underwent MSA and $13,388 (9951-16,261) for patients with LNF, p = 0.02. In patients who underwent MSA, the median reimbursement related to the upper gastrointestinal disease was $ 305 PMPM, at 12 months prior to surgery and $ 104 at 12 months after surgery, representing 66% decrease in cost. These values were $ 233 PMPM and $126 PMPM for patients who underwent LNF, representing a 46% decrease (p = 0.0001). At 12 months following surgery, the reimbursement for overall medical expenses had decreased by 10.7% in the MSA group and 1.4% in the LNF group when compared to the preoperative baseline reimbursement. The reimbursement for PPI use after surgery showed a 95% decrease in the MSA group and 90% among LNF group when compared to the preoperative baseline (p = 0.10). CONCLUSION: When compared with LNF, MSA results in a reduction of disease-related expenses for the payer in the year following surgery. While MSA is associated with a higher procedural payer cost compared to LNF, payer costs may offset due to reduction in the expenses after surgery.

Objective Evidence of Reflux Control After Magnetic Sphincter Augmentation: One Year Results From a Post Approval Study.

OBJECTIVE: To report 1-year results from a 5-year mandated study. SUMMARY BACKGROUND DATA: In 2012, the United States Food and Drug Administration approved magnetic sphincter augmentation (MSA) with the LINX Reflux Management System (Torax Medical, Shoreview, MN), a novel device for the surgical treatment of gastroesophageal reflux disease (GERD). Continued assessment of safety and effectiveness has been monitored in a Post Approval Study. METHODS: Multicenter, prospective study of patients with pathologic acid reflux confirmed by esophageal pH testing undergoing MSA. Predefined clinical outcomes were assessed at the annual visit including a validated, disease-specific questionnaire, esophagogastricduodenoscopy and esophageal pH monitoring, and use of proton pump inhibitors. RESULTS: A total of 200 patients (102 males, 98 females) with a mean age of 48.5 years (range 19.7-71.6) were treated with MSA between March 2013 and August 2015. At 1 year, the mean total acid exposure time decreased from 10.0% at baseline to 3.6%, and 74.4% of patients had normal esophageal acid exposure time (% time pH<4 ≤5.3%). GERD Health-Related Quality of Life scores improved from a median score of 26.0 at baseline to 4.0 at 1 year, with 84% of patients meeting the predefined success criteria of at least a 50% reduction in total GERD Health-Related Quality of Life score compared with baseline. The device removal rate at 1 year was 2.5%. One erosion and no serious adverse events were reported. CONCLUSIONS: Safety and effectiveness of magnetic sphincter augmentation has been demonstrated outside of an investigational setting to further confirm MSA as treatment for GERD.

The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation.

OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients. METHODS: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation. RESULTS: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure. CONCLUSIONS: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.

Serial Endoscopic Evaluation of Esophageal Disease in a Cancer Model: A Paradigm Shift for Esophageal Adenocarcinoma (EAC) Drug Discovery and Development.

A rat model of surgically induced reflux recapitulates the development and progression of human esophageal adenocarcinoma (EAC). In this study, reflux was induced in rats followed by postoperative endoscopy with biopsy, to diagnose and monitor disease progression. Overall, percentage agreement between visual endoscopy and gold standard histology was 95%, with disease-specific classification accuracies of 100% and 75% for Barrett's with dysplasia and EAC, respectively. Additionally, the percentage agreement for biopsy in tumors >4 mm was 75%. Thereby, establishing endoscopic evaluation as a reliable tool to assess disease progression and provide biopsies for downstream correlates in a de novo EAC model.

Nitrous oxide cryotherapy for treatment of esophageal squamous cell neoplasia: initial multicenter international experience with a novel portable cryoballoon ablation system (with video).

BACKGROUND AND AIMS: Early esophageal squamous cell neoplasia (ESCN) can be successfully treated by EMR, endoscopic submucosal dissection (ESD), or radiofrequency ablation. A new portable, battery-powered cryotherapy system using nitrous oxide (cryoballoon focal ablation system [CbFAS]) has been used for Barrett's esophagus. It consists of a small hand-held device containing liquid nitrous oxide, which converts to gas within a low-pressure-compliant through-the-scope balloon and freezes targeted mucosa in contact with the balloon. This study evaluated the feasibility of endoscopic eradication of early ESCN with the CbFAS. METHODS: Patients with early ESCN (defined as low-grade intraepithelial neoplasia [LGIN], high-grade intraepithelial neoplasia [HGIN], or early T1 squamous mucosal cancer) were treated with the CbFAS. After chromoendoscopy, all Lugol's unstained lesions (USLs) were targeted with 8, 10, or 12 seconds of ice per site, and treatment was repeated until biopsy samples demonstrated eradication of ESCN. Postprocedure adverse events were recorded. RESULTS: Ten patients (4 men; median age, 69.5 years) with LGIN (n=2), HGIN (n=7), or esophageal squamous cell carcinoma (ESCC; n=1, after EMR) in 24 USLs were treated. The median maximum diameter of the largest USL was 1.5 cm (interquartile range, 1-2 cm), and median total length of all neoplastic USLs was 2 cm (range, 1-10 cm). Patients with focal disease received a median of 2 cryoablations, whereas 4 patients with large and/or multifocal circumferential neoplasia had 6 to 12 ablations per procedure. The median procedure time was 34 minutes (range, 18-57 minutes). Treatment was completed in all patients. No major adverse events occurred. Four patients developed mild self-limited chest pain requiring narcotic analgesics immediately after the procedure. Two patients who received circumferential ablation developed a stricture responding to dilation, with no recurrence. Complete endoscopic and pathologic response was achieved in all patients at 3 months. One year follow-up biopsy specimens in 7 patients showed no USL or ESCN. All patients were disease free at last visit, with a median follow-up time of 10.7 months (interquartile range, 4-14 months). CONCLUSIONS: We report the first application of nitrous cryoballoon ablation for curative treatment of early primary or recurrent ESCN. Our initial experience suggests that efficacy is high and the safety profile is reasonable. Prospective trials are needed to optimize cryogen dosimetry and assess safety and efficacy.