Racial Differences and Injury Pattern Variation: Impact of COVID-19 on a Bronx Trauma Center.

BACKGROUND: New York City (NYC) became the epicenter of the COVID-19 pandemic in 2020. The Bronx, with the highest rates of poverty and violent crime of all NYC boroughs and a large Black and Hispanic population, was at increased risk of COVID-19 and its sequelae. We aimed to identify temporal associations among COVID-19 and trauma admission volume, demographics, and mechanism of injury (MOI). METHODS: A retrospective review of prospectively collected data was conducted from a Level II trauma center in the Bronx. January 1st-September 30th for both 2019 (Pre-COVID) and 2020 (COVID) were compared. Pre-COVID and COVID cohorts were subdivided into EARLY (March-May) and LATE (June-September) subgroups. Demographics and trauma outcomes were compared. RESULTS: Trauma admissions were similar between Pre-COVID and COVID. During COVID, there was an increased percentage of Black patients (Black Hispanic 20.1% vs 15.2% and Black Non-Hispanic 39.4% vs 34.1%, P < .05), younger patients (26-35 years old: 22.6% vs 17.6%, P < .05), and out-of-pocket payors (6.0% vs 1.6%, P < .05). Trauma severity outcomes were mixed-some measures supported increased severity; others showed no difference or decreased severity. During COVID, there was a rise in total penetrating injuries (27.4% vs 20.8%, P < .05), MVC (13.2% vs 7.1, P < .05), and firearm injuries (11.6% vs 6.0%, P < .05). Additionally, during LATE COVID, there was a resurgence of total penetrating, total blunt, MVC, falls, cyclists/pedestrians struck, and firearm injuries. DISCUSSION: Our results emphasize MOI variations and racial differences of trauma admissions to a Level II trauma center in the Bronx during COVID-19. These findings may help trauma centers plan during pandemics and encourage outreach between trauma centers and community level organizations following future healthcare disasters.

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.

Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a deadly disease with limited treatment options. STING is a transmembrane protein that activates transcription of interferon genes, resulting in stimulation of APCs and enhanced CD8+ T-cell infiltration. The present study evaluates STING agonists, alone and in combination with radiation to determine durable anticancer activity in solid tumors. MATERIALS AND METHODS: Esophagojejunostomy was performed on rats to induce reflux leading to the development of EAC. At 32 weeks post operatively, rats received intratumorally either 50 µg STING (ADU-S100) or placebo (PBS), +/- 16Gy radiation. Drug activity was evaluated by pre- and post- treatment MRI, histology, immunofluorescence and RT-PCR. RESULTS: Mean MRI tumor volume decreased by 30.1% and 50.8% in ADU-S100 and ADU-S100 + radiation animals and increased by 76.7% and 152.4% in placebo and placebo + radiation animals, respectively (P < 0.0001). Downstream gene expression, pre- to on- and post- treatment, demonstrated significant upregulation of IFNß, TNFα, IL-6, and CCL-2 in the treatment groups vs. placebo. On- or post- treatment, radiation alone, ADU-S100 alone, and ADU-S100 + radiation groups demonstrated enhanced PD-LI expression, induced by upregulation of CD8+ T-cells (p < 0.01). CONCLUSIONS: ADU-S100 +/- radiation exhibits potent antitumor activity and a promising immunomodulatory profile in a de novo EAC.

Efficacy of Magnetic Sphincter Augmentation Across the Spectrum of GERD Disease Severity.

BACKGROUND: The performance and durability of various types of fundoplication are variable when stratified by disease severity. To date, magnetic sphincter augmentation (MSA) has not been evaluated in this context. We designed this study to determine the efficacy of MSA in the treatment of severe GERD. STUDY DESIGN: Guided by previous studies, a DeMeester score (DMS) ≥ 50 was used as a cutoff point to define severe reflux disease. Subjects were divided into 2 groups using this cutoff, and outcomes of severe cases were compared with those with less severe disease (DMS < 50). RESULTS: A total of 334 patients underwent MSA. Patients with severe disease had a higher mean preoperative DMS compared with those with mild to moderate GERD (79.2 [53.2] vs 22.8 [13.7], p < 0.0001). At a mean postoperative follow-up of 13.6 (10.4) months, there was no difference between the mean GERD Health-Related Quality of Life (HRQL) total scores in patients with severe disease compared with those with less severe GERD (8.8 [10] vs 9.2 [10.8], p = 0.9204). Postoperative mean DMS was not different between groups (17.3[23.0] vs 14.1[33.9], p = 0.71), and there was no difference in the prevalence of esophagitis (p = 0.52). Patients with severe disease were less likely to be free from use of proton pump inhibitors after surgery (85% vs 93.1%, p = 0.041). There were similar rates of postoperative dysphagia (10% vs 14%, p = 0.42) and need for device removal (3% vs 5%, p = 0.7463). CONCLUSIONS: MSA is an effective treatment in patients with severe GERD and leads to significant clinical improvement across the spectrum of disease severity, with few objective outcomes being superior in patients with mild-to-moderate reflux disease.

Clinical Outcomes and Predictors of Favorable Result after Laparoscopic Magnetic Sphincter Augmentation: Single-Institution Experience with More than 500 Patients.

BACKGROUND: Magnetic sphincter augmentation (MSA) is a promising surgical treatment for patients with GERD. The aim of this study was to evaluate the outcomes of MSA in a large cohort of patients with GERD and to determine the factors predicting a favorable outcome. METHODS: This was a retrospective review of prospectively collected data of 553 patients who underwent MSA at our institution in a 5-year period. Preoperative clinical, endoscopic, manometric, and pH data were used in a univariate analysis. This was followed by a regression multivariable analysis to determine the factors predicting a favorable outcome. Favorable outcome was defined as freedom from proton pump inhibitors and ≥50% improvement in Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) total score. RESULTS: At a mean (SD) follow-up of 10.3 (10.6) months after MSA, 92.7% of the patients were free of proton pump inhibitor use and 84% reported at least 50% improvement in their GERD-HRQL total score. The GERD-HRQL total score was improved from a mean (SD) baseline value of 33.8 (18.7) to 7.2 (9.0) (p < 0.001) and 76.1% of the patients had normalization of their esophageal acid exposure. Independent predictors of a favorable outcome after MSA included age younger than 45 years (odds ratio [OR] 4.2; 95% CI, 1.1 to 15.2; p = 0.0305), male sex (OR 2.5; 95% CI, 1.1 to 5.7; p = 0.0301), GERD-HRQL total score >15 (OR 7.5; 95% CI, 3.3 to 16.8; p < 0.0001), and abnormal DeMeester score (OR, 2.6; 95% CI, 1.1 to 5.7; p = 0.0225). CONCLUSIONS: In this largest single-institution series, we demonstrate that MSA implantation is associated with very good clinical and objective outcomes. Age younger than 45 years, male sex, GERD-HRQL total score >15, and abnormal DeMeester score are the 4 preoperative factors predicting a favorable outcome and can be used in patient counseling and MSA use.

Magnetic Sphincter Augmentation and Postoperative Dysphagia: Characterization, Clinical Risk Factors, and Management.

INTRODUCTION: Magnetic sphincter augmentation (MSA) results in less severe side effects compared with Nissen fundoplication, but dysphagia remains the most common side effect reported by patients after MSA. This study aimed to characterize and review the management of postoperative dysphagia and identify the preoperative factors that predict persistent dysphagia after MSA. MATERIAL AND METHODS: This is a retrospective review of prospectively collected data of patients who underwent MSA between 2013 and 2018. Preoperative objective evaluation included upper endoscopy, esophagram, high-resolution impedance manometry (HRIM), and esophageal pH testing. Postoperative persistent dysphagia was defined as a postoperative score of > 3 for the dysphagia-specific item within the GERD-HRQL at a minimum of 3 months following MSA. A timeline of dysphagia and dilation rates was constructed and correlated with the evolution of our patient management practices and modifications in surgical technique. RESULTS: A total of 380 patients underwent MSA, at a mean (SD) follow up of 11.5 (8.7) months, 59 (15.5%) patients were experiencing persistent dysphagia. Thirty-one percent of patients required at least one dilation for dysphagia or chest pain and the overall response rate to this procedure was 67%, 7 (1.8%) patients required device removal specifically for dysphagia. Independent predictors of persistent dysphagia based on logistic regression model included (1) absence of a large hernia (OR 2.86 (95% CI 1.08-7.57, p = 0.035)); (2) the presence of preoperative dysphagia (OR 2.19 (95% CI 1.05-4.58, p = 0.037)); and (3) having less than 80% peristaltic contractions on HRIM (OR 2.50 (95% CI 1.09-5.73, p = 0.031)). Graded cutoffs of distal contractile integral (DCI), mean wave amplitude, DeMeester score, sex, and body mass index were evaluated within the model and did not predict postoperative dysphagia. Frequent eating after surgery, avoidance of early dilation, and increase in the size of the LINX device selected decreased the need for dilation. CONCLUSION: In a large cohort of patients who underwent MSA, we report 15.5% rate of persistent postoperative dysphagia. The overall response rate to dilation therapy is 67%, and the efficacy of dilation with each subsequent procedure reduces. Patients with normal hiatal anatomy, significant preoperative dysphagia, and less than 80% peristaltic contractions of the smooth muscle portion of the esophagus should be counseled that they have an increased risk for persistent postoperative dysphagia.

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.

Prognostic immune markers for recurrence and survival in locally advanced esophageal adenocarcinoma.

Treatment options and risk stratification for esophageal adenocarcinomas (EAC) currently rely on pathological criteria such as tumor staging. However, with advancement in immune modulated treatments, there is a need for accurate predictive biomarkers that will help identify high-risk patients and provide novel therapeutic targets. Hence, we analyzed as prognostic classifiers a host of histopathological parameters in conjunction with novel immune biomarkers. Specifically, gene expression levels for CXCL9, IDO1, LAG3, and TIM3 were established in treatment naïve samples. Additionally, PD-L1 and CD8 positivity was determined by immunohistochemical staining. Based on our finding, a Cox model consisting of pathological complete response (CR), LAG3, and CXCL9 provided improved predictability for disease-free survival (DFS) compared to CR alone, and it demonstrated statistical significance for predictability of recurrence (p=0.0001). Likewise, for overall survival (OS), a Cox model constituted of TIM3, CR, and IDO1 performed better than CR alone, and it demonstrated statistical significance for predictability of survival (p = 0.0004). TIM3 was identified as the best predictor for OS (HR=4.43, p=0.0023). In conclusion, given the paucity of treatment options for EAC, evaluation of these biomarkers early in the disease course will lead to better risk stratification of patients and much needed alternatives for improved therapy.