Variation in surgical approach and postoperative complication among older adults undergoing ventral hernia repair.

BACKGROUND: Surgical decision-making for preference-sensitive operations among older adults is understudied. Ventral hernia repair (VHR) is one operation where granular data are limited to guide preoperative decision-making. We aimed to determine risk for VHR in older adults given clinically nuanced data including surgical and hernia characteristics. METHODS: We performed a retrospective analysis of the Michigan Surgical Quality Collaborative Core Optimization Hernia Registry from January 2020 to March 2023. The primary outcome was postoperative complication across age groups: 18-64, 65-74, and ≥ 75 years, with secondary outcome of surgical approach. Mixed-effects logistic regression evaluated association between minimally invasive surgery (MIS) and 30-day complications, controlling for patient and hernia characteristics. RESULTS: Among 8,659 patients, only 7% were 75 or older. MIS rates varied across hospitals [Median = 31.4%, IQR: (14.8-51.6%)]. The overall complication rate was 2.2%. Complication risk for undergoing open versus MIS approach did not vary between age groups; however, patients over age 75 undergoing laparoscopic repair had increased risk (aOR = 4.58, 95% CI 1.13-18.67). Other factors associated with risk included female sex (aOR = 2.10, 95% CI 1.51-2.93), higher BMI (aOR = 1.18, 95% CI 1.03-1.34), hernia width ≥ 6 cm (aOR = 3.15, 95% CI 1.96-5.04), previous repair (aOR = 1.44, 95% CI 1.02-2.05), and component separation (aOR = 1.98, 95% CI 1.28-3.05). Patients most likely to undergo MIS were female (aOR = 1.21, 95% CI 1.09-1.34), black (aOR = 1.30, 95% CI 1.12-1.52), with larger hernias: 2-5.9 cm (aOR = 1.76, 95% CI 1.57-1.97), or intraoperative mesh placement (aOR = 14.4, 95% CI 11.68-17.79). There was no difference in likelihood to receive MIS across ages when accounting for hospital (SD of baseline likelihood = 1.53, 95% CI 1.14-2.05) and surgeon (SD of baseline likelihood = 2.77, 95% CI 2.46-3.11) variation. CONCLUSIONS: Our findings demonstrate that hernia, intraoperative, and patient characteristics other than age increase probability for complication following VHR. These findings can empower surgeons and older patients considering preoperative risk for VHR.

Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death.

Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

Assessing donor-recipient size metrics for heart transplant outcomes: UNOS database analysis.

STUDY: There is no widely accepted donor to recipient size-match metric to predict outcomes in cardiac transplant. The predictive ability of size-match metrics has not been studied when recipients are stratified by heart failure etiology. We sought to assess the performance of commonly used size metrics to predict survival after heart transplant, accounting for restrictive versus non-restrictive pathology. METHODS: The UNOS registry was queried from 2000 to 2017 for all primary isolated heart transplants. Donor-recipient ratios were calculated for commonly used size metrics and their association with survival was assessed using continuous, nonlinear analysis. RESULTS: 29 817 patients were identified. Height (P < .001), predicted heart mass (PHM) (P = .003), ideal body weight (IBW) (P < .001) and body mass index (BMI) (P = .003) ratios were significantly associated with survival, while weight and body surface area (BSA) ratios were not. When stratified, only BMI ratio retained significance for both restrictive (P = .051) and non-restrictive (P = .003) subsets. Recipients with restrictive etiology had increased risk of mortality with both a lower and higher BMI ratio. CONCLUSIONS: While many metrics show association with survival in the non-restrictive subset, BMI is the only metric that retains significance in the restrictive subset. Recipients with restrictive and non-restrictive etiologies of heart failure tolerate size mismatch differently.

Global knockout of ROMK potassium channel worsens cardiac ischemia-reperfusion injury but cardiomyocyte-specific knockout does not: Implications for the identity of mitoKATP.

The renal-outer-medullary­potassium (ROMK) channel, mutated in Bartter's syndrome, regulates ion exchange in kidney, but its extra-renal functions remain unknown. Additionally, ROMK was postulated to be the pore-forming subunit of the mitochondrial ATP-sensitive K+ channel (mitoKATP), a mediator of cardioprotection. Using global and cardiomyocyte-specific knockout mice (ROMK-GKO and ROMK-CKO respectively), we characterize the effects of ROMK knockout on mitochondrial ion handling, the response to pharmacological KATP channel modulators, and ischemia/reperfusion (I/R) injury. Mitochondria from ROMK-GKO hearts exhibited a lower threshold for Ca2+-triggered permeability transition pore (mPTP) opening but normal matrix volume changes during oxidative phosphorylation. Isolated perfused ROMK-GKO hearts exhibited impaired functional recovery and increased infarct size when I/R was preceded by an ischemic preconditioning (IPC) protocol. Because ROMK-GKO mice exhibited severe renal defects and cardiac remodeling, we further characterized ROMK-CKO hearts to avoid confounding systemic effects. Mitochondria from ROMK-CKO hearts had unchanged matrix volume responses during oxidative phosphorylation and still swelled upon addition of a mitoKATP opener, but exhibited a lower threshold for mPTP opening, similar to GKO mitochondria. Nevertheless, I/R induced damage was not exacerbated in ROMK-CKO hearts, either ex vivo or in vivo. Lastly, we examined the response of ROMK-CKO hearts to ex vivo I/R injury with or without IPC and found that IPC still protected these hearts, suggesting that cardiomyocyte ROMK does not participate significantly in the cardioprotective pathway elicited by IPC. Collectively, our findings from these novel strains of mice suggest that cardiomyocyte ROMK is not a central mediator of mitoKATP function, although it can affect mPTP activation threshold.

A novel class of cardioprotective small-molecule PTP inhibitors.

Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.

Perfused murine heart optical transmission spectroscopy using optical catheter and integrating sphere: Effects of ischemia/reperfusion.

Tissue transmission optical absorption spectroscopy provides dynamic information on metabolism and function. Murine genetic malleability makes it a major model for heart research. The diminutive size of the mouse heart makes optical transmission studies challenging. Using a perfused murine heart center mounted in an integrating sphere for light collection with a ventricular cavity optical catheter as an internal light source provided an effective method of optical data collection in this model. This approach provided high signal to noise optical spectra which when fit with model spectra provided information on tissue oxygenation and redox state. This technique was applied to the study of cardiac ischemia and ischemia reperfusion which generates extreme heart motion, especially during the ischemic contracture. The integrating sphere reduced motion artifacts associated with a fixed optical pickup and methods were developed to compensate for changes in tissue thickness. During ischemia, rapid decreases in myoglobin oxygenation occurred along with increases in cytochrome reduction levels. Surprisingly, when ischemic contracture occurred, myoglobin remained fully deoxygenated, while the cytochromes became more reduced consistent with a further, and critical, reduction of mitochondrial oxygen tension during ischemic contraction. This optical arrangement is an effective method of monitoring murine heart metabolism.

3D organ modeling with open-source software.

To date, 3D organ modeling has not reached widespread clinical use, despite showing promise in medical literature. The majority of anatomic modeling that is presented in the literature is performed with proprietary software, presenting certain barriers to use, such as price for usage rights. Open-source software not only circumvents this barrier, but also often provides greater customization offered by global communities. In this proof-of-concept experiment, a HeartMate II LVAD inflow cannula was "virtually fit" in a patient's left ventricle using only open-source software. Open-source programs provide a legitimate alternative to the proprietary software options.

Device exchange versus nonexchange modalities in left ventricular assist device-specific infections: A systematic review and meta-analysis.

No standardized treatment algorithm exists for the management of continuous-flow left ventricular assist device (CF-LVAD)-specific infections. The aim of this systematic review and meta-analysis was to compare the outcomes of CF-LVAD-specific infections as managed by device exchange to other treatment modalities not involving device exchange. Electronic search was performed to identify all studies in the English literature relating to the management of CF-LVAD-specific infections. All identified articles were systematically assessed for selection criteria. Thirteen studies with 158 cases of CF-LVAD-specific infection were pooled for analysis. Overall, 18/158 (11.4%) patients underwent CF-LVAD exchange, and 140/158 (88.6%) patients were treated with non-exchange modalities. The proportion of patients with isolated driveline infections or pump or pocket infections did not differ significantly between the groups. During a mean follow-up of 290 days, there were no significant differences in the overall mortality [exchange 17.6% (4.3-50.6) vs. non-exchange 23.3% (15.8-32.9), P = 0.67] and infection recurrence rates [exchange 26.7% (8.7-58.0) vs. non-exchange 38.6% (15.4-68.5), P = 0.56]. In the setting of CF-LVAD-specific infections, device exchange does not appear to confer an advantage in the overall mortality and infection recurrence as compared to non-exchange modalities.

The value of shoulder replacement and rotator cuff surgery: the patients' perspective.

BACKGROUND: With the continued rise in health care costs, value-based care in orthopedics is more important than ever. Health care providers, policymakers, and insurance companies all have input into defining and setting the level of this value. The purpose of this study was to evaluate patient perception of value in rotator cuff repair (RCR) and total shoulder replacement (TSA) using a population composed only of patients who underwent the procedure. METHODS: We were able to obtain complete data from 191 of the 250 patients in the RCR cohort and 211 of the 250 patients in the TSA cohort. Patients were asked what they believe a surgeon should be reimbursed for performing RCR or TSA, what they would be willing to pay for the procedure, and to rate the importance of each aspect of their care. Patients then estimated what Medicare reimbursed for the procedure they underwent. RESULTS: The mean result for patients surveyed regarding a reasonable fee for surgeons was $9870 for RCR and $14,231 for TSA. The mean patient estimate for actual Medicare reimbursement was $5705 for RCR and $9372 for TSA. Fifty-seven percent thought that payment for RCR was too low, and 76% thought that it was too low for TSA. When asked to rate the importance of each aspect of their care, RCR patients felt that 46% should go to the surgeon. TSA patients felt that surgeons should receive 47%. CONCLUSION: In agreement with prior studies, patients perceived the monetary value of RCR and TSA to be much higher than current Medicare schedules.

Is nonoperative management of partial distal biceps tears really successful?

BACKGROUND: The current treatment of partial distal biceps tears is a period of nonoperative management, followed by surgery, if symptoms persist. Little is known about the success rate and outcomes of nonoperative management of this illness. METHODS: We identified 132 patients with partial distal biceps tears through an International Classification of Diseases, Ninth Revision code query of our institution's database. Patient records were reviewed to abstract demographic information and confirm partial tears of the distal biceps tendon based on clinical examination findings and confirmatory magnetic resonance imaging (MRI). Seventy-four patients completed an outcome survey. RESULTS: In our study, 55.7% of the contacted patients who tried a nonoperative course (34 of 61 patients) ultimately underwent surgery, and 13 patients underwent immediate surgery. High-need patients, as defined by occupation, were more likely to report that they recovered ideally if they underwent surgery, as compared with those who did not undergo surgery (odds ratio, 11.58; P = .0138). For low-need patients, the same analysis was not statistically significant (P = .139). There was no difference in satisfaction scores between patients who tried a nonoperative course before surgery and those who underwent immediate surgery (P = .854). An MRI-diagnosed tear of greater than 50% was a predictor of needing surgery (odds ratio, 3.0; P = .006). CONCLUSIONS: This study has identified clinically relevant information for the treatment of partial distal biceps tears, including the following: the failure rate of nonoperative treatment, the establishment of MRI percent tear as a predictor of failing nonoperative management, the benefit of surgery for the high-need occupational group, and the finding that nonoperative management does not negatively affect outcome if subsequent surgery is necessary.

Biofilm-derived oxylipin 10-HOME mediated immune response in women with breast implants.

Breast implant illness (BII) is a poorly understood disease in which patients develop symptoms typical of autoimmune conditions following breast implantation. There is no known underlying cause, and patients often resort to breast implant removal and capsulectomy to alleviate symptoms. In this issue of the JCI, Khan and colleagues examined 86 breast explants from patients that reported BII symptoms and 55 control explants. The BII group showed a disproportionally high degree of biofilm, which was associated with oxylipin (10-HOME) on the implant surfaces. Injections of 10-HOME in the mammary fat pad of a murine model recapitulated BII symptoms and increased Th1 cell populations. Notably, macrophages in the periprosthetic tissue from BII patients were more likely to exhibit a proinflammatory phenotype, and naive T cells exposed to 10-HOME caused naive macrophages to differentiate to a proinflammatory phenotype. This work provides a pathophysiologic mechanism for a currently understudied and poorly characterized disease.

Outcomes of nonemergency cardiac surgery after overnight operative workload: A statewide experience.

Objective: Cardiac surgeons experience unpredictable overnight operative responsibilities, with variable rest before same-day, first-start scheduled cases. This study evaluated the frequency and associated impact of a surgeon's overnight operative workload on the outcomes of their same-day, first-start operations. Methods: A statewide cardiac surgery quality database was queried for adult cardiac surgical operations between July 1, 2011, and March 1, 2021. Nonemergency, first-start, Society of Thoracic Surgeons predicted risk of mortality operations were stratified by whether or not the surgeon performed an overnight operation that ended after midnight. A generalized mixed effect model was used to evaluate the effect of overnight operations on a Society of Thoracic Surgeons composite outcome (5 major morbidities or operative mortality) of the first-start operation. Results: Of all first-start operations, 0.4% (239/56,272) had a preceding operation ending after midnight. The Society of Thoracic Surgeons predicted risk of morbidity and mortality was similar for first-start operations whether preceded by an overnight operation or not (overnight operation: 11.3%; no overnight operation: 11.7%, P = .42). Unadjusted rates of the primary outcome were not significantly different after an overnight operation (overnight operation: 13.4%; no overnight operation: 12.3%, P = .59). After adjustment, overnight operations did not significantly impact the risk of major morbidity or mortality for first-start operations (adjusted odds ratio, 1.1, P = .70). Conclusions: First-start cardiac operations performed after an overnight operation represent a small subset of all first-start Society of Thoracic Surgeons predicted risk operations. Overnight operations do not significantly influence the risk of major morbidity or mortality of first-start operations, which suggests that surgeons exercise proper judgment in determining appropriate workloads.

The histone methyltransferase mixed-lineage-leukemia-1 drives T cell phenotype via notch signaling in diabetic tissue repair.

Immune cell mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+T cells in normal or diabetic wound repair, however, the imbalance of CD4+TH17/Treg cells has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase MLL1 directly regulates the TH17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Further, we found that Notch receptor signaling regulates CD4+TH cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+T cells resulted in the loss of CD4+TH cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling were upregulated in wound CD4+TH cells, driving CD4+ T cells towards the TH17 cell phenotype. Treatment of diabetic wound CD4T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+TH17 cells and IL17A. This is the first study to identify the MLL1-mediated mechanisms responsible for regulating the TH17/Treg balance in normal and diabetic wounds and define the complex role of Notch signaling in CD4+T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+TH cells may decrease pathologic inflammation through regulation of CD4+T cell differentiation.

The relationship between discharge location and cardiac rehabilitation use after cardiac surgery.

BACKGROUND: Cardiac rehabilitation (CR) is a guideline-recommended risk-reduction program offered to cardiac surgical patients. Despite CR's association with better outcomes, attendance remains poor. The relationship between discharge location and CR use is poorly understood. METHODS: This study was a nationwide, retrospective cohort analysis of Medicare fee-for-service claims for beneficiaries undergoing coronary artery bypass grafting and/or surgical aortic valve repair between July 1, 2016, and December 31, 2018. The primary outcome was attendance of any CR session. Discharge location was categorized as home discharge or discharge to extended care facility (ECF) (including skilled nursing facility, inpatient rehabilitation, and long-term acute care). Multivariable logistic regression models evaluated the association between discharge location, CR attendance, and 1-year mortality. RESULTS: Of the 167,966 patients who met inclusion criteria, 34.1% discharged to an ECF. Overall CR usage rate was 53.9%. Unadjusted and adjusted CR use was lower among patients discharged ECFs versus those discharged home (42.1% vs 60.0%; adjusted odds ratio, 0.66; P < .001). Patients discharged to long-term acute care were less likely to use CR than those discharged to skilled nursing facility or inpatient rehabilitation (reference category: home; adjusted odds ratio for long-term acute care, 0.36, adjusted odds ratio for skilled nursing facility, 0.69, and adjusted odds ratio for inpatient rehabilitation, 0.71; P < .001). CR attendance was associated with a greater reduction in adjusted 1-year mortality in patients discharged to ECFs (9.7% reduction) versus those discharged home (4.3% reduction). CONCLUSIONS: In this national analysis of Medicare beneficiaries, discharge to ECF was associated with lower CR use, despite a greater association with improved 1-year mortality. Interventions aimed at increasing CR enrollment at ECFs may improve CR use and advance surgical quality.

Interhospital variability in cardiac rehabilitation use after cardiac surgery among Medicare beneficiaries.

OBJECTIVE: Despite guideline recommendation, cardiac rehabilitation (CR) after cardiac surgery remains underused, and the extent of interhospital variability is not well understood. This study evaluated determinants of interhospital variability in CR use and outcomes. METHODS: This retrospective cohort study included 166,809 Medicare beneficiaries undergoing cardiac surgery who were discharged alive between July 1, 2016, and December 31, 2018. CR participation was identified in outpatient facility claims within a year of discharge. Hospital-level CR rates were tabulated, and multilevel models evaluated the extent to which patient, organizational, and regional factors accounted for interhospital variability. Adjusted 1-year mortality and readmission rates were also calculated for each hospital quartile of CR use. RESULTS: Overall, 90,171 (54.1%) participated in at least 1 CR session within a year of discharge. Interhospital CR rates ranged from 0.0% to 96.8%. Hospital factors that predicted CR use included nonteaching status and lower-hospital volume. Before adjustment for patient, organizational, and regional factors, 19.3% of interhospital variability was attributable to the admitting hospital. After accounting for covariates, 12.3% of variation was attributable to the admitting hospital. Patient (0.5%), structural (2.8%), and regional (3.7%) factors accounted for the remaining explained variation. Hospitals in the lowest quartile of CR use had greater adjusted 1-year mortality rates (Q1 = 6.7%, Q4 = 5.2%, P < .001) and readmission rates (Q1 = 37.6%, Q4 = 33.9%, P < .001). CONCLUSIONS: Identifying best practices among high CR use facilities and barriers to access in low CR use hospitals may reduce interhospital variability in CR use and advance national improvement efforts.

Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells. This increased IL-17A cytokine, in excess, impairs tissue repair. Here, using human tissue and murine wound healing models, we found that diabetic wound pDCs produced excess IL-6 and TGF-ß and that these cytokines skewed naive CD4+ T cells toward a Th17 inflammatory phenotype following cutaneous injury. Further, we identified that increased IL-6 cytokine production by diabetic wound pDCs is regulated by a histone demethylase, Jumonji AT-rich interactive domain 1C histone demethylase (JARID1C). Decreased JARID1C increased IL-6 transcription in diabetic pDCs, and this process was regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. When inhibited in nondiabetic wound pDCs, JARID1C skewed naive CD4+ T cells toward a Th17 phenotype and increased IL-17A production. Together, this suggests that diabetic wound pDCs are epigenetically altered to increase IL-6 expression that then affects T cell phenotype. These findings identify a therapeutically manipulable pathway in diabetic wounds.

Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling.

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model ( Jmjd3 flox/flox Myh11 CreERT ), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.

Role of IL4 and GMCSF in Predicting Survival in Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) originates in the setting of chronic inflammation. Although previous studies have sought to understand the role of inflammatory signaling in EC, the effect of these immunologic changes on patient outcomes remains understudied. This study's objective was to identify relationships between cytokine levels and prognosis in a mixed cohort of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) patients. STUDY DESIGN: A total of 37 serum cytokines were profiled at the time of resection using multiplex ELISA in 47 patients (42 esophageal adenocarcinoma, 5 esophageal squamous cell carcinoma). Cytokine levels were median-binarized and assessed using Cox regression models. Findings were validated at the RNA level using The Cancer Genome Atlas EC cohort (81 esophageal adenocarcinoma, 81 esophageal squamous cell carcinoma). RESULTS: Univariable analysis revealed high serum interleukin 4 (IL4) and granulocyte-macrophage colony-stimulating factor (GMCSF) were negatively associated with overall survival (p = 0.046, p = 0.040). Multivariable analysis determined both high serum IL4 or high serum GMCSF were negatively associated with survival independent of important clinical factors (hazard ratio [HR] 7.55, p < 0.001; HR 5.24, p = 0.001). These findings were validated at the RNA level in The Cancer Genome Atlas EC cohort, where multivariable analysis identified high IL4 expression, high CSF2 expression (encodes GMCSF), and advanced pathologic stage as independent negative predictors of survival when controlled for clinical factors (HR 2.35, p = 0.012; HR 1.97, p = 0.040). CONCLUSIONS: These results show that high IL4/GMCSF levels are negatively associated with survival in EC. These relationships are independent of pathologic stage and are identified across modalities, histologic subtypes, and the presence/absence of neoadjuvant therapy.