Robot-Assisted-Minimally Invasive-Transhiatal Esophagectomy (RAMI-THE).

The authors review the development and steps of the robotic-assisted minimally invasive transhiatal esophagectomy. Key goals of the robot-assisted approach have been to address some of the concerns raised about the technical challenges with the traditional open transhiatal esophagectomy while keeping most of the steps consistent with the open approach.

Rural Women Have a Prolonged Recovery Process after Esophagectomy.

BACKGROUND: Gender and geographic access to care play a large role in health disparities in esophageal cancer care. The aim of our study was to evaluate disparities in peri-operative outcomes for patients undergoing esophagectomy based on gender and geographic location. METHODS: A retrospective cohort of prospectively collected data from patients who underwent esophagectomy from 2003 to 2022 was identified and analyzed based on gender and county, which were aggregated into existing state-level "metropolitan" versus "rural" designations. The demographics, pre-operative treatment, surgical complications, post-operative outcomes, and length of stay (LOS) of each group were analyzed using chi-squared, paired t-tests and single-factor ANOVA. RESULTS: Of the 1545 patients, men (83.6%) and women (16.4%) experienced similar rates of post-operative complications, but women experienced significantly longer hospital (p = 0.002) and ICU (p = 0.03) LOSs as compared with their male counterparts, with no differences in 30-day mortality. When separated by geographic criteria, rural women were further outliers, with significantly longer hospital LOSs (p < 0.001) and higher rates of ICU admission (p < 0.001). CONCLUSIONS: Rural female patients undergoing esophagectomy were more likely to have a longer inpatient recovery process compared with their female metropolitan or male counterparts, suggesting a need for more targeted interventions in this population.

Comprehensive sampling of the lung microbiome in early-stage non-small cell lung cancer.

Objectives: Data are scarce on whether the composition of the lung microbiome (extending from the nasopharynx to the peripheral lung tissue) varies according to histology or grade of non-small cell lung cancer. We hypothesized that the composition of the lung microbiome would vary according to the histology and the grade of non-small cell lung cancer. Methods: We collected naso-oral and central lobar (cancer affected, ipsilateral unaffected, and contralateral unaffected) bronchoalveolar lavage fluid and brushing samples from patients with clinical early-stage lung cancer between July 2018 and February 2020 at a single academic center. We performed bacterial 16S rRNA sequencing and then compared clinical and pathologic findings with microbiome signatures. Results: Samples were collected from 28 patients. Microbial composition in affected lobes displayed unique enrichment of oropharyngeal bacterial species that was significantly different compared with that from the unaffected contralateral lobes; patients with chronic obstructive pulmonary disease had similar diversity to those without chronic obstructive pulmonary disease (P = .1312). The lung microbiome diversity in patients with adenocarcinoma was similar to those with squamous cell cancer (P = .27). There were no differences in diversity or composition in the unaffected lobes of patients with adenocarcinoma versus squamous cell cancer. There was a trend toward lower lung microbial diversity in poorly differentiated adenocarcinomas compared with well-differentiated adenocarcinomas (P = .08). Conclusions: The lung microbiota differs between cancer affected and unaffected lobes in the same patient. Furthermore, poorly differentiated lung cancers were associated with lower microbial diversity. Larger studies will be required to confirm these findings.

Impact of cryoablation on operative outcomes in thoracotomy patients.

OBJECTIVES: Cryoablation is increasingly being utilized as an alternative to epidurals for patients undergoing thoracotomies. Current evidence suggests cryoablation may decrease postoperative analgesia utilization, but could increase operative times. We hypothesized that the adoption of intraoperative cryoablation to manage post-thoracotomy pain would result in reduced length of stay and reduced perioperative analgesia compared to routine epidural use. METHODS: A retrospective analysis was performed from a single, quaternary referral centre, prospective database on patients receiving thoracotomies between January 2020 and March 2022. Patients undergoing transthoracic hiatal hernia repair, lung resection or double-lung transplant were divided between epidural and cryoablation cohorts. Primary outcomes were length of stay, intraoperative procedure time, crossover pain management and oral narcotic usage the day before discharge. RESULTS: During the study period, 186 patients underwent a transthoracic hiatal hernia repair, lung resection or double-lung transplant with 94 receiving a preoperative epidural and 92 undergoing cryoablation. Subgroup analysis demonstrated no significant differences in demographics, operative length, length of stay or perioperative narcotic use. Notably, over a third of patients in each cryoablation subgroup received a postoperative epidural (45.5% transthoracic hiatal hernia repair, 38.5% lung resection and 45.0% double-lung transplant) for further pain management during their admission. CONCLUSIONS: Cryoablation use was not associated with an increase in procedure time, a decrease in narcotic use or length of stay. Surprisingly, many cryoablation patients received epidurals in the postoperative period for further pain control. Additional analysis is needed to fully understand the benefits and costs of epidural versus cryoablation strategies.

Endometriosis first presenting in pleural fluid cytology.

Most patients with thoracic endometriosis present with catamenial pneumothorax, a rare condition in which recurrent episodes occur within 72 h before or after the start of menstruation. We report a case of thoracic endometriosis presenting with recurrent bloody pleural effusions without pneumothorax diagnosed on pleural fluid cytology. We describe the cytomorphology and immunoprofile of thoracic endometriosis and discuss the differential diagnoses, including neoplastic processes. We also highlight the importance of communication with clinicians for timeliness of diagnosis and treatment, especially when thoracic endometriosis is not suspected.

Quality improvement mechanisms to improve lymph node staging for lung cancer: Trends from a statewide database.

OBJECTIVE: Our statewide thoracic quality collaborative has implemented multiple quality improvement initiatives to improve lung cancer nodal staging. We subsequently implemented a value-based reimbursement initiative to further incentivize quality improvement. We compare the impact of these programs to steer future quality improvement initiatives. METHODS: Since 2016, our collaborative focused on improving lymph node staging for lung cancer by leveraging unblinded, hospital-level metrics and collaborative feedback. In 2021, a value-based reimbursement initiative was implemented with statewide yearly benchmark rates for (1) preoperative mediastinal staging for ≥T2N0 lung cancer, and (2) sampling ≥5 lymph node stations. Participating surgeons would receive additional reimbursement if either benchmark was met. We reviewed patients from January 2015 to March 2023 at the 21 participating hospitals to determine the differential effects on quality improvement. RESULTS: We analyzed 6228 patients. In 2015, 212 (39%) patients had ≥5 nodal stations sampled, and 99 (51%) patients had appropriate preoperative mediastinal staging. During 2016 to 2020, this increased to 2253 (62%) patients and 739 (56%) patients, respectively. After 2020, 1602 (77%) patients had ≥5 nodal stations sampled, and 403 (73%) patients had appropriate preoperative mediastinal staging. Interrupted time-series analysis demonstrated significant increases in adequate nodal sampling and mediastinal staging before value-based reimbursement. Afterward, preoperative mediastinal staging rates briefly dropped but significantly increased while nodal sampling did not change. CONCLUSIONS: Collaborative quality improvement made significant progress before value-based reimbursement, which reinforces the effectiveness of leveraging unblinded data to a collaborative group of thoracic surgeons. Value-based reimbursement may still play a role within a quality collaborative to maintain infrastructure and incentivize participation.

The Society of Thoracic Surgeons Looking to the Future Scholarship Program: A 15-Year Review.

BACKGROUND: It has been postulated that a possible barrier to pursuing cardiothoracic surgery is a lack of exposure and mentorship during training. In 2006, The Society of Thoracic Surgeons began the Looking to the Future Scholarship to expand interest in the field. Undecided trainees with limited exposure were prioritized in the selection process. This report summarizes the career outcomes of general surgery resident and medical student recipients. METHODS: Scholarship recipients and nonrecipients (control) were queried in a Google search. The percentage of those who were cardiothoracic surgeons or in cardiothoracic training (%CTS) was calculated, as well as the percentage of female surgeons in cardiothoracic surgery. RESULTS: From 2006 to 2021, there were 669 awardees. The %CTS was 63.7% for resident recipients and 31.4% for students, respectively. There was no significant difference in %CTS between resident and student recipients compared to nonrecipients. Notably, the percentage of female cardiothoracic surgeons was significantly greater for both resident and student recipients. CONCLUSIONS: The majority of resident recipients are now in cardiothoracic surgery, comparable to nonrecipients. While there was no significant difference between the percentage of recipients and non-recipients in cardiothoracic surgery, these groups differed substantially as nonrecipients had greater exposure and commitment to the field at the time of application.

Factors affecting timing of surgery following neoadjuvant chemoradiation for esophageal cancer.

Background: Neoadjuvant chemoradiation with esophagectomy is standard management for locally advanced esophageal cancer. Studies have shown that surgical timing following chemoradiation is important for minimizing postoperative complications, however in practice timing is often variable and delayed. Although postoperative impact of surgical timing has been studied, less is known about factors associated with delays. Materials and methods: A retrospective review was performed for 96 patients with esophageal cancer who underwent chemoradiation then esophagectomy between 2018 and 2020 at a single institution. Univariable and stepwise multivariable analyses were used to assess association between social (demographics, insurance) and clinical variables (pre-operative weight, comorbidities, prior cardiothoracic surgery, smoking history, disease staging) with time to surgery (≤8 weeks "on-time" vs. >8 weeks "delayed"). Results: Fifty-one patients underwent esophagectomy within 8 weeks of chemoradiation; 45 had a delayed operation. Univariate analysis showed the following characteristics were significantly different between on-time and delayed groups: weight loss within 3 months of surgery (3.9 ± 5.1 kg vs. 1.5 ± 3.6 kg; P = 0.009), prior cardiovascular disease (29% vs. 49%; P = 0.05), prior cardiothoracic surgery (4% vs. 22%; P = 0.01), history of ever smoked (69% vs. 87%; P = 0.04), absent nodal metastasis on pathology (57% vs. 82%; P = 0.008). Multivariate analysis demonstrated that prior cardiothoracic surgery (OR 8.924, 95%CI 1.67-47.60; P = 0.01) and absent nodal metastasis (OR 4.186, 95%CI 1.50-11.72; P = 0.006) were associated with delayed surgery. Conclusions: Delayed esophagectomy following chemoradiotherapy is associated with prior cardiothoracic surgery and absent nodal metastasis. Further investigations should focus on understanding how these factors contribute to delays to guide treatment planning and mitigate sources of outcome disparities.

Epidemiology of Postoperative Complications After Esophagectomy: Implications for Management.

BACKGROUND: Despite advances in operative techniques and postoperative care, esophagectomy remains a morbid operation. Leveraging complication epidemiology and the correlation of these complications may improve rescue and refine early recovery pathways. METHODS: This study retrospectively reviewed all esophagectomies performed at a tertiary academic center from 2014 to 2021 and quantified the timing of the most common complications. Daily incidence values for index complications were calculated, and a covariance matrix was created to examine the correlation of the complications with each other. Study investigators performed a Cox proportional hazards analysis to clarify the association between early diagnosis of postoperative atrial fibrillation and pneumonia with subsequent anastomotic leak. RESULTS: The study analyzed 621 esophagectomies, with 580 (93.4%) cervical anastomoses and 474 (76%) patients experiencing complications. A total of 159 (25.6%) patients had postoperative atrial fibrillation, and 155 (25.0%) had an anastomotic leak. The median (interquartile range [IQR]) postoperative day of these complications was day 2 (IQR, days 2-3) and day 8 (IQR, days 7-11), respectively. Our covariance matrix found significant associations in the variance of the most common postoperative complications, including pneumonia, atrial fibrillation, anastomotic leak, and readmissions. Early postoperative atrial fibrillation (hazard ratio, 8.1; 95% CI, 5.65-11.65) and postoperative pneumonia (hazard ratio, 3.8; 95% CI, 1.98-7.38) were associated with anastomotic leak. CONCLUSIONS: Maintaining a high index of suspicion for early postoperative complications is crucial for rescuing patients after esophagectomy. Early postoperative pneumonia and atrial fibrillation may be sentinel complications for an anastomotic leak, and their occurrence may be used to prompt further clinical investigation. Early recovery protocols should consider the development of early complications into postoperative feeding and imaging algorithms.

Increased Variation in Esophageal Cancer Treatment and Geographic Healthcare Disparity in Michigan.

BACKGROUND: Regional variation in complex healthcare is shown to negatively impact health outcomes. We sought to characterize geographic variance in esophageal cancer operation in Michigan. STUDY DESIGN: Data for patients with locoregional esophageal cancer from the Michigan Cancer Surveillance Program from 2000 to 2013 was analyzed. We reviewed the incidence of esophageal cancer by county and region, and those with locoregional disease receiving an esophagectomy. Counties were aggregated into existing state-level "urban vs rural" designations, regions were aggregated using the Michigan Economic Recovery Council designations, and data was analyzed with ANOVA, F-test, and chi-square test. RESULTS: Of the 8,664 patients with locoregional disease, 2,370 (27.4%) were treated with operation. Men were significantly more likely to receive esophagectomy than women (p < 0.001). Likewise, White, insured, and rural patients were more likely than non-White (p < 0.001), non-insured (p = 0.004), and urban patients (p < 0.001), respectively. There were 8 regions and 83 counties, with 61 considered rural and 22 urban. Region 1 (Detroit metro area, southeast) comprises the largest urban and suburban populations; with 4 major hospital systems it was considered the baseline standard for access to care. Regions 2 (west; p = 0.011), 3 (southwest; p = 0.024), 4 (east central; p = 0.012), 6 (northern Lower Peninsula; p = 0.008), and 8 (Upper Peninsula; p < 0.001) all had statistically significant greater variance in annual rates of operation compared with region 1. Region 8 had the largest variance and was the most rural and furthest from region 1. The variance in operation rate between urban and rural differed significantly (p = 0.005). CONCLUSIONS: A significant increase in variation of care was found in rural vs urban counties, as well as in regions distant to larger hospital systems. Those of male sex, White race, rural residence, and those with health insurance were significantly more likely to receive operation.

Clinical Implications of Removing Race-Corrected Pulmonary Function Tests for African American Patients Requiring Surgery for Lung Cancer.

Importance: Removal of race correction in pulmonary function tests (PFTs) is a priority, given that race correction inappropriately conflates race, a social construct, with biological differences and falsely assumes worse lung function in African American than White individuals. However, the impact of decorrecting PFTs for African American patients with lung cancer is unknown. Objectives: To identify how many hospitals providing lung cancer surgery use race correction, examine the association of race correction with predicted lung function, and test the effect of decorrection on surgeons' treatment recommendations. Design, Setting, and Participants: In this quality improvement study, hospitals participating in a statewide quality collaborative were contacted to determine use of race correction in PFTs. For hospitals performing race correction, percent predicted preoperative and postoperative forced expiratory volume in 1 second (FEV1) was calculated for African American patients who underwent lung cancer resection between January 1, 2015, and September 31, 2022, using race-corrected and race-neutral equations. US cardiothoracic surgeons were then randomized to receive 1 clinical vignette that differed by the use of Global Lung Function Initiative equations for (1) African American patients (percent predicted postoperative FEV1, 49%), (2) other race or multiracial patients (percent predicted postoperative FEV1, 45%), and (3) race-neutral patients (percent predicted postoperative FEV1, 42%). Main Outcomes and Measures: Number of hospitals using race correction in PFTs, change in preoperative and postoperative FEV1 estimates based on race-neutral or race-corrected equations, and surgeon treatment recommendations for clinical vignettes. Results: A total of 515 African American patients (308 [59.8%] female; mean [SD] age, 66.2 [9.4] years) were included in the study. Fifteen of the 16 hospitals (93.8%) performing lung cancer resection for African American patients during the study period reported using race correction, which corresponds to 473 African American patients (91.8%) having race-corrected PFTs. Among these patients, the percent predicted preoperative FEV1 and postoperative FEV1 would have decreased by 9.2% (95% CI, -9.0% to -9.5%; P < .001) and 7.6% (95% CI, -7.3% to -7.9%; P < .001), respectively, if race-neutral equations had been used. A total of 225 surgeons (194 male [87.8%]; mean [SD] time in practice, 19.4 [11.3] years) were successfully randomized and completed the vignette items regarding risk perception and treatment outcomes (76% completion rate). Surgeons randomized to the vignette with African American race-corrected PFTs were more likely to recommend lobectomy (79.2%; 95% CI, 69.8%-88.5%) compared with surgeons randomized to the other race or multiracial-corrected (61.7%; 95% CI, 51.1%-72.3%; P = .02) or race-neutral PFTs (52.8%; 95% CI, 41.2%-64.3%; P = .001). Conclusions and Relevance: Given the findings of this quality improvement study, surgeons should be aware of changes in PFT testing because removal of race correction PFTs may change surgeons' treatment decisions and potentially worsen existing disparities in receipt of lung cancer surgery among African American patients.

Quantitative assessment of gastric ischemic preconditioning on conduit perfusion in esophagectomy: propensity score weighting study.

BACKGROUND: Gastric ischemic preconditioning prior to esophagectomy has been studied as a method to improve gastric conduit perfusion and reduce anastomotic complications, without conclusive results. The aim of this study is to evaluate the feasibility and safety of gastric ischemic preconditioning in terms of post-operative outcomes and quantitative gastric conduit perfusion. METHODS: Patients who underwent an esophagectomy with gastric conduit reconstruction between January 2015 and October 2022 at a single high-volume academic center were reviewed. Patient characteristics, surgical approach, post-operative outcomes, and indocyanine green fluorescence angiography data (ingress index for arterial inflow and ingress time for venous outflow, and the distance from the last gastroepiploic branch to the perfusion assessment point) were analyzed. Two propensity score weighting methods were used to investigate whether gastric ischemic preconditioning reduces anastomotic leaks. Multiple linear regression analysis was used to evaluate the conduit perfusion quantitatively. RESULTS: There were 594 esophagectomies with gastric conduit performed, with 41 having a gastric ischemic preconditioning. Among 544 with cervical anastomoses, leaks were seen in 2/30 (6.7%) in the ischemic preconditioning group and 114/514 (22.2%) in the control group (p = 0.041). Gastric ischemic preconditioning significantly reduced anastomotic leaks on both weighting methods (p = 0.037 and 0.047, respectively). Ingress index and time of the gastric conduit with ischemic preconditioning were significantly better than those without preconditioning (p = 0.013 and 0.025, respectively) after removing the effect of the distance from the last gastroepiploic branch to the perfusion assessment point. CONCLUSION: Gastric ischemic preconditioning results in a statistically significant improvement in conduit perfusion and reduction in post-operative anastomotic leaks.

Implementation and Effectiveness of Opioid Prescribing Guidelines After Hiatal Hernia Repair.

INTRODUCTION: We defined institutional opioid prescribing patterns, established prescribing guidelines, and evaluated the adherence to and effectiveness of these guidelines in association with opioid prescribing after hiatal hernia repair (HHR). METHODS: A retrospective chart review was completed for patients who underwent transthoracic (open) or laparoscopic HHR between January and December 2016. Patient-reported opioid use after surgery was used to establish prescribing recommendations. Guideline efficacy was then evaluated among patients undergoing HHR after implementation (August 2018 to June 2019). Data are reported in oral morphine equivalents (OMEs). RESULTS: The initial cohort included n = 87 patients (35 open; 52 laparoscopic) with a 68% survey response rate. For open repair, median prescription size was 338 mg OME (interquartile range [IQR] 250-420) with patient-reported use of 215 mg OME (IQR 78-308) (P = 0.002). Similarly, median prescription size was 270 mg OME (IQR 200-319) with patient-reported use of 100 mg OME (IQR 4-239) (P < 0.001) for laparoscopic repair. Opioid prescribing guidelines were defined as the 66th percentile of patient-reported opioid use. Postguideline implementation cohort included n = 108 patients (36 open; 72 laparoscopic). Median prescription amount decreased by 54% for open and 43% laparoscopic repair, with no detectable change in the overall refill rate after guideline implementation. Patient education, opioid storage, and disposal practices were also characterized. CONCLUSIONS: Evidence-based opioid prescribing guidelines can be successfully implemented for open and laparoscopic HHR with a high rate of compliance and without an associated increase in opioid refills.

Pulmonary Open, Robotic, and Thoracoscopic Lobectomy (PORTaL) Study: Survival Analysis of 6646 Cases.

OBJECTIVE: The aim of this study was to analyze overall survival (OS) of robotic-assisted lobectomy (RL), video-assisted thoracoscopic lobectomy (VATS), and open lobectomy (OL) performed by experienced thoracic surgeons across multiple institutions. SUMMARY BACKGROUND DATA: Surgeons have increasingly adopted RL for resection of early-stage lung cancer. Comparative survival data following these approaches is largely from single-institution case series or administrative data sets. METHODS: Retrospective data was collected from 21 institutions from 2013 to 2019. Consecutive cases performed for clinical stage IA-IIIA lung cancer were included. Induction therapy patients were excluded. The propensity-score method of inverse-probability of treatment weighting was used to balance baseline characteristics. OS was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to evaluate association among OS and relevant risk factors. RESULTS: A total of 2789 RL, 2661 VATS, and 1196 OL cases were included. The unadjusted 5-year OS rate was highest for OL (84%) followed by RL (81%) and VATS (74%); P =0.008. Similar trends were also observed after inverse-probability of treatment weighting adjustment (RL 81%; VATS 73%, OL 85%, P =0.001). Multivariable Cox regression analyses revealed that OL and RL were associated with significantly higher OS compared with VATS (OL vs. VATS: hazard ratio=0.64, P <0.001 and RL vs. VATS: hazard ratio=0.79; P =0.007). CONCLUSIONS: Our finding from this large multicenter study suggests that patients undergoing RL and OL have statistically similar OS, while the VATS group was associated with shorter OS. Further studies with longer follow-up are necessary to help evaluate these observations.

Comparison of Pre-Diagnosis Physical Activity and Its Correlates between Lung and Other Cancer Patients: Accelerometer Data from the UK Biobank Prospective Cohort.

Purpose: Physical activity (PA) plays an important role in health outcomes for people with cancer, and pre-diagnosis PA influences PA behaviors after cancer treatment. Less is known about the PA of lung cancer patients, and the strong history of smoking could influence pre-diagnosis levels of PA and place them at risk for health problems. This study aimed to compare pre-diagnosis PA and its correlates in patients with lung cancer and other types of cancer (female breast, colorectal, and prostate cancer) and examine the relationship between pre-diagnosis PA and all-cause mortality. Methods: This study used data from the UK Biobank, which is a national cohort study with accelerometry data. We included 2662 participants and used adjusted linear regressions and survival analyses. Results: Male and female lung cancer groups spent a mean of 78 and 91 min/day in pre-diagnosis moderate to vigorous PA (MVPA), respectively; this is lower than the 3 other types of cancer (p < 0.001). Younger age and faster walking pace had a strong association with PA in all the four types of cancer (p < 0.01). Smoking status had a strong association with PA in the lung cancer group, while obesity had a strong association with PA in female breast, colorectal, and prostate cancer (p < 0.01). Higher levels of pre-diagnosis MVPA (≥1.5 h/day) were associated with a significantly lower all-cause mortality risk. Conclusions: The present study suggests that lung cancer patients are the most inactive population before diagnosis. The identified difference in correlates of PA suggest that cancer-specific approaches are needed in PA research and practices. This study also highlights the importance of high PA for individuals with high cancer risk.

Wider Gastric Conduit Morphology Is Associated with Improved Blood Flow During Esophagectomy.

BACKGROUND: It remains unclear what is the ideal conduit shape. The aim of this study was to evaluate association between specific gastric conduit morphology, considering width and length, with its perfusion and the incidence of anastomotic leaks after esophagectomy. METHODS: Patients who underwent an esophagectomy with cervical esophagogastric anastomosis between 2015 and 2021 were evaluated. Indocyanine green angiography was performed to evaluate gastric conduit perfusion, and ingress index (arterial inflow) and ingress time (venous outflow) were measured. The conduit width at the middle of the conduit and the short gastric length as the length from the last gastroepiploic branch to the perfusion assessment point were measured. Propensity score matching was performed to compare wide conduits with narrow conduits. Narrow and wide conduits were defined as < 4 and ≥ 5 cm, respectively. RESULTS: Three hundred fifty-eight patients were reviewed. After applying matching, the wide conduits had higher ingress index (48.2 vs 33.3%, p < 0.001) and shorter ingress time (51.2 vs 66.3 s, p = 0.004) compared to the narrow conduits. Including the short gastric length in analysis, creating a wide conduit is a significant factor for better ingress index (p = 0.001), especially when the perfusion assessment point is 5 cm or farther from the last gastroepiploic branch. Anastomotic leaks did not differ between the groups. CONCLUSIONS: Conduit width is a significant factor of gastric conduit perfusion, especially when the estimated anastomotic site was > 5 cm from the last gastroepiploic branch. Wide conduits seem to have better perfusion and creating a wider conduit might reduce anastomotic leaks.

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.