GRAIL1 stabilizes misfolded mutant p53 through a ubiquitin ligase-independent, chaperone regulatory function.

Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's (BE) progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL - gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and, stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for Hsp40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain, or a cell permeable peptide (Pep-J) encoding the above 10 amino acids, can bind and inhibit DNAJ-Hsp70 co-chaperone activity thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic BE and EAC cells and inhibit growth of patient-derived dysplastic BE organoids (PDOs) in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J is comparable to simvastatin, a cholesterol lowering drug, that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. Implications: We identified a novel ubiquitin ligase independent, chaperone regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential.

ISG15/GRAIL1/CD3 axis influences survival of patients with esophageal adenocarcinoma.

Immunosuppression is a common feature of esophageal adenocarcinoma (EAC) and has been linked to poor overall survival (OS). We hypothesized that upstream factors might negatively influence CD3 levels and T cell activity, thus promoting immunosuppression and worse survival. We used clinical data and patient samples of those who progressed from Barrett's to dysplasia to EAC, investigated gene (RNA-Seq) and protein (tissue microarray) expression, and performed cell biology studies to delineate a pathway impacting CD3 protein stability that might influence EAC outcome. We showed that the loss of both CD3-ε expression and CD3+ T cell number correlated with worse OS in EAC. The gene related to anergy in lymphocytes isoform 1 (GRAIL1), which is the prominent isoform in EACs, degraded (ε, γ, δ) CD3s and inactivated T cells. In contrast, isoform 2 (GRAIL2), which is reduced in EACs, stabilized CD3s. Further, GRAIL1-mediated CD3 degradation was facilitated by interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein. Consequently, the overexpression of a ligase-dead GRAIL1, ISG15 knockdown, or the overexpression of a conjugation-defective ISG15-leucine-arginine-glycine-glycine mutant could increase CD3 levels. Together, we identified an ISG15/GRAIL1/mutant p53 amplification loop negatively influencing CD3 levels and T cell activity, thus promoting immunosuppression in EAC.

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.

Isoform alterations in the ubiquitination machinery impacting gastrointestinal malignancies.

The advancement of RNAseq and isoform-specific expression platforms has led to the understanding that isoform changes can alter molecular signaling to promote tumorigenesis. An active area in cancer research is uncovering the roles of ubiquitination on spliceosome assembly contributing to transcript diversity and expression of alternative isoforms. However, the effects of isoform changes on functionality of ubiquitination machineries (E1, E2, E3, E4, and deubiquitinating (DUB) enzymes) influencing onco- and tumor suppressor protein stabilities is currently understudied. Characterizing these changes could be instrumental in improving cancer outcomes via the identification of novel biomarkers and targetable signaling pathways. In this review, we focus on highlighting reported examples of direct, protein-coded isoform variation of ubiquitination enzymes influencing cancer development and progression in gastrointestinal (GI) malignancies. We have used a semi-automated system for identifying relevant literature and applied established systems for isoform categorization and functional classification to help structure literature findings. The results are a comprehensive snapshot of known isoform changes that are significant to GI cancers, and a framework for readers to use to address isoform variation in their own research. One of the key findings is the potential influence that isoforms of the ubiquitination machinery have on oncoprotein stability.

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.

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.

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.

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.

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.

Evidence-based opioid prescribing guidelines after lung resection: a prospective, multicenter analysis.

Background: Opioid prescribing guidelines have significantly decreased overprescribing and post-discharge use after cardiac surgery; however, limited recommendations exist for general thoracic surgery patients, a similarly high-risk population. We examined opioid prescribing and patient-reported use to develop evidence-based, opioid prescribing guidelines after lung cancer resection. Methods: This prospective, statewide, quality improvement study was conducted between January 2020 to March 2021 and included patients undergoing surgical resection of a primary lung cancer across 11 institutions. Patient-reported outcomes at 1-month follow-up were linked with clinical data and Society of Thoracic Surgery (STS) database records to characterize prescribing patterns and post-discharge use. The primary outcome was quantity of opioid used after discharge; secondary outcomes included quantity of opioid prescribed at discharge and patient-reported pain scores. Opioid quantities are reported in number of 5-mg oxycodone tablets (mean ± standard deviation). Results: Of the 602 patients identified, 429 met inclusion criteria. Questionnaire response rate was 65.0%. At discharge, 83.4% of patients were provided a prescription for opioids of mean size 20.5±13.1 pills, while patients reported using 8.2±13.0 pills after discharge (P<0.001), including 43.7% who used none. Those not taking opioids on the calendar day prior to discharge (32.4%) used fewer pills (4.4±8.1 vs. 11.7±14.9, P<0.001). Refill rate was 21.5% for patients provided a prescription at discharge, while 12.5% of patients not prescribed opioids at discharge required a new prescription before follow-up. Pain scores were 2.4±2.5 for incision site and 3.0±2.8 for overall pain (scale 0-10). Conclusions: Patient-reported post-discharge opioid use, surgical approach, and in-hospital opioid use before discharge should be used to inform prescribing recommendations after lung resection.

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.

Clinically Occult Diffuse Pleural Mesothelioma in Patients Presenting With Spontaneous Pneumothorax.

OBJECTIVES: To report histologic features of unsuspected diffuse pleural mesothelioma (DPM) in surgical specimens for pneumothorax and demonstrate how ancillary markers support a diagnosis of malignancy in this context. We explored whether pneumothorax may be a clinical manifestation of mesothelioma in situ (MIS). METHODS: A single-institution database search identified patients who underwent surgical resection for spontaneous pneumothorax (n = 229) and/or were diagnosed with DPM (n = 88) from 2000 to 2020. RESULTS: Spontaneous pneumothorax without clinical, radiologic, or intraoperative suspicion of mesothelioma was the initial presentation in 2 (2.3%) of 88 patients diagnosed with DPM. This represented 0.9% (2/229) of all patients undergoing surgical management of pneumothorax but accounted for a larger proportion of older patients (12.5% older than 70 years). Immunohistochemistry for BAP-1 and/or MTAP confirmed the diagnosis of DPM in 2 cases. Mesothelioma in situ was identified retrospectively by immunohistochemistry in 1 case of spontaneous pneumothorax from a 77-year-old man who developed invasive DPM 25 months later. No additional cases of MIS were identified in 19 surgical lung resections for spontaneous pneumothorax. CONCLUSIONS: Histologic examination of bleb resections with ancillary testing for cases with ambiguous features is essential for detection of early DPM. It is uncertain whether spontaneous pneumothorax may represent a clinical manifestation of MIS.

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.

Hospital-Level Segregation Among Medicare Beneficiaries Undergoing Lung Cancer Resection.

BACKGROUND: Recent research has raised concern that health care segregation, the high concentration of racial groups within a subset of hospitals, is a key contributor to persistent disparities in surgical care. However, to date the extent and effect of hospital level segregation among patients undergoing resection for lung cancer remains unclear. METHODS: We used 100% Medicare fee-for-service claims to evaluate the degree of hospital-level racial segregation for patients undergoing resection for lung cancer between 2014 and 2018. Hospitals serving a high volume of minority patients were defined as the top decile of hospitals by volume of racial and ethnic minority beneficiaries served. Multivariable logistic regression analysis was used to compare surgical outcomes between hospitals serving high vs low volumes of minority patients. RESULTS: A total of 122,943 patients were included, with racial/ethnic composition of 360 American Indian or Native American (0.3%), 2077 Asian or Pacific Islander (1.7%), 1146 Hispanic or Latino (0.9%), 8707 non-Hispanic Black (7.1%), and 108,665 non-Hispanic White patients. Overall, 31.6%, 15.9%, 15.0%, and 7.8% of all hospitals performed 90% of lung cancer resection for Black, Asian, Hispanic, and Native American patients, respectively. Hospitals performing higher volumes of operations for racial and ethnic minorities had higher mortality (3.9% vs 3.1%; odds ratio [OR], 1.19; 95% CI, 1.15-1.23; P < .001), complications (18.1% vs 15.9%; OR, 1.17; 95% CI, 1.14-1.19; P < .001), and readmissions (11.7% vs 11.2%; OR, 1.04; 95% CI, 1.02-1.05; P < .001) for resections for lung cancer. CONCLUSIONS: Our findings suggest that a small proportion of hospitals provide a disproportionate amount of surgical care for racial and ethnic minorities with lung cancer with inferior surgical outcomes.

The Role of Lung Cancer Surgical Technique on Lymph Node Sampling and Pathologic Nodal Upstaging.

BACKGROUND: The role of operative approach in surgical lymphadenectomies and pathologic nodal upstaging for lung cancer remains unclear. METHODS: This study retrospectively reviewed patients who underwent lobectomy for non-small cell lung cancer from January 2015 to December 2020 at 16 centers within a statewide quality improvement collaborative in Michigan. Patients were stratified by operative approach, and our primary end points were number of LN recovered, number of LN stations sampled, and rates of nodal upstaging with nodal upstaging defined as a higher final pathologic nodal stage compared with preoperative clinical nodal staging. RESULTS: A total of 3036 patients were included: 608 (20.0%) with open lobectomies, 1362 (41.3%) with video-assisted thoracoscopic surgery (VATS), and 1233 (37.4%) with robot-assisted thoracoscopic surgery (RATS) lobectomies. Using multivariable logistic regression, study investigators found that VATS was associated with lower rates of nodal upstaging (odds ratio [OR], 0.71; 95% CI, 0.54-0.94; P = .015) and harvesting ≥10 LNs (OR, 0.40; 95% CI, 0.31-0.50; P < .001) as compared with open surgery, whereas no significant difference was found between RATS and open techniques. Compared with open surgery, VATS had lower rates of sampling at ≥5 nodal stations (OR, 0.66; 95% CI, 0.53-0.84; P = .001), whereas RATS rates were higher (OR, 2.38; 95% CI, 1.85-3.06; P < .001). CONCLUSIONS: VATS lobectomies were associated with lower rates of harvesting ≥10 LNs, sampling ≥5 LN stations, and pathologic nodal upstaging compared with open and RATS lobectomies. Compared with open procedures, RATS lobectomies were associated with higher rates of sampling ≥5 LN stations, but there was no significant difference between open and RATS approaches in rates of nodal upstaging or harvesting ≥10 LNs.

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.