Understanding Racial Differences in Lung Cancer Surgery Through a Statewide Quality Collaborative.

BACKGROUND: Persistent racial disparities in lung cancer incidence, treatment, and survival are well documented. Given the importance of surgical resection for lung cancer treatment, racial disparities in surgical quality were investigated using a statewide quality collaborative. METHODS: This retrospective study used data from the Michigan Society of Cardiothoracic Surgeons General Thoracic database, which includes data gathered for the Society of Thoracic Surgeons General Thoracic Surgery Database at 17 institutions in Michigan. Adult patients undergoing resection for lung cancer between 2015 and 2021 were included. Propensity score-weighting methodology was used to assess differences in surgical quality, including extent of resection, adequate lymph node evaluation, 30-day mortality, and 30-day readmission rate between white and black patients. RESULTS: The cohort included 5073 patients comprising 357 (7%) black and 4716 (93%) white patients. The black patients had significantly higher unadjusted rates of wedge resection than the white patients, but after propensity score-weighting for clinical factors, wedge resection did not differ from lobectomy (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.78-1.49; P = 0.67). The black patients had fewer lymph nodes collected (incidence rate ratio [IRR], 0.77; 95% CI, 0.73-0.81; P < 0.0001) and lymph node stations sampled (IRR, 0.89; 95% CI, 0.84-0.94; P < 0.0001). The black patients did not differ from the white patients in terms of mortality (OR, 0.65; 95% CI, 0.19-2.34; P = 0.55) or readmission (OR, 0.79; 95 % CI, 0.49-1.27; P = 0.32). The black patients had longer hospital stays (OR, 1.08; 95% CI, 1.02-1.14; P = 0.01). CONCLUSION: In a statewide quality collaborative that included high-volume centers, black patients received a less extensive lymph node evaluation, with fewer non-anatomic wedge resections performed, and a more limited lymph node evaluation with lobectomy.

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.

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.

Tracheobronchomalacia and Excessive Dynamic Airway Collapse: Current Concepts and Future Directions.

Tracheobronchomalacia (TBM) and excessive dynamic airway collapse (EDAC) are airway abnormalities that share a common feature of expiratory narrowing but are distinct pathophysiologic entities. Both entities are collectively referred to as expiratory central airway collapse (ECAC). The malacia or weakness of cartilage that supports the tracheobronchial tree may occur only in the trachea (ie, tracheomalacia), in both the trachea and bronchi (TBM), or only in the bronchi (bronchomalacia). On the other hand, EDAC refers to excessive anterior bowing of the posterior membrane into the airway lumen with intact cartilage. Clinical diagnosis is often confounded by comorbidities including asthma, chronic obstructive pulmonary disease, obesity, hypoventilation syndrome, and gastroesophageal reflux disease. Additional challenges include the underrecognition of ECAC at imaging; the interchangeable use of the terms TBM and EDAC in the literature, which leads to confusion; and the lack of clear guidelines for diagnosis and treatment. The use of CT is growing for evaluation of the morphology of the airway, tracheobronchial collapsibility, and extrinsic disease processes that can narrow the trachea. MRI is an alternative tool, although it is not as widely available and is not used as frequently for this indication as is CT. Together, these tools not only enable diagnosis, but also provide a road map to clinicians and surgeons for planning treatment. In addition, CT datasets can be used for 3D printing of personalized medical devices such as stents and splints. An invited commentary by Brixey is available online. Online supplemental material is available for this article. ©RSNA, 2022.

Quantitative perfusion assessment of gastric conduit with indocyanine green dye to predict anastomotic leak after esophagectomy.

Impaired gastric conduit perfusion is a risk factor for anastomotic leak after esophagectomy. The aim of this study is to evaluate the feasibility of intraoperative quantitative assessment of gastric conduit perfusion with indocyanine green fluorescence angiography as a predictor for cervical esophagogastric anastomotic leak after esophagectomy. Indocyanine green fluorescence angiography using the SPY Elite system was performed in patients undergoing a transhiatal or McKeown esophagectomy from July 2015 through December 2020. Ingress (dye uptake) and Egress (dye exit) at two anatomic landmarks (the tip of a conduit and 5 cm from the tip) were assessed. The collected data in the leak group and no leak group were compared by univariate and multivariable analyses. Of 304 patients who were evaluated, 70 patients developed anastomotic leak (23.0%). There was no significant difference in patients' demographic between the groups. Ingress Index, which represents a proportion of blood inflow, at both the tip and 5 cm of the conduit was significantly lower in the leak group (17.9 vs. 25.4% [P = 0.011] and 35.9 vs. 44.6% [P = 0.019], respectively). Ingress Time, which represents an estimated time of blood inflow, at 5 cm of the conduit was significantly higher in the leak group (69.9 vs. 57.1 seconds, P = 0.006). Multivariable analysis suggested that these three variables can be used to predict future leak. Variables of gastric conduit perfusion correlated with the incidence of cervical esophagogastric anastomotic leak. Intraoperative measurement of gastric conduit perfusion can be predictive for anastomotic leak following esophagectomy.

Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells.

BACKGROUND & AIMS: Barrett's esophagus (BE) can progress to dysplasia and esophageal adenocarcinoma (EAC), accompanied by mutations in TP53 that increase the stability of its product, p53. We analyzed BE tissues for messenger RNAs (mRNAs) that associate with BE progression and identified one that affects the stabilization of p53. METHODS: We obtained 54 BE samples collected from patients with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), from 1992 through 2015, and performed RNA sequence analyses, including isoform-specific analyses. We performed reverse-transcription polymerase chain reaction analyses of 166 samples and immunohistochemical analyses of tissue microarrays that contained BE tissues from 100 patients with HGD or EAC and normal esophageal squamous mucosa (controls). Proteins were expressed from transfected plasmids or knocked down with small interfering RNAs in BE cells and analyzed by immunoblots and in immunoprecipitation and ubiquitin ligase assays. Athymic nude mice bearing EAC xenograft tumors (grown from OE-33 cells) were given intraperitoneal injections of simvastatin; tumor growth was monitored and tumors were collected and analyzed by immunoblotting for levels of RNF128, p53, and acetylated p53. RESULTS: Progression of BE to HGD or EAC associated with changes in expression of mRNAs that encoded mucins and promoted inflammation and activation of ATM and the DNA damage response. As tissues progressed from BE to HGD to EAC, they increased expression of mRNAs encoding isoform 1 of RNF128 (Iso1) and decreased expression of Iso2 of RNF128. RNF128 is an E3 ubiquitin ligase that targets p53 for degradation. Incubation of BE cells with interferon gamma caused them to increase expression of Iso1 and reduce expression of Iso2. Iso1 was heavily glycosylated with limited ubiquitin ligase activity for p53, resulting in p53 stabilization. Knockdown of Iso1 in BE and EAC cells led to degradation of the mutant form of p53 and reduced clonogenic survival. In contrast, Iso2 was a potent ligase that reduced levels of the mutant form of p53 in BE cells. In BE cells, Iso2 was hypoglycosylated and degraded, via ATM and GSK3ß-mediated phosphorylation and activation of the beta-TrCP1-containing SCF ubiquitin ligase complex. Simvastatin, which degrades the mutant form of p53, also degraded RNF128 Iso1 protein in BE cells and slowed growth of EAC xenograft tumors in mice. CONCLUSIONS: We found that isoform 2 of RNF128 is decreased in BE cells, resulting in increased levels of mutant p53, whereas isoform 1 of RNF128 is increased in BE cells, further promoting the stabilization of mutant p53.

Adaptive and Maladaptive Coping Mechanisms Used by Patients With Esophageal Cancer After Esophagectomy.

BACKGROUND: Esophagectomy patients have high rates of postoperative complications. Maladaptive coping mechanisms such as smoking, alcoholism, and obesity-related reflux are risk factors for esophageal cancer and could affect recovery after surgery. In this study, coping mechanisms used among postesophagectomy patients were identified and maladaptive mechanisms correlated with smoking, alcohol use, or BMI. MATERIALS AND METHODS: Patients who received an esophagectomy from 2017 to 2018 at an academic medical center were surveyed using the validated Brief Coping Orientation to Problems Experienced, which includes 14 coping mechanisms (both adaptive and maladaptive) using a 4-point Likert scale. A Fischer's exact and chi-square was performed to measure the significance of difference between groups. RESULTS: There was a 67.2% response rate (43/64). 61.3% (27/43) were obese. Sixty-three percent (62.8%, 27/43) had at least 10 pack-years smoking tobacco history; average smoking tobacco usage was 27 pack-years. 30.2% (13/43) had alcohol use. All 14 coping strategies were used by at least one patient. Twenty patients used only adaptive coping strategies, with acceptance being the most used (100%, 20/20 patients). Twenty-three patients used at least one maladaptive coping strategy, with self-distraction being the most used (91.3%, 21/23). All patients used some adaptive coping. There was a significant difference in mean number of coping strategies between groups (P-value <0.0001). Patients with maladaptive coping also demonstrated greater rates of active coping and humor (P < 0.05). There was no correlation between maladaptive coping and smoking, alcohol use, or increased BMI. CONCLUSIONS: Most postesophagectomy patients use at least one maladaptive coping strategy; however, history of smoking, alcohol use, or obesity does not predict maladaptive coping in the postesophagectomy period.

Long-Term Quality of Life Following Endoscopic Therapy Compared to Esophagectomy for Neoplastic Barrett's Esophagus.

INTRODUCTION: Endoscopic therapy (ET) and esophagectomy result in similar survival for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC), but the long-term quality of life (QOL) has not been compared. AIMS: We aimed to compare long-term QOL between patients who had undergone ET versus esophagectomy. METHODS: Patients were included if they underwent ET or esophagectomy at the University of Michigan since 2000 for the treatment of HGD or T1a EAC. Two validated survey QOL questionnaires were mailed to the patients. We compared QOL between and within groups (ET = 91, esophagectomy = 62), adjusting for covariates. RESULTS: The median time since initial intervention was 6.8 years. Compared to esophagectomy, ET patients tended to be older, had a lower prevalence of EAC, and had a shorter duration since therapy. ET patients had worse adjusted physical and role functioning than esophagectomy patients. However, the adjusted odds ratio (OR) of having symptoms was significantly less with ET for diarrhea (0.287; 95% confidence interval [CI] = 0.114, 0.724), trouble eating (0.207; 0.0766, 0.562), choking (0.325; 0.119, 0.888), coughing (0.291; 0.114, 0.746), and speech difficulty (0.306; 0.0959, 0.978). Amongst the ET patients, we found that the number of therapy sessions and need for dilation were associated with worse outcomes. DISCUSSION: Multiple measures of symptom status were better with ET compared to esophagectomy following treatment of BE with HGD or T1a EAC. We observed worse long-term physical and role functioning in ET patients which could reflect unmeasured baseline functional status rather than a causal effect of ET.

Care Coordination for Patients on Chronic Opioid Therapy Following Surgery: A Cohort Study.

OBJECTIVE: To describe if patients with chronic opioid use with a consistent usual prescriber (UP) prior to surgery and if early return to that UP (<30 d) would be associated with fewer high risk prescribing events in the postoperative period. SUMMARY BACKGROUND DATA: Over 10 million people each year are prescribed opioids for chronic pain. There is little evidence regarding coordination of opioid management and best practices for patients on long-term opioid therapy patients following surgery. METHODS: The study design is a retrospective cohort study. We identified 5749 commercially insured patients aged 18 to 64 with chronic opioid use who underwent elective surgery between January 2008 and March 2015. The predictors were presence of a UP and early return (<30 d from surgery) to a UP. The primary outcome was new high-risk opioid prescribing in the 90-day postoperative period (multiple prescribers, overlapping opioid and/or benzodiazepine prescriptions, new long acting opioid prescriptions, or new dose escalations to > 100 mg OME). RESULTS: In this cohort, 73.8% of patients were exposed to high risk prescribing postoperatively. Overall, 10% of patients did not have a UP preoperatively, and were more likely to have prescriptions from multiple prescribers (OR 2.23 95% CI 1.75-2.83) and new long acting opioid prescriptions (OR 1.69, 95% CI 1.05-2.71). Among patients with a UP, earlier return was associated with decreased odds of receiving prescriptions from multiple prescribers (OR 0.80, 95% CI 0.68-0.95). CONCLUSION: Patients without a UP prior to surgery are more likely to be exposed to high-risk opioid prescribing following surgery. Among patients who have a UP, early return visits may enhance care coordination with fewer prescribers.

Aorto-esophageal Fistula Management.

Aorto-esophageal fistula is a rare but life-threatening source of massive upper gastrointestinal bleeding. Prompt diagnosis and intervention are key for patient survival. Treatments consist of aortic resection, thoracic endovascular aortic repair, esophagectomy with diversion, and primary esophageal repair. The appropriate treatment is dependent on patient hemodynamics and fitness and familiarity with operative approaches by the treating team.

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.

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.

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.

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.

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.

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.

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.

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.