Real-world Decision-making Process for Stereotactic Body Radiotherapy Versus Minimally Invasive Surgery in Early-stage Lung Cancer Patients.

OBJECTIVE: To generate a prediction model for selection of treatment modality for early-stage non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Stereotactic body radiotherapy (SBRT) and minimally invasive surgery (MIS) are used in the local treatment of early-stage NSCLC. However, selection of patients for either SBRT or MIS remains challenging, due to the multitude of factors influencing the decision-making process. METHODS: We analyzed 1291 patients with clinical stage I NSCLC treated with intended MIS or SBRT from January 2020 to July 2023. A prediction model for selection for SBRT was created based on multivariable logistic regression analysis. The receiver operating characteristic curve analysis stratified the cohort into 3 treatment-related risk categories. Post-procedural outcomes, recurrence and overall survival (OS) were investigated to assess the performance of the model. RESULTS: In total, 1116 patients underwent MIS and 175 SBRT. The prediction model included age, performance status, previous pulmonary resection, MSK-Frailty score, FEV1 and DLCO, and demonstrated an area-under-the-curve of 0.908 (95%CI, 0.876-0.938). Based on the probability scores (n=1197), patients were stratified into a low-risk (MIS, n=970 and SBRT, n=28), intermediate-risk (MIS, n=96 and SBRT, n=53) and high-risk category (MIS, n=10 and SBRT, n=40). Treatment modality was not associated with OS (HR of SBRT, 1.67 [95%CI: 0.80-3.48]; P=0.20). CONCLUSION: Clinical expertise can be translated into a robust predictive model, guiding the selection of stage I NSCLC patients for MIS versus SBRT and effectively categorizing them into three distinct risk groups. Patients in the intermediate category could benefit most from multidisciplinary evaluation.

Commission on Cancer Standards for Lymph Node Sampling and Oncologic Outcomes After Lung Resection.

BACKGROUND: The newest Commission on Cancer standards recommend sampling 3 mediastinal and 1 hilar lymph node stations, 3 (N2) 1 (N1), for lung cancer resections. However, the relationship between the Commission on Cancer standards and outcomes has not been thoroughly investigated. METHODS: A prospective institutional database was queried for clinical stage I-III lung resections before the implementation of the new standards. The relationship between the 3 (N2) 1 (N1) standard ("guideline concordant") and outcomes (upstaging, complications, receipt of adjuvant therapy, locoregional/distant recurrence, and survival) was assessed with multivariable models and stratified by stage. RESULTS: Of 9289 pulmonary resections, 3048 (33%) were guideline concordant and 6241 (67%) were not. Compared with nonconcordant, those that were guideline concordant had higher rates of nodal upstaging (21% vs 13%; odds ratio [OR], 1.32 [95% CI, 1.14-1.51]; P < .001) and in-hospital complications (34% vs 27%; OR, 1.17 [95% CI, 1.05-1.30]; P = .004) but similar adjuvant systemic therapy administration (19% vs 13%; OR, 1.09 [95% CI, 0.95-1.24]; P = .2; 98% chemotherapy). Locoregional and distant recurrences were not significantly improved with guideline concordance across clinical stage I, II, and III subsets. Overall survival was similar in clinical stages I and II, but improved survival was observed for guideline concordant clinical stage III patients (hazard ratio, 0.85 [95% CI, 0.74-0.97]; P = .02). CONCLUSIONS: Sampling 3 (N2) 1 (N1) was associated with increased upstaging and complications but not with decreased recurrence or mortality in clinical stage I or II patients. Survival was improved for concordant, clinical stage III patients. Further study is indicated to determine the ideal lymph node sampling strategy across heterogeneous lung cancer patients.

A Novel Frailty Index Can Predict the Short-Term Outcomes of Esophagectomy in Older Patients with Esophageal Cancer.

Background: Frailty, rather than age, is associated with postoperative morbidity and mortality. We sought to determine whether preoperative frailty as defined by a novel scoring system could predict the outcomes among older patients undergoing esophagectomy. Methods: We identified patients 65 years or older who underwent esophagectomy between 2011 and 2021 at our institution. Frailty was assessed using the MSK-FI, which consists of 1 component related to functional status and 10 medical comorbidities. We used a multivariable logistic regression model to test for the associations between frailty and short-term outcomes, with continuous frailty score as the predictor and additionally adjusted for age and Eastern Cooperative Oncology Group performance status. Results: In total, 447 patients were included in the analysis (median age of 71 years [interquartile range, 68-75]). Most of the patients underwent neoadjuvant treatment (81%), an Ivor Lewis esophagectomy (86%), and minimally invasive surgery (55%). A total of 22 patients (4.9%) died within 90 days of surgery, 144 (32%) had a major complication, 81 (19%) were readmitted, and 31 (7.2%) were discharged to a facility. Of the patients who died within 90 days, 19 had a major complication, yielding a failure-to-rescue rate of 13%. The risk of 30-day major complications (OR, 1.24 [95% CI, 1.09-1.41]; p = 0.001), readmissions (OR, 1.31 [95% CI, 1.13-1.52]; p < 0.001), and discharge to a facility (OR, 1.86 [95% CI, 1.49-2.37]; p < 0.001) increased with increasing frailty. Frailty and 90-day mortality were not associated. Conclusions: Frailty assessment during surgery decision-making can identify patients with a high risk of morbidity.

Determinants of successful minimally invasive surgery for resectable non-small cell lung cancer after neoadjuvant therapy.

OBJECTIVE: Minimally invasive surgery (MIS) (video-assisted thoracoscopic surgery and robot-assisted thoracoscopic surgery) for pulmonary resection is standard in early-stage non-small cell lung cancer because it is associated with better perioperative outcomes than thoracotomy. MIS for resection of more advanced non-small cell lung cancer (Stages IB-IIIB) treated with neoadjuvant therapy has been utilized. However, the determinants of success are not well defined. METHODS: A single institution retrospective review of a prospectively maintained database was conducted, querying for patients with clinical Stage IB through IIIB non-small cell lung cancer who had resection after neoadjuvant systemic therapy without radiation from 2013 to 2022. Patients were grouped by surgical approach; that is, open versus MIS. Successful MIS was defined by no conversion, R0 resection, and no major (grade 3 or greater) morbidity. Analyses by intent-to-treat assessed outcomes by Wilcoxon rank-sum test and Fisher exact test. (Multivariable regression analysis identified variables that contributed to successful MIS resection.) RESULTS: Of 627 eligible patients, 360 (57%) had open and 267 (43%) had MIS procedures. Most patients (79.1%) received neoadjuvant platinum-based chemotherapy, and 21.9% were treated with immunotherapy or targeted therapy alone or combined with chemotherapy. Among MIS resections, 179 (67%) were performed by video-assisted thoracoscopic surgery and 88 (33%) by robot-assisted thoracoscopic surgery. The conversion rate was 16% (n = 43). Successful MIS resection was achieved in 77% of patients. Multivariable regression analysis showed that pretreatment clinical N stage was a significant determinant of success, but not pretreatment clinical T stage or type of neoadjuvant therapy. CONCLUSIONS: Following neoadjuvant systemic therapy for clinical stage IB or IIIB non-small cell lung cancer, MIS resection can be successfully accomplished and should be considered in appropriate patients. Presence of pretreatment nodal disease is associated with higher odds of conversion, major morbidity, and incomplete resection.

Gastric preconditioning via percutaneous angioembolization before esophagectomy in patients at high risk for esophageal leak.

Anastomotic leaks and stenoses remain critical complications in esophagectomy and are related to conduit perfusion. Surgical gastric preconditioning has been described but requires additional surgery and creates scar tissue, potentially hindering future operation. We sought to evaluate the feasibility and safety of percutaneous gastric preconditioning by angioembolization to improve perfusion of gastric conduits before esophagectomy in a high-risk patient cohort. Patients pending an esophagectomy for cancer and deemed to be high risk for anastomotic complications underwent preconditioning by image-guided angioembolization. Preconditioning was performed on an outpatient basis by means of superselective embolization of the left gastric and short gastric arteries. Intraoperative conduit perfusion evaluation with indocyanine green and postoperative surgical outcomes was reviewed. Seventeen patients underwent gastric preconditioning, with no complications observed. Thirteen of the 17 patients ultimately underwent esophagectomy; the remaining four patients were not candidates for an operation. Patients proceeded to surgery a median of 23 days (interquartile range, 21-27 days) after preconditioning. The intraoperative indocyanine green perfusion of all conduits was appropriate, with no tip demarcation and with a median time to dye uptake of 20s (interquartile range, 15-20s). There were no anastomotic stenoses or leaks noted within the series. Gastric conduit preconditioning by percutaneous angioembolization of the left gastric and short gastric arteries can be performed safely and without operative delay in high-risk patients. Further evaluation of preconditioning for conduit optimization is warranted to limit the critical complications of anastomotic leak and stenosis in esophagectomy.

The incremental contribution of mobile cone-beam computed tomography to the tool-lesion relationship during shape-sensing robotic-assisted bronchoscopy.

Introduction: This study aims to answer the question of whether adding mobile cone-beam computed tomography (mCBCT) imaging to shape-sensing robotic-assisted bronchoscopy (ssRAB) translates into a quantifiable improvement in the tool-lesion relationship. Methods: Data from 102 peripheral lung lesions with ≥2 sequential mCBCT orbital spins and from 436 lesions with 0-1 spins were prospectively captured and retrospectively analysed. The primary outcome was the tool-lesion relationship status across the first and the last mCBCT spins. Secondary outcomes included 1) the change in distance between the tip of the sampling tool and the centre of the lesion between the first and the last spins and 2) the per-lesion diagnostic yield. Results: Compared to lesions requiring 0-1 spins, lesions requiring ≥2 spins were smaller and had unfavourable bronchus sign and intra-operative sonographic view. On the first spin, 54 lesions (53%) were designated as non-tool-in-lesion (non-TIL) while 48 lesions (47%) were designated as TIL. Of the 54 initially non-TIL cases, 49 (90%) were converted to TIL status by the last spin. Overall, on the last spin, 96 out of 102 lesions (94%) were defined as TIL and six out of 102 lesions (6%) were defined as non-TIL (p<0.0001). The mean distance between the tool and the centre of the lesion decreased from 10.4 to 6.6 mm between the first and last spins (p<0.0001). The overall diagnostic yield was 77%. Conclusion: Targeting traditionally challenging lung lesions, intra-operative volumetric imaging allowed for the conversion of 90% of non-TIL status to TIL. Guidance with mCBCT resulted in a significant decrease in the distance between the tip of the needle to lesion centre.

Late recurrence of completely resected stage I to IIIA lung adenocarcinoma.

OBJECTIVE: Research into the risk factors associated with late recurrence (>2 years after surgery) of lung adenocarcinoma is limited. We investigated the incidence of and clinicopathologic and genomic features associated with late recurrence of resected stage I-IIIA lung adenocarcinoma. METHODS: We performed a retrospective analysis of patients with completely resected pathologic stage I-IIIA lung adenocarcinoma (2010-2019). Patients with a history of lung cancer, neoadjuvant therapy, or mucinous or noninvasive lung adenocarcinoma, or with follow-up of less than 2 years were excluded. Cox and logistic regression modeling were used to compare clinicopathologic variables among patients with no, early (≤2 years), and late recurrence. Comparisons of genomic mutations were corrected for multiple testing. RESULTS: Of the 2349 patients included, 537 developed a recurrence during follow-up. Most recurrences (55% [297/537]) occurred early; 45% (240/537) occurred late. A larger proportion of late recurrences than early recurrences were locoregional (37% vs 29%; P = .047). Patients with late recurrence had more aggressive pathologic features (International Association for the Study of Lung Cancer grade 2 and 3, lymphovascular invasion, visceral pleural invasion) and higher stage than patients without recurrence. Pathologic features were similar between patients with early and late recurrence, except stage IIIA disease was more common in the early cohort. No genomic mutations were associated with late recurrence. CONCLUSIONS: Late recurrence of lung adenocarcinoma after resection is more common than previously reported. Patients without disease more than 2 years after surgery who had aggressive pathologic features at the time of resection have an elevated risk of recurrence and may benefit from more aggressive follow-up.

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis.

Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

Outcomes of Patients Undergoing Segmentectomy for Occult Node-Positive Clinical Stage IA Lung Cancer.

BACKGROUND: Results of recent clinical trials suggest that segmentectomy may be an acceptable alternative to lobectomy for selected patients with early-stage non-small cell lung cancer (NSCLC). Increased use of segmentectomy may result in a concomitant increase in occult node-positive (N+) disease on surgical pathology examination. The optimal management for such patients remains unknown. METHODS: Clinicopathologic data were abstracted from a prospective institutional database to identify patients with pathologic N+ disease after segmentectomy for cT1 N0 M0 NSCLC. Propensity score matching identified a comparable lobectomy cohort for assessment of cumulative incidence of recurrence and overall survival (OS). RESULTS: Of 759 included patients, 27 (4%) had nodal upstaging on the final pathology report. Of these 27 patients, 4 (15%) had skip metastasis to N2 stations, and 20 (74%) received adjuvant therapy; no completion lobectomies were performed. Ten patients (37%) had disease recurrence: 3 isolated locoregional (11%) and 7 distant (26%). The median time to recurrence among patients with recurrence was 1.8 years; OS after recurrence was 3.4 years. After 5:1 matching with 109 patients who underwent lobectomy, all variables were balanced between the groups, except pathologic N2 stage and open surgical approach. The 5-year cumulative incidence of recurrence was not significantly different between segmentectomy and lobectomy (42% vs 52%, respectively; Gray's P = .1). The 5-year OS (63% and 50%) and rate of locoregional recurrence (12% vs 13%) were not statistically different between the groups. CONCLUSIONS: Patients with occult N+ disease after segmentectomy for cT1 N0 M0 NSCLC had limited isolated locoregional recurrences and outcomes similar to those in patients who underwent lobectomy. Lobectomy may not provide an advantage in these patients.

Characterizing a learning curve for robotic-assisted bronchoscopy: Analysis of skills acquisition in a high-volume academic center.

OBJECTIVE: Shape-sensing robotic-assisted bronchoscopy is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the shape-sensing robotic-assisted bronchoscopy learning curve at an academic center. METHODS: Shape-sensing robotic-assisted bronchoscopy procedures performed by 9 proceduralists at a single institution were analyzed. Cumulative sum analyses were performed to examine diagnostic sampling and procedure time over each operator's first 50 cases, with the acceptable yield threshold set to 73%. RESULTS: During the study period, 442 patients underwent sampling of 551 lesions. Each operator sampled 61 lesions (interquartile range, 60-63 lesions). Lesion size was 1.90 cm (interquartile range, 1.33-2.80 cm). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P < .001). The overall diagnostic yield was 72% (range, 58%-83%). Six of 9 operators achieved proficiency over the study period. An aggregated cumulative sum analysis of those who achieved competency demonstrated a steep improvement between lesions 1 and 21 and crossing of the competency threshold by lesion 25. Temporal analysis of yield-related lesion characteristics demonstrated that at approximately lesion 20, more challenging lesions were increasingly targeted, as evidenced by smaller target size, higher rates of unfavorable radial endobronchial ultrasound views, and a negative bronchus sign. CONCLUSIONS: Skills acquisition in shape-sensing robotic-assisted bronchoscopy is variable. Approximately half of proceduralists become facile with the technology within 25 lesions. After the initial learning phase, operators increasingly target lesions with more challenging features. Overall, these findings can inform certification and competency standards and provide new users with expectations related to performance over time.

A Real-World Assessment of Stage I Lung Cancer Through Electronic Nose Technology.

INTRODUCTION: Electronic nose (E-nose) technology has reported excellent sensitivity and specificity in the setting of lung cancer screening. However, the performance of E-nose specifically for early-stage tumors remains unclear. Therefore, the aim of our study was to assess the diagnostic performance of E-nose technology in clinical stage I lung cancer. METHODS: This phase IIc trial (NCT04734145) included patients diagnosed with a single greater than or equal to 50% solid stage I nodule. Exhalates were prospectively collected from January 2020 to August 2023. Blinded bioengineers analyzed the exhalates, using E-nose technology to determine the probability of malignancy. Patients were stratified into three risk groups (low-risk, [<0.2]; moderate-risk, [≥0.2-0.7]; high-risk, [≥0.7]). The primary outcome was the diagnostic performance of E-nose versus histopathology (accuracy and F1 score). The secondary outcome was the clinical performance of the E-nose versus clinicoradiological prediction models. RESULTS: Based on the predefined cutoff (<0.20), E-nose agreed with histopathologic results in 86% of cases, achieving an F1 score of 92.5%, based on 86 true positives, two false negatives, and 12 false positives (n = 100). E-nose would refer fewer patients with malignant nodules to observation (low-risk: 2 versus 9 and 11, respectively; p = 0.028 and p = 0.011) than would the Swensen and Brock models and more patients with malignant nodules to treatment without biopsy (high-risk: 27 versus 19 and 6, respectively; p = 0.057 and p < 0.001). CONCLUSIONS: In the setting of clinical stage I lung cancer, E-nose agrees well with histopathology. Accordingly, E-nose technology can be used in addition to imaging or as part of a "multiomics" platform.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

BACKGROUND AND OBJECTIVE: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. METHODS: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. RESULTS: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 µSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. CONCLUSION: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.

High-risk features associated with recurrence in stage I lung adenocarcinoma.

OBJECTIVE: There is a lack of knowledge regarding the use of prognostic features in stage I lung adenocarcinoma (LUAD). Thus, we investigated clinicopathologic features associated with recurrence after complete resection for stage I LUAD. METHODS: We performed a retrospective analysis of patients with pathologic stage I LUAD who underwent R0 resection from 2010 to 2020. Exclusion criteria included history of lung cancer, induction or adjuvant therapy, noninvasive or mucinous LUAD, and death within 90 days of surgery. Fine and Gray competing-risk regression assessed associations between clinicopathologic features and disease recurrence. RESULTS: In total, 1912 patients met inclusion criteria. Most patients (1565 [82%]) had stage IA LUAD, and 250 developed recurrence: 141 (56%) distant and 109 (44%) locoregional only. The 5-year cumulative incidence of recurrence was 12% (95% CI, 11%-14%). Higher maximum standardized uptake value of the primary tumor (hazard ratio [HR], 1.04), sublobar resection (HR, 2.04), higher International Association for the Study of Lung Cancer grade (HR, 5.32 [grade 2]; HR, 7.93 [grade 3]), lymphovascular invasion (HR, 1.70), visceral pleural invasion (HR, 1.54), and tumor size (HR, 1.30) were independently associated with a hazard of recurrence. Tumors with 3 to 4 high-risk features had a higher cumulative incidence of recurrence at 5 years than tumors without these features (30% vs 4%; P < .001). CONCLUSIONS: Recurrence after resection for stage I LUAD remains an issue for select patients. Commonly reported clinicopathologic features can be used to define patients at high risk of recurrence and should be considered when assessing the prognosis of patients with stage I disease.

A New Functional Threshold for Minimally Invasive Lobectomy.

OBJECTIVE: To assess the performance of a lower predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung for carbon monoxide (DLCO) (ppoFEV1/ppoDLCO) threshold to predict cardiopulmonary complications after minimally invasive surgery (MIS) lobectomy. SUMMARY BACKGROUND DATA: Although MIS is associated with better postoperative outcomes than open surgery, MIS uses risk-assessment algorithms developed for open surgery. Moreover, several different definitions of cardiopulmonary complications are used for assessment. METHODS: All patients who underwent MIS lobectomy for clinical stage I-II lung cancer from 2018 to 2022 at our institution were considered. The performance of a ppoFEV1/ppoDLCO threshold of <45% was compared against that of the current guideline threshold of <60%. Three different definitions of cardiopulmonary complications were compared: Society of Thoracic Surgeons (STS), European Society of Thoracic Surgeons (ESTS), and Berry et al. RESULTS: In 946 patients, the ppoFEV1/ppoDLCO threshold of <45% was associated with a higher proportion correctly classified (79% [95% CI, 76%-81%] vs. 65% [95% CI, 62%-68%]; P<0.001). The complication with the biggest difference in incidence between ppoFEV1/ppoDLCO of 45%-60% and >60% was prolonged air leak (33 [13%] vs. 34 [6%]; P<0.001). The predicted probability curves for cardiopulmonary complications were higher for the STS definition than for the ESTS or Berry definitions across ppoFEV1 and ppoDLCO values. CONCLUSIONS: The ppoFEV1/ppoDLCO threshold of <45% more accurately classified patients for cardiopulmonary complications after MIS lobectomy, emphasizing the need for updated risk-assessment guidelines for MIS lobectomy to optimize additional cardiopulmonary function evaluation.

Treatment of esophageal adenocarcinoma in patients with a history of bariatric surgery.

BACKGROUND: The relationship among obesity, bariatric surgery, and esophageal adenocarcinoma (EAC) is complex, given that some bariatric procedures are thought to be associated with increased incidence of reflux and Barrett's esophagus. Previous bariatric surgery may complicate the use of the stomach as a conduit for esophagectomy. In this study, we presented our experience with patients who developed EAC after bariatric surgery and described the challenges encountered and the techniques used. METHODS: We conducted a retrospective review of our institutional database to identify all patients at our institution who were treated for EAC after previously undergoing bariatric surgery. RESULTS: In total, 19 patients underwent resection with curative intent for EAC after bariatric surgery, including 10 patients who underwent sleeve gastrectomy. The median age at diagnosis of EAC was 63 years; patients who underwent sleeve gastrectomy were younger (median age, 56 years). The median time from bariatric surgery to EAC was 7 years. Most patients had a body mass index (BMI) score of >30 kg/m2 at the time of diagnosis of EAC; approximately 40% had class III obesity (BMI score > 40 kg/m2). Six patients (32%) had known Barrett's esophagus before undergoing a reflux-increasing bariatric procedure. Sleeve gastrectomy patients underwent esophagectomy with gastric conduit, colonic interposition, or esophagojejunostomy. Only 1 patient had an anastomotic leak (after esophagojejunostomy). CONCLUSION: Endoscopy should be required both before (for treatment selection) and after all bariatric surgical procedures. Resection of EAC after bariatric surgery requires a highly individualized approach but is safe and feasible.

The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK.

BRCA1-associated protein 1 (BAP1) has emerged as a major tumor suppressor gene in diverse cancer types, notably in malignant pleural mesothelioma (DPM), and has also been identified as a germline cancer predisposition gene for DPM and other select cancers. However, its role in the response to DNA damage has remained unclear. Here, we show that BAP1 inactivation is associated with increased DNA damage both in Met-5A human mesothelial cells and human DPM cell lines. Through proteomic analyses, we identified PRKDC as an interaction partner of BAP1 protein complexes in DPM cells and 293 T human embryonic kidney cells. PRKDC encodes the catalytic subunit of DNA protein kinase (DNA-PKcs) which functions in the nonhomologous end-joining (NHEJ) pathway of DNA repair. Double-stranded DNA damage resulted in prominent nuclear expression of BAP1 in DPM cells and phosphorylation of BAP1 at serine 395. A plasmid-based NHEJ assay confirmed a significant effect of BAP1 knockdown on cellular NHEJ activity. Combination treatment with X-ray irradiation and gemcitabine (as a radiosensitizer) strongly suppressed the growth of BAP1-deficient cells. Our results suggest reciprocal positive interactions between BAP1 and DNA-PKcs, based on phosphorylation of BAP1 by the latter and deubiquitination of DNA-PKcs by BAP1. Thus, functional interaction of BAP1 with DNA-PKcs supports a role for BAP1 in NHEJ DNA repair and may provide the basis for new therapeutic strategies and new insights into its role as a tumor suppressor.

The Emerging Role of Immunotherapy in Resectable Non-Small Cell Lung Cancer.

BACKGROUND: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC. METHODS: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies. RESULTS: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes. CONCLUSIONS: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials.