p53 governs an AT1 differentiation programme in lung cancer suppression.

Lung cancer is the leading cause of cancer deaths worldwide1. Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis1-4, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.

Complications of Outpatient Chest Tube Management for Prolonged Air Leaks After Pulmonary Surgery.

PURPOSE: Air leaks are common after pulmonary surgery. Prolonged air leaks (PALs) may persist through discharge and often are managed with one-way valve devices (OWD). We sought to determine the course and complications of patients discharged with OWDs, risk factors for complications, and to evaluate the utility of clamp trials before chest tube (CT) removal. METHODS: Single-institution, retrospective review of patients discharged with a OWD after pulmonary surgery between 2008 and 2022. Charts were examined for the presence of complications and CT duration. Differences in CT duration were compared by using the Wilcoxon rank-sum test. RESULT: Sixty-four of 1917 (3.3%) pulmonary surgeries resulted in OWD use. Twelve of 64 (19%) patients discharged with a OWD suffered a complication. Nine of 64 (14%) had a CT-related readmission, and seven of 64 (11%) required PAL intervention. Patients sustaining a complication demonstrated longer CT durations before complication compared with duration in patients without complications, with median days of 13 [IQR 6-21] vs. 7 [IQR 6-12], p = 0.04). Five (7.8%) OWD patients developed an empyema; only one (20%) occurred before a CT duration of 14 days. Sixteen of 64 (25%) patients underwent a clamp trial before CT removal. One of ten (10%) failed even with no air leak present, whereas one of six (17%) failed with a present/questionable air leak. CONCLUSIONS: One-way valve device use has a substantial complication rate, and chest tube duration is a risk factor. In-hospital interventions might benefit patients with larger leaks that likely require prolonged OWD use. Because clamp trials occasionally fail, we contend that a clamp trial is the safest course before CT removal.

Treatment and Outcomes of Proximal Esophageal Squamous Cell Carcinoma.

INTRODUCTION: This study evaluated the treatment of proximal (cervical or upper thoracic) esophageal squamous cell carcinoma (SCC), for which chemoradiation is the recommended therapy. METHODS: Treatment and outcomes of patients with cT1-3N0-1M0 proximal esophageal SCC in the National Cancer Database between 2004 and 2016 was evaluated using logistic regression, Kaplan-Meier analysis, and propensity-score matching. RESULTS: Therapy of 2159 patients was chemoradiation (n = 1500, 69.5%), no treatment (n = 205, 9.5%), surgery (n = 203, 9.4%), radiation alone (n = 190, 8.8%), and chemotherapy alone (n = 61, 2.8%). Factors associated with definitive therapy with either chemoradiation or surgery were younger age, non-Black race, being insured, cervical tumor location, clinical T2 and T3 stage, clinical nodal involvement, and treatment at a research/academic program. Five-year survival was significantly better in patients treated with definitive therapy than patients not treated definitively (34.0% vs. 13.3%, p < 0.001). In multivariable survival analysis, receiving definitive therapy (hazard ratio [HR] 0.39, p = 0.017) was associated with improved survival, while increasing age, male sex, clinical T3 stage, positive clinical nodal involvement, and increasing Charlson Comorbidity Index were associated with worse survival. Esophagectomy was not associated with improved survival in multivariable analysis of the definitive therapy cohort (HR 0.84, p = 0.08) or propensity matched analysis. However, the pathologic complete response was only 33.3% (40/120) for patients who did have an esophagectomy after chemoradiation. CONCLUSIONS: This national analysis supports definitive chemoradiation for not only cervical but also proximal thoracic esophageal SCC. Routine surgery does not appear to be necessary but may have a role in patients with residual disease after chemoradiation.

Impact of Delaying Surgery After Chemoradiation on Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND: Performing selective esophagectomy for locally advanced squamous cell carcinoma may spare patients morbidity, but delayed surgery may infer higher risks. This study evaluated the impact of length of time between chemoradiation and esophagectomy on perioperative outcomes and long-term survival. METHODS: The impact of surgical timing, stratified by surgery performed < 180 and ≥ 180 days from starting radiation, on perioperative outcomes and survival in patients treated with chemoradiation and esophagectomy for cT1N + M0 and cT2-4, any N, M0 squamous cell carcinoma of the mid-distal esophagus in the National Cancer Database (2006-2016) was evaluated with logistic regression, Kaplan-Meier curves, Cox proportional-hazards methods, and propensity-matched analysis. RESULTS: Median time between starting radiation and esophagectomy in 1641 patients was 93 (IQR 81-114) days. Most patients (96.8%, n = 1589) had surgery within 180 days of starting radiation, while 52 patients (3.2%) had delayed surgery. Black race and clinical T stage were associated with delayed surgery. Rates of pathologic upstaging, downstaging, complete response, and positive margins were not significantly different between the groups. Patients with delayed surgery had increased major morbidity as measured by a composite of length of hospital stay, readmission, and 30-day mortality [42.3% (22/52) vs 22.3% (355/1589), p = 0.001]. However, delayed surgery was not associated with a significant difference in survival in both univariate [5-year survival 32.8% (95% CI 21.1-50.7) vs 47.3% (44.7-50.1), p = 0.19] and multivariable analysis [hazard ratio (HR) 1.23 (0.85-1.78), p = 0.26]. CONCLUSIONS: Delaying surgery longer than 180 days after starting chemoradiation for esophageal squamous cell carcinoma is associated with worse perioperative outcomes but not long-term survival.

Characterization of Epidural Analgesia Interruption and Associated Outcomes After Esophagectomy.

INTRODUCTION: Interruption of thoracic epidural analgesia may impact the postoperative course following esophagectomy. This study investigates the incidence and causes of epidural interruption in esophagectomy patients along with associated postoperative outcomes. METHODS: This single-institution retrospective analysis examined patients undergoing esophagectomy who received a thoracic epidural catheter from 2016 to 2020. Patients were stratified according to whether epidural catheter infusion was interrupted or not postoperatively. Outcomes were compared between the two groups, and predictors of epidural interruption and postoperative complications were estimated using multivariable logistic regression. RESULTS: Of the 168 patients who received a thoracic epidural before esophagectomy, 60 (35.7%) required epidural interruption and 108 (64.3%) did not. Interruption commonly occurred on postoperative day 1 and was due to hypotension 80% of the time. Heart failure (10.0% versus 0.9%, P = 0.009), atrial fibrillation (20.0% versus 3.7%, P = 0.002), preoperative opioid use (30.0% versus 16.7%, P = 0.043), and higher American Society of Anesthesiology classification (88.4% versus 70.4%, P = 0.008) were more prevalent in the epidural interruption cohort. The female gender was associated with epidural interruption on multivariable logistic regression (adjusted odds ratio [AOR] 2.45, P = 0.039). Patients in the epidural interruption cohort had a higher incidence of delirium (30.5% versus 13.9%, P = 0.010), sepsis (13.6% versus 3.7%, P = 0.028), and severe anastomotic leak (18.3% versus 7.4%, P = 0.032). On adjusted analysis, heart disease (AOR 4.26, P = 0.027), BMI <18.5 (AOR 9.83, P = 0.031), and epidural interruption due to hypotension (AOR 3.51, P = 0.037) were associated with severe anastomotic leak. CONCLUSIONS: Early epidural interruption secondary to hypotension in esophagectomy patients may be a harbinger of postoperative complications such as sepsis and severe anastomotic leak. Patients requiring epidural interruption due to hypotension should have a low threshold for additional workup and early intervention.

Perioperative Outcomes After Combined Esophagectomy and Lung Resection.

INTRODUCTION: The impact of concomitant lung resection during esophagectomy on short-term outcomes is not well characterized. This study tests the hypothesis that lung resection at the time of esophagectomy is not associated with increased perioperative morbidity or mortality. METHODS: Perioperative outcomes for esophageal cancer patients who underwent esophagectomy alone (EA) were compared to patients who had concurrent esophagectomy and lung resection (EL) using the NSQIP database between 2006-2017. Predictors of morbidity and mortality, including combined surgery, were evaluated using multivariable logistic regression. RESULTS: Among the 6,225 study patients, 6,068 (97.5%) underwent EA and 157 (2.5%) underwent EL. There were no differences in baseline characteristics between the two groups. Operating time for EL was longer than EA (median 416 versus 371 minutes, P < 0.01). Median length of stay was 10 d for both groups. Perioperative mortality was not significantly different between EL and EA patients (5.1% versus 2.8%, P = 0.08). EL patients had higher rates of postoperative pneumonia (22.3% versus 16.2%, P = 0.04) and sepsis (11.5% versus 7.1%, P = 0.03), however major complication rates overall were similar (40.8% versus 35.3%, P = 0.16). Combining lung resection with esophagectomy was not independently associated with increased postoperative morbidity (AOR 1.21 [95% CI 0.87-1.69]) or mortality (AOR 1.63 [95% CI 0.74-3.58]). CONCLUSIONS: Concurrent lung resection during esophagectomy is not associated with increased mortality or overall morbidity, but is associated with higher rates of pneumonia beyond esophagectomy alone. Surgeons considering combined lung resection with esophagectomy should carefully evaluate the patient's risk for pulmonary complications and pursue interventions preoperatively to optimize respiratory function.

Cancer diagnoses and survival rise as 65-year-olds become Medicare-eligible.

BACKGROUND: A Medicare effect has been described to account for increased health care utilization occurring at the age of 65 years. The existence of such an effect in cancer care, where it would be most likely to reduce mortality, has been unclear. METHODS: Patients aged 61 to 69 years who were diagnosed with lung, breast, colon, or prostate cancer from 2004 to 2016 were identified with the Surveillance, Epidemiology, and End Results database and were dichotomized on the basis of eligibility for Medicare (61-64 vs 65-69 years). With age-over-age (AoA) percent change calculations, trends in cancer diagnoses and staging were characterized. After matching, uninsured patients who were 61 to 64 years old (pre-Medicare group) were compared with insured patients who were 65 to 69 years old (post-Medicare group) with respect to cancer-specific mortality. RESULTS: In all, 134,991 patients were identified with lung cancer, 175,558 were identified with breast cancer, 62,721 were identified with colon cancer, and 238,823 were identified with prostate cancer. The AoA growth in the number of cancer diagnoses was highest at the age of 65 years in comparison with all other ages within the decade for all 4 cancers (P < .01, P < .001, P < .01, and P < .001, respectively). In a comparison of diagnoses at the age of 65 years with those in the 61- to 64-year-old cohort, the greatest difference for all 4 cancers was seen in stage I. In matched analyses, the 5-year cancer-specific mortality was worse for lung (86.3% vs 78.5%; P < .001), breast (32.7% vs 11.0%; P < .001), colon (57.1% vs 35.6%; P < .001), and prostate cancer (16.9% vs 4.8%; P < .001) in the uninsured pre-Medicare group than the insured post-Medicare group. CONCLUSIONS: The age threshold of 65 years for Medicare eligibility is associated with more cancer diagnoses (particularly stage I), and this results in lower long-term cancer-specific mortality for all cancers studied. LAY SUMMARY: Contributing to the current debate regarding Medicare for all, this study shows that the expansion of Medicare would improve cancer outcomes for the near elderly.

Estimating the Impact of Extended Delay to Surgery for Stage I Non-small-cell Lung Cancer on Survival.

OBJECTIVE: The purpose of this study is to evaluate the impact of extended delay to surgery for stage I NSCLC. SUMMARY OF BACKGROUND DATA: During the COVID-19 pandemic, patients with NSCLC may experience delays in care, and some national guidelines recommend delays in surgery by >3 months for early NSCLC. METHODS: Using data from the National Lung Screening Trial, a multi-center randomized trial, and the National Cancer Data Base, a multi-institutional oncology registry, the impact of "early" versus "delayed" surgery (surgery received 0-30 vs 90-120 days after diagnosis) for stage I lung adenocarcinoma and squamous cell carcinoma (SCC) was assessed using multivariable Cox regression analysis with penalized smoothing spline functions and propensity score-matched analyses. RESULTS: In Cox regression analysis of the National Lung Screening Trial (n = 452) and National Cancer Data Base (n = 80,086) cohorts, an increase in the hazard ratio was seen the longer surgery was delayed. In propensity score-matched analysis, no significant differences in survival were found between early and delayed surgery for stage IA1 adenocarcinoma and IA1-IA3 SCC (all P > 0.13). For stage IA2-IB adenocarcinoma and IB SCC, delayed surgery was associated with worse survival (all P < 0.004). CONCLUSIONS: The mortality risk associated with an extended delay to surgery differs across patient subgroups, and difficult decisions to delay care during the COVID-19 pandemic should take substage and histologic subtype into consideration.

Strong for Surgery: Association Between Bundled Risk Factors and Outcomes After Major Elective Surgery in the VA Population.

BACKGROUND: Strong for Surgery (S4S) is a public health campaign focused on optimizing patient health prior to surgery by identifying evidence-based modifiable risk factors. The potential impact of S4S bundled risk factors on outcomes after major surgery has not been previously studied. This study tested the hypothesis that a higher number of S4S risk factors is associated with an escalating risk of complications and mortality after major elective surgery in the VA population. METHODS: The Veterans Affairs Surgical Quality Improvement Program (VASQIP) database was queried for patients who underwent major non-emergent general, thoracic, vascular, urologic, and orthopedic surgeries between the years 2008 and 2015. Patients with complete data pertaining to S4S risk factors, specifically preoperative smoking status, HbA1c level, and serum albumin level, were stratified by number of positive risk factors, and perioperative outcomes were compared. RESULTS: A total of 31,285 patients comprised the study group, with 16,630 (53.2%) patients having no S4S risk factors (S4S0), 12,323 (39.4%) having one (S4S1), 2,186 (7.0%) having two (S4S2), and 146 (0.5%) having three (S4S3). In the S4S1 group, 60.3% were actively smoking, 35.2% had HbA1c > 7, and 4.4% had serum albumin < 3. In the S4S2 group, 87.8% were smokers, 84.8% had HbA1c > 7, and 27.4% had albumin < 3. Major complications, reoperations, length of stay, and 30-day mortality increased progressively from S4S0 to S4S3 groups. S4S3 had the greatest adjusted mortality risk (adjusted odds radio [AOR] 2.56, p = 0.04) followed by S4S2 (AOR 1.58, p = 0.02) and S4S1 (AOR 1.34, p = 0.02). CONCLUSION: In the VA population, patients who had all three S4S risk factors, namely active smoking, suboptimal nutritional status, and poor glycemic control, had the greatest risk of postoperative mortality compared to patients with fewer S4S risk factors.

Stereotactic Body Radiotherapy Versus Delayed Surgery for Early-stage Non-small-cell Lung Cancer.

OBJECTIVE: To evaluate the overall survival of patients with operable stage IA non-small-cell lung cancer (NSCLC) who undergo "early" SBRT (within 0-30 days after diagnosis) versus "delayed" surgery (90-120 days after diagnosis). SUMMARY OF BACKGROUND DATA: During the COVID-19 pandemic, national guidelines have recommended patients with operable stage IA NSCLC to consider delaying surgery by at least 3 months or, alternatively, to undergo SBRT without delay. It is unknown which strategy is associated with better short- and long-term outcomes. METHODS: Multivariable Cox proportional hazards modeling and propensity score-matched analysis was used to compare the overall survival of patients with stage IA NSCLC in the National Cancer Data Base from 2004 to 2015 who underwent "early" SBRT (0-30 days after diagnosis) versus that of patients who underwent "delayed" wedge resection (90-120 days after diagnosis). RESULTS: During the study period, 570 (55%) patients underwent early SBRT and 475 (45%) underwent delayed wedge resection. In multivariable analysis, delayed resection was associated with improved survival [adjusted hazard ratio 0.61; (95% confidence interval (CI): 0.50-0.76)]. Propensity-score matching was used to create 2 groups of 279 patients each who received early SBRT or delayed resection that were well-matched with regard to baseline characteristics. The 5-year survival associated with delayed resection was 53% (95% CI: 45%-61%) which was better than the 5-year survival associated with early SBRT (31% [95% CI: 24%-37%]). CONCLUSION: In this national analysis, for patients with stage IA NSCLC, extended delay of surgery was associated with improved survival when compared to early treatment with SBRT.

Thromboelastography After Murine TBI and Implications of Beta-Adrenergic Receptor Knockout.

BACKGROUND: The source of coagulopathy in traumatic brain injury (TBI) is multifactorial and may include adrenergic stimulation. The aim of this study was to assess coagulopathy after TBI using thromboelastography (TEG), and to investigate the implications of ß-adrenergic receptor knockout. METHODS: Adult male wild type c57/bl6 (WT) and ß1/ß2-adrenergic receptor knockout (BKO) mice were assigned to either TBI (WT-TBI, BKO-TBI) or sham injury (WT-sham, BKO-sham). Mice assigned to TBI were subject to controlled cortical impact (CCI). At 24 h post-injury, whole blood samples were obtained and taken immediately for TEG. RESULTS: At 24 h after injury, a trend toward increased fibrinolysis was seen in WT-TBI compared to WT-sham although this did not reach significance (EPL 8.1 vs. 0 %, p = 0.18). No differences were noted in fibrinolysis in BKO-TBI compared to BKO-sham (LY30 2.6 vs. 2.5 %, p = 0.61; EPL 3.4 vs. 2.9 %, p = 0.61). In addition BKO-TBI demonstrated increased clot strength compared to BKO-sham (MA 76.6 vs. 68.6, p = 0.03; G 18.2 vs. 11.3, p = 0.03). CONCLUSIONS: In a mouse TBI model, WT mice sustaining TBI demonstrated a trend toward increased fibrinolysis at 24 h after injury while BKO mice did not. These findings suggest ß-blockade may attenuate the coagulopathy of TBI and minimize progression of intracranial hemorrhage by reducing fibrinolysis and increasing clot strength.

Impact of body mass index on injury in abdominal stab wounds: implications for management.

BACKGROUND: Although it is assumed that obese patients are naturally protected against anterior abdominal stab wounds, the relationship has never been formally studied. We sought to examine the impact of body mass index (BMI) on severity of sustained injury, need for operation, and patient outcomes. MATERIALS AND METHODS: We conducted a review of all patients presenting with abdominal stab wounds at an urban level I trauma center from January 2000-December 2012. Patients were divided into groups based on their BMI (<18.5, 18.5-29.9, 30-35, and >35). Data abstracted included baseline demographics, physiologic data, and characterization of whether the stab wound had violated the peritoneum, caused intra-abdominal injury, or required an operation that was therapeutic. The one-sided Cochran-Armitage trend test was used for significance testing of the protective effect. RESULTS: Of 281 patients with abdominal stab wounds, 249 had complete data for evaluation. Chest and abdomen abbreviated injury scale trends decreased with increasing BMI, as did overall injury severity score, the percent of patients severely injured (injury severity score ≥ 25), and length of intensive care unit stay. Rates of peritoneal violation (100%, 84%, 77%, and 74%; P = 0.077), visceral injury (83%, 56%, 50%, and 30%; P = 0.022), and injury requiring a therapeutic operation (67%, 45%, 40%, and 20%; P = 0.034) all decreased with increasing BMI. Patients in the thinnest group required an operation three times more often than those in the most obese. CONCLUSIONS: Increased BMI protects patients with abdominal stab wounds and is associated with lower incidence of severe injury and need for operation. Heavier patients may be more suitable to observation and serial examinations, whereas very thin patients are more likely to require an operation and be critically injured.

Management of Paraesophageal Hernias.

Paraesophageal hernias are classified according to the altered anatomic relationships between the gastroesophageal junction or stomach and the diaphragmatic hiatus. Herniation of these structures into the mediastinum may produce common complaints such as reflux, chest pain, and dysphagia. The elective repair of these hernias is well tolerated and significantly improves quality of life among patients with symptomatic disease. The hallmarks of a quality repair include the circumferential mobilization of the esophagus to generate 3 cm of tension-free intra-abdominal length and the performance of a fundoplication.

Surgical revision of the postesophagectomy gastric conduit to address poor emptying.

Introduction: The configuration of the gastric conduit after esophagectomy can lead to chronic gastrointestinal and respiratory issues. Surgical revision of the gastric conduit has been described in small series but appears to be infrequently used. We investigated outcomes of revising dilated or redundant conduit in patients with severe quality-of-life issues. Methods: We identified all patients from 2016 to 2022 at our institution who underwent gastric conduit revision after previous esophagectomy either at our or another institution. Chart review was performed to assess prerevision course and perioperative outcomes. Pre- and postrevision imaging was compared for all patients to assess the impact of surgery on anatomic configuration. Patient-reported gastrointestinal and respiratory issues before and after surgery were examined. Results: The use of right thoracotomy combined with laparotomy to reduce redundancy and improve gastric emptying was performed in 8 patients. The symptoms necessitating reoperation included intolerance to oral intake and poor gastric emptying associated with both acute and chronic aspiration episodes. The median length of stay was 8 [4, 25] days, and there were no perioperative mortalities. Seven (87.5%) patients were tolerating oral intake at discharge. All patients had improvement in their prerevision symptoms on follow-up. Conclusions: Gastric conduit revision can improve severe postesophagectomy gastrointestinal and respiratory symptoms in patients with dilated/redundant conduits with limited perioperative morbidity.

Lepidic-Type Lung Adenocarcinomas: Is It Safe to Observe for Growth Before Treating?

BACKGROUND: Lepidic-type adenocarcinomas (LPAs) can be multifocal, and treatment is often deferred until growth is observed. This study investigated the potential downside of that strategy by evaluating the relationship of nodal involvement with tumor size and survival. METHODS: The impact of tumor size on lymph node involvement and survival was evaluated for National Cancer Database patients who underwent surgery without induction therapy as primary treatment for cT1-3 N0 M0 histologically confirmed LPA from 2006 to 2019 by using logistic regression, Kaplan-Meier, and Cox analyses. RESULTS: Positive nodes occurred in 442 of 8286 patients (5.3%). The incidence of having positive nodes approximately doubled with each 1-cm increment increase in size. Patients with positive nodes were more likely to have larger tumors (27 mm vs 20 mm, P < .001) and clinical ≥T2 disease (40.7% vs 26.8%, P < .001) compared with node-negative patients. However, tumor size was the only significant independent predictor of having positive nodal disease in logistic regression analysis, and this association grew stronger with each incremental centimeter increase in size. Patients with positive nodes were more likely to undergo adjuvant radiotherapy (23.5% vs 1.1%, P < .001) and chemotherapy (72.9% vs 7.9%, P < .001), and expectedly, had worse survival compared with the node-negative group in univariate (5-year overall survival, 50.9% vs 81.1%, P < .001) and multivariable (hazard ratio, 2.56; 95% CI, 2.14-3.05; P < .001) analyses. CONCLUSIONS: Nodal involvement is relatively uncommon in early-stage LPAs but steadily increases with tumor size and is associated with dramatically worse survival. These data can be used to inform treatment decisions when evaluating LPA patients.

What Is an Adequate Margin During Sublobar Resection of ≤3 cm N0 Subsolid Lung Adenocarcinomas?

BACKGROUND: Sublobar resection offers noninferior survival vs lobectomy for ≤2 cm non-small cell lung cancer and is commonly used for subsolid tumors. Although data exist for solid tumors, the minimum adequate margin of resection for subsolid adenocarcinomas remains unclear. METHODS: This was a retrospective review of 1101 adenocarcinoma resections at our institution from 2006 to 2022. Inclusion criteria were tumors ≤3 cm with ≥10% radiographic ground glass, excised by sublobar resection. Exclusions were positive nodes or positive or unreported margin. The primary outcome was the rate of local recurrence (LR) at multiple thresholds of margin distance. The relationship between margin distance and solid component size was also explored. RESULTS: Inclusion criteria were met by 194 patients. Median (interquartile range) tumor diameter and margin distance were 12 mm (9-17 mm) and 10 mm (5-17 mm), respectively. Median follow-up was 42.5 months. There was a progressive increase in LR with diminishing margin (0.1-cm decrements) from 1.5 cm to 0.5 cm. The difference in the rate of LR between "over" (n = 143) and "under" (n = 51) was most significant at 0.5 cm (8 of 51 [15.7%] vs 6 of 143 [4.2%]; P = .01) but did not reach α adjusted for multiple comparisons. On Cox regression for LR-free survival, margin ≤0.5 cm (P = .19) and solid component percentage (P = .14) trended to significance. Combining these using a ratio of margin distance-to-solid component size, a ratio of ≤1 showed a significantly higher rate of LR (7 [14.3%] vs 2 [2.0%], P = .009). Treatment of LRs provided at least intermediate-term survival in 87% of recurrences (median postrecurrence follow-up was 44 months). CONCLUSIONS: During sublobar resection of subsolid lung adenocarcinomas, a margin distance-to-solid component size ratio of >1.0 appears to be a more reliable factor than margin distance alone to minimize local recurrence. Local recurrence, however, may not impact survival in patients with subsolid adenocarcinomas if timely treatment is administered.

Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma.

Background: Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma. Methods: Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected. Results: We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043). Conclusions: Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.

The Impact of Immunotherapy Use in Stage IIIA (T1-2N2) NSCLC: A Nationwide Analysis.

Introduction: Multiple clinical trials have revealed the benefit of immunotherapy (IO) for NSCLC, including unresectable stage III disease. Our aim was to investigate the impact of IO use on treatment and outcomes of potentially resectable stage IIIA NSCLC in a broader nationwide patient cohort. Methods: We queried the National Cancer Database (2004-2019) for patients with stage IIIA (T1-2N2) NSCLC. Treatment and survival were evaluated with descriptive statistics, logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling. Results: Overall, 5.5% (3777 of 68,335) of patients received IO. IO use was uncommon until 2017, but by 2019, it was given to 40.1% (1544 of 2308) of stage IIIA patients. The increased use of IO after 2017 was associated with increased definitive chemoradiation treatment (54.2% [6800 of 12,535] from years 2017 to 2019 versus 46.9% [26,251 of 55,914] from 2004 to 2016, p < 0.001) and less use of surgery (18.1% [2266 of 12,535] from years 2017 to 2019 versus 22.0% [12,300 of 55,914] from 2004 to 2016, p < 0.001). IO treatment was associated with significantly better 5-year survival in the entire cohort (36.9% versus 23.4%, p < 0.001) and the subsets of patients treated with chemoradiation (37.2% versus 22.7%, p < 0.001) and surgery (48.6% versus 44.3%, p < 0.001). Pneumonectomy use decreased with increased IO treatment (5.1% of surgical patients [116 of 2266] from years 2017 to 2019 versus 9.2% [1127 of 12,300] from 2004 to 2016, p < 0.001). Conclusions: Increased use of IO was associated with a change in treatment patterns and improved survival for patients with stage IIIA(N2) NSCLC.