Prediction of Spread Through Air Spaces (STAS) By Intraoperative Frozen Section for Patients with cT1N0M0 Invasive Lung Adenocarcinoma: A Multi-Center Observational Study (ECTOP-1016).

OBJECTIVE: To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma. BACKGROUND: Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection. METHODS: We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections. RESULTS: This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Inter-observer agreement was substantial (κ=0.756) among the three pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. Additionally, true positive cases showed more high-grade histological patterns and more advanced p-TNM stages than false negative cases. CONCLUSIONS: This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed.

Long-Term Outcomes of Selected Patients with IIIA-N2 Non-small Cell Lung Cancer Receiving Upfront Surgical Resection.

BACKGROUND: Stage IIIA non-small cell lung cancer (NSCLC) is a diverse group that requires multimodality treatment. The aim of this study was to report the long-term outcomes for patients with IIIA-N2 disease. METHODS: We conducted a retrospective review of cases with IIIA-N2 (T1-2N2) NSCLC who underwent upfront surgery. Kaplan-Meier curves and Cox proportional hazard analyses were used to assess the impact of various variables on survival. RESULTS: A total of 475 patients were ultimately included. With a median follow-up time of 108 months, the 5- and 10-year overall survival (OS) rates were 42.2% and 27.7%, respectively. R0 resection was found to be associated with improved progression-free survival (PFS) and OS compared with R1/R2 resection (p = 0.041 for PFS; p = 0.015 for OS). Patients with single-station N2 disease demonstrated significantly better PFS and OS than those with multiple-station N2 disease (p < 0.001 for PFS; p = 0.002 for OS). Following surgical resection, adjuvant therapy was significantly correlated with prolonged PFS and OS compared with those patients without any treatment. However, there was no significant difference in PFS and OS between chemotherapy and radiochemotherapy (p = 0.915 for PFS; p = 0.287 for OS). Patients with EGFR exon 19 deletion had significantly improved OS compared with those with L858R (p = 0.040). CONCLUSIONS: Our study shows promising long-term outcomes for selected patients with stage IIIA-N2 NSCLC treated with upfront surgery followed by adjuvant therapy, especially those with R0 resection and single-station N2. This study sheds light on the potential management and treatment options for this challenging population.

Impact of Prior Cancer History on Outcomes of Resected Lung Cancer.

BACKGROUND: Previous studies concerning the impact of prior cancer on newly diagnosed lung cancer are mainly based on databases and obtained mixed results. Utilizing a large study population, we aimed to reveal this impact. PATIENTS AND METHODS: Lung cancer patients from January 2008 to April 2021 were enrolled. The Kaplan-Meier method was used to perform survival analyses. To investigate the impact of prior cancer, a Cox proportional hazards model was conducted. To minimize the influence of the heterogeneity of prior cancer, stratified analyses were carried out. RESULTS: In total, 17,423 lung cancer patients were reviewed, among which we identified 1469 (8.4%) patients with a history of prior cancer. Cox regression analysis revealed that prior cancer was an independent poor prognostic factor on overall survival (HR = 1.430, 95% CI: 1.147-1.784, p = 0.001) but did not affect lung cancer-specific survival (HR = 1.120, 95% CI: 0.876-1.434, p = 0.366). Interestingly, in further stratified analyses, we found that prior cancer history affected overall survival only in pTNM stage 0/I patients (HR = 1.670, 95% CI: 1.247-2.237, p = 0.001), but not in pTNM stage II/III/IV patients (HR = 1.237, 95% CI: 0.877-1.743, p = 0.226). Similarly, prior cancer was an independent poor prognostic factor on overall survival only for pN0 patients. Subsequently, subgroup analyses indicated that the impact of prior cancer varied in pTNM stage 0/I patients according to the type of prior cancer and the interval time. CONCLUSIONS: Considering that prior cancer affects overall survival in patients with clinically curable lung cancer, clinicians should pay attention to this effect and improve the management of these patients to achieve a better prognosis.

Prognostic Factors for Survival of Stage IB Non-small Cell Lung Cancer Patients: A 10-Year Follow-Up Retrospective Study.

BACKGROUND: This study aimed to determine the prognostic factors for the long-term outcome of stage IB non-small cell lung cancer (NSCLC). METHODS: Surgically resected patients with stage IB NSCLC diagnosed (based on TNM 8th edition) between April 2008 and December 2013 were retrospectively reviewed. The prognosis and possible risk factors among the stage IB NSCLC patients were evaluated. RESULTS: Of the 349 patients identified for the study, 80 (22.9%) received post-surgery adjuvant chemotherapy (ACT). The median follow-up time after surgery was 123.3 months. The 10-year overall survival (OS) rate was 69.6%, and the 10-year recurrence-free survival (RFS) rate was 62.8%. The patients in this cohort were divided into three groups (T1 with visceral pleural invasion [VPI], T2a without VPI, and T2a with VPI), and no significant differences in OS or RFS were found among the groups. Furthermore, survival analysis indicated that the absence of ground-glass opacity (GGO) components portends an adverse long-term OS and RFS. In a subgroup of patients with solid nodules, age older than 65 years (hazard ratio [HR] 1.987; 95% confidence interval [CI] 1.312-3.010; p = 0.001) and ACT (HR 0.392; 95% CI 0.225-0.684; p < 0.001) were independent prognostic factors for OS, whereas lymphovascular invasion (HR 1.792; 95% CI 0.995-3.227; p = 0.052) should be considered as an independent unfavorable prognostic factor for RFS. CONCLUSIONS: As an upstaging factor, VPI did not further stratify prognosis for the stage IB patients in our cohort. The presence of GGO components had a notable impact on a favorable prognosis in stage IB NSCLCs.

Distribution and concordance of PD-L1 expression by routine 22C3 assays in East-Asian patients with non-small cell lung cancer.

BACKGROUND: Currently, programmed death ligand-1 (PD-L1) expression has been widely applied in clinical trials and real-world clinical practice as a major biomarker for the efficacy of immune-checkpoint inhibitors. The purpose of this study is to reveal the distribution and concordance of PD-L1 expression in a large-scale consecutive cohort from East-Asian patients with non-small cell lung cancer (NSCLC). METHODS: PD-L1 testing was conducted using 22C3 assays, and cases were categorized into the high, low, and no expression of PD-L1 based on the tumor proportion score (TPS). Target-capture next-generation sequencing was used to identify molecular events. RESULTS: A total of 4550 patients and 4622 tests of PD-L1 expression were enrolled. There were 3017 (66.3%) patients with no PD-L1 expression (TPS < 1%), 1013 (22.3%) with low PD-L1 expression (TPS 1-49%), 520 (11.4%) with high PD-L1 expression (TPS ≥ 50%). Higher proportions of positive PD-L1 expression (TPS ≥ 1%) were observed in smokers, males, squamous cell carcinoma, and high-grade lung adenocarcinoma. Further analyses revealed fair agreement in primary and metastatic lesions (kappa = 0.533), poor agreement in multi-focal primary tumors (kappa = 0.045), and good agreement in biopsy and resection samples (kappa = 0.662) / two biopsy samples (kappa = 0.711). Mutational analyses revealed association between high PD-L1 expression (TPS ≥ 50%) and EGFR wild-type, KRAS mutation, ALK rearrangement, and TP53 mutation. CONCLUSION: The study reveals the unique distribution pattern of PD-L1 expression in a large-scale East-Asian cohort with NSCLC, the concordance of multiple PD-L1 tests, and the association between PD-L1 expression and molecular events. The results shed a light on the optimization of PD-L1 testing in clinical practice.

The Overlooked Cornerstone in Precise Medicine: Personalized Postoperative Surveillance Plan for NSCLC.

Non-small cell lung cancer recurrence after curative-intent surgery remains a challenge despite advancements in treatment. We review postoperative surveillance strategies and their impact on overall survival, highlighting recommendations from clinical guidelines and controversies. Studies suggest no clear benefit from more intensive imaging, whereas computed tomography scans reveal promise in detecting recurrence. For early-stage disease, including ground-glass opacities and adenocarcinoma in situ or minimally invasive adenocarcinoma, less frequent surveillance may suffice owing to favorable prognosis. Liquid biopsy, especially circulating tumor deoxyribonucleic acid, holds potential for detecting minimal residual disease. Clinicopathologic factors and genomic profiles can also provide information about site-specific metastases. Machine learning may enable personalized surveillance plans on the basis of multi-omics data. Although precision medicine transforms non-small cell lung cancer treatment, optimizing surveillance strategies remains essential. Tailored surveillance strategies and emerging technologies may enhance early detection and improve patients' survival, necessitating further research for evidence-based protocols.

Dissecting the clinicopathological, genomic, and prognostic significance of ALK rearrangement in resected lung adenocarcinoma.

OBJECTIVES: The ALINA trial introduced anaplastic lymphoma kinase (ALK) inhibitors in an early-stage context, generating notable interest. This study aims to investigate the characteristics and prognostic implications of ALK rearrangement in patients with resected lung adenocarcinoma (LUAD). METHODS: We retrospectively evaluated resected LUAD cases with documented ALK status from 2008 to 2020. The association between ALK positivity and clinicopathological characteristics, molecular profiles, and outcomes was explored. RESULTS: Among 4944 cases, 238 (4.8%) were ALK-positive, correlating with younger age and non-smokers. ALK positivity was also significantly associated with pure-solid nodules, spread through air spaces, and solid-predominant adenocarcinoma. ALK-positive tumors exhibited an overall low frequency of co-mutations (e.g., TP53, STK11). ALK positivity was associated with inferior recurrence-free survival (RFS) in stage I patients who did not receive adjuvant chemotherapy while with prolonged RFS in stage II and III patients who received adjuvant chemotherapy. Notably, six patients treated with adjuvant ALK inhibitors experienced no recurrence or metastasis during the follow-up period. Additionally, the administration of ALK inhibitors significantly improved post-recurrence survival in ALK-positive patients. CONCLUSIONS: ALK positivity was associated with specific aggressive pathological features and inferior RFS in stage I LUAD. ALK-positive patients seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.

Resected lung adenocarcinoma with lymph node metastasis: is ground glass opacity component a prognostic factor?

Background: Ground glass opacity (GGO)-featured lung adenocarcinoma generally has excellent prognosis, and here is rarely the occurrence of lymph node metastasis. We conducted a retrospective cohort study to explore the prognostic impact of GGO component in node-positive lung adenocarcinomas. Methods: A total of 669 patients with pathologic N1/N2 lung adenocarcinoma receiving R0 resection and systemic lymph node dissection from 2008 to 2015 were reviewed, including 635 solid and 34 part-solid lesions. Propensity score matching (PSM) was performed to compare survival outcomes of solid and part-solid lesions, in order to determine the prognostic value of GGO component. Cox proportional hazard model was performed to identify significant prognostic factors for resected node positive lung adenocarcinoma. Results: About 5.1% (34 of 669) of resected node-positive lung adenocarcinoma presented as part-solid nodules on computed tomography (CT) images in this cohort. The median nodule size on CT of the 34 part-solid lesions was 31 mm (range, 15-68 mm), median solid component size on CT was 24 mm (range, 12-62 mm), and median consolidation/tumor ratio was 0.8 (range, 0.64-0.95). After 1:4 PSM, 136 patients and 34 patients were matched from the solid and part-solid groups. No significant difference in either recurrence-free survival (RFS) (P=0.71) or overall survival (OS) (P=0.82) was found between the solid and part-solid groups. Multivariable Cox regression showed that pN stage was the strongest prognostic factor for RFS and OS. GGO component was not an independent prognostic factor toward for RFS [P=0.75; hazard ratio (HR) =0.93; 95% confidence interval (CI): 0.59-1.46] or OS (P=0.53; HR =1.19; 95% CI: 0.69-2.05). Conclusions: A minority of resected node-positive lung adenocarcinoma presents as GGO component on CT. The presence of GGO component does not predict better prognosis in node-positive lung adenocarcinoma.

Prognostic value of KRAS G12V mutation in lung adenocarcinoma stratified by stages and radiological features.

OBJECTIVE: KRAS G12V is one of the most common KRAS mutation variants in lung adenocarcinoma (LUAD), and yet its prognostic value is still unrevealed. In this study, we investigated the clinicopathologic characteristics and prognostic value of the KRAS G12V mutation in LUAD. METHODS: Data of 3829 patients who underwent LUAD resection between 2008 and 2020 were collected. Mutations were classified as wild-type, G12V, or non-G12V. The clinicopathologic characteristics, postoperative outcomes, and recurrence pattern were analyzed among groups. RESULTS: In total, 3554 patients were wild-type and 275 patients harbored a KRAS mutation: 60 patients with G12V (22.2%) and 215 patients with non-G12V (77.8%). The KRAS G12V mutation was more frequent in male patients, older patients (≥60 years), former/current smokers, those patients with radiologic solid nodules, and those with highly invasive histologic subtypes. Tumors carrying KRAS G12V mutation exhibited elevated programmed death-ligand 1 expression in comparison with wild-type tumors. KRAS G12V was more prevalent in older patients and had less lymphovascular invasion compared with other mutation types. FGF3, RET, and KDR co-mutations occurred more frequently in the KRAS G12V group. Multivariate analysis demonstrated that the KRAS G12V mutation was an independent prognostic factor in stage Ⅰ tumors, whereas the KRAS non-G12V mutation was not. KRAS G12V was associated with early recurrence and locoregional recurrence. CONCLUSIONS: The KRAS G12V mutation was associated with aggressive clinical-pathologic phenotype and early recurrence. To note, this mutation exhibited a significantly worse prognosis in patients with part-solid and stage Ⅰ lung adenocarcinoma. Meanwhile, the prognostic significance of KRAS G12C and G12V variants was comparable.

Systemic immune index predicts tumor-infiltrating lymphocyte intensity and immunotherapy response in small cell lung cancer.

Background: Despite recent progresses in immune checkpoint blockade (ICB) in small-cell lung cancer (SCLC), a lack of understanding regarding the systemic tumor immune environment (STIE) and local tumor immune microenvironment (TIME) makes it difficult to accurately predict clinical outcomes and identify potential beneficiaries from ICB therapy. Methods: We enrolled 191 patients with stage I-III SCLC and comprehensively evaluated the prognostic role of STIE by several quantitative measurements, and further integrate it with a local immune score system (LISS) established by eXtreme Gradient Boosting (XGBoost) machine learning algorithm. We also test the value of STIE in beneficiary selection in our independent advanced SCLC cohort receiving programmed cell death 1 ligand 1 (PD-L1) blockade therapy. Results: Among several systemic immune markers, the STIE as assessed by prognostic nutritional index (PNI) was correlated with disease-free survival (DFS) and overall survival (OS), and remained as an independent prognostic factor for SCLC patients [hazard ratio (HR): 0.473, 95% confidence interval (CI): 0.241-0.929, P=0.030]. Higher PNI score was closely associated with inflamed SCLC molecular subtype and local tumor-infiltrating lymphocytes (TILs). We further constructed a LISS which combined top three important local immune biomarkers (CD8+ T-cell count, PD-L1 expression on CD8+ T-cell and CD4+ T-cell count) and integrated it with the PNI score. The final integrated immune risk system was an independent prognostic factor and achieved better predictive performance than Tumor Node Metastasis (TNM) stages and single immune biomarker. Furthermore, PNI-high extensive-stage SCLC patients achieved better clinical response and longer progression-free survival (PFS) (11.8 vs. 5.9 months, P=0.012) from PD-L1 blockade therapy. Conclusions: This study provides a method to investigate the prognostic value of overall immune status by combining the PNI with local immune biomarkers in SCLC. The promising clinical application of PNI in efficacy prediction and beneficiary selection for SCLC immunotherapy is also highlighted.

Evolutionary proteogenomic landscape from pre-invasive to invasive lung adenocarcinoma.

Lung adenocarcinoma follows a stepwise progression from pre-invasive to invasive. However, there remains a knowledge gap regarding molecular events from pre-invasive to invasive. Here, we conduct a comprehensive proteogenomic analysis comprising whole-exon sequencing, RNA sequencing, and proteomic and phosphoproteomic profiling on 98 pre-invasive and 99 invasive lung adenocarcinomas. The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18, thus suppressing mitophagy and promoting cell invasion. Proteomics reveals diverse enriched pathways in normal lung tissues and pre-invasive and invasive adenocarcinoma. Proteomic analyses identify three proteomic subtypes, which represent different stages of tumor progression. We also illustrate the molecular characterization of four immune clusters, including endothelial cells, B cells, DCs, and immune depression subtype. In conclusion, this comprehensive proteogenomic study characterizes the molecular architecture and hallmarks from pre-invasive to invasive lung adenocarcinoma, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease.

Prediction of the pathological subtypes by intraoperative frozen section for patients with cT1N0M0 invasive lung adenocarcinoma (ECTOP-1015): a prospective multicenter study.

BACKGROUND: This study aims to assess the diagnostic accuracy of the intraoperative frozen section (FS) in determining the pathological subtypes among patients diagnosed with cT1N0M0 invasive lung adenocarcinoma. MATERIALS AND METHODS: This was a prospective, multicenter (seven centers in China) clinical trial of Eastern Cooperative Thoracic Oncology Projects (ECTOP-1015). Patients with cT1N0M0 invasive lung adenocarcinoma were enrolled in the study. Pathological images obtained from FS and final pathology (FP) were reviewed by at least two pathologists. The primary endpoint was the concordance between FS and FP diagnoses. The interobserver agreement for identifying pathological subtypes on FS was evaluated among three pathologists. RESULTS: A total of 935 patients were enrolled. The best sensitivity of diagnosing the predominant subtype was 78.2% in the evaluation of the acinar pattern. The presence of an acinar pattern diagnosed by FS was an independent factor for the concordance between FS and FP ( P =0.007, 95% confidence interval: 2.332-4.736). Patients with tumor size >2 cm measured by pathology showed a better concordance rate for the predominant subtype (81.6% vs. 74.6%, P =0.023). The presence of radiological ground glass opacity component did not affect the diagnosis accuracy of FS for the predominant subtype (concordance rate: 76.4% vs. 75.2%, P =0.687). Patients with ground glass opacity component showed better accuracy of the identification in the presence of lepidic pattern-predominant adenocarcinoma (82.1% vs. 71.0%, P =0.026). Substantial agreement between the FS diagnosis from three pathologists for the predominant pathological pattern was revealed with κ=0.846. CONCLUSIONS: This is the largest prospective trial evaluating FS diagnosing pathological subtype in cT1N0M0 invasive lung adenocarcinoma. A favorable concordance in the assessment of the pathological subtypes between FS and FP was observed, indicating the feasibility of utilizing accurate intraoperative pathological diagnoses from FS in guiding surgical strategies. A combination of radiology could improve the precision of FS.

Ten-Year Follow-up Results of Pure Ground-Glass Opacity-Featured Lung Adenocarcinomas After Surgery.

BACKGROUND: Previously, we have demonstrated that the 5-year recurrence-free survival after surgery of pure ground-glass opacity (GGO)-featured lung adenocarcinoma is 100%. This study aimed to reveal the long-term outcomes of these patients 10 years after surgery. METHODS: Lung adenocarcinoma patients who underwent surgery between December 2007 and December 2013 were reviewed. Patients with pure GGO-featured lung adenocarcinoma were enrolled. Postoperative survival and the risk of developing second primary lung cancer were analyzed. RESULTS: Overall, 308 cases of pure GGO-featured lung adenocarcinomas were included. Of these patients, 226 (73.4%) were female, 268 (87.0%) were nonsmokers, and 187 (60.7%) underwent sublobar resection. The median follow-up period after surgery was 112 months. The 10-year recurrence-free survival rate of these patients was 100%, and 10-year overall survival rate was 96.9%. Both 5-year and 10-year lung cancer-specific survival were 100%. There was no difference in 10-year recurrence-free survival rates between patients who underwent lobectomy or sublobar resection (P = .697). EGFR mutations were detected in 55.6% (84 of 151) of patients who underwent mutational analysis. The risk of developing secondary primary lung cancer for pure GGO-featured lung adenocarcinoma patients at 10 years after resection was 2.4%, and was not correlated with EGFR mutation status (P = .452). CONCLUSIONS: No recurrence was observed in patients with pure GGO-featured lung adenocarcinomas 10 years after surgery, even when pathologically evaluated as invasive adenocarcinoma. Pure GGO can be cured by surgery. Surgery is recommended for the appropriate time window with the view to cure. Our study emphasizes that radiologic pure GGO-featured lung adenocarcinomas should be distinguished from other lung adenocarcinomas.

Pregnancy may have little influence on ground-glass opacities suspected for lung adenocarcinoma.

PURPOSE: Owing to the popularity of low-dose computed tomography in lung cancer screening, young women spotted with ground-glass opacities (GGO) is a growing subgroup in clinical practice. We aim to investigate the influence of pregnancy on GGOs suspected for lung adenocarcinoma. METHODS: This retrospective study collected a series of female patients who were pregnant in follow-up of GGO lesions. The last CT images of GGO before pregnancy (CT1) and the first CT images after pregnancy (CT2) were reviewed to assess any radiologic change. Young female patients who were not pregnant in long-term (> 12 months) follow-up of GGO were enrolled as a comparison group. We also enrolled patients who gave birth within 2 years before surgical resection of GGOs. RESULTS: Four patients were enrolled according to the criteria. There was no significant change of the GGOs in all four patients with a median follow-up duration of 45.5 (range 17-86) months. Two patients were diagnosed pathologically to be minimally invasive adenocarcinoma, one was invasive adenocarcinoma and one did not underwent surgery. Six patients were enrolled in the comparison group and no significant change was witnessed in all the nodules. In those patients who gave birth within two years before surgical resection of GGOs, we found that the majority present as preinvasive lesions, and those with invasive adenocarcinomas were bigger in size and possess more solid component radiologically. CONCLUSION: Pregnancy seems to have little impact on GGOs suspected for lung adenocarcinoma. Therefore, pregnancy might be safely planned during the follow-up of GGOs.

Excellent survival of pathological N0 small cell lung cancer patients following surgery.

BACKGROUND: Current clinical guidelines recommend surgery only for cT1-2N0M0 small cell lung cancer (SCLC) patients. In light of recent studies, the role of surgery in the treatment of SCLC needs to be reconsidered. METHODS: We reviewed all SCLC patients who underwent surgery from November 2006 to April 2021. Clinicopathological characteristics were retrospectively collected from medical records. Survival analysis was performed by the Kaplan-Meier method. Independent prognostic factors were evaluated by Cox proportional hazard model. RESULTS: 196 SCLC patients undergoing surgical resection were enrolled. The 5-year overall survival for the entire cohort was 49.0% (95% CI: 40.1-58.5%). PN0 patients had significantly superior survival to pN1-2 patients (p < 0.001). The 5-year survival rate of pN0 and pN1-2 patients were 65.5% (95% CI: 54.0-80.8%) and 35.1% (95% CI: 23.3-46.6%), respectively. Multivariate analysis revealed that smoking, older age, and advanced pathological T and N stages were independently associated with poor prognosis. Subgroup analyses demonstrated similar survival among pN0 SCLC patients regardless of pathological T stages (p = 0.416). Furthermore, multivariate analysis showed factors, including age, smoking history, type of surgery, and range of resection, were not independently prognostic factors for the pN0 SCLC patients. CONCLUSION: Pathological N0 stage SCLC patients have significantly superior survival to pN1-2 patients, regardless of features, including T stage. Thorough preoperative evaluation should be applied to estimate the status of lymph node involvement to achieve better selection of patients who might be candidate for surgery. Studies with larger cohort might help verify the benefit of surgery, especially for T3/4 patients.

Clinical characteristics and progression of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET rearrangements: a retrospective cohort study.

Background: Patients harboring anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangements are usually diagnosed at a relatively late stage with nodal and distant metastasis, and rapid progression course of ALK/RET fusion-positive lung cancer were well-known. However, clinical characteristics and course of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET fusions are poorly described. Identifying patients with gene fusions at early stage may offer surgical options that could cure those patients. Methods: We retrospectively included patients with surgically resected pre-/minimally invasive lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations or ALK/RET rearrangements, and further compared the patient clinical characteristics, nodule natural course, and survival outcomes. Radiological characteristics including ground-glass component, cystic airspace, pleural attachment, etc. were specially assessed for this study. EGFR (exons 18-22) was detected by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the ALK/RET rearrangements. Lung cancer-specific survival (LCSS), relapse-free survival (RFS), and overall survival (OS) were all evaluated. Results: Of 238 patients with pre-/minimally invasive lung adenocarcinomas, 226 patients had EGFR mutations, 7 patients had ALK fusions, and 5 patients had RET fusions. Average age at surgery was 45.3 years for ALK/RET-positive group and 52.6 years for EGFR-positive group (P=0.049). Radiologically, among the 12 patients with ALK/RET fusions, the majority of lesions (10/12) manifested as mixed ground-glass opacities (mGGOs), which was significantly more prevalent when compared with patients with EGFR mutations (83.4% vs. 24.3%, P<0.001). Moreover, a substantial proportion of cystic airspace was found in ALK/RET-positive group but not in EGFR-positive group (66.7% vs. 14.2%, P<0.001). Among four patients with ALK/RET fusions undergoing surveillance over 1 year before surgery, two of them developed rapid radiologic progression. The 5-year LCSS and RFS were 100%, 100% for ALK/RET-positive group, and 100%, 100% for EGFR-positive group, respectively. Conclusions: ALK/RET-positive pre-/minimally invasive lung adenocarcinomas were mostly characterized as mGGOs with cystic airspace developing rapid nodule progression, and no recurrence occurred during long-term follow-up after resection. This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.

Tumor-derived Vimentin as a novel biomarker for distinct subtypes predicting adjuvant chemotherapy resistance and T-cell-inflamed phenotype in small cell lung cancer.

Despite recent progress in subtype classification for small cell lung carcinoma (SCLC), little is known about the biomarker for triple-negative (ASCL1, NEUROD1, and POU2F3 negative) tumors. The long-term survival, adjuvant chemotherapy (ACT) response, and immune milieu in different SCLC subtypes have also not been well established. Here, we retrospectively collected a large cohort of 192 primary SCLC tumors and reported that ASCL1-, NEUROD1- and POU2F3-dominant subtypes counted for 61.38%, 19.31%, and 6.21%, respectively. Subtype intra-tumoral heterogeneity and co-expression at the single-cell level existed substantially. The expression of tumor-derived Vimentin (VIM) was nearly restricted to triple-negative SCLC tumors (15/19, 78.9%) while YAP1 expression was distributed widely in other subtypes. The SCLC subtyping model was independently prognostic of OS and RFS (p <  0.001 and p = 0.043). In particular, patients with ASCL1-positive SCLC tumors can benefit more from ACT, and VIM-positive tumors did the opposite. Compared with other subtypes, the VIM-dominant SCLC subtype was associated with abundant but functionally impaired CD4+ and CD8+ T-cells, which highly expressed inhibitory checkpoints and potentially benefit from PD-L1 blockade therapy. Our study showed that tumor-derived SCLC-V subtype could independently predict ACT response. The distinct immune landscape between subtypes may help inform personalized immune therapeutic approaches.

Prognostic effect of ground-glass opacity in subcentimeter invasive lung adenocarcinoma.

Background: Although subcentimeter nodules represent precursor or minimally invasive lung cancer in most cases, there are still a few that are subcentimeter invasive adenocarcinoma (IAC). The aim of this study was to investigate the prognostic effect of ground-glass opacity (GGO) and the optimal surgical procedure in this special group. Methods: Patients with subcentimeter IAC were enrolled and were categorized into pure GGO, part-solid, and solid nodules based on the radiological appearance. Cox proportional hazards model and the Kaplan-Meier method were used for survival analyses. Results: A total of 247 patients were enrolled. Among them, 66 (26.7%) were in the pure-GGO group, 107 (43.3%) were in the part-solid group, and 74 (30.0%) were in the solid group. Survival analysis demonstrated a significantly worse survival in the solid group. Cox multivariate analyses confirmed that the absence of GGO component was an independent risk factor for worse recurrence-free survival (RFS) and overall survival (OS). As for surgical procedures, lobectomy did not provide a significant better RFS or OS than sublobar resection in the whole cohort or in a subgroup of patients with solid nodules. Conclusions: The radiological appearance stratified the prognosis of IAC with size of smaller than or equal to 1 cm. Sublobar resection may be feasible for subcentimeter IAC, even for those appearing as solid nodules; however, caution should be taken when applying wedge resection.