Identifying optimal surgical approach among T1N2-3M0 non-small cell lung cancer patients: a population-based analysis.

Background: Whether stage T1N2-3M0 non-small cell lung cancer (NSCLC) patients could benefit from surgery and the optimal surgical procedure have remained controversial and unclear. This study aimed to investigate whether stage T1N2-3M0 NSCLC can benefit from different surgery types and develop a tool for survival prediction. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with stage T1N2-3M0 NSCLC between 2000 and 2015. A 1:1 propensity score-matched (PSM) analysis was used to balance the distribution of clinical characteristics. Survival analyses were performed by using the Kaplan-Meier (KM) curves and Cox proportional hazards regression. All patients were randomly split at a ratio of 7:3 into training and validation cohorts. The nomogram was constructed by integrating all independent predictors for overall survival (OS) and cancer-specific survival (CSS). The model's performance was evaluated by discrimination, calibration ability, and risk stratification ability. Results: A total of 4,671 patients were enrolled. After 1:1 PSM, the distribution proportions of clinical characteristics in 1,146 patients were balanced (all P>0.05). The non-surgical approach was associated with worse survival compared with sublobectomy and lobectomy in the unmatched and matched cohorts. The multivariate Cox analysis showed that sublobectomy and lobectomy were both related to better OS and CSS rates compared with no surgery (P<0.001). Moreover, the results of subgroup analyses based on age, N stage, and radiotherapy or chemotherapy strategy were consistent. A total of 801 patients were included in the training cohort and 345 cases constituted the validation cohort. The nomogram constructed for the 1-, 3-, and 5-year OS and CSS prediction showed good discrimination, performance, and calibration both in the training and validation sets. Significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed (all P<0.001). Conclusions: Stage T1N2-3M0 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provides better survival benefits. We developed and validated nomograms, which could offer clinicians instructions for strategy making.

Prognostic factors of resectable anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients: a retrospective analysis based on a single center.

Background: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) exhibited a higher propensity for lymph node metastasis (LNM). This study aimed to investigate risk factors of occult lymph node metastasis (OLNM) and recurrence in resectable ALK-rearranged NSCLC patients. Methods: This retrospective analysis included patients with ALK-rearranged NSCLC receiving lung resections at Shanghai Pulmonary Hospital from June 2016 to August 2021. Logistic regression analysis was used to ascertain predictors of OLNM, and Cox regression analysis to identify risk factors of recurrence. Results: A total of 603 resectable ALK-rearranged NSCLC patients were included. The mean age was 55 years old. There were 171 patients (28.4%) pathologically confirmed to have LNM, 51.5% of which were occult. Logistic regression analysis identified clinical tumor size and computed tomography (CT) density as independent factors for OLNM. Cox regression analysis showed that pleural invasion and pathological tumor size were independent prognosticators for recurrence in pathologically nodal negative patients. Among pathologically nodal positive patients, adjuvant ALK-tyrosine kinase inhibitors (TKI) showed a similar recurrence-free survival (RFS) to chemotherapy (hazard ratio, 0.454; 95% confidence interval, 0.111-1.864). Conclusions: Assessing the potential risk of OLNM is required for ALK-rearranged NSCLC patients with large tumors characterized by high CT densities. Patients with large pathological tumor size or pleural infiltration should be closely monitored despite being pathologically nodal negative. Additionally, adjuvant ALK-TKI may present a comparable RFS to chemotherapy in pathologically nodal positive patients.

The impact of oncogenic driver mutations on neoadjuvant immunotherapy outcomes in patients with resectable non-small cell lung cancer.

BACKGROUND: Neoadjuvant immunotherapy has been demonstrated to be effective and safe in resectable non-small cell lung cancer (NSCLC) patients. However, the presence of different oncogenic driver mutations may affect the tumor microenvironment and consequently influence the clinical benefit from immunotherapy. METHODS: This retrospective study included consecutive NSCLC patients (stage IIA to IIIB) who underwent radical surgery after receiving neoadjuvant immunotherapy at a single high-volume center between December 2019 and August 2022. Pathological response and long-term outcomes were compared based on the driver oncogene status, and RNA sequencing analysis was conducted to investigate the transcriptomic characteristics before and after treatment. RESULTS: Of the 167 patients included in this study, 47 had oncogenic driver mutations. KRAS driver mutations were identified in 28 patients, representing 59.6% of oncogenic driver mutations. Of these, 17 patients had a major pathological response, which was significantly higher than in the non-KRAS driver mutation group (60.7% vs. 31.6%, P = 0.049). Multivariate Cox regression analysis further revealed that the KRAS driver mutation group was an independent prognostic factor for prolonged disease-free survival (hazard ratio: 0.10, P = 0.032). The median proportion of CD8+ T cells was significantly higher in the KRAS driver mutation NSCLCs than in the non-driver mutation group (18% vs. 13%, P = 0.030). Furthermore, immune-related pathways were enriched in the KRAS driver mutation NSCLCs and activated after immunotherapy. CONCLUSION: Our study suggests that NSCLC patients with KRAS driver mutations have a superior response to neoadjuvant immunotherapy, possibly due to their higher immunogenicity. The findings highlight the importance of considering oncogenic driver mutations in selecting neoadjuvant treatment strategies for NSCLC patients.

Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study.

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Multiparametric MRI for evaluation of pathological response to the neoadjuvant chemo-immunotherapy in resectable non-small-cell lung cancer.

OBJECTIVES: This study aimed to explore the predictive value of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and diffusion kurtosis imaging (DKI) quantitative parameters for the response to neoadjuvant chemo-immunotherapy (NCIT) in resectable non-small-cell lung cancer (NSCLC) patients, so as to provide a basis for clinical individualized precision treatment. METHODS: Treatment naive locally advanced NSCLC patients who enrolled in 3 prospective, open-label, and single-arm clinical trials and received NCIT were retrospectively analyzed in this study. Functional MRI imaging was performed at baseline and following 3 weeks of treatment as an exploratory endpoint to evaluate treatment efficacy. Univariate and multivariate logistic regressions were used to identify independent predictive parameters for NCIT response. Prediction models were built with statistically significant quantitative parameters and their combinations. RESULTS: In total of 32 patients, 13 were classified as complete pathological response (pCR) and 19 were non-pCR. Post-NCIT ADC, ΔADC, and ΔD values in the pCR group were significantly higher than those in the non-pCR group, while the pre-NCIT D, post-NCIT Kapp, and ΔKapp were significantly lower than those in non-pCR group. Multivariate logistic regression analysis demonstrated that pre-NCIT D and post-NCIT Kapp values were independent predictors for NCIT response. The combined predictive model, which consisted of IVIM-DWI and DKI, showed the best prediction performance with AUC of 0.889. CONCLUSIONS: The pre-NCIT D, post-NCIT parameters (ADC and Kapp) and Δ parameters (ΔADC, ΔD, and ΔKapp) were effective biomarkers for predicting pathologic response, and pre-NCIT D and post-NCIT Kapp values were independent predictors of NCIT response for NSCLC patients. CLINICAL RELEVANCE STATEMENT: This exploratory study indicated that IVIM-DWI and DKI MRI imaging would predict pathologic response of neoadjuvant chemo-immunotherapy in locally advanced NSCLC patients at initial state and early treatment, which could help make clinical individualized treatment strategies. KEY POINTS: • Effective NCIT treatment resulted in increased ADC and D values for NSCLC patients. • The residual tumors in non-pCR group tend to have higher microstructural complexity and heterogeneity, as measured by Kapp. • Pre-NCIT D and post-NCIT Kapp values were independent predictors of NCIT response.

Does the number of cycles of neoadjuvant therapy affect the efficacy of neoadjuvant chemoimmunotherapy for non-small cell lung cancer in locally advanced stage? Retrospective experience based on a single center.

BACKGROUND: The number of cycles of neoadjuvant therapy programmed cell death 1 (PD-1) inhibitor for locally advanced non-small cell lung cancer (NSCLC) remains controversial. METHODS: From October 2019 to March 2022, neoadjuvant chemoimmunotherapy followed by radical surgery for NSCLC patients with stage II-III were retrospectively reviewed in Shanghai Pulmonary Hospital. The radiologic response was assessed according to the Response Evaluation Criteria for Solid Tumors version 1.1. The major pathological response was defined as no more than 10% residual tumor. Student's t-test, chi-square test, and Mann-Whitney test were used for univariate analysis, logistic regression analysis was used for multivariate analysis. All statistical analyses were calculated by SPSS software (version 26). RESULTS: Among 108 patients, the number of patients who received 2-cycle (2-cycle group) and more than 2-cycle (>2-cycle group) neoadjuvant chemoimmunotherapy were 75 (69.4%) and 33 (30.6%), respectively. Compared with patients in the >2-cycle group, patients in the 2-cycle group had significantly smaller diagnostic radiological tumor size (37.0 mm vs. 49.6 mm, p = 0.022) and radiological tumor regression rate (36% vs. 49%, p = 0.007). However, no significant difference in pathological tumor regression rate was observed between patients in the 2-cycle group and >2-cycle group. Further logistic regression analysis demonstrated that the neoadjuvant chemoimmunotherapy cycle could independently affect the radiographic response (odds ratio [OR]: 0.173, 95% confidence interval [CI]: 0.051-0.584, p = 0.005) but not for pathological response (OR: 0.450, 95% CI: 0.161-1.257, p = 0.127). CONCLUSIONS: For patients diagnosed with stage II-III NSCLC, the number of neoadjuvant cycles administered can significantly influence the radiographic efficacy of chemoimmunotherapy.

Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing.

BACKGROUND: Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. METHODS: We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). RESULTS: Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. CONCLUSIONS: Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

The efficacy of neoadjuvant EGFR-TKI therapy combined with radical surgery for stage IIIB lung adenocarcinoma harboring EGFR mutations: A retrospective analysis based on single center.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could provide survival benefits for locally advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). However, the role of radical surgery for EGFR-TKI treated stage IIIB EGFRm NSCLC remains controversial. This study attempted to assess the feasibility of neoadjuvant EGFR-TKI followed by radical surgery for stage IIIB EGFRm NSCLC. Patients and Methods: Between 2013 and 2020, EGFRm lung adenocarcinoma (LUAD) patients in clinical stage IIIB undergoing neoadjuvant EGFR-TKI followed by surgery (T-S-Arm) and EGFR-TKI alone (T-Arm) were reviewed retrospectively in Shanghai Pulmonary Hospital (SPH). The chi-square test, Student's t-test or Fisher's exact test was performed for analysis of baseline characteristics. Progression-free survival (PFS) was estimated using the Kaplan-Meier analysis. Multivariate Cox regression analysis was used to identify independent predictors of progression. Results: A total of 43 patients were divided into T-S-Arm (n = 21) and T-Arm (n = 22). Patients were well-balanced between the two arms. The majority of patients were female (n = 25, 58.1%), non-smokers (n = 35, 81.4%), first-generation of EGFR-TKI treatment (n = 39, 90.7%), and exon 19 deletions (19-DEL) (n = 26, 60.5%). The median diagnostic age was 63.0 years [interquartile range (IQR), 54.0-67.5 years). At the cut-off date with June 30th 2022, median follow-up time was 28 months (IQR, 20-39 months). Neoadjuvant EGFR-TKI treatment followed by radical surgery could significantly improve the median PFS compared with patients underwent EGFR-TKI alone (23.0 months vs 14.5 months, P = 0.002). Multivariate Cox regression analysis demonstrated that radical surgery (T-S-Arm vs. T-Arm, HR: 0.406; 95% CI: 0.207-0.793, P = 0.027) was the only independent predictor for disease progression. The stratified analysis demonstrated patients with N2 disease could benefit from radical surgery (HR, 0.258; 95% CI, 0.107-0.618), especially for patients harboring L858R mutation (HR, 0.188; 95% CI, 0.059-0.604). Conclusions: For stage IIIB EGFRm NSCLC patients, the prognosis might be improved by neoadjuvant EGFR-TKI followed by radical surgery versus EGFR-TKI alone, especially for those with N2 disease and harboring L858R mutation.

The efficacy and safety of wedge resection for peripheral stage IA lung adenocarcinoma: a real-world study based on a single center.

Background: The effectiveness of segmentectomy for stage IA lung adenocarcinoma (IA-LUAD) has been well-documented. However, the efficacy and safety of wedge resection for peripheral IA-LUAD remains controversial. This study evaluated the feasibility of wedge resection in patients with peripheral IA-LUAD. Methods: Patients with peripheral IA-LUAD who underwent wedge resection by video-assisted thoracoscopic surgery (VATS) at Shanghai Pulmonary Hospital were reviewed. Cox proportional hazards modeling was performed to identify predictors of recurrence. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cutoffs of identified predictors. Results: A total of 186 patients (female/male, 115/71; mean age, 59.9 years) were included. Mean maximum dimension of consolidation component (MCD) was 5.6 mm, consolidation-to-tumor ratio (CTR) was 37%, and mean computed tomography value of tumor (CTVt) was -285.4 HU. With a median follow-up of 67 months (interquartile range, 52-72 months), the 5-year recurrence rate was 4.84%. Ten patients occurred recurrence postoperatively. No recurrence was observed adjacent to the surgical margin. Increasing MCD, CTR, and CTVt were associated with a higher risk of recurrence, with corresponding hazard ratios (HRs) of 1.212 [95% confidence interval (CI): 1.120-1.311], 1.054 (95% CI: 1.018-1.092), and 1.012 (95% CI: 1.004-1.019) with optimal cutoffs for predicting recurrence of 10 mm, 60%, and -220 HU, respectively. When a tumor had characteristics under these respective cutoffs, no recurrence was observed. Conclusions: Wedge resection can be considered to be a safe and efficacious management strategy for patients with peripheral IA-LUAD, especially for MCD less than 10 mm, CTR less than 60% and CTVt less than -220 HU.

Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial.

BACKGROUND: This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC). METHODS: Patient eligibility mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. RESULTS: In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). CONCLUSIONS: Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. TRIAL REGISTRATION: ChiCTR1900024014, June 22, 2019.

Efficacy evaluation of surgery combined with chemotherapy for stage IIIA small cell lung cancer patients: a retrospective analysis.

Background: The efficacy of surgery in combination of chemotherapy for stage IIIA small cell lung cancer (IIIA-SCLC) is controversial. The aim of the present study was to analyze the efficacy of surgery combined with chemotherapy, especially in the setting of neoadjuvant chemotherapy (NAC) followed by surgery for IIIA-SCLC. Methods: Between 2004 and 2015, we reviewed 2,199 chemotherapy-treated stage IIIA (N1/2) SCLC cases in the Surveillance, Epidemiology, and End Results (SEER) database, and 32 NAC + intentional radical resection-treated, centrally-located IIIA-SCLC cases at Shanghai Pulmonary Hospital (SPH). Outcomes were compared between surgically and non-surgically treated patients from the SEER database after propensity score matching (PSM), and comparing lobectomy/bi-lobectomy and pneumonectomy patients from SPH. Prognostic factors were evaluated by Kaplan-Meier method and the Cox proportional hazards regression model. Results: There was significantly higher overall survival (OS) in surgically treated IIIA-SCLC patients (OS, 44.8 vs. 21.2 months, P=0.048), and similar efficacy was observed between sub-lobectomy and lobectomy/bi-lobectomy patients (OS: 55.6 vs. 30.3 months, P=0.167) in SEER database. At SPH, significantly higher OS was associated with T1 stage (before NAC: T1 vs. T2-4, 48.7 vs. 32.2 months, P=0.025; after NAC: T1 vs. T2-4, 42.7 vs. 21.3 months, P=0.048). Female sex [hazard ratio (HR): 0.078, P=0.009], T1 stage (HR: 13.048, P=0.026), and pneumonectomy (HR: 0.095, P=0.009) were independent prognostic factors for IIIA-SCLC patients who received NAC + intentional radical resection. Conclusions: For stage IIIA SCLC patients, complete resection combined with chemotherapy might improve the prognosis than patients without surgery. Post-NAC lobectomy was not found to be superior to sub-lobectomy, while pneumonectomy was considered suitable for central-type IIIA-SCLC patients after NAC treatment.

The modification of T description according to visceral pleural invasion and tumor size from 3.1 cm to 4.0 cm in non-small cell lung cancer: A retrospective analysis based on the SEER database.

OBJECTIVES: As a poor prognostic factor, visceral pleural invasion (VPI) was incorporated into non-small cell lung cancer (NSCLC) staging system. For modifying the T description of NSCLC, the prognostic value of VPI was assessed. MATERIALS AND METHODS: From 2010-2015, data on stage pT2N0M0 NSCLC patients with tumor size (TS) from 3.1 cm to 5.0 cm who received surgery from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled retrospectively. Propensity score matching was utilized to balance the baseline factors according to different TS intervals. Overall survival (OS) was assessed by the Kaplan-Meier method and log-rank test. Univariate and multivariate analysis were applied to identify the prognostic factors. The risk factors of VPI were calculated by logistic regression model. RESULT: The sum of 4005 resected stage pT2N0M0 NSCLC patients with TS from 3.1 cm to 5.0 cm were recruited, which had 1084 patients with VPI and 2921 patients without VPI respectively. As TS interval of 3.1-4.0 cm, the 5-year OS of patients without VPI was significantly better than those with VPI (62.6 % vs 58.7 %, P = 0.015), while the 5-year OS of patients with VPI and TS interval of 3.1-4.0 cm had no significant difference compared with patients whose TS interval of 4.1-5.0 cm (58.7 % vs 58.8 %, P = 0.918). Logistic regressive analysis manifested that older age, female, worse differentiation grade and larger TS had higher incidence of VPI (OR = 1.01, 1.25, 1.25, 1.16, respectively; P < 0.05 for all). CONCLUSION: This study underlined the prognostic effect of VPI and suggested that early-stage NSCLC with VPI and TS interval of 3.1-4.0 cm could be appropriately upstaged from pT2a (stage pIB) to pT2b (modified stage pIIA).

Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significant benefits to patients with non­small cell lung cancer (NSCLC) harboring EGFR­activating mutations; however, acquired resistance limits their long­term efficacy. Therefore, it remains an urgent requirement to discover the underlying mechanisms and investigate novel therapeutic strategies for overcoming the resistance to EGFR TKIs. The present study aimed to determine the mechanism underlying the resistance of NSCLC cells to osimertinib, a third­generation EGFR tyrosine kinase inhibitor, the osimertinib­resistant NSCLC cell sub­line HCC827/OR was established in the present study. It was found that the expression levels of Bcl­2 and Bcl­xL were significantly upregulated in resistant cells compared with sensitive cells. Furthermore, the suppression of Bcl­2 and Bcl­xL through small interfering RNA­mediated gene knockdown or using a small molecule specific inhibitor ABT­263 re­sensitized HCC827/OR cells to osimertinib treatment. Moreover, the combined treatment of HCC827/OR cells with ABT­263 and osimertinib enhanced the rate of cell apoptosis through the mitochondrial apoptotic pathway. Finally, ABT­263 was able to overcome the resistance of osimertinib in xenograft tumor models. In conclusion, these findings may provide an improved concept for the development of a novel combined therapeutic strategy for the treatment of NSCLC resistance to EGFR TKIs.

Immunohistochemistry biomarker TP53 expression predicts the survival of thymomas.

BACKGROUND: Thymomas are rare malignancies. Thymectomy is the optimal therapy which could prolong the survival of patients. However, prognostic factors of thymomas are not clear. METHODS: Thymomas patients were enrolled from 2001 to 2016. Clinical and pathological prognostic factors of thymomas were evaluated by univariate and multivariate analyses. RESULTS: A total number of 98 patients was eligible for this study. All patients were received complete resection (CR). Diagnostic age [elder than the median 60 vs. younger than 60, hazard ratio (HR) =2.325, P=0.027], Masaoka stage (III vs. I, HR =10.756, P<0.001; IV vs. I, HR =6.558, P=0.014), and diabetes mellitus (DM) (with vs. without, HR =0.142, P=0.004) were independent prognostic factors for overall survival (OS). Immunohistochemistry (IHC) biomarker TP53 expression also influenced OS significantly (positive vs. negative, HR =5.157, P=0.018). Furthermore, age (elder than 60 vs. younger than 60, HR =2.980, P=0.022) was independent prognostic factors for recurrence free survival (RFS). CONCLUSIONS: We found that diagnostic age, clinical stages, DM, TP53 expression in IHC, and quality perioperative nursing are prognostic factors in thymomas.

18F-FDG PET/CT in lung adenosquamous carcinoma and its correlation with clinicopathological features and prognosis.

OBJECTIVE: Lung adenosquamous carcinoma (ASC) is a rare histological subtype of non-small cell lung cancer (NSCLC). Due to its rarity, the studies about 18F-FDG PET/CT in this kind of pulmonary tumor were quite limited. Thus, this study investigated 18F-FDG PET/CT findings in ASC and its correlation with clinicopathological features and clinical outcomes. METHODS: Preoperative 18F-FDG PET/CT findings and parameters of maximum standard uptake value (SUVmax), metabolic tumor volume and total lesion glycolysis of primary lesion (MTV-P, TLG-P), combination of primary lesion and metastases (MTV-C, TLG-C), and clinicopathological features were retrospectively investigated in patients with ASC. Moreover, progression-free survival (PFS) was also analyzed. RESULTS: All 41 patients (25 men; 16 women; age: 60 ± 7 years) had single ASC with the mean diameter of 33 ± 14 mm. Six lesions were located centrally and 35 peripherally. Serum tumor markers were abnormally increased sporadically. Twenty-two cases were at TNM stage I, 9 at II, and 10 at III. The primary tumors were FDG-avid in all cases, with the average SUVmax of 11.5 ± 6.0. SUVmax was significantly associated with tumor location, size, and TNM stage (P < 0.05). Forty-one lesions were subgrouped into 23 AC-predominant and 18 SCC-predominant lesions, and significant differences were observed for age, tumor size, and SUVmax in two groups (P < 0.05). The median PFS of 41 cases was 19 months, and 12-month and 24-month PFS rates were 72.1% and 36.1%, respectively. SUVmax, MTV-P, and TLG-C were significantly associated with PFS (P < 0.05). CONCLUSIONS: ASC of the lung displayed high SUVmax on 18F-FDG PET/CT, which was associated with tumor location, size, TNM stage, and predominant histologic component. Moreover, metabolic parameters of 18F-FDG PET/CT were independent prognostic factors of this rare lung malignancy.

Tracheo-bronchial adenoid cystic carcinoma: A retrospective study.

OBJECTIVES: Adenoid cystic carcinoma (ACC) of the trachea and bronchus is rare, representing 1% of all respiratory tract cancers. We presented our experiences in treating tracheal-bronchial ACC and the results of long-term surveillance. METHODS: We conducted a retrospective study of treating tracheo-bronchial ACC. From 2009 to 2014, 42 patients presented to our department. All of them received surgical resection and adjunctive therapy. RESULTS: R0 resections were achieved in 33 patients, whereas 15 patients whose lesions spread outside the tracheo-bronchial lumens. Nine patients had R1 resections followed by radiation and chemotherapy. The 5 year survival rate of R1 resection group showed no difference compared to the R0 resection group, but the 5 year disease-free survival rate showed difference in extra-lumenal invasion (ELI) and non-ELI group (P = 0.0357 < 0.05), although no difference was seen in the overall survival rate in these two groups. CONCLUSIONS: ACC of the trachea and bronchus is a rare and low-to-moderate grade malignant tumor. When the R0 resection is over risky or may cause mortal complication, the R1 resection with adjunctive therapy is acceptable for patients to obtain a promising prognosis, whereas pathological ELI is an adverse prognostic indicator.

Broncholithiasis: retrospect of 15 surgical treatment patients.

BACKGROUND: Broncholithiasis is a rare disease with life-threatening event. The purpose of this study was to describe our experience in patients with broncholithiasis managed by surgical treatment. METHODS: From May 2008 to November 2014, 15 patients were diagnosed with broncholithiasis in Shanghai Pulmonary Hospital. They all received surgical treatment. RESULTS: A total of 15 patients, including 2 males and 13 females, were identified with a median age of 54 years (range, 36 to 70 years). The indication for operation was the patients who had single symptom or several symptoms, such as persistent or recurrent cough, hemoptysis, chest pain etc. Furthermore, asymptomatic patients who were suspected of malignant were also surgically treated. Postoperative complications occurred in 4 patients (26.7%). Four patients (26.7%) had cough and/or hemoptysis after surgeries. Moreover, 1 patient recurrent (6.7%) with broncholithiasis appearing in a new location and 2 patients had the postoperative infection (13.3%). Thoracotomy was performed on 13 patients. In this group, 2 of them infected within 1 month after the surgery. The other 2 patients accepted video-assisted thoracic surgery (VATS) and 1 of them occurred recurrence 9 months after surgery. CONCLUSIONS: Surgical resection is a crucial and conventional treatment for broncholithiasis with low risk of mortality and morbidity. However, VATS is a new technique that makes patients have the potential of recurrence. Therefore, this paper suggests that thoracotomy is the best surgical treatment for patients of broncholithiasis who need to accept surgical treatment.

The secondary surgery provides significant benefits to recurrent thymoma: a retrospective analysis based on Surveillance, Epidemiology and End Results database.

BACKGROUND: Recurrent thymoma (RT) with appropriate therapies has acceptable survival. The role of secondary surgery for RT remains controversial. METHODS: Surgical treated thymoma patients were reviewed from Surveillance, Epidemiology and End Results database (SEER). Propensity score matching (PSM) was utilized to match baseline factors to balance secondary surgical treated RT and thymoma without recurrence (NRT). Univariate and multivariate analyses were performed to evaluate the role of secondary surgery for RT. RESULTS: According to analysis, 815 patients were NRT, and 185 were RT. Surgical treated RT had significantly better overall survival (OS) than conservative treated RT (P<0.001). Survival between surgical treated RT and NRT had no significant difference. Focused on surgical treated RT and NRT, after PSM, elder diagnostic age, advanced clinical stage, upgraded pathologic grade predicted worse OS (P<0.01, for all), whereas, secondary surgery for RT provided comparable outcomes to NRT. CONCLUSIONS: Masaoka stage I-III RT with secondary surgery causes acceptable outcomes compared to NRT. In addition, elder patients, advanced Masaoka stage, upgraded pathologic grade, and without PORT indicate significantly worse OS in thymoma.

The comparison of predictive factors regarding prognoses and invasion of thymic neuroendocrine tumors preoperatively and postoperatively.

BACKGROUND: Thymic neuroendocrine tumors (TNT), in the anterior mediastinum, are extremely rare diseases which have significantly poor prognoses. Studies have rarely provided conclusive evidence of the prognostic factors of TNT. Standard therapies have been controversial. METHODS: TNT patients (n=173) were enrolled from Surveillance, Epidemiology and End Results database (SEER). Univariate and multivariate analyses were utilized to evaluate predictive factors of prognoses. Logistic regression analysis was used to assess the plausible correlation between histological grade, and cancer invasion. Stratification analysis was used to evaluate the effectiveness of adjuvant therapies. RESULTS: According to our analysis, local Masaoka stage, surgery, radiotherapy, and non-chemotherapy predicted better overall survival (OS) (P<0.05, for all) in 173 TNT patients. We found that the higher the histological grade of the tumor, the greater the rate of metastasis (P<0.05). The focus was on 125 surgically treated patients, who were females with poor prognostic factors of OS, upgraded histological grade, and advanced Masaoka stage (P<0.01, for all). The effectiveness of radiotherapy treatments had discrepancies at different clinical stages. In the local stage, radiotherapy caused significantly worse OS (P=0.011), while in the advanced stage, patients demonstrated significantly better OS with this treatment (P=0.028). Chemotherapy caused worse OS, primarily, in females (P=0.028). CONCLUSIONS: Surgery, Masaoka stage, and adjuvant treatments were prognostic factors. With surgically treated TNT, gender, histological grade, and Masaoka stage predicted significantly worse OS. Chemotherapy decreased female patients' OS. Radiotherapy significantly promoted advanced and local advanced patients' OS; however, it decreased local stage patients' OS. Predicted TNT invasiveness significantly correlated with histological grade.

Thymoma size significantly affects the survival, metastasis and effectiveness of adjuvant therapies: a population based study.

BACKGROUND: Thymoma, though a rare tumor disease, is the most common tumor of the anterior mediastinum. However, tumor size, as a critical factor, has been underestimated. RESULTS: Age, advanced tumor stage, and preoperative radiotherapy were poor prognostic factors of overall survival (OS) and disease specific survival (DSS) (P < 0.05 for all). Besides, tumor size was significantly related to survival. The larger tumor size indicated the less OS and DSS (P < 0.001 for all). Multivariate analysis revealed elder age, advanced stage, larger size were independent adverse predictors for survival (P < 0.05 for all). Logistic analysis revealed larger tumor size had greater rate of metastasis (P < 0.001). In the group with tumors smaller than 90mm, chemotherapy was a negative predictive factor of DSS (P < 0.05 for all), and it significantly decreased OS especially with tumor sizes between 50 and 90 mm (P < 0.001). MATERIALS AND METHODS: A total of 1,272 thymoma patients were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Survival based on thymoma size and other characteristics of tumors were analyzed by univariate and multivariate analysis. Correlation between thymoma size and thymoma metastatic status was contributed by logistic regression analysis. The efficiency of adjuvant therapy was analysis by stratification analysis. CONCLUSIONS: Thymoma size could predict postoperative survival and guide chemotherapeutic regimens of patients. Larger tumor size indicated worse survival and higher metastatic rate. If thymoma is smaller than 90mm, traditional chemotherapy should be prohibited. While chemotherapy could be performed moderately when thymoma larger than 90 mm.