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Abstract Introduction The estimated dose of radiation to immune cells (EDRIC) has been shown to correlate with the overall survival (OS) of patients who receive definitive thoracic radiotherapy. However, the planning target volume (PTV) may be a confounding factor. We assessed the prognostic value of EDRIC for non-small cell lung cancer (NSCLC) in patients who underwent postoperative radiotherapy (PORT) with homogeneous PTV. Methods Patients with NSCLC who underwent PORT between 2004 and 2019 were included. EDRIC was computed as a function of the number of radiation fractions and mean doses to the lungs, heart, and remaining body. The correlations between EDRIC and OS, disease-free survival (DFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed using univariate and multivariate Cox models. Kaplan–Meier analysis was performed to assess the survival difference between low- and high-EDRIC groups. Results In total, 345 patients were analyzed. The mean EDRIC was 6.26 Gy. Multivariate analysis showed that higher EDRIC was associated with worse outcomes in terms of OS (hazard ratio [HR] 1.207, P = .007), DFS (HR 1.129, P = .015), LRFS (HR 1.211, P = .002), and DMFS (HR 1.131, P = .057). In the low- and high-EDRIC groups, the 3-year OS was 81.2% and 74.0%, DFS 39.8% and 35.0%, LRFS 70.4% and 60.5%, and DMFS 73.9% and 63.1%, respectively. Conclusions EDRIC is an independent prognostic factor for survival in patients with NSCLC undergoing PORT. Higher doses of radiation to the immune system are associated with tumor progression and poor survival. Organs at risk for the immune system should be considered during radiotherapy planning.

Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB), are recognized as promising predictors of prognoses and responses to immune checkpoint inhibitors (ICIs), despite insufficient sensitivity of single biomarker detection. This research aims to determine whether the combinatorial utility of longitudinal ctDNA with bTMB analysis could improve the prognostic and predictive effects. Methods: This prospective two-center cohort trial, consisting of discovery and validation datasets, enrolled unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) patients and assigned them to chemoradiotherapy (CRT) or CRT + consolidation ICI cohorts from 2018 to 2022. Blood specimens were collected pretreatment, 4 weeks post-CRT, and at progression to assess bTMB and ctDNA using 486-gene next-generation sequencing. Dynamic ∆bTMB was calculated as post-CRT bTMB minus baseline bTMB levels. Decision curve analyses were performed to calculate Concordance index (C-index). Results: One hundred twenty-eight patients were enrolled. In the discovery dataset (n = 73), patients treated with CRT and consolidation ICI had significantly longer overall survival (OS; median not reached [NR] vs 20.2 months; P < 0.001) and progression-free survival (PFS; median 25.2 vs 11.4 months; P = 0.011) than those without ICI. Longitudinal analysis demonstrated a significant decrease in ctDNA abundance post-CRT (P < 0.001) but a relative increase with disease progression. Post-CRT detectable residual ctDNA correlated with significantly shorter OS (median 18.3 months vs NR; P = 0.001) and PFS (median 7.3 vs 25.2 months; P < 0.001). For patients with residual ctDNA, consolidation ICI brought significantly greater OS (median NR vs 14.8 months; P = 0.005) and PFS (median 13.8 vs 6.2 months; P = 0.028) benefit, but no significant difference for patients with ctDNA clearance. Dynamic ∆bTMB was predictive of prognosis. Patients with residual ctDNA and increased ∆bTMB (∆bTMB > 0) had significantly worse OS (median 9.0 vs 23.0 months vs NR; P < 0.001) and PFS (median 3.4 vs 7.3 vs 25.2 months; P < 0.001). The combinatorial model integrating post-CRT ctDNA with ∆bTMB had optimal predictive effects on OS (C-index = 0.723) and PFS (C-index = 0.693), outperforming individual features. In the independent validation set, we confirmed residual ctDNA predicted poorer PFS (median 50.8 vs 14.3 months; P = 0.026) but identified more consolidation ICI benefit (median NR vs 8.3 months; P = 0.039). The combined model exhibited a stable predictive advantage (C-index = 0.742 for PFS). Conclusions: The multiparameter assay integrating qualitative residual ctDNA testing with quantitative ∆bTMB dynamics improves patient prognostic risk stratification and efficacy predictions, allowing for personalized consolidation therapy for LA-NSCLC.

Abstract Background The value of postoperative radiotherapy (PORT) for patients with non-small cell lung cancer (NSCLC) remains controversial. A subset of patients may benefit from PORT. We aimed to identify patients with NSCLC who could benefit from PORT. Methods Patients from cohorts 1 and 2 with pathological Tany N2 M0 NSCLC were included, as well as patients with non-metastatic NSCLC from cohorts 3 to 6. The radiomic prognostic index (RPI) was developed using radiomic texture features extracted from the primary lung nodule in preoperative chest CT scans in cohort 1 and validated in other cohorts. We employed a least absolute shrinkage and selection operator-Cox regularisation model for data dimension reduction, feature selection, and the construction of the RPI. We created a lymph-radiomic prognostic index (LRPI) by combining RPI and positive lymph node number (PLN). We compared the outcomes of patients who received PORT against those who did not in the subgroups determined by the LRPI. Results In total, 228, 1003, 144, 422, 19, and 21 patients were eligible in cohorts 1–6. RPI predicted overall survival (OS) in all six cohorts: cohort 1 (HR = 2.31, 95% CI: 1.18–4.52), cohort 2 (HR = 1.64, 95% CI: 1.26–2.14), cohort 3 (HR = 2.53, 95% CI: 1.45–4.3), cohort 4 (HR = 1.24, 95% CI: 1.01–1.52), cohort 5 (HR = 2.56, 95% CI: 0.73–9.02), cohort 6 (HR = 2.30, 95% CI: 0.53–10.03). LRPI predicted OS (C-index: 0.68, 95% CI: 0.60–0.75) better than the pT stage (C-index: 0.57, 95% CI: 0.50–0.63), pT + PLN (C-index: 0.58, 95% CI: 0.46–0.70), and RPI (C-index: 0.65, 95% CI: 0.54–0.75). The LRPI was used to categorize individuals into three risk groups; patients in the moderate-risk group benefited from PORT (HR = 0.60, 95% CI: 0.40–0.91; p = 0.02), while patients in the low-risk and high-risk groups did not. Conclusions We developed preoperative CT-based radiomic and lymph-radiomic prognostic indexes capable of predicting OS and the benefits of PORT for patients with NSCLC.

Abstract Background Consolidative thoracic radiotherapy (cTRT) has previously shown benefit to patients with extensive stage small cell lung cancer (ES‐SCLC) who respond to chemotherapy. However, the optimum dose of cTRT is unknown. The purpose of this randomized trial is to compare the efficacy of 45 Gy in 15 fractions with 30 Gy in 10 fractions cTRT in ES‐SCLC. Methods This phase III, multicenter, randomized trial is designed to evaluate the safety and efficacy of different cTRT dose in ES‐SCLC. Eligible patients with pathologically confirmed ES‐SCLC who responded to 4–6 cycles of etoposide plus cisplatin (EP) or carboplatin (EC) chemotherapy were randomized 1:1 to receive either 30 Gy in 10 fractions (standard dose) or 45 Gy in 15 fractions (high dose) cTRT. The primary endpoint is 2‐year overall survival (OS). Secondary endpoints include 2‐year progression‐free survival (PFS), 2‐year local control (LC) and treatment related toxicity as measured by adverse events according to the Common Terminology Criteria for Adverse Events (version 4.0). Discussion The present study is the first randomized phase III trial designed to evaluate the efficacy of higher versus lower dose cTRT in ES‐SCLC, providing evidence for future clinical practice in prolonging survival of patients with ES‐SCLC.

Objective: To optimize the extraction method of total flavonoids from Peony purpurea seeds with microwave-assisted deep eutectic solvent, and to investigate its antioxidant activity in vitro. Methods: Microwave-assisted technology using deep eutectic solvent as extraction solvent was used to extract total flavonoids from Paeonia rockii seeds. Single factorial experiments and response surface methodology optimized the extraction process. The in vitro antioxidant activity of the total flavonoids was evaluated in terms of the rate of scavenging of DPPH radicals and the rate of scavenging of hydroxyl radicals. Results: Under the deep eutectic solvent system with chloride as hydrogen bond acceptor and urea as hydrogen bond donor, the deep eutectic solvent system with a molar ratio of 1:3 and a water content of 41.80% (V/V) was optimal. The ratio of material to liquid was 1:19 g/mL, the power of the microwave was 110 W and the time of the microwave was 3.00 min. The total flavonoid yield from Paeonia rockii seeds was 1.76 mg/g. When the total flavonoid concentration of the extract was 80 μg/mL, the scavenging rate of DPPH reached 82.00%. And the scavenging rate of hydroxyl radicals was 42.10% when the total flavonoid concentration of the extract was up to 80 μg/mL. Conclusion: Microwave-assisted deep eutectic solvent extraction of total flavonoids from Paeonia rockii seeds has high content, antioxidant activity and DPPH free radical scavenging rate of more than 80%.

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis. It is still being explored in depth due to its complex molecular mechanisms of occurrence and development. Lipids play a crucial role in cells by participating in energy supply, biofilm formation, and signal transduction processes, and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors. More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning, progress, and treatment resistance. The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism. Therefore, we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer, and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer, as well as its significance in exploring potential therapeutic targets and biomarkers.

Abstract Background Radiotherapy‐induced esophagitis (RE) diminishes the quality of life and interrupts treatment in patients with non‐small cell lung cancer (NSCLC) undergoing postoperative radiotherapy. Dosimetric models showed limited capability in predicting RE. We aimed to develop dosiomic models to predict RE. Methods Models were trained with a real‐world cohort and validated with PORT‐C randomized controlled trial cohort. Patients with NSCLC undergoing resection followed by postoperative radiotherapy between 2004 and 2015 were enrolled. The endpoint was grade ≥2 RE. Esophageal three‐dimensional dose distribution features were extracted using handcrafted and convolutional neural network (CNN) methods, screened using an entropy‐based method, and selected using minimum redundancy and maximum relevance. Prediction models were built using logistic regression. The areas under the receiver operating characteristic curve (AUC) and precision‐recall curve were used to evaluate prediction model performance. A dosimetric model was built for comparison. Results A total of 190 and 103 patients were enrolled in the training and validation sets, respectively. Using handcrafted and CNN methods, 107 and 4096 features were derived, respectively. Three handcrafted, four CNN‐extracted and three dosimetric features were selected. AUCs of training and validation sets were 0.737 and 0.655 for the dosimetric features, 0.730 and 0.724 for handcrafted features, and 0.812 and 0.785 for CNN‐extracted features, respectively. Precision‐recall curves revealed that CNN‐extracted features outperformed dosimetric and handcrafted features. Conclusions Prediction models may identify patients at high risk of developing RE. Dosiomic models outperformed the dosimetric‐feature model in predicting RE. CNN‐extracted features were more predictive but less interpretable than handcrafted features.

Objectives: To investigate the health-related quality of life (HRQL) of long-term survivors of inoperable esophageal squamous cell carcinoma (ESCC) treated with definitive radiation therapy, the real-world trends in the use of advanced radiation techniques, and their impact on the survival outcomes of ESCC patients. Methods: In this multicenter retrospective observational study, the medical records related to demographics and treatment of ESCC patients who were treated with definitive radiation therapy at 14 provincial hospitals in China from 1 January 2015 to 31 December 2016 were analyzed. A HRQL questionnaire was completed by survivors and collected by doctors at the final follow-up. The difference in quality of life between patients with or without recurrence was compared using the Wilcoxon–Mann–Whitney test. Overall survival (OS) was estimated using the Kaplan–Meier method and the group differences were assessed by unstratified log-rank test. The Cox proportional hazards model with Efron's method of tie handling was used to calculate the risk factors for OS. Results: The data of a total of 3,308 patients were collected for this study, 248 were excluded because of missing data, and a final of 3,060 patients were included in the analysis. Most patients (2,901; 94.8%) received intensity-modulated radiotherapy (IMRT)/volumetric-modulated arc therapy (VMAT)/tomotherapy (TOMO). The 5-year OS rate was 30%. Patients who received either two-dimensional radiotherapy (2DRT; HR, 2.43 [95% CI, 1.70–3.47]; P 80% patients did not experience weight loss. Nearly 80% patients found life very enjoyable or were fairly enjoying life. Conclusions: This large, multicenter retrospective study on ESCC patients who received definitive radiation therapy found that most ESCC survivors are satisfied with their quality of life. Most patients received advanced radiation technology. Patients who received either 2DRT or 3DRT had a significantly increased risk of death compared to those who received advanced radiation technology.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for locally advanced non-small-cell lung cancer (LA-NSCLC), whereas responses to anti-programmed cell death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) are heterogeneous. Though consolidation ICI following concurrent chemoradiotherapy (cCRT) improves survival of NSCLC, this regimen is challenging for patients with bulky tumors due to excessive target volumes and radiation-resistant hypoxia during upfront cCRT, leading to higher risk of pneumonitis and inferior local-regional control. Recent trials have demonstrated neoadjuvant ICI brought greater benefit to stage III than stage I-II NSCLC. Our previous study also supported the therapeutic advantage of 2-cycle induction ICI for patients with bulky unresectable stage III NSCLC. In the context of induction immunotherapy, radiotherapy is more likely to exert immune synergistic effects, reverse anti-PD-1 resistance, and activate abscopal immune responses. Prospective trials to determine the efficacy and safety of induction ICI for bulky LA-NSCLC are necessary.MethodsThis randomized, open-label, two-arm phase II study aims to explore whether 2 cycles of induction anti-PD-1 toripalimab plus chemotherapy can improve progression-free survival (PFS) in bulky LA-NSCLC. Bulky tumors are defined as primary lesion ≥5 cm in greatest dimension or metastatic lymph nodes ≥2 cm in shortest diameter. A total of 50 patients with bulky unresectable stage III NSCLC will be recruited and 1:1 randomized into the experimental arm: 2-cycle induction PD-1 inhibitor toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab; or control arm: 2-cycle induction chemotherapy followed by cCRT and consolidation toripalimab. Patients are stratified by pathology (squamous versus non-squamous). The primary endpoint is PFS. Secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and incidence of adverse events. Exploratory analyses include PD-L1 expression and liquid biopsy-based biomarker testing, tumor microenvironment profiling at single-cell levels, and quality-of-life assessments.DiscussionThe InTRist study is the first randomized phase II trial to investigate the feasibility of induction anti-PD-1 toripalimab plus chemotherapy followed by cCRT and consolidation toripalimab in bulky LA-NSCLC, providing novel evidence for the synergistic strategy combining anti-PD-1 blockade with radiotherapy to prolong immunotherapy benefits, overcome resistance, and enhance abscopal immune response.Clinical trial registrationClinicalTrials.gov, identifier NCT05888402.

Abstract Background Gadolinium-based nanoparticles (GdNPs) are clinically used agents to increase the radiosensitivity of tumor cells. However, studies on the mechanisms and biological modeling of GdNP radio-enhancement are still preliminary. This study aims to investigate the mechanism of radio-enhancement of GdNPs for kilovoltage photons using Monte Carlo (MC) simulations, and to establish local effect model (LEM)-based biological model of GdNP radiosensitization. Methods The spectrum and yield of secondary electrons and dose enhancement around a single GdNP and clustered GdNPs were calculated in a water cube phantom by MC track-structure simulations using TOPAS code. We constructed a partial shell-like cell geometry model of pancreatic cancer cell based on transmission electron microscope (TEM) observations. LEM-based biological modeling of GdNP radiosensitization was established based on the MC-calculated nano-scale dose distributions in the cell model to predict the cell surviving fractions after irradiation. Results The yield of secondary electrons for GdNP was 0.16% of the yield for gold nanoparticle (GNP), whereas the average electron energy was 12% higher. The majority of the dose enhancement came from the contribution of Auger electrons. GdNP clusters had a larger range and extent of dose enhancement than single GdNPs, although GdNP clustering reduced radial dose per interacting photon significantly. For the dose range between 0 and 8 Gy, the surviving fraction predicted using LEM-based biological model laid within one standard deviation of the published experimental results, and the deviations between them were all within 25%. Conclusions The mechanism of radio-enhancement of GdNPs for kilovoltage photons was investigated using MC simulations. The prediction results of the established LEM-based biological model for GdNP radiosensitization showed good agreement with published experimental results, although the deviation of simulation parameters can lead to large disparity in the results. To our knowledge, this was the first LEM-based biological model for GdNP radiosensitization.

Abstract Introduction This study aims to compare the real‐world effectiveness and safety of Endostar in combination with chemotherapy in the treatment of advanced non‐small cell lung cancer (NSCLC) in different age groups. Methods Electronic medical records of patients with NSCLC who received Endostar combined with chemotherapy from June 2012 to August 2019 in 7 cancer centers were retrospectively collected. Baseline characteristics before and after propensity score matching (PSM), effectiveness evaluation, and safety data of two age groups were analyzed. Tumor response was evaluated according to RECIST v1.1. Adverse events (AEs) were graded according to NCI‐CTCAE 5.0. Results In this study, 554 and 571 patients were assigned to ≤60 years non‐aged group and >60 years aged group, respectively. After propensity score matching (PSM) was introduced, 166 patients in each age group were analyzed. The median PFS for the two groups was 8.9 and 8.0 months, with the overall response rate was 24.7% and 26.5% (p = 0.7060), disease control rate was 64.5% versus 68.7% (p = 0.4600), respectively. Cox regression result showed that advanced age has no significant influence on PFS (hazard ratio = 1.02, 95% CI: 0.98−1.06, p = 0.3034) in contrast with younger patients. The most common AEs in both age groups were myelosuppression, gastrointestinal reactions, and hepatic impairment. The total incidence for the above AEs in the two groups was 18.67% versus 24.10%, 22.89% versus 21.69%, 12.05% versus 7.23%, with no statistically significant difference. Conclusion Compared with treating patients with NSCLC younger than 60 years old, the effectiveness of Endostar combined with chemotherapy in treating advanced patients showed no significant differences, with tolerable adverse events.

Objective: To investigate the optimal management of patients with epidermal growth factor receptor gene (EGFR) mutant locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Patients with unresectable stage III lung adenocarcinoma (LAC) harboring EGFR mutations from 2012 to 2018 were analyzed retrospectively, and were categorized into three groups according to the primary treatment: chemoradiotherpy (CRT) (group 1), combined radiation therapy (RT) and EGFR-tyrosine kinase inhibitors (TKI) with/without chemotherapy (group 2), and EGFR-TKI alone until tumor progression (group 3). Inverse probability of multiple treatment weighting (IPTW) of propensity score was used to compare overall survival (OS) and progression free survival (PFS) between treatments and account for confounding. Results: A total of 104, 105, and 231 patients were categorized into groups 1, 2, and 3, respectively. After IPTW adjustment, the median PFS for each group was 12.4, 26.2, and 16.2 months (log-rank P < 0.001), and the median OS was 51.0, 67.4 and 49.3 months (log-rank P = 0.084), respectively. Compared with those in group 1, patients in group 2 had significantly improved PFS [adjusted hazard ratio HR (aHR), 0.40; 95% confidence interval (CI): 0.29, 0.54; P < 0.001] and OS (aHR, 0.61; 95% CI: 0.38, 0.98; P = 0.039). Patients in group 3 had prolonged PFS (aHR, 0.66; 95% CI: 0.50, 0.87; P = 0.003), but not OS (aHR, 0.90; 95% CI: 0.62, 1.32; P = 0.595). Doubly robust IPTW analysis and multivariable Cox regression analysis yielded similar findings. Conclusions: EGFR-TKIs after chemoradiation or combined with radiation alone correlated with the longest PFS and OS (versus CRT or TKIs alone) in patients with EGFR-mutant unresectable LA-NSCLC. Well-designed prospective trials were warranted.

Purpose: Cardiopulmonary toxic effects may reduce the efficacy of postoperative radiation therapy (PORT) in patients with non-small cell lung cancer (NSCLC). However, few studies have examined whether the heart and lung doses affect overall survival (OS). We investigated the correlation of heart and lung doses with OS in patients with NSCLC undergoing PORT. Methods and Materials: This retrospective analysis included 307 patients with NSCLC undergoing PORT. The total dose was 50 Gy. Landmark analyses were performed at 36 months, with hazard ratios (HRs) calculated separately for events occurring up to 36 months (early survival) and after 36 months (long-term survival). Stabilized inverse probability of treatment weighting (sIPTW) was performed to balance the characteristics of the high- and low-dose groups. We performed sensitivity analyses at 24 and 48 months. Results: The median follow-up period was 67.42 months. Heart doses were significantly correlated with long-term survival (HR, 1.14; P = .015) but not with early survival (HR, 0.97; P = .41) or whole survival (HR, 1.02; P = .58). Lung doses were marginally significantly correlated with early survival (HR, 1.03; P = .07) but not with long-term survival (HR, 1.00; P = .85) or whole survival (HR, 1.02; P = .12). Higher heart and lung doses were associated with decreased long-term and early survival, respectively, before and after sIPTW. Landmark analyses at 24 and 48 months showed consistent results. Conclusions: For patients with NSCLC undergoing PORT, a higher heart dose was associated with decreased long-term survival, whereas a higher lung dose was associated with decreased early survival.

Abstract Objectives Whether curative‐intent radiotherapy could be safely applied to lung cancer patients with interstitial lung diseases (ILD) remains unclear. We aim to evaluate radiation induced lung toxicities (RILTs) and the efficacy of intensity‐modulated radiotherapy (IMRT) in these patients. ILD is characterized by inflammation or fibrosis in the interstitial tissue of the lung. Materials and Methods Stage III non–small cell lung cancer (NSCLC) and ILD patients treated with curative‐intent IMRT between 2010 and 2019 were retrospectively reviewed. Pre‐radiation computed tomography (CT) was scored according to a thin‐section CT scoring system for idiopathic pulmonary fibrosis. Results A total of 85 of 1261 stage III NSCLC patients were found with ILD. Seventeen (20%) of them developed G3+ (greater than or equal to grade 3) RILTs. The incidence abruptly dropped to 11.1%, 3.8%, and 0% for patients with honeycombing score ≤1, V20 1 and V20 ≥20% were independently associated with higher risk of G3+ RILTs. The median overall survival (OS) and progression‐free survival (PFS) were 14.0 months and 7.4 months in the whole group, whereas 26.5 months and 10.6 months in the low‐risk group (patients with honeycombing score 1 and V20 ≥20% were associated with high incidence of RILTs. However, patients with low risk might benefit from IMRT with acceptable toxicities and durable OS.

Abstract Recombinant human endostatin (Endostar) plus vinorelbine/cisplatin (NP) had been approved for the treatment of non-small cell lung cancers (NSCLC). But the real-world treatment pattern and effectiveness of Endostar plus other combination chemotherapy, namely docetaxel/platinum (DP), gemcitabine/platinum (GP), pemetrexed/platinum (PP), and paclitaxel/platinum (TP) in both treatment-naïve and re-treatment patients with advanced NSCLC were still unclear. A retrospective observational study was conducted based on the electronic medical record (EMR) system and advanced patients with NSCLC were identified from 7 cancer hospitals in China from 2012 to 2019. These patients were divided into five groups, Endostar plus NP, Endostar plus DP, Endostar plus GP, Endostar plus PP, and Endostar plus TP groups. The disease control rate (DCR), overall response rate (ORR), and the progression-free survival (PFS) were evaluated. Of the eligible 512 advanced patients with NSCLC, 10.35% were in Endostar plus NP group, while the numbers were 15.43%, 32.42%, 26.56%, 15.23% in Endostar plus DP group, Endostar plus GP group, Endostar plus PP group, and Endostar plus TP group, respectively. The ORRs were 31%, 28%, 22%, 41% and 27%, and the DCRs were 71%, 72%, 57%, 72% and 76%, respectively. The median of PFSs for the above groups were 7.9, 6.8, 5.6, 13.7, and 5.4 months. Compared with Endostar plus NP group, the hazard ratios (HRs) and 95%CIs of Endostar plus other chemotherapy were 1.86 (0.75–4.61), 2.15 (0.83–5.60), 1.33 (0.51–3.44), and 2.42 (0.86–6.81). This real-world study found the effectiveness of Endostar plus DP, Endostar plus GP, Endostar plus PP, and Endostar plus TP were of no statistically significant differences compared with Endostar plus NP and reflected the good effectiveness of Endostar plus different chemotherapy in advanced patients with NSCLC.

Background: Systematic inflammation is believed to play a crucial role in tumorigenesis and metastasis. This study aims at evaluating the prognostic value of time-series behavior of systematic inflammation-immune status before and after definitive chemoradiotherapy (dCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Methods: The relationship between systematic inflammation-immune score (SIS, defined as pretreatment peripheral platelet count × neutrophil count/lymphocyte count) and the prognosis was tested in a retrospective study of 386 consecutive LA-NSCLC patients (Group A) with pretreatment SIS and 161 patients (Group B) with SIS before and one month after the dCRT. Results: SIS of 1400 × 109 was found to be an optimal cutoff point to stratify the patients into high (>1400 × 109) and low (≤1400 × 109) SIS groups. Univariate and multivariate analyses revealed that the SIS, whether before or after dCRT, was an independent predictor for overall survival (OS), progress-free survival (PFS), and distant metastasis-free survival (DMFS). High SIS (>1400 × 109) was shown to predict poor 3-year OS (P=0.006, hazard ratio [HR]=2.427), PFS (P=0.001, HR=2.442) and DMFS (P=0.015, HR=2.119). However, SIS was not related to local regional recurrence-free survival in either Group A (P=0.346) or Group B (P=0.486). Further, the area under the receiver operating characteristic curve of the SIS for OS was higher than the neutrophil count/lymphocyte count ratio, platelet count/lymphocyte count ratio, and other conventional clinic-pathological indices. Conclusions: The SIS is a stable and more sensitive survival predictor than other inflammation-based factors and conventional clinical indices, which may aid in more accurately stratifying patients for risk assessment and treatment decisions.

Abstract Background Esophageal squamous cell carcinoma (ESCC) has unfavorable outcomes with the highest incidence seen in China. Accordingly, exploring effective molecular biomarkers is of great value. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and modulate numerous biological processes in tumors. Our study aimed to identify prognostic miRNAs and investigate their role in ESCC. Methods Prognosis-related plasma miRNAs were detected by miRNA microarray and qRT-PCR. Functional assays and molecular mechanism studies were used to investigate the role of miRNA in ESCC. Results Over-expression of miR-323a-3p was associated with a favorable prognosis. MiR-323a-3p negatively regulated proliferation, migration, and invasion. Through biological predictions, the fragile X mental retardation 1 (FMR1) was found to be a potential target of miR-323a-3p. Further investigation revealed that miR-323a-3p directly targeted and suppressed FMR1. MiR-323a-3p and FMR1 mRNA, as well as miR-323a-3p and the FMR1-encoded protein FMRP, showed negative correlations. Luciferase activity of FMR1-3′-UTR, but not mutant counterparts, was decreased by mimic compared with that of the control. The compromised cell proliferation, migration, and invasion induced by transfection with miR-323a-3p mimic were rescued by transfection with a FMR1 expression plasmid. Tumors induced by miR-323a-3p overexpressed ESCC cells grew significantly slower in vivo and resulted in smaller tumor masses. Metastatic lung colonization was also inhibited by miR-323a-3p overexpression. Conclusions MiR-323a-3p was significantly associated with survival and acted as a tumor suppressor by inhibiting proliferation, migration, and invasion via the regulation of FMR1. MiR-323a-3p is a promising biomarker and may be a potential therapeutic target.

Abstract Background This study aimed to establish a predictive nomogram integrating epidermal growth factor receptor (EGFR) mutation status for 3‐ and 5‐year overall survival (OS) in unresectable/inoperable stage III non‐small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. Methods A total of 533 stage III NSCLC patients receiving chemoradiotherapy from 2013 to 2017 in our institution were included and divided into training and testing sets (2:1). Significant factors impacting OS were identified in the training set and integrated into the nomogram based on Cox proportional hazards regression. The model was subject to bootstrap internal validation and external validation within the testing set and an independent cohort from a phase III trial. The accuracy and discriminative capacity of the model were examined by calibration plots, C‐indexes and risk stratifications. Results The final multivariate model incorporated sex, smoking history, histology (including EGFR mutation status), TNM stage, planning target volume, chemotherapy sequence and radiation pneumonitis grade. The bootstrapped C‐indexes in the training set were 0.688, 0.710 for the 3‐ and 5‐year OS. For external validation, C‐indexes for 3‐ and 5‐year OS were 0.717, 0.720 in the testing set and 0.744, 0.699 in the external testing cohort, respectively. The calibration plots presented satisfying accuracy. The derivative risk stratification strategy classified patients into distinct survival subgroups successfully and performed better than the traditional TNM staging. Conclusions The nomogram incorporating EGFR mutation status could facilitate survival prediction and risk stratification for individual stage III NSCLC, providing information for enhanced immunotherapy decision and future trial design.

The application of metal nanoparticles (MNPs) as sensitization materials is a common strategy that is used to study dose enhancement in radiotherapy. Recent in vitro tests have revealed that magnetic gold nanoparticles (NPs) can be used in cancer therapy under a magnetic field to enhance the synergistic efficiency in radiotherapy and photothermal therapy. However, magnetic gold NPs have rarely been studied as sensitization materials. In this study, we obtained further results of the sensitization properties of the magnetic gold NPs (Fe3O4@AuNPs) with or without magnetic field using the TOPAS-nBio Monte Carlo (MC) toolkit. We analyzed the properties of Fe3O4@AuNP in a single NP model and in a cell model under monoenergetic photons and brachytherapy, and we investigated whether the magnetic field contributes to the physical sensitization process. Our results revealed that the dose enhancement factor (DEF) of Fe3O4@AuNPs was lower than that of gold nanoparticles (AuNPs) in a single NP and in a cell irradiated by monoenergetic photons. But it’s worth mentioning that under a magnetic field, the DEF of targeted Fe3O4@AuNPs in a cell model with a clinical brachytherapy source was 22.17% (cytoplasm) and 6.89% (nucleus) higher than those of AuNPs (50 mg/mL). The Fe3O4@AuNPs were proved as an effective sensitization materials when combined with the magnetic field in MC simulation for the first time, which contributes to the research on in vitro tests on radiosensitization as well as clinical research in future.

ObjectiveHigh activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.Materials and methodsSystemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration.ResultsIn 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079).ConclusionFavorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.

PurposeWhilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer.Methods and MaterialsFrom January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables.ResultsWith a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004).ConclusionsTreatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.

Abstract Background Concurrent epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) with radiotherapy in patients with EGFR‐mutant unresectable stage III non‐small cell lung cancer (NSCLC) might improve survival. However, both treatments carry a potential risk of pneumonitis. Methods Between May 2012 and December 2017, patients with unresectable stage III NSCLC treated with concurrent radiotherapy and EGFR‐TKI were enrolled in this retrospective study. The baseline characteristics were evaluated to determine correlations with toxicity development. Results Among 45 eligible patients, 20 (44.4%) had an EGFR mutation and 44 (97.8%) received 50–66 Gy of radiotherapy. The median follow‐up was 62.7 months. The median progression free survival (PFS) and overall survival (OS) for patients with EGFR‐mutations were 27.9 (95% CI: 18.7–37.2) and 49.7 (95% CI: 27.7–71.8) months, and 13.8 (95% CI: 8.8–18.9) and 31.1 (95% CI: 9.8–52.4) months for EGFR wild‐type/unknown patients. A total of 17 patients (37.7%) developed radiation pneumonitis/pneumonitis (14 grade 2, 3 grade 3). In 16 patients, pneumonitis occurred within the radiation field and one patient had bilateral pneumonitis. The median time from the initial radiotherapy to pneumonitis was 74 days. Logistic regression analysis revealed a trend between the time of EGFR‐TKI and the development of G2+ pneumonitis. For late toxicity, only two patients had G2+ fibrosis. The daily dyspnea symptoms of patients with G2+ pneumonitis recovered significantly after the phase of pneumonitis (P = 0.007). Conclusions Combined EGFR‐TKI and radiotherapy showed favorable survival in EGFR‐mutant patients with inoperable stage III NSCLC, with a 6.7% incidence of grade 3 radiation pneumonitis/pneumonitis, despite a higher incidence of mild‐to‐moderate radiation pneumonitis. Key points Significant findings of the study We evaluated the outcomes and radiation pneumonitis after EGFR‐TKI during interval radiotherapy. EGFR‐TKI plus radiotherapy increased survival in patients with EGFR‐mutant inoperable stage III NSCLC. The mild‐to‐moderate radiation pneumonitis incidence increased but no grade 4–‐5 adverse events occurred. What this study adds The combination of EGFR‐TKI and radiotherapy might carry a risk of pneumonitis; however, there are limited data concerning dose constraints. Our results showed a slightly higher incidence of mild or moderate radiation pneumonitis by strict dose limitation.

The passivation interfaces of GaN-based MIS-HEMTs with Si3N4 and ZrO2/Si3N4 bilayers were investigated through atomic resolution scanning transmission electron microscope–energy dispersive spectroscopy–differential phase contrast microscopy methods. It is found that the Si3N4/GaN interface exhibits atomic disorder fluctuation, and the GaN surface is discontinuous at the depth of 1–2 atomic layers. An oxide layer of ∼2 nm is formed at the ZrO2/GaN interface, and the GaN surface is atomically flat. Furthermore, the local minimum of the potential is located at the Si3N4/GaN interface, while it is distributed in the GaN side at the ZrO2/GaN interface. The electric field or potential distribution is affected by the crystal orientation of the polycrystalline ZrO2 layer. Finally, the difference in passivation mechanism is discussed.

Background The PACIFIC study has defined a new standard of care for patients with unresectable stage III non‐small cell lung cancer (NSCLC) in the form of immune checkpoint inhibitor (ICI) consolidation therapy. However, there is little specific data pertaining to the safety and efficacy of this approach in Chinese NSCLC patients. Methods This was a prospective multicenter cohort study. Between September 2018 and January 2020, patients with unresectable stage III NSCLC that had undergone chemoradiation therapy (CRT) and ICI consolidation treatment were enrolled in this study. The short‐term safety, tolerability, and efficacy of ICI combination with CRT were evaluated in these patients. Results Of the 20 Chinese patients eligible for inclusion, 17 (85.0%) underwent concurrent CRT treatment. In these patients, a median period of 40.5 days (range: 1–85 days) passed between the end of CRT and initiation of consolidation therapy. Pneumonitis occurred in 80.0% of patients, with seven (35.0%) being diagnosed with grade 1 pneumonitis and nine (45.0%) with grade 2 pneumonitis. No patients experienced grade 3 or higher pneumonitis or other ICI‐related toxicities. Lung V20 ≥ 20% was associated with higher grade 2 pneumonitis (77.8%; ≥20% vs. 18.2%;

Abstract Background The objectives of this study were to determine the objective effective response rate, survival, and safety of radiotherapy combined with gefitinib in patients with locally advanced non-small cell lung cancer (NSCLC) who were unfit for surgery or concurrent chemoradiotherapy. Methods The patients with the locally advanced NSCLC who were unfit to receive surgery or concurrent chemoradiotherapy, received thoracic intensity-modulated radiotherapy (IMRT) combined with gefitinib 250 mg daily. Results 29 patients were enrolled between July 2014 and March 2017. 28 patients was in the analysis. Of the 28 patients, 21 (75.0%) experienced a partial response, 5 (17.9%) had stable disease, and 2 (7.1%) experienced progression of disease. The objective response rate was 75.0%, and the disease control rate was 92.9%. The median follow-up time was 51 months. The disease progression showed in 25 (89.3%) patients, including local progression in 19 (67.9%) and distant metastasis in 16 (57.1%). The median overall survival and progression-free survival time (PFS) were 26 and 11 months, respectively. The 3-, 4-, 5-year survival rates were 39.0, 30.1 and 30.1%, respectively. The 3-, 4-, 5-year PFS rates were 14.3, 9.5 and 9.5%. Two patients developed grade 3 acute adverse events. Seven patients developed grade 2 acute irradiation pneumonitis, and there was no grade 3 acute irradiation pneumonitis. Conclusions For patients with locally advanced NSCLC who are not eligible for surgery or concurrent chemoradiotherapy, IMRT combined with gefitinib can improve the objective effective rate and is generally well-tolerated.

Abstract Background There is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial. Methods Patients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT). Results A total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0–1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078). Conclusions CCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings. Trial registration ClinicalTrials.gov registration number: NCT01494558 . (Registered 19 December 2011).

Background: EGFR tyrosine kinase inhibitor (TKI) is recommended as the first-line therapy for patients with EGFR-mutant metastatic non-small cell lung cancer (NSCLC). Yet, resistance often occurs in 1 year after therapy and most progressions occur at the initial sites of disease. Addition of local therapy to the first-line TKI therapy may delay the progression and provide survival benefit to the patients. Methods: From 2010 to 2017, metastatic NSCLC patients with EGFR activating mutations who received first-line TKI and relatively radical local therapy (RRLT) were reviewed. RRLT was defined as local curative therapy to the main site or any intensity of local therapy to all sites of disease. The Kaplan-Meier method and log-rank test were used for survival estimation and comparison. Results: A total of 45 patients were included in this retrospective study with a median follow-up of 48.0 months. The median progression-free survival (PFS) and overall survival (OS) was 17.0 months (95% confidence interval [CI]: 14.6-19.3) and 55.0 months (95% CI: 49.3-60.6), respectively. Univariate analysis indicated that age ⩽ 60 years ( P = .019), first-line TKI duration ⩾ 10 months ( P = .028), and accumulated TKI duration ⩾ 20 months ( P = .016) were significantly associated with favorable OS. Among the 36 patients who progressed during the follow-up, 55.8% of the progressions occurred at the new sites. RRLT combined with TKI did not show any severe toxicity to the patients. Conclusions: Combined application of RRLT and first-line TKI may improve the survival and alter the pattern of failure for metastatic NSCLC patients with EGFR activating mutations.

Sarcomatoid carcinoma (SC) is a rare lung cancer subtype with poor prognosis and lack of effective treatment regimens. Studies concerning SC indicated common programmed death ligand-1 (PD-L1) overexpression and higher tumor mutational burden, leading to potential benefits from immunotherapy. The present case is the first report employing PD-L1 inhibitor durvalumab following definitive concurrent chemoradiotherapy (cCRT) in a patient with mediastinal lymph node metastatic SC, which was considered as a high probability of pulmonary origin but unclear primary lesion. After the 19-month follow-up, there was neither local recurrence nor distant metastasis. The patient was in a good condition, with the thoracic lesion controlled at Partial response-Response Evaluation Criteria in Solid Tumors (PR-RECIST). Except for grade 2 esophagitis, none of the other adverse events was observed. Our first attempt to adopt the consolidation immunotherapy after cCRT in unresectable locally advanced mediastinal SC exhibited improved local control, manageable safety, and potential survival benefits, representing a novel and promising therapeutic option for SC and encouraging further research exploration of this regimen in the future.

PurposeTo investigate whether progression-free survival (PFS) or time to progression (TTP) could be a valid surrogate endpoint for overall survival (OS) in patients with limited-stage small-cell lung cancer (LS-SCLC) receiving combined chemoradiotherapy.MethodsLiterature searching was performed in PubMed, Embase, and The Cochrane Library up to 2021. Prediction models were firstly established using data from phase III randomized controlled trials (RCTs) and then externally validated in phase II and retrospective studies. Correlation analysis was evaluated by a weighted linear regression model at both trial and arm levels. Cross-validation was performed to assess the consistency and robustness of the established models.Results37 studies, including 15 phase III RCTs, 12 phase II studies, and 10 retrospective studies, were selected in the final analysis. In trial-level surrogacy, a very good correlation was observed between hazard ratios (HRs) of PFS/TTP and OS (R2 = 0.783, 95% CI 0.771–0.794). In arm-level surrogacy, very good correlations were also observed between 2-year (R2 = 0.823, 95% CI 0.814–0.832), 3-year (R2 = 0.843, 95% CI 0.833–0.850), 5-year (R2 = 0.852, 95% CI 0.843–0.859) PFS/TTP, and 5-year OS. An excellent correlation was observed between 4-year PFS/TTP and 5-year OS (R2 = 0.906, 95% CI 0.901–0.910). Cross-validation demonstrated reasonable overall consistency. External validation in phase II and retrospective studies showed good agreement (R2, 0.728–0.824).ConclusionsPFS/TTP was a valid surrogate endpoint for OS in patients with LS-SCLC receiving combined chemoradiotherapy. The finding provides high-level evidence to support PFS/TTP as the primary endpoint in clinical trials so as to speed up introducing novel agents to the treatment of LS-SCLC.

BackgroundBrain metastasis (BM) is one of the most common failure patterns of pIIIA-N2 non-small cell lung cancer (NSCLC) after complete resection. Prophylactic cranial irradiation (PCI) can improve intracranial control but not overall survival. Thus, it is particularly important to identify the risk factors that are associated with BM and subsequently provide instructions for selecting patients who will optimally benefit from PCI.Methods and MaterialsBetween 2011 and 2014, patients with pIIIA-N2 NSCLC who underwent complete resection in our institution were reviewed and enrolled in the study. Clinical characteristics, pathological parameters, treatment mode, BM time, and overall survival were analyzed. A nomogram was built based on the corresponding parameters by Fine and Gray’s competing risk analysis to predict the 1-, 3-, and 5-year probabilities of BM. Receiver operating characteristic curves and calibration curves were chosen for validation. A statistically significant difference was set as P

Abstract Background Consistent results are lacking as regards the comparative effectiveness of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) versus conventional intensity-modulated radiotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). Therefore, we conducted a retrospective analysis to demonstrate the role of SIB-IMRT for patients. Methods Patients who had histologically confirmed NSCLC, stage III disease and received thoracic IMRT between 2014 and 2016 were retrospectively reviewed. The survival, toxicities and dose to organs at risk (OAR) were compared among patients irradiated with different techniques. The SIB-IMRT plans were designed to deliver 45–59.4Gy (median: 50.4Gy) to PTV while simultaneously delivering 50-70Gy (median: 59.92Gy) to PGTV. As for conventional IMRT plans, a total dose of 50-70Gy (median: 60Gy) was delivered to PTV. Results 426 patients with stage III NSCLC were eligible for analysis, including 128 with SIB-IMRT and 298 with conventional IMRT. The SIB-IMRT group had more stage IIIB disease (69.5% vs. 53%, P = 0.002), larger planning treatment volumes (median: 504 ml vs. 402 ml, P

Abstract Background There were few reports of postoperative radiotherapy (PORT) in stage pIII-N2 Non-small-cell Lung Cancer (NSCLC) patients receiving pneumonectomy followed by adjuvant chemotherapy. This study aims to evaluate safety and efficacy of PORT among these patients. Methods Between Jan. 2004 and Dec. 2015, stage pIII-N2 NSCLC patients receiving pneumonectomy and adjuvant chemotherapy with or without PORT in our institution were retrospectively reviewed. Results Totally 119 patients were included, 32 patients receiving adjuvant chemotherapy and PORT (PORT group) and 87 receiving adjuvant chemotherapy alone (Control group). There were more patients with non-R0 resection in PORT group than Control group (25% vs. 8%, p = 0.031). In PORT group, ≥Grade 2 radiation-induced pneumonitis was 2/32. No severe radiation-related heart injury was observed. There was no PORT-related death. Of all patients, median follow-up time was 25 months. Median overall survival time (mOS) and median disease-free survival time (mDFS) were 46 months and 15 months, respectively. The PORT group had significantly better OS (not reached vs. 34 months, p = 0.003), DFS (19 months vs. 13 months, p = 0.024), local recurrence free survival (LRFS, p = 0.012), and distant metastasis free survival (DMFS, p = 0.047) than the Control group. As for failure pattern, PORT significantly reduced local regional failure rate (39.1% vs. 15.6%, p = 0.016). In subgroup analysis, patients with R0 resection (n = 104), OS and LRFS in PORT group were significantly longer, and PORT tended to increase DFS and DMFS. Conclusion For patients with stage pIII-N2 NSCLC after pneumonectomy and adjuvant chemotherapy, PORT can improve OS, DFS, LRFS and DMFS with tolerable toxicity.

Abstract Background Programmed death ligand 1 (PD-L1) is a ligand for the inhibitory programmed cell death protein 1 (PD-1), which are targeted by several anti-PD-1 and PD-L1 drugs for a variety of human cancers. However, only a few studies have evaluated PD-L1 expression in esophageal squamous cell carcinoma (ESCC) with a large Chinese cohort. Our present study is to evaluate the association of PD-L1 expression with clinicopathological features on ESCC. Methods Using tissue microarray and immunohistochemistry, PD-L1 expression on tumor cells and tumor-infiltrating immune cells was studied in 378 advanced ESCC patients without neoadjuvant chemoradiotherapy. Its correlation with clinicopathological parameters was analyzed. Results PD-L1 was expressed on 29.9% (113/378) ESCC tumor cells and 40.2% (152/378) tumor-infiltrating immune cells. PD-L1 expression in tumor cells was significantly correlated with age, degree of differentiation, T stage, N stage and metachronous hematogenous metastasis, and PD-L1 expression in tumor-infiltrating immune cells was significantly associated with N stage (P

ObjectiveCirculating tumor cells (CTCs) can predict the efficacy of anti-cancer treatments and indicate prognosis. Here we investigate the significance of CTCs in relation to the prediction of treatment efficacy and prognosis in patients with small cell lung cancer (SCLC) who have received prophylactic cranial irradiation (PCI).MethodsCTCs were detected in 20 patients with SCLC before and after PCI using the oHSV1-hTERT-GFP method. The primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsEleven patients had limited-stage SCLC, and nine had extensive-stage SCLC. All patients completed chemo-radiotherapy and received PCI. The median baseline CTC count before PCI was 12. After PCI, the median CTC count was 4. The median follow-up time for all enrolled patients was 39.2 months. The median PFS and OS were significantly reduced in patients with ≥4 CTCs after PCI compared to those with

[This corrects the article DOI: 10.1371/journal.pgen.1007888.].

OBJECTIVES: This study aimed to: (1) assess the prognostic significance of serum tumor markers in locally advanced squamous cell carcinoma in lung (LA-SCCL); (2) generate a nomogram to predict the overall survival (OS) and (3) identify a prognostic stratification to assist the therapeutic decision-making. METHODS: LA-SCCL patients receiving definitive radiotherapy and baseline tumor marker measurement were eligible for this retrospective study. Cox proportional hazards regression was used to determine independent factors associated with various survival indexes and a nomogram was created to estimate the 5-year OS probability for individual patient. The identified prognostic factors were recruited into a recursive partitioning analysis (RPA) for OS to stratify patients with distinct outcome. RESULTS: A total of 224 patients were eligible for analysis. Increased cytokeratin-19 fragment (CYFRA 21-1) was independently associated with inferior OS, progression free survival (PFS) and a borderline decreased local-regional progression free survival (LRPFS). Elevated carcino-embryonic antigen (CEA) served as an unfavorable determinant for OS and increased neuron-specific enolase (NSE) was predictive of poor distant metastasis free survival (DMFS). A nomogram integrating KPS, TNM stage, CEA and CYFRA 21-1 was created, resulting in a c-index of 0.62. RPA identified 4 prognostic classifications, with median OS of 27.6, 19.9, 17.3 and 10.9 months for low, intermediate, high and very-high risk groups, respectively. CONCLUSIONS: Baseline tumor marker panel including CYFRA 21-1, CEA and NSE can be prognostic of outcome for LA-SCCL receiving definitive radiotherapy. The RPA identified four prognostic subgroups, which could assist personalized therapy and clinical trial design in LA-SCCL.

Abstract Background The Th1 cell-specific transcription factor TBX21 functions as a regulator of expression of a Th1 cytokine, interferon gamma (IFN-γ). However, the specific function of TBX21 correlated with cancer stemness remains unclear. Methods Using univariate and multivariate survival analysis, TBX21was identified as an independent predictive factor and was associated with poor prognosis in 1389 patients with lung adenocarcinoma (LUAD). Its mechanism in the prognosis was explored by functional enrichment analysis and validated in bioexperiments. Results In the training and test sets, TBX21 could classify 1389 LUAD patients into high and low-risk groups with significantly different prognosis (P < 0.01). Its prognostic power was independent of other clinical factors including stage, age, gender and smoking status. Functional studies indicated that downregulating TBX21 in lung cancer cells decreased the fraction of cancer stem cells and their sphere and tumor initiation frequency. Furthermore, the study showed that TBX21 activation transduced a TBX21–IL-4 signaling cascade to promote tumor initiation, tumor growth and expression of stemness markers. Conclusions These data demonstrated a key role of TBX21 in the maintenance of cancer stemness and that the TBX21–IL-4 pathway is a crucial factor contributing to lung carcinogenesis. Graphical abstract TBX21 prognostic model correlated with cancer stemness via TBX21-IL-4 pathway in LUAD patients

OBJECTIVES: MicroRNAs (miRNAs) play a key role in governing posttranscriptional regulation through binding to the mRNAs of target genes. This study is to assess miRNAs expression profiles for identifying brain metastasis-related miRNAs to develop the predictive model by microarray in tumor tissues. METHODS: For this study, we screened the significant brain metastasis-related miRNAs from 77 lung adenocarcinoma (LUAD) patients with brain metastasis (BM+) or non-brain metastasis (BM−). A predictive model was developed from the training set (n = 42) using a random Forest supervised classification algorithm and a Class Centered Method, and then validated in a test set (n = 35) and further analysis in GSE62182 (n = 73). The independence of this signature in BM prediction was measured by multivariate logistic regression analysis. RESULTS: From the training set, the predictive model (including hsa-miR-210, hsa-miR-214 and hsa-miR-15a) stratified the patients into two groups with significantly different BM subtypes (90.4% of accuracy). The similar predictive power (91.4% of accuracy) was obtained in the test cohort. As an independent predictive factor, it was closely associated with BM and had high sensitivity and specificity in predicting BM in clinical practice. Moreover, functional enrichment analysis demonstrated that this signature involved in the signaling pathways positively correlated with cancer metastasis. CONCLUSION: These results suggested that the three-miRNA signature could develop a new random Forest model to predict the BM of LUAD patients. These findings emphasized the importance of miRNAs in diagnosing BM, and provided evidence for selecting treatment decisions and designing clinical trials.

Abstract Background Heath-related quality of life (HRQoL) among survivors with unresectable locally-advanced non-small cell lung cancer (LA-NSCLC) treated with radiotherapy and chemotherapy still is not clear. The current study were performed to determine HRQoL for long-term survivors with unresectable LA-NSCLC and to identify risk factors for poor HRQoL. Methods Among patients with LA-NSCLC receiving radiotherapy and chemotherapy between January 2006 and December 2010, 82 long-term survivors beyond 5 years were identified in this cross-sectional study. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and the lung cancer-specific questionnaire QLQ-LC13 were employed to gather information on HRQoL. HRQoL scores were compared between different subgroups to analyze factors related to HRQoL. Results Fifty-five out of 82 (67%) long-term survivors completed the HRQoL survey. They reported a mild reduction in global health status and physical and emotional functioning. Fatigue, dyspnea, coughing, and financial difficulties ranked the highest scores in the symptom scales. Analysis of risk factors for HRQoL showed age, exercise, smoking status, and treatment regimen were associated with global health status and functional scores, while age, gender, radiation pneumonitis, weight loss, and exercise were associated with symptom scores. Conclusions This study provides the first description of the HRQoL of long-term LA-NSCLC survivors receiving radiotherapy and chemotherapy who may experience a relatively high HRQoL. Factors related to poorer HRQoL are potential targets for intervention.

Purpose: The efficiency of radiation delivery via volumetric modulated arc therapy (VMAT) is indisputable, but outcomes after VMAT for thoracic esophageal carcinoma are largely unknown. Methods and materials: We retrospectively analyzed 65 patients with thoracic esophageal cancer who received VMAT to 50.4 Gy (range, 45-50.4 Gy) with concurrent chemotherapy from November 2012 to March 2016 at a single tertiary cancer center. We then used propensity score matching to match these 65 patients with 130 other patients treated with step-and-shoot intensity modulated radiation therapy (ssIMRT) and concurrent chemotherapy. Differences in continuous and categorical variables were examined with independent-sample t or Wilcoxon tests and χ2 tests. Results: Dosimetrically, VMAT had a higher conformity index (87.75 ± 10.70 VMAT vs 83.20 ± 9.42 ssIMRT, P = .003), a higher heart V5, and a lower V50 than ssIMRT, but lung V5-20, heart V30, heart V40, cordmax, and homogeneity index were similar. At median follow-up intervals of 14.3 months (range, 3.8-34.5 months) for VMAT and 31.8 months (range, 1.8-117.2 months) for ssIMRT, overall survival rates were similar between the treatments (93.5% VMAT vs 91.5% ssIMRT at 1 year; 60.0% VMAT and 61.4% ssIMRT at 2 years; P = .868). Recurrence-free survival rates were similar (73.3% VMAT vs 79.5% ssIMRT at 1 year, 59.9% VMAT and 61.8% ssIMRT at 2 years; P = .614), as were pathologic complete response rates (31.2% VMAT vs 23.3% ssIMRT; P = .41) and toxicity and postoperative complications (radiation pneumonitis 9% VMAT vs 15.4% ssIMRT; pericardial effusion 2% VMAT vs 7% ssIMRT; esophageal fistula and stricture 9% VMAT vs 13% ssIMRT; all P > .05). Conclusion: Compared with ssIMRT, VMAT had better target conformity with similar organ sparing and comparable rates of survival, recurrence, and toxicity. These results suggest that VMAT can be safe and effective for esophageal cancer.

Purpose: To investigate whether a deep learning-assisted contour (DLAC) could provide greater accuracy, inter-observer consistency, and efficiency compared with a manual contour (MC) of the clinical target volume (CTV) for non-small cell lung cancer (NSCLC) receiving postoperative radiotherapy (PORT).Materials and Methods: A deep dilated residual network was used to achieve the effective automatic contour of the CTV. Eleven junior physicians contoured CTVs on 19 patients by using both MC and DLAC methods independently. Compared with the ground truth, the accuracy of the contour was evaluated by using the Dice coefficient and mean distance to agreement (MDTA). The coefficient of variation (CV) and standard distance deviation (SDD) were rendered to measure the inter-observer variability or consistency. The time consumed for each of the two contouring methods was also compared.Results: A total of 418 CTV sets were generated. DLAC improved contour accuracy when compared with MC and was associated with a larger Dice coefficient (mean ± SD: 0.75 ± 0.06 vs. 0.72 ± 0.07, p < 0.001) and smaller MDTA (mean ± SD: 2.97 ± 0.91 mm vs. 3.07 ± 0.98 mm, p < 0.001). The DLAC was also associated with decreased inter-observer variability, with a smaller CV (mean ± SD: 0.129 ± 0.040 vs. 0.183 ± 0.043, p < 0.001) and SDD (mean ± SD: 0.47 ± 0.22 mm vs. 0.72 ± 0.41 mm, p < 0.001). In addition, a value of 35% of time saving was provided by the DLAC (median: 14.81 min vs. 9.59 min, p < 0.001).Conclusions: Compared with MC, the DLAC is a promising strategy to obtain superior accuracy, consistency, and efficiency for the PORT-CTV in NSCLC.

Brain metastasis (BM) is a major complication of lung adenocarcinoma (LAD). An investigation of the pathogenic mechanisms of BM, as well as the identification of appropriate molecular markers, is necessary. The aim of this study was to determine the expression patterns of microRNAs (miRNAs) in LAD with BM, and to investigate the biological role of these miRNAs during tumorigenesis. miRNA array profiles were used to identify BM-associated miRNAs. These miRNAs were independently validated in 155 LAD patients. Several in vivo and in vitro assays were performed to verify the effects of miRNAs on BM. We identified six miRNAs differentially expressed in patients with BM as compared to patients with BM. Of these, miR-4270 and miR-423-3p were further investigated. miR-4270 and miR-423-3p directly targeted MMP19 and P21, respectively, to influence cell viability, migration, and colony formation in vitro. miR-4270 downregulation and miR-423-3p upregulation was associated with an increased risk of BM in LAD patients. Thus, our results suggested that miR-4270 and miR-423-3p might play an important role in BM pathogenesis in LAD patients, and that these miRNAs might be useful prognostic and clinical treatment targets.

Small-cell lung cancer (SCLC) is one of the most aggressive cancers, yet the molecular mechanisms underlying its devastating clinical outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict the clinical outcomes of SCLC patients. A total of 82 patients with limited SCLC, who were treated with surgical resection and adjuvant chemotherapy, were enrolled in this study. First, we surveyed the expression of 924 miRNAs from 42 SCLC patients to discover survival-relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases using quantitative real-time PCR. We found that the miR-150/miR-886-3p signature was significantly correlated with the overall survival (OS) of SCLC patients (p = 0.02) in the training set, and both miRNA expression levels were much lower in the SCLC samples than normal lung samples. The miRNA signature also proved to be a significant predictor of survival in the validation set. Patients with high-risk miRNA signatures had poor overall survival (p = 0.005) and progression-free survival (p = 0.017) compared with those with low-risk scores. These findings retained statistical significance after adjusting for age, gender and smoking status (HR: 0.26, 95%: CI 0.10-0.69, p = 0.007), which suggested it may be an independent predictor of survival. In summary, we developed a prognostic miR-150/miR-886-3p signature and validated expression in an independent dataset of resectable SCLC. These preliminary results indicated that miRNAs may serve as promising molecular prognostic markers and new therapeutic targets for SCLC.