Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represents a major clinical challenge in the management of non-small cell lung cancer (NSCLC). Chromosome 4q12 locus is an important gene locus associated with progression-free survival (PFS) in NSCLC patients receiving EGFR-TKIs therapy. However, it remains poorly characterized how genes at this locus function in NSCLC development and resistance to EGFR-TKIs. Here, we found that CLOCK at this locus is highly expressed in NSCLC tissues and correlates with unfavorable PFS of patients. CLOCK promotes malignant proliferation and metastasis of NSCLC in vitro and in vivo. CLOCK could attenuate treatment efficacies of gefitinib (one of the first-generation EGFR-TKIs) or osimertinib (one of the third-generation EGFR-TKIs). Mechanistically, CLOCK functions as a transcriptional factor to upregulate LAMC2 transcription and expression in NSCLC cells. There was significantly elevated LAMC2 expressed in NSCLC tissues and its high levels were associated with shortened survival of patients. Indeed, CLOCK could activate multiple kinase signaling pathways, such as the PI3K-Akt signaling and the MAPK signaling, by facilitating either the LAMC2-ITGB1 interaction and the LAMC2-EGFR interaction and thereby accelerating NSCLC proliferation and conferring EGFR-TKI resistance. Collectively, these findings for the first time identify CLOCK as a critical mediator of EGFR-TKIs resistance and a promising target to overcome EGFR-TKIs resistance in NSCLC.

Background:Management of non-small cell lung cancer (NSCLC) after acquired resistance to third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is an unmet clinical need with no consensus on optimal strategies. Encouraging efficacy of subsequent dacomitinib treatment was observed in clinical practice, yet unproven. Therefore, this study aimed to evaluate the efficacy and safety of dacomitinib in patients with advanced EGFR-L858R-mutated NSCLC after acquired resistance to third-generation EGFR-TKIs, with exploratory assessment of intracranial activity in patients with brain metastases. Methods:A retrospective real-world study enrolled consecutive advanced EGFR-L858R-mutated NSCLC patients with third-generation EGFR-TKI resistance from Shandong Cancer Hospital and Institute (November 2020-March 2024). All received dacomitinib. Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Results:Forty-two patients were included, with a median follow-up of 16.3 months (3.0-35.0 months) and 4 median treatment lines. ORR and DCR were 33.3% and 78.6%, respectively. Median PFS was 5.7 months [95% confidence interval (CI): 4.4-6.9], and median OS was 26.5 months (95% CI: 15.2-37.8). Exploratory analysis showed no significant differences in median PFS (5.4 vs. 6.2 months, P=0.29) or OS (18.1 vs. 26.5 months, P=0.73) between patients with and without brain metastasis (BM). Median intracranial PFS (iPFS) was 12.9 months (95% CI: 8.7-17.1); intracranial ORR and DCR in BM patients were 19.0% and 64.3%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 14.3% (n=6) of patients, with no grade 5 events. Conclusions:Dacomitinib is a promising, well-tolerated option for EGFR 21-L858R-mutated NSCLC patients with third-generation EGFR-TKI resistance, warranting prospective clinical trials for validation.

Loss or lack tumor immunogenicity promotes immune escape and resistance to immunotherapy. Arginine methylation, a key protein post-translational modification, participates in tumor progression and therapy resistance. However, whether arginine methylation directly influences the tumor immunogenicity and thereby modulates antitumor immune responses remains poorly understood. Here, we report that protein arginine methyltransferase 3 (PRMT3) exhibited a significantly negative association with antitumor immune signatures and survival outcomes in multiple cancers. Tumor-intrinsic PRMT3 deletion markedly delays tumor growth by promoting CD8+ T cell infiltration and functional activation through the modulation of type I interferon (IFN) signaling. Mechanistically, PRMT3 catalyzes arginine asymmetric-dimethylation at the conserved Arg364 residue of cGAS, suppressing its capacity to activate the downstream STING signaling, which ultimately affects the tumor immunogenicity and overall antitumor immune responses. Combining PRMT3 deletion or pharmacological inhibition with anti-PD-1 antibody therapy achieved profoundly synergistic tumor control and elicited tumor-specific immunological memory. Collectively, our findings delineate a critical regulatory role of PRMT3 on tumor-intrinsic cGAS-mediated adaptive immunity, proposing immunogenicity-enhanced cancer treatment as a transformative strategy to achieve potentiated antitumor efficacy.

Background:Patients with extensive-stage small cell lung cancer (ES-SCLC) and liver metastases (LM) are known to have particularly poor clinical outcomes, creating a significant therapeutic dilemma regarding optimal management of hepatic metastases beyond conventional systemic therapies. Objectives:This study sought to investigate the impact of adding LM-directed radiotherapy to systemic therapy on survival outcomes and treatment-related adverse events in patients with ES-SCLC and liver metastases. Design:This retrospective study enrolled ES-SCLC patients with LM treated at our institution between January 2019 and March 2025, all of whom received at least one cycle of systemic therapy. Patients were grouped by whether they received LM‑directed radiotherapy after LM diagnosis. Methods:Propensity score matching (PSM) was used to balance baseline characteristics between patients in the two groups. Kaplan-Meier survival curves were plotted to estimate survival endpoints. Treatment-related adverse events were graded per Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Results:After PSM, a total of 495 patients were analyzed, among whom 138 underwent LM-directed radiotherapy. After a median follow-up of 38.1 months, patients in the radiotherapy group had a median overall survival (OS) of 12.1 months, significantly longer than the 6.7 months observed in the nonradiotherapy group (hazard ratios (HR), 0.51; 95% confidence intervals (CI): 0.41-0.63; p < 0.001). The 1-year OS rates were 50.1% and 21.2%, respectively. Among patients who received LM-directed radiotherapy during first-line systemic treatment, both systemic progression-free survival (PFS) (5.1 vs 3.7 months; HR, 0.71; 95% CI: 0.54-0.93; p = 0.012) and intrahepatic PFS (6.7 vs 3.9 months; HR, 0.59; 95% CI: 0.45-0.79; p < 0.001) were significantly prolonged compared with systemic therapy alone. Treatment-related toxicity was mild, with only one patient experiencing grade ⩾3 transaminase elevation and one patient with grade ⩾3 hyperbilirubinemia. The incidence of grade ⩾3 hematologic toxicity was low, and leukocytopenia was the most common event at 14.50%. Conclusion:In patients with ES-SCLC and LM, the addition of LM-directed radiotherapy to systemic therapy provides a significant survival benefit with acceptable treatment-related toxicity. These findings suggest that LM-directed radiotherapy can serve as a safe and effective treatment option for this patient population with poor prognosis.

Background Limited-stage small cell lung cancer (LS-SCLC) frequently progresses to extensive-stage disease (ES-SCLC) after standard therapy. However, evidence regarding the efficacy and safety of various treatment regimens for this specific patient population remains limited. Objectives This study aimed to evaluate the efficacy and safety of various treatment regimens among patients who progressed from LS-SCLC to ES-SCLC after standard chemoradiotherapy. Design Survival analyses using propensity score matching (PSM) were conducted in patients with LS-SCLC who progressed to ES-SCLC to assess the efficacy and safety of multiple treatment regimens, especially immunotherapy. Methods This retrospective study included 378 patients with LS-SCLC who progressed to ES-SCLC at Shandong Cancer Hospital from January 2018 to December 2024. After propensity score matching (PSM), patients were divided into immunotherapy and non-immunotherapy groups. Data on treatment regimens and clinical outcomes, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), were collected. Kaplan–Meier analysis estimated PFS and OS, and Cox regression identified factors influencing OS. Results Median overall survival (mOS) and median progression-free survival (mPFS) in the immunotherapy group were longer than those in the non-immunotherapy group (16.4 vs 12.3 months, P < 0.05; 5.3 vs 4.9 months, P < 0.05, respectively). In an exploratory subgroup analysis, platinum-based regimens were associated with longer OS only in patients with a treatment-free interval (TFI) of 3 months or longer (median 19.3 vs 12.5 months; HR = 0.65, 95% CI 0.44–0.95, P < 0.05). Conclusion Our exploratory real-world data suggest that immunotherapy is associated with improved patient outcomes in patients with LS-SCLC who progress to ES-SCLC. Platinum-based regimens may be associated with better prognosis in the subgroup with a TFI of 3 months or longer. Given the exploratory nature, further prospective randomized trials are needed to confirm these observations.

This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy. A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan–Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients. At the end of the last follow-up period, 176 patients (74.3

To evaluate the efficacy and safety of aumolertinib in treating non-small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) and epidermal growth factor receptor (EGFR) mutations. We conducted a retrospective analysis of clinical data from 79 patients with EGFR-mutated advanced NSCLC treated with aumolertinib after being diagnosed with LM at Shandong Cancer Hospital and Institute between April 2020 and July 2023. We evaluated overall survival (OS), progression-free survival (PFS), LM-PFS, and safety. Patient prognosis was assessed using Kaplan–Meier and Cox regression analyses. The median follow-up duration was 19.8 months (95

Background: Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is associated with a complex array of resistance pathways. Epithelial-mesenchymal transition (EMT) represents a mechanism contributing to resistance development in epidermal growth factor receptor (EGFR)-TKI treatment. Previous research suggests that the downregulation of Snail, a transcription factor linked to EMT, can delay the onset of osimertinib resistance. Slug, another member of the Snail family, remains underexplored in its impact on EMT-related osimertinib resistance. Dihydroartemisinin (DHA) has demonstrated efficacy in inhibiting the proliferation, invasion, and metastasis of various types of tumor cells, including lung cancer. This study confirmed that DHA could downregulate Slug expression and inhibit the metastasis and invasion of tumor cells. Methods: The cultured osimertinib-resistant lung adenocarcinoma cell line was named H1975/OE. Real-time polymerase chain reaction (RT-PCR), western blotting, and Transwell assays were employed to confirm EMT occurrence in H1975/OE cells. To investigate the mechanism of EMT in osimertinib resistance, we evaluated EMT-related markers in H1975 parental cells and H1975/OE-resistant cells. Complete silencing of the regulator Slug in H1975/OE cells using small interfering RNA (siRNA) was followed by an examination of alterations in the expression levels of EMT-associated markers. Finally, DHA, a natural inhibitor, was used to assess its interference with osimertinib resistance linked to EMT. Results: Evaluation of EMT-specific markers in the H1975 parental cell line and H1975/OE resistant cell line revealed upregulated N-cadherin expression and downregulated E-cadherin expression in H1975/OE cells. The enhanced invasiveness of H1975/OE indicated that EMT occurred in the resistant cell line. Subsequent experiments confirmed that Slug expression was upregulated in the resistant cell line and that knockout of Slug facilitated a delay in the occurrence of osimertinib resistance in H1975/OE cells. Further investigation demonstrated that DHA could inhibit Slug expression, alleviating osimertinib resistance associated Conclusions: Slug plays a pivotal role in osimertinib resistance associated with EMT. DHA effectively overcomes osimertinib resistance linked to EMT by inhibiting Slug expression.

Background and Purpose Epidermal growth factor receptor (EGFR)-mutant lung cancers are associated with a high risk of developing brain metastases (BM). Craniocerebral radiotherapy is a cornerstone for the treatment of BM, and EGFR-TKIs act on craniocerebral metastases”. However, whether EGFR-TKIs combined with craniocerebral radiotherapy can further increase the efficacy and improve the prognosis of patients is unclear. This study aimed to evaluate the difference in efficacy between targeted-therapy alone and targeted-therapy combined with radiotherapy in EGFR-mutant lung adenocarcinoma patients with BM. Materials and Methods A total of 291 patients with advanced non-small cell lung cancer (NSCLC) and EGFR mutations were enrolled in this retrospective cohort study. Propensity score matching (PSM) was conducted using a nearest-neighbor algorithm (1:1) to adjust for demographic and clinical covariates. Patients were divided into two groups: EGFR-TKIs alone and EGFR-TKIs combined with craniocerebral radiotherapy. Intracranial progression-free survival (iPFS) and overall survival (OS) were calculated. Kaplan–Meier analysis was used to compare iPFS and OS between the two groups. Brain radiotherapy included WBRT, local radiotherapy, and WBRT+Boost. Results The median age at diagnosis was 54 years (range: 28–81 years). Most patients were female (55.9%) and non-smokers (75.5%). Fifty-one pairs of patients were matched using PSM. The median iPFS for EGFR-TKIs alone (n=37) and EGFR-TKIs+craniocerebral radiotherapy (n=24) was 8.9 and 14.7 months, respectively. The median OS for EGFR-TKIs alone (n=52) and EGFR-TKIs+craniocerebral radiotherapy (n=52) was 32.1 and 45.3 months, respectively. Conclusion In EGFR-mutant lung adenocarcinoma patients with BM, targeted therapy combined with craniocerebral radiotherapy is an optimal treatment.

唾液酸结合免疫球蛋白样凝集素-15(sialic acid-binding immunoglobulin-like lectin,Siglec-15)作为新发现的一种免疫检查点抑制剂(immune checkpoint inhibitors,ICIs),其广泛表达于多种肿瘤细胞,并与程序性死亡受体1(programmed cell death 1,PD-1)和程序性死亡受体-配体1(programmed cell death ligand 1,PD-L1)的表达互斥,可以作为一个新的ICIs治疗靶点,为PD-1/PD-L1治疗无响应的患者提供另一种治疗选择.本文拟从Siglec-15的特征通路、参与免疫调节机制以及在肿瘤相关的表达等方面的近期研究成果综述.分析研究Siglec-15抗体的临床应用结果,探讨Siglec-15在非小细胞肺癌(non-small cell lung cancer,NSCLC)治疗中的应用意义以及治疗前景.

IntroductionTo confirm the efficacy of magnetic resonance-diffusion weighted imaging (MR-DWI) in esophageal squamous cell carcinoma (ESCC) early pathological response prediction and assessment to neoadjuvant chemoradiotherapy (nCRT) using patient-derived xenografts (PDXs)MethodsPDX-bearing mice were randomly divided into two groups: the experimental group receiving cisplatin combined with radiotherapy, whereas the control group receiving normal saline. MRI scans were performed in treatment groups in the before, middle, and end of treatment. The correlations between tumor volumes, ADC values and tumor pathological response at different time nodes were explored. Then, expression of proliferation marker and apoptotic marker were detected using immunohistochemistry, and apoptosis rate was detected by TUNEL assay to further verify the results observed in the PDX models.ResultsThe ADC values of the experimental group were significantly higher than the control group in the both middle and end stage of treatment (all P< 0.001), however, significant difference was only observed in tumor volume at the end stage of treatment (P< 0.001). Furthermore, the △ADCmid-pre in our study may able to identify tumors with or without pCR to nCRT at an early stage, due to these changes were prior to the changes of tumor volume after treatment. Finally, TUNEL results also showed that the apoptosis rate of the experiment groups increased the most in the middle stage of treatment, especially the groups with pCR, but the highest apoptosis rate occurred in the end of the treatment. Further, the two PDX models with pCR exhibited the highest levels of apoptotic marker (Bax), and lowest levels of proliferation marker (PCNA and Ki-67) in the both middle and end stage of the treatment.ConclusionsADC values could be used to determine the tumor’s response to nCRT, especially in the middle stages of treatment and before the tumor tissue morphology changes, and further, the ADC values were consistent with the potential biomarkers reflecting histopathological changes. Therefore, we suggest that radiation oncologists could refer to the ADC values in the middle stages of treatment when predicting the tumor histopathological response to n CRT in patients with ESCC.

Background and Purpose:This study aimed to investigate inter-/intra-observer delineation variability in GTVs of primary esophageal carcinomas (ECs) based on planning CT with reference to different combinations of diagnostic multimodal images from endoscopy/EUS, esophagography and FDG-PET/CT.Materials and Methods:Fifty patients with pathologically proven thoracic EC who underwent diagnostic multimodal images before concurrent chemoradiotherapy were enrolled. Five radiation oncologist independently delineated the GTVs based on planning CT only (GTVC), CT combined with endoscopy/EUS (GTVCE), CT combined with endoscopy/EUS and esophagography (X-ray) (GTVCEX), and CT combined with endoscopy/EUS, esophagography, and FDG-PET/CT (GTVCEXP). The intra-/inter-observer variability in the volume, longitudinal length, generalized CI (CIgen), and position of the GTVs were assessed.Results:The intra-/inter-observer variability in the volume and longitudinal length of the GTVs showed no significant differences (p>0.05). The mean intra-observer CIgen values for all observers was 0.73 ± 0.15. The mean inter-observer CIgen values for the four multimodal image combinations was 0.67 ± 0.11. The inter-observer CIgen for the four combined images was the largest, showing significant differences with those for the other three combinations. The intra-observer CIgen among different observers and inter-observer CIgen among different combinations of multimodal images showed significant differences (p<0.001). The intra-observer CIgen for the senior radiotherapists was larger than that for the junior radiotherapists (p<0.001).Conclusion:For radiation oncologists with advanced medical imaging training and clinical experience, using diagnostic multimodal images from endoscopy/EUS, esophagography, and FDG-PET/CT could reduce the intra-/inter-observer variability and increase the accuracy of target delineation in primary esophageal carcinomas.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are effective targeted therapy drugs for advanced non-small cell lung cancer (NSCLC) patients carrying sensitized EGFR mutations. The rapid development of EGFR-TKIs resistance represents a major clinical challenge for managing NSCLC. The chromosome 4q12 is the first genome-wide association study (GWAS)-reported locus associated with progression-free survival (PFS) of NSCLC patients treated with EGFR-TKIs. However, the biological significance of the noncoding transcripts at 4q12 in NSCLC remains elusive. In the present study, we identified two 4q12 long noncoding RNAs (lncRNAs) LCETRL3 and LCETRL4 which could significantly dimmish EGFR-TKIs efficiency. In line with their oncogenic role, evidently higher LCETRL3 and LCETRL4 levels were observed in NSCLC tissues as compared with normal specimens. Importantly, lncRNA LCETRL3 can interact with oncoprotein TDP43 and inhibit ubiquitination and degradation of TDP43. Similarly, lncRNA LCETRL4 can bind and stabilize oncoprotein EIF2S1 through reducing ubiquitin-proteasome degradation of EIF2S1. In particular, elevated levels of LCETRL3 or LCETRL4 in NSCLC cells resulted in stabilization of TDP43 or EIF2S1, increased levels of NOTCH1 or phosphorylated PDK1, activated AKT signaling and, thus, EGFR-TKIs resistance. Taken together, our data revealed a novel model that integrates two lncRNAs transcribed from the 4q12 locus into the regulation of EGFR-TKIs resistance in NSCLC. These findings shed new light on the importance of functionally annotating lncRNAs in the GWAS loci and provided insights to declare novel druggable targets, i.e., lncRNAs, which may unlock the therapeutic potential of EGFR-TKIs resistant NSCLC in the clinic.

奥希替尼是一种获批用于治疗非小细胞肺癌(non-small cell lung cancer,NSCLC)的小分子靶向抗肿瘤药物,为第三代表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI).目前获批并推荐应用于Ⅳ期EGFR突变NSCLC的一线治疗及一/二代TKI一线治疗失败再次活检提示T790M阳性群体.奥希替尼同样需要面对EGFR-TKI治疗后期不可避免的耐药现状,根据个体的用药时机不同,相应的耐药机制也有所差别,需要的治疗策略亦不同.本文拟从奥希替尼继发性耐药机制及相应治疗策略的近期研究成果进行综述,为延缓奥希替尼耐药和应对奥希替尼治疗失败后继续治疗进一步分析和探索.

Background and PurposeThis study aimed to evaluate the geometrical differences in and metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) performed before and during radiotherapy (RT) for patients with esophageal cancer based on the three-dimensional CT (3DCT) medium and explore whether the high signal area derived from DW-MRI can be used as a tool for an individualized definition of the volume in need of dose escalation for esophageal squamous cancer.Materials and MethodsThirty-two patients with esophageal squamous cancer sequentially underwent repeated 3DCT, 18F-FDG PET-CT, and enhanced MRI before the initiation of RT and after the 15th fraction. All images were fused with 3DCT images through deformable registration. The gross tumor volume (GTV) was delineated based on PET Edge on the first and second PET-CT images and defined as GTVPETpre and GTVPETdur, respectively. GTVDWIpre and GTVDWIdur were delineated on the first and second DWI and corresponding T2-weighted MRI (T2W-MRI)-fused images. The maximum, mean, and peak standardized uptake values (SUVs; SUVmax, SUVmean, and SUVpeak, respectively); metabolic tumor volume (MTV); and total lesion glycolysis(TLG) and its relative changes were calculated automatically on PET. Similarly, the minimum and mean apparent diffusion coefficient (ADC; ADCmin and ADCmean) and its relative changes were measured manually using ADC maps.ResultsThe volume of GTVCT exhibited a significant positive correlation with that of GTVPET and GTVDWI (both p < 0.001). Significant differences were observed in both ADCs and 18F-FDG PET metabolic parameters before and during RT (both p < 0.001). No significant correlation was observed between SUVs and ADCs before and during RT (p = 0.072–0.944) and between ∆ADCs and ∆SUVs (p = 0.238–0.854). The conformity index and degree of inclusion of GTVPETpre to GTVDWIpre were significantly higher than those of GTVPETdur to GTVDWIdur (both p < 0.001). The maximum diameter shrinkage rate (∆LDDWI) (24%) and the tumor volume shrinkage rate (VRRDWI) (60%) based on DW-MRI during RT were significantly greater than the corresponding PET-based ∆LDPET (14%) and VRRPET (41%) rates (p = 0.017 and 0.000, respectively).ConclusionBased on the medium of CT images, there are significant differences in spatial position, biometabolic characteristics, and the tumor shrinkage rate for GTVs derived from 18F-FDG PET-CT and DW-MRI before and during RT for esophageal squamous cancer. Further studies are needed to determine if DW-MRI will be used as tool for an individualized definition of the volume in need of dose escalation.

Background: Multimodality therapy for oesophageal cancer (EC) can cause a variety of treatment-related sequelae, especially pulmonary toxicities. The accurate prediction of radiation pneumonitis（RP）is essential to facilitate individualized radiation dosing that leads to maximized therapeutic gain. In this study, we performed a retrospective analysis to determine important factors that predict RP after radiotherapy (RT) for thoracic segment EC. Methods: Two hundred and forty-seven patients with locally advanced EC who received RT or chemoradiotherapy（CRT）were enrolled. The factors associated with RP in different grades were analyzed by univariate and multivariate analyses, such as basic pulmonary disease, smoking index(SI), three mainstream RT techniques, and dose-volume histogram(DVH). Results: The median RT dose was 60Gy, and the median follow-up time was 10 months. There were 118 cases of RP in 247 cases of EC patients who underwent RT or CRT. Among them, there were 54 cases of symptomatic pneumonitis (≥2 grade). The overall rate of symptomatic pneumonitis was 21.9%. In terms of RT techniques, there was no significant difference in the incidence of RP among three dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) , and tomography (TOMO) (P>0.05). V 5 -V 40 and MLD were associated with all grades of RP（P<0.05). Target volume, lung volume and their ratio were correlated with the incidence of RP（P<0.05). Among clinical factors, the highest risk of RP（≥3 grade）was in patients > 400 of SI. Chronic obstructive pulmonary disease (COPD) is also related to the occurrence of RP (≥1 grade). In addition, V 5 and V 40 were an independent risk factor for RP grade≥1 (AUC 55.74%, 4.13%). MLD was an independent risk factor for RP grade≥2(AUC 11.91Gy). V 5 was an independent risk factor for RP grade≥3 (AUC 57.60%). Conclusions: There was no significant difference in the incidence of RP regardless of radiation therapy technique (3D-CRT, IMRT , and TOMO) and treatment-related factors. SI and COPD are closely related to the occurrence of the corresponding grades of RP. Several lung dosimetric parameters (V 5 , V 40 , MLD) may be the most effective predictive factor of RP.

Introduction The aim of this study was to investigate the role of local radiotherapy in the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) treated with EGFR tyrosine kinase inhibitors (TKIs). Materials and Methods Patients with stage IV EGFR-mutant NSCLC treated with radiotherapy concomitant to EGFR TKIs from May 2010 to December 2017 were retrospectively identified. Overall survival (OS) was the primary endpoints of the study. Results A total of 205 patients were enrolled in the study. One hundred eleven patients received one-time single-site radiotherapy (SSR), and 94 patients received multiple-site radiotherapy (MSR). Patients who received MSR had longer OS (median OS, 40.0 months; 95% confidence interval [CI], 29.6 to 50.4) than those who received SSR (median OS, 28.9 months; 95% CI, 24.3 to 33.5; P=0.031). Thoracic radiotherapy was associated with prolonged median OS (41.7 months, 95% CI, 29.0 to 54.4 vs 27.1 months, 95% CI 22.7 to 31.5; log-rank P<0.001). Multivariate analysis confirmed that thoracic radiotherapy was independently associated with improved OS (adjusted hazard ratio [HR], 0.514; 95% CI 32.3% to 81.8%; P=0.005). Conclusion MSR improves survival outcomes in patients with advanced-stage, EGFR-mutant, lung adenocarcinoma, with thoracic radiotherapy having the most significant effect on prognosis.

Objective:To evaluate the spatial position and functional parameters of 18F-FDG PET-CT and diffusion-weighted imaging (DWI) before and during radiotherapy (RT) based on the medium of 3DCT in patients with esophageal cancer and to explore whether the high-signal area derived from DWI can be used for individualized definition of the volume in need of dose-escalation for esophageal cancer. Methods:Thirty-two patients with esophageal cancer treated with concurrent chemoradiotherapy or neoadjuvant chemoradiation sequentially underwent repeated 3DCT, 18F-FDG PET-CT and enhanced MRI scans before RT and at the 15 th time of RT. All images were fused with the 3DCT images by deformable registration. The gross tumor volume (GTV) was delineated based on PET Edge on the first and second 3DCT, PET-CT and DWI and corresponding T 2-weighted MRI (T 2W-MRI) fused images, and defined as GTV CTpre and GTV CTdur, GTV PETpre, GTV PETdur, GTV DWIpre and GTV DWIdur, respectively. SUV (SUV max, SUV mean, SUV peak), MTV, TLG, ADC (ADC min and ADC mean) values and △SUV (△SUV max, △SUV mean, △SUV peak), △MTV, △TLG, △ADC (△ADC mean and △ADC min) of lesions were measured before and during RT. Results:The differences in SUV (SUV max, SUV mean, SUV peak), MTV, TLG, ADC mean and ADC min of the GTV before and during RT were statistically significant (all P<0.001). The tumor ADC and SUV values before and during RT showed no significant correlation, and there was no correlation between △ADC and △SUV (both P>0.05). The conformity index (CI) of GTV PETpre to GTV DWIpre was significantly higher than that of GTV PETdur to GTV DWIdur ( P<0.001). The shrinkage rate of maximum diameter (△LD DWI)(24%) and the shrinkage rate of tumor volume (VRR DWI)(60%) based on DWI during RT were significantly greater than the corresponding PET-based △LD PET (14%) and VRR PET (41%)( P=0.017 and P<0.001). Conclusions:The location of high residual FDG uptake based on PET-CT yields poor spatial matching compared with the area with residual high signal based on DWI during RT. Tumor ADC and SUV values may play complementary roles as imaging markers for prediction of patterns of failure and for definition of the volume in need of dose-escalation. In addition, the shrinkage rates of tumor maximum diameter/volume based on DWI during RT are significantly faster than those based on PET-CT. Therefore, the feasibility of selecting boosting of the high signal area derived from DWI for individualized definition of the volume for esophageal cancer is not clear.

Despite advancements in therapeutic options, the overall prognosis for non-small-cell lung cancer (NSCLC) remains poor. Further exploration of the etiology and targets for novel treatments is crucial for managing NSCLC. In this study, we revealed the significant potential of EPB41 for inhibiting NSCLC proliferation, invasion and metastasis in vitro and in vivo. Consistent with its tumor suppressor role in NSCLC, the expression of EPB41 in NSCLC specimens evidently decreased compared to that in normal tissues, and low EPB41 expression was associated with poor prognoses for NSCLC patients. We further demonstrated the importance of EPB41 protein as a novel inhibitor of the Wnt signaling, which regulates β-Catenin stability, and elucidated the crucial role of the EPB41/ALDOC/GSK3β/β-Catenin axis in NSCLC. Suppression of EPB41 expression in cancer cells elevated the levels of free ALDOC protein released from the EPB41-ALDOC complex, leading to disassembly of the β-catenin destruction complex, reduced proteolytic degradation of β-catenin, elevated cytoplasmic accumulation and nuclear translocation of β-catenin, thereby activating the expression of multiple oncogenes and, thus, NSCLC pathogenesis. Our study highlights the potential of EPB41 as a future therapeutic target for lung cancer.