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Objectives: Despite excellent 5-year survival, there are limited data on the long-term prognostic characteristics of clinical stage IA part-solid lung adenocarcinoma. The objective was to elucidate the dynamics of prognostic characteristics through conditional survival analysis., Methods: Consecutive patients who underwent complete resection for clinical stage IA part-solid lung adenocarcinoma between 2011 and 2015 were retrospectively reviewed. Conditional survival is defined as the probability of surviving further y years, conditional on the patient has already survived x years. The conditional recurrence-free survival (CRFS) and conditional overall survival (COS) were analysed to evaluate prognosis over time, with conditional Cox regression analysis performed to identify time-dependent prognostic factors., Results: A total of 1539 patients were included with a median follow-up duration of 98.4 months, and 80 (5.2%) patients experienced recurrence. Among them, 20 (1.3%) recurrence cases occurred after 5 years of follow-up with 100% intrathoracic recurrence. The 5-year CRFS increased from 95.8% to 97.4%, while the 5-year COS maintained stable. Multivariable Cox analysis revealed that histologic subtype was always an independent prognostic factor for CRFS even after 5 years of follow-up, while the independent prognostic value of consolidation-to-tumour ratio, visceral pleural invasion and lymph node metastasis was observed only within 5 years. Besides, age, pathologic size and lymph node metastasis maintained independent predictive value for COS during long-term follow-up, while consolidation-to-tumour ratio was predictive for COS only within 5 years of follow-up., Conclusions: The independent prognostic factors for clinical stage IA part-solid lung adenocarcinoma changed over time, along with gradually increasing 5-year CRFS and stable 5-year COS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: The purpose of this study was to analyze the correlation between specified dual time-point fluorine-18 fluorodeoxyglucose ( 18 F-FDG) PET/computed tomography (CT) imaging parameters and pathological characteristics in non-small cell lung cancer (NSCLC) patients., Methods: This study retrospectively analyzed 47 patients with NSCLC. All patients underwent dual time-point 18 F-FDG PET/CT imaging. We obtained the metabolic parameters, standardized uptake value (SUV) maximum, SUV mean , delayed standardized uptake value (DSUV) maximum, DSUV mean , delay index standardized uptake value (DISUV) maximum, and DISUV mean , of the primary tumor. The tumor size was measured by CT. All lymph nodes had a definite pathological diagnosis. We next evaluated the status of the lymph node metastases (LNM) and the correlations between metabolic parameters and clinical characteristics. Receiver operating characteristic curves were drawn for the prediction of LNM., Results: We found that the DSUV max , DISUV max , DSUV mean , and tumor size were significantly related to LNM ( P  = 0.036, 0.009, and 0.049, respectively). Multivariate analysis revealed that tumor size and DISUV max were independent risk factors for LNM in lung cancer patients. According to the receiver operating characteristic curve analysis, the optimal cutoff values for DISUV max and tumor size were 0.33 and 2.8 cm, respectively. When these two parameters were combined, the area under the curve for predicting LNM in NSCLC was 0.768, and the sensitivity was 95.7% for predicting LNM in lung cancer patients. We further allocated the patients to three groups: the high-risk group (tumor size ≥ 2.8 cm, DISUV max  ≥ 0.33), the moderate-risk group (tumor size ≥ 2.8 cm, DISUV max  < 0.33, or tumor size < 2.8 cm, DISUV max  ≥ 0.33), and the low-risk group (tumor size < 2.8 cm, DISUV max  < 0.33). The rates of LNM were 70, 50, and 0%, respectively., Conclusion: Tumor size and DISUV max are risk factors for predicting LNM, and they are more useful in combination. Compared with standard PET/CT imaging, dual time-point PET/CT imaging has added value in predicting LNM in NSCLC patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Due to invasive and serial examinations of bioactive molecules, liquid biopsy (LB) has emerged as a rapid and reliable solution for early disease detection and monitoring. Developing portable devices with high specificity and sensitivity for LB is highly valuable. To realize a generalized approach to increase the sensitivity of LB, we developed an ultrasensitive diagnostic biochip based on the amplification of miRNA by recombinase polymerase amplification and the significant enhancement of fluorescence signals by photonic crystal (PC) materials. The PCs-RPA biochip has a detection limit as low as 0.24 aM, a wide linear range of 8 orders of magnitude, and excellent specificity. Such advantages realize the accurate detection of circulating miRNAs with very low content in clinical serum samples for the precise diagnosis of nonsmall cell lung cancer.

Background: This study aims to clarify the N6-methyladenosine (m6A) modification of LINC01006, which is involved in migration, invasion and proliferation of non-small cell lung cancer (NSCLC)., Materials and Methods: LINC01006 and METTL3 expressions were analyzed in TCGA-LUAD cohort. Colony formation assay, wound-healing assay and transwell assay were performed to evaluate the ability of colony formation, migration and invasion. Q-PCR and western blot analysis determined gene expressions. M6A-RNA immunoprecipitation and m6A quantification assay were used to evaluate m6A modification. qChIP assay was used to validate transcriptional target. Luciferase assay validated the miRNA targets and transcriptional targets. In-situ xenograft model were included to evaluate tumor proliferation in vivo., Results: LINC01006 and METTL3 expressions were elevated in NSCLC cells and tissues. LINC01006 promoted the migration and invasion of NSCLC via epithelial - mesenchymal transition (EMT). The expression of LINC01006 was positively correlated to the expression of METTL3. METTL3 promoted tumor formation and proliferation in the in-situ xenograft model of NSCLC. The expression of LINC01006 was increased by METTL3 via m6A modification. c-MYC directly induced METTL3. Both c-MYC and LINC01006 were commonly targeted by miR-34a/b/c and miR-2682, and thereby c-MYC/METTL3/LINC01006 formed a positive feedback loop through miRNA targets in NSCLC., Conclusions: LINC01006 is an oncogenic lncRNA, which induces migration, invasion and proliferation of NSCLC. METTL3 increases LINC01006 expression through stabilizing LINC01006 mRNA. c-MYC, as a transcription factor, activates METTL3, which results in an elevated level of LINC01006. c-MYC, METTL3 and LINC01006 form a positive feedback loop through multiple miRNA targets in NSCLC., Competing Interests: Conflicts of interest The authors have no relevant financial or non-financial interests to disclose., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose: Immune checkpoint inhibitors (ICIs) targeting tumor-specific PD-1/PD-L1 significantly improve the overall survival rate of patients with advanced cancer by reactivating the immune system to attack cancer cells. To explore their tumor killing effect, we used the radionuclide iodine-131 ( 131 I) to label the anti-PD-L1 antibody Atezolizumab ( 131 I-PD-L1 mAb)., Method: We prepared the radioimmunoassay molecular probe 131 I-PD-L1 mAb by the chloramine-T method and evaluated its affinity using Lewis lung cancer (LLC) cells. The uptake of 131 I-PD-L1 mAb by transplanted tumors was examined through SPECT and its in vivo distribution. We then compared the in vitro and in vivo anti-tumor efficacy of groups treated with control, PD-L1 mAb, 131 I-PD-L1 mAb, and 131 I-PD-L1 mAb + PD-L1 mAb combined treatment. We performed H&E staining to examine the changes in tumor, as well as the damage in major tissues and organs caused by potential side effects. The anti-tumor mechanism of 131 I-PD-L1 mAb was analyzed by Western blot, RT-qPCR and immunohistochemistry (IHC)., Result: 131 I-PD-L1 mAb was highly stable and specific, and easily penetrated into tumor. 131 I-PD-L1 mAb suppressed cancer cell proliferation in vitro, and inhibited tumor growth in vivo by inducing ferroptosis, thus prolonging the survival of experimental animals while demonstrating biological safety., Conclusion: Therefore, our study suggested that 131 I-PD-L1 mAb affected the expression of tumor-related factors through β-rays and thus promoted ferroptosis in tumor. Combined treatment showed better anti-tumor effect compared to single ICI treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1. In this study we investigated whether the combination of RA and GR could exert anti-metastatic effects against CRC. MC38 tumor xenograft mouse model with lung metastasis was established. The mice were administered RA (100 mg·kg -1 ·d -1 , i.g.) alone or in combination with GR (100 mg·kg -1 ·d -1 , i.p.). We showed that RA (50, 100, 150 μM) or a COX-2 inhibitor Celecoxib (1, 3, 9 μM) concentration-dependently inhibited the migration and invasion of MC38 cells in vitro. We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of filopodia. In the MC38 tumor xenograft mice, RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning; RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer. Compared to COX-2 inhibitors and immune checkpoint inhibitors, RA and GR displayed better safety profiles without disrupting the tissue structures of the liver, stomach and colon, offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune checkpoint molecule that suppresses CD8 + T-cell function in cancer. However, the expression profile and functional significance of TIGIT in the immune microenvironment of lung adenocarcinoma (LUAD) remain elusive. Interleukin (IL)-15 has emerged as a promising candidate for enhancing CD8 + T-cell mediated tumour eradication. Exploring therapeutic strategies that combine IL-15 with TIGIT blockade in LUAD is warranted., Methods: We investigated the regulatory network involving coinhibitory TIGIT and CD96, as well as costimulatory CD226 in LUAD using clinical samples. The potential role of TIGIT in regulating the pathogenesis of LUAD was addressed through a murine model with transplanted tumours constructed in Tigit -/- mice. The therapeutic strategy that combines TIGIT blockade with IL-15 stimulation was verified using a transplanted tumour murine model and a patient-derived organoid (PDO) model., Results: The frequency of TIGIT + CD8 + T cells was significantly increased in LUAD. Increased TIGIT expression indicated poorer prognosis in LUAD patients. Furthermore, the effector function of TIGIT + CD8 + tumour-infiltrating lymphocytes (TILs) was impaired in LUAD patients and TIGIT inhibited antitumour immune response of CD8 + TILs in tumour-bearing mice. Mechanistically, IL-15 enhanced the effector function of CD8 + TILs but stimulated the expression of TIGIT on CD8 + TILs concomitantly. The application of IL-15 combined with TIGIT blockade showed additive effects in enhancing the cytotoxicity of CD8 + TILs and thus further increased the antitumour immune response in LUAD., Conclusions: Our findings identified TIGIT as a promising therapeutic target for LUAD. LUAD could benefit more from the combined therapy of IL-15 stimulation and TIGIT blockade., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

To discuss the value of dual-source CT dual-energy parameters combined with serum detection of vascular endothelial growth factor (VEGF) and carcinoembryonic antigen (CEA) in the diagnosis of early lung cancer (LC). In total, 100 patients with lung lesions in our hospital from January 2020 to January 2022 were selected for retrospective study, and were divided into the lung cancer group (group A) and benign lung disease group (group B) according to the final results of pathological diagnosis, using dual-source CT dual-energy scanning combined with serum detection of VEGF and CEA to analyze the diagnostic values of single detection and combined detection. Among the 100 patients with lung lesions, there were 58 patients with LC and 42 patients with benign lung diseases after pathological examination, with no statistical difference in normalized iodine concentration (NIC) and the increased value of iodine at arterial phase between the two groups (P > 0.05). The NIC value of group A was higher than group B at venous phase (P < 0.05). The serum levels of VEGF and CEA in group A were higher than group B (P < 0.05). The area under the curve, specificity, sensitivity, Youden index and 95% CI of combined diagnosis were higher than single detection of NIC, VEGF and CEA at venous phase. The combined application of dual-source CT dual-energy parameters and serum detection of VEGF and CEA has higher diagnostic value in patients with early LC, which can provide effective reference for clinical diagnosis and treatment, with higher application value in clinic.

Background/aims: Response to therapy after using immune checkpoint inhibitors (ICIs) is unpredictable due to significant interindividual variation in efficacy among advanced non-small cell lung cancer (NSCLC) patients. The current study centered on the identification of perivascular blood biomarkers for predicting the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) treatment and progression-free survival (PFS) in advanced NSCLC patients, that could be applied to help determine how to change treatment plans therapeutic regimens for optimizing clinical benefits., Methods: A comprehensive review of 100 advanced or recurrent NSCLC patients receiving anti-PD-1 therapy (Camrelizumab, pembrolizumab, sintilimab, or nivolumab) was conducted between January 2018 and April 2021 in Tianjin Medical University Cancer Hospital. The cutoff values of D-dimer were selected from rom our previous study, and interleukin-6 (IL-6) was divided according to the median. Using computed tomography, tumor response was evaluated in accordance with the Response Assessment Criteria in Solid Tumors, version 1.1., Results: High IL-6 level in advanced NSCLC patients was predictive of low efficacy and a short PFS duration after anti-PD-1 therapy. An increased D-dimer value of 981 ng/mL was significantly predictive of disease progression in NSCLC patients treated with anti-PD-1 and high D-dimer expression predictive of short duration of PFS. Further studies on the correlation between IL-6, D-dimer, and anti-PD-1 efficacy in NSCLC patients stratified by gender revealed that D-dimer and IL-6 levels were significantly associated with the risk of PFS in male patients., Conclusions: High IL-6 content in peripheral blood in patients with advanced non-small cell lung cancer may contribute to poor anti-PD-1 efficacy and short duration of PFS through inducing alterations in the tumor microenvironment. D-dimer in peripheral blood is predictive of hyperfibrinolysis and contributes to the release of tumor-driven specific factors, leading to poor effects of anti-PD-1 therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Lung cancer (LC) is the most common malignancy in the world. It is well that hypoxia is common in lung cancer, which contributes to lung cancer progression and metastasis [1]. miRNA-27a as a repressor factor is a lowly expression within non-small cell lung cancer (NSCLC). However, the molecular mechanism between miR-27a and hypoxia in lung cancer progression remains poorly understood. This study aims to explore hypoxia promotes epithelial-mesenchymal transition in lung cancer cells via regulating the NRF2/miR‑27a/BUB1 pathway., Methods: We detect the expression of miR-27a after exposure to hypoxia conditions in lung cancer cells via qPCR. Using MTT assay and colony assay to assess the ability of proliferation in lung cancer cells under hypoxia or transfect miR-27a mimics. The capability of migration and invasion was evaluated by wound healing assay and Boyden-chamber assay. The mRNA and protein expression of EMT markers was respectively detected by qPCR and western blot. We detected NRF2 occupancy at the miR-27a promoter by ChIP-Seq analysis. Meanwhile, the luciferase assay verified BUB1 as a direct target of miR-27a., Results: We found hypoxia promotes lung cancer cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process by inhibiting the miR-27a expression. miR-27a mimics significantly reduced the promotion effect of hypoxia on the invasion and proliferation of lung cancer cells. NRF2 as regulating the oxidation/anti-oxidation factor was activated under hypoxia conditions. The activation of NRF2 repressed miR-27a expression. On the contrary, the inhibitory effect of hypoxia on miR-27a was reversed when the NFE2L2 gene was silenced. Ectopic expression of NRF2 inhibited miR-27a expression under normoxia. We further validated BUB1 as a direct target of the miR-27a by luciferase assay., Conclusion: Hypoxia promotes invasion and epithelial-mesenchymal transition of Lung cancer cells by regulating the NRF2/miR-27a/BUB1 axis., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Objective: To investigate the effectiveness of a CTC-based classifier in stratifying stage IB LUAD., Summary of Background Data: Stage IB LUADs have an approximately 70% 5-year survival rate. The clinical application of ACT is controversial due to inconsistent results in a series of trials and few useful guide biomarkers. Thus, there is a pressing need for robust biomarkers to stratify stage IB patients to define which group would most likely benefit from ACT. Methods: Two hundred twelve stage IB LUAD patients were enrolled and were divided into 3 independent cohorts. The aptamer-modified NanoVelcro system was used to enrich the CTCs., Results: A cutoff of <4 or >4 CTCs as the optimal prognostic threshold for stage IB LUAD was generated to stratify the patients in a 70-patient cohort into low-risk and high-risk groups. Patients with ≥ 4 CTCs in the training cohort had shorter progression-free survival ( P < 0.0001) and overall survival ( P < 0.0001) than patients with <4 CTCs. CTC number remained the strongest predictor of progression-free survival and overall survival even in a multivariate analysis including other clinicopathological parameters. Furthermore, a nomogram based on the CTC count was developed to predict the 3-year and 5-year survival in the training cohort and performed well in the other 2 validation cohorts (C-index: 0.862, 0.853, and 0.877)., Conclusion: The presence of >4 CTCs can define a high-risk subgroup, providing a new strategy to make optimal clinical decisions for stage IB LUAD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although four-dimensional cone-beam computed tomography (4D-CBCT) is valuable to provide onboard image guidance for radiotherapy of moving targets, it requires a long acquisition time to achieve sufficient image quality for target localization. To improve the utility, it is highly desirable to reduce the 4D-CBCT scanning time while maintaining high-quality images. Current motion-compensated methods are limited by slow speed and compensation errors due to the severe intraphase undersampling., Purpose: In this work, we aim to propose an alternative feature-compensated method to realize the fast 4D-CBCT with high-quality images., Methods: We proposed a feature-compensated deformable convolutional network (FeaCo-DCN) to perform interphase compensation in the latent feature space, which has not been explored by previous studies. In FeaCo-DCN, encoding networks extract features from each phase, and then, features of other phases are deformed to those of the target phase via deformable convolutional networks. Finally, a decoding network combines and decodes features from all phases to yield high-quality images of the target phase. The proposed FeaCo-DCN was evaluated using lung cancer patient data., Results: (1) FeaCo-DCN generated high-quality images with accurate and clear structures for a fast 4D-CBCT scan; (2) 4D-CBCT images reconstructed by FeaCo-DCN achieved 3D tumor localization accuracy within 2.5 mm; (3) image reconstruction is nearly real time; and (4) FeaCo-DCN achieved superior performance by all metrics compared to the top-ranked techniques in the AAPM SPARE Challenge., Conclusion: The proposed FeaCo-DCN is effective and efficient in reconstructing 4D-CBCT while reducing about 90% of the scanning time, which can be highly valuable for moving target localization in image-guided radiotherapy., (© 2022 American Association of Physicists in Medicine.)

Alveolar type II (AT II) is a key structure of the distal lung epithelium and essential to maintain normal lung homeostasis. Dedifferentiation of AT II cells is significantly correlated with lung tumor progression. However, the potential molecular mechanism and clinical significance of AT II-associated genes for lung cancer has not yet been fully elucidated. In this study, we comprehensively analyzed the gene expression, prognosis value, genetic alteration, and immune cell infiltration of eight AT II-associated genes (AQP4, SFTPB, SFTPC, SFTPD, CLDN18, FOXA2, NKX2-1, and PGC) in Nonsmall Cell Lung Cancer (NSCLC). The results have shown that the expression of eight genes were remarkably reduced in cancer tissues and observably relating to clinical cancer stages. Survival analysis of the eight genes revealed that low-expression of CLDN18, FOXA2, NKX2-1, PGC, SFTPB, SFTPC, and SFTPD were significantly related to a reduced progression-free survival (FP), and low CLDN18, FOXA2, and SFTPD mRNA expression led to a short postprogression survival (PPS). Meanwhile, the alteration of 8 AT II-associated genes covered 273 out of 1053 NSCLC samples (26%). Additionally, the expression level of eight genes were significantly correlated with the infiltration of diverse immune cells, including six types of CD4+T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. In summary, this study provided clues of the values of eight AT II-associated genes as clinical biomarkers and therapeutic targets in NSCLC and might provide some new inspirations to assist the design of new immunotherapies., Competing Interests: The authors declared no conflicts of interest., (Copyright © 2022 Liping Ren et al.)

Objective: To explore the effects of cyclophosphamide combined with vinorelbine in advanced small cell lung cancer (SCLC) and anteroposterior changes in MRI., Methods: The clinical data of 90 patients with advanced SCLC admitted to our hospital from April 2020 to April 2021 were retrospectively analyzed. They were divided into the control group and the study group according to the order of admission, with 45 cases in each group. The control group received the routine treatment, while the study group was treated with cyclophosphamide and vinorelbine to compare the indexes of imaging data and clinical indicators between the two groups before and after treatment., Results: There was no significant difference in the indexes of imaging data between the two groups before treatment ( P > 0.05), and the indexes of imaging data in the study group were visibly lower than those in the control group after treatment ( P < 0.001). The DCR in the study group was significantly higher than that in the control group after treatment ( P < 0.05), while the QLQ-C30 scores and serum indices of the study group after treatment were significantly lower than those of the control group ( P < 0.001)., Conclusion: Patients with advanced SCLC were treated with cyclophosphamide and vinorelbine, which can effectively improve the quality of life and reduce the expression of inflammatory factors. This treatment model has a higher application value, and the treatment value is also reflected compared with the routine treatment. At the same time, the permeability parameters obtained by MRI can predict the therapeutic effects of cyclophosphamide and vinorelbine, and further studies are helpful to establish a better solution for patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Zhichun Li and Liliang Ren.)

Background: The extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear., Methods: The expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models., Results: In the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice., Conclusion: Our findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis., (© 2022. The Author(s).)

Lung cancer is by far the leading cause of cancer death worldwide, and 85% of patients are diagnosed with non-small cell lung cancer (NSCLC), which is still very difficult to treat. Skp2 functions as an oncogene that participates in processes of many cancers. Here, we report a novel Skp2 inhibitor AAA-237 that binds to Skp2 protein and inhibits the proliferation of the NSCLC cells. We further investigated the anti-NSCLC mechanism of AAA-237 and found that it arrested the cell cycle at the G0/G1 phase by targeting Skp2 to reduce the degradation of p21Cip1 and p27Kip1 or by transcriptionally activating FOXO1 to increase the mRNA expression of p21Cip1 and p27Kip1. More importantly, we found that treatment of a high concentration AAA-237 could induce apoptosis of NSCLC cells and treatment of a low AAA-237 concentration for a longer time could induce senescence of NSCLC cells. Similar results were found in nude mice xenografted with A549 cells. AAA-237 inhibited tumor growth by inducing apoptosis and senescence in a dose-dependent manner. Considering these results, we propose that AAA-237 could be a promising therapeutic drug for treating patients with NSCLC., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective. 4D-CBCT provides phase-resolved images valuable for radiomics analysis for outcome prediction throughout treatment courses. However, 4D-CBCT suffers from streak artifacts caused by under-sampling, which severely degrades the accuracy of radiomic features. Previously we developed group-patient-trained deep learning methods to enhance the 4D-CBCT quality for radiomics analysis, which was not optimized for individual patients. In this study, a patient-specific model was developed to further improve the accuracy of 4D-CBCT based radiomics analysis for individual patients. Approach. This patient-specific model was trained with intra-patient data. Specifically, patient planning 4D-CT was augmented through image translation, rotation, and deformation to generate 305 CT volumes from 10 volumes to simulate possible patient positions during the onboard image acquisition. 72 projections were simulated from 4D-CT for each phase and were used to reconstruct 4D-CBCT using FDK back-projection algorithm. The patient-specific model was trained using these 305 paired sets of patient-specific 4D-CT and 4D-CBCT data to enhance the 4D-CBCT image to match with 4D-CT images as ground truth. For model testing, 4D-CBCT were simulated from a separate set of 4D-CT scan images acquired from the same patient and were then enhanced by this patient-specific model. Radiomics features were then extracted from the testing 4D-CT, 4D-CBCT, and enhanced 4D-CBCT image sets for comparison. The patient-specific model was tested using 4 lung-SBRT patients' data and compared with the performance of the group-based model. The impact of model dimensionality, region of interest (ROI) selection, and loss function on the model accuracy was also investigated. Main results. Compared with a group-based model, the patient-specific training model further improved the accuracy of radiomic features, especially for features with large errors in the group-based model. For example, the 3D whole-body and ROI loss-based patient-specific model reduces the errors of the first-order median feature by 83.67%, the wavelet LLL feature maximum by 91.98%, and the wavelet HLL skewness feature by 15.0% on average for the four patients tested. In addition, the patient-specific models with different dimensionality (2D versus 3D) or loss functions (L1 versus L1 + VGG + GAN) achieved comparable results for improving the radiomics accuracy. Using whole-body or whole-body+ROI L1 loss for the model achieved better results than using the ROI L1 loss alone as the loss function. Significance. This study demonstrated that the patient-specific model is more effective than the group-based model on improving the accuracy of the 4D-CBCT radiomic features analysis, which could potentially improve the precision for outcome prediction in radiotherapy., (© 2022 Institute of Physics and Engineering in Medicine.)

Background: Aberrant expression of m6A-related proteins contributes to the occurrence and progression of non-small cell lung cancer (NSCLC). Current studies mainly focus on single m6A regulatory genes and their underlying mechanisms, and the expression of multiple m6A regulatory proteins in NSCLC remains unclear. Therefore, it is necessary to systematically examine these proteins, particularly in clinical specimens., Methods: Bioinformatic analysis was used to determine the expression of m6A regulatory genes and their correlation with common gene mutations, such as TP53, EGFR and KRAS, using The Cancer Genome Atlas (TCGA) and the AE-meta databases. Immunohistochemistry was employed to analyze the protein expression of m6A regulatory proteins in 61 benign lung tissues and 316 NSCLC tissues. Statistical analysis was performed to calculate the correlation between the expression of m6A regulatory proteins and clinicopathological features, survival, and common gene mutations in lung carcinoma patients., Results: Analysis of the mRNA levels of 13 core m6A regulators, using information from TCGA and the AE-meta databases, revealed that YTHDF1 levels were upregulated in NSCLC compared to those in adjacent normal tissues. Immunohistochemical staining showed that the expression of METTL3, ALKBH5, YTHDC2 and YTHDF1 was significantly upregulated in NSCLC tissues. Further analyses demonstrated a positive correlation between differentially expressed m6A regulatory proteins, including METTL3, ALKBH5, YTHDC2 and YTHDF1, and the poor clinicopathological features and survival of NSCLC patients. According to the statistics of NSCLC patients enrolled in the present study, the protein levels of METTL3 in patients with EGFR exon-19 mutation were higher than those in patients with wild-type EGFR., Conclusions: Our results indicate that m6A regulators, including METTL3, ALKBH5, YTHDC2 and YTHDF1, could serve as predictive markers of NSCLC, which will facilitate the early detection and diagnosis of NSCLC., (© 2021 John Wiley & Sons, Ltd.)

Purpose: Lung stereotactic ablative body radiotherapy (SABR) is a radiation therapy success story with level 1 evidence demonstrating its efficacy. To provide real-time respiratory motion management for lung SABR, several commercial and preclinical markerless lung target tracking (MLTT) approaches have been developed. However, these approaches have yet to be benchmarked using a common measurement methodology. This knowledge gap motivated the MArkerless lung target Tracking CHallenge (MATCH). The aim was to localize lung targets accurately and precisely in a retrospective in silico study and a prospective experimental study., Methods: MATCH was an American Association of Physicists in Medicine sponsored Grand Challenge. Common materials for the in silico and experimental studies were the experiment setup including an anthropomorphic thorax phantom with two targets within the lungs, and a lung SABR planning protocol. The phantom was moved rigidly with patient-measured lung target motion traces, which also acted as ground truth motion. In the retrospective in silico study a volumetric modulated arc therapy treatment was simulated and a dataset consisting of treatment planning data and intra-treatment kilovoltage (kV) and megavoltage (MV) images for four blinded lung motion traces was provided to the participants. The participants used their MLTT approach to localize the moving target based on the dataset. In the experimental study, the participants received the phantom experiment setup and five patient-measured lung motion traces. The participants used their MLTT approach to localize the moving target during an experimental SABR phantom treatment. The challenge was open to any participant, and participants could complete either one or both parts of the challenge. For both the in silico and experimental studies the MLTT results were analyzed and ranked using the prospectively defined metric of the percentage of the tracked target position being within 2 mm of the ground truth., Results: A total of 30 institutions registered and 15 result submissions were received, four for the in silico study and 11 for the experimental study. The participating MLTT approaches were: Accuray CyberKnife (2), Accuray Radixact (2), BrainLab Vero, C-RAD, and preclinical MLTT (5) on a conventional linear accelerator (Varian TrueBeam). For the in silico study the percentage of the 3D tracking error within 2 mm ranged from 50% to 92%. For the experimental study, the percentage of the 3D tracking error within 2 mm ranged from 39% to 96%., Conclusions: A common methodology for measuring the accuracy of MLTT approaches has been developed and used to benchmark preclinical and commercial approaches retrospectively and prospectively. Several MLTT approaches were able to track the target with sub-millimeter accuracy and precision. The study outcome paves the way for broader clinical implementation of MLTT. MATCH is live, with datasets and analysis software being available online at https://www.aapm.org/GrandChallenge/MATCH/ to support future research., (© 2021 American Association of Physicists in Medicine.)

miR-34, whose mimic was used on phase I clinical trial, has been extensively reported since its dysfunction in various cancers including non-small-cell lung cancer (NSCLC). However, the roles of miR-34 family members in the progression of lung squamous carcinoma (SCC) in patients who have occupational-exposure experience are unclear yet. Here, we comprehensively investigated the expression levels of miR-34 family members in SCC patients and compared the roles of them in SCC in vitro and vivo. The results showed that the average levels of miR-34a and miR-34b/c were decreased in patients. The analysis of miR-34a to miR-34b/c levels in patients graded different stages or metastases or recurrence showed that miR-34b/c was reduced earlier and more significantly than miR-34a. In vitro assays demonstrated that both miR-34a and miR-34b/c inhibits SCC cells proliferation, migration and invasion via Notch1 pathway, while miR-34b/c effects more than miR-34a does. As miR-34a was significantly decreased in cancer recurrence, the further analysis of relationship between miR-34a and stem cell adhesion molecular CD44 showed that miR-34a was significantly correlated with CD44 levels in patients. Knockdown of CD44 significantly blocked miR-34a mediated inhibition of cell migration and invasion. Treating the purified CD44 hi cells with miR-34 overexpression lentivirus inhibited the tumor outgrowth. By contrast, anti-miR-34 facilitated tumor development of CD44 low cells. Our study showed that miR-34 family members are negative regulator for SCC development, even though the inhibition is mediated by multiple and complicated signal pathways, which provides theoretical basis for SCC treatment and a biomarker candidate for SCC prognosis., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The genomic mutation and immune feature landscape of ERBB2 exon 20 insertion (ERBB2-ex20ins)-driven non-small cell lung cancer and the features associated with the response to chemoimmunotherapy are currently unknown., Methods: The genomic landscape of ERBB2-ex20ins lung adenocarcinoma (LUAD) patients was characterized by next-generation sequencing (NGS) of 1021 cancer genes. The clinical outcomes of chemoimmunotherapy were evaluated among 13 patients with stage IV ERBB2-ex20ins LUAD, and potential biomarkers of the response to chemoimmunotherapy were explored using NGS and T cell receptor sequencing., Results: Among 8247 LUAD patients, 207 (2.5%) had ERBB2-ex20ins, of whom 181 (87.4%) harbored more than one comutation. The most common comutations were in TP53. Patients with ERBB2-ex20ins had a low tumor mutational burden (TMB; median, 4.2 mutations/Mb), and most (66.7%) were PD-L1 negative. Thirteen of the 207 patients received chemoimmunotherapy, for whom the objective response rate, disease control rate, and median progression-free survival were 31%, 77%, and 8.0 months, respectively. Responders exhibited a higher TMB and a trend toward lower clonality in tumors compared with nonresponders (p = 0.0067 and p = 0.085, respectively). A high TMB combined with mutations in DNA damage repair pathways and SWI/SNF chromatin remodeling complexes was associated with a benefit from chemoimmunotherapy., Conclusions: The efficacy and outcome of chemoimmunotherapy were encouraging among ERBB2-ex20ins LUAD patients, who were characterized by low TMB and negative PD-L1 expression. The combination of TMB and comutations is a potential biomarker to identify patients who will benefit from chemoimmunotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lung cancer is the fastest growth rate of morbidity and mortality in nearly a decade, and remains difficult to treat. Furthermore, the molecular mechanisms underlying its development are still unclear. In this study, bioinformatics analysis showed that MELK was highly expressed in lung cancer and negatively correlated to the survival of lung adenocarcinoma (LUAD). Immunohistochemistry analysis of LUAD patient tissues revealed there were a high level of MELK expression in LUAD. Knockdown of MELK expression inhibits the migration and invasion of LUAD cells, which may be mediated by Twist1, Slug, MMP7, and N-catenin. Overexpression of MELK promoted the growth of LUAD cells in medium, 3D Matrigel, and nude mice. Inhibition of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway, and triggered apoptosis-mediated pyroptosis. Together, these data indicate that MELK is critical for metastasis, mitotic progression, and programmed death of LUAD and may be a promising therapeutic target for LUAD.

Purpose: To find serum tumor markers for predicting the presence of lymphatic metastasis in patients with lung adenocarcinoma, and to explore the diagnostic value of IGFBP7 in predicting if lymphatic metastasis occurs in lung adenocarcinoma., Methods: The concentration of IGFBP7 in the peripheral blood of 90 serum samples, including 30 patients with lung adenocarcinoma in situ, 30 patients with lung adenocarcinoma metastasis, and 30 normal controls were detected by ELISA. The data were analyzed statistically., Results: The concentration of IGFBP7 and D-dimer in the metastatic lung adenocarcinoma group was significantly higher than that in the lung adenocarcinoma in situ group (P < 0.05). The expression level of IGFBP7 in serum of patients with lung adenocarcinoma was associated with the clinical stage (P < 0.05) and lymphatic metastasis (P < 0.05). Using the receiver operating characteristic (ROC) curve, the area under the ROC curve of IGFBP7 was 0.901 (95% Confidence Interval was 0.806 to 0.996), and 0.5 was outside the 95% confidence interval (P < 0.05). The difference was statistically significant., Conclusions: IGFBP7 can predict if the lung adenocarcinoma has lymphatic metastasis, which is helpful to improve the treatment of lung adenocarcinoma, and can be used as a new tumor marker to predict whether the lung adenocarcinoma has lymphatic metastasis or not., (Copyright © 2020. Published by Elsevier Inc.)

Multi-walled carbon nanotubes (MWCNTs) are one of the most widely used types of novel nano-fiber materials. The aim of this study was to establish an experimental system based on actual exposure dosage and environments and explore the roles and mechanisms of inflammation in the malignant transformation of pleural mesothelial cells induced by MWCNTs after low doses and long-term exposure. Here, we established an in vitro system by co-culturing macrophages and mesothelial cells and exposing these cells to high aspect ratio MWCNTs (0.1 μg/mL) for three months. Results indicated that IL-1β, secreted by macrophages stimulated by MWCNTs, may significantly enhance the release of inflammatory cytokines, such as IL-8, TNF-α, and IL-6, from mesothelial cells. Results obtained from proliferation, migration, invasion, colony formation, and chromosomal aberration studies indicated that MWCNTs may promote malignant transformation of mesothelial cells after long-term and low-dose exposure via inflammation. Furthermore, the obtained results demonstrated that the NF-κB/IL-6/STAT3 pathway was active in the malignant transformation of Met 5A cells, induced by MWCNTs, and played an important role in the process. In conclusion, our results showed that the NF-κB (p65)/IL-6/STAT3 molecular pathway, which was mediated by inflammation, played an important role in the malignant transformation of pleural mesothelial cells induced by MWCNTs. These findings also provide novel ideas and references for the treatment of mesothelioma and offers options for the occupational safety of nanomaterial practitioners.

Background: Hypoxia is a hallmark of cancer and is associated with poor prognosis. However, the molecular mechanism by which hypoxia promotes tumor progression remains unclear. MicroRNAs dysregulation has been shown to play a critical role in the tumor and tumor microenvironment. Here, we investigated the roles of miR-495 and miR-5688 in human non-small cell lung cancer (NSCLC) and their underlying mechanism., Methods: The expression levels of miR-495 and miR-5688 in human NSCLC tissue specimens were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Deferoxamine (DFO) was used to determine whether the regulation of miR-495 and miR-5688 under hypoxia was dependent on hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, the functions of miR-495 and miR-5688 in tumor progression were evaluated using colony formation, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), wound healing, transwell assays, and xenograft model. Two algorithms, PicTAR and Targetscan, were used to predict the target gene of these two miRNAs, and dual-luciferase reporter assay was conducted to confirm the target. The unpaired two-tailed t test, Pearson correlation analysis, and Fisher's exact probability test were performed for statistical analyses., Results: Two miRNAs, miR-495 and miR-5688, were found to participate in NSCLC progression under hypoxia. They were down-regulated in NSCLC tissues compared with normal tissues. We determined that hypoxia led to the down-regulation of miR-495 and miR-5688 in NSCLC cells, which was independent of HIF-1α and cellular metabolic energy. In addition, miR-495 and miR-5688 suppressed cell proliferation, migration, and invasion in vitro. The NSCLC xenograft model showed that miR-495 and miR-5688 inhibited tumor formation in vivo. Interestingly, we found that miR-495 and miR-5688 had the same target, interleukin-11 (IL-11). Recombinant human IL-11 counteracted the effects of miR-495 and miR-5688 on NSCLC cells, suggesting that miR-495 and miR-5688 executed their tumor suppressive role by repressing IL-11 expression., Conclusion: We found that hypoxia down-regulated the expression levels of miR-495 and miR-5688 in NSCLC to enhance IL-11 expression and tumor progression, indicating that the miR-495/miR-5688/IL-11 axis may serve as a therapeutic target and potential biomarker for NSCLC., (© 2020 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Purpose: Lung cancer (LC) is one of the fastest-growing malignant tumors in the world in terms of morbidity and mortality. CYP3A4 plays a crucial role in the occurrence of LC. Little is known about the contribution of CYP3A4 polymorphisms for non-small cell lung cancer (NSCLC) risk. This study aimed to explore the correlation of CYP3A4 genetic variants (rs3735451, rs4646440, rs35564277, and rs4646437) with NSCLC risk., Methods: Four single nucleotide polymorphisms (SNPs) were genotyped by Agena MassARRAY in this case-control study (507 NSCLC patients and 505 controls) among a Shaanxi Han population. Hardy-Weinberg equilibrium (HWE) of each SNP in controls was evaluated by exact test. The association of CYP3A4 polymorphisms with NSCLC risk was explored by calculating odds ratios (OR) and 95% confidence intervals (CI) using logistic regression analysis with adjustment for age and gender., Results: Our research revealed that rs4646440 was significantly associated with an increased risk of NSCLC (OR 2.64, p = .005), while rs4646437 played a protective role in NSCLC risk (OR 0.48, p = 4.00 × 10 -7 ). Stratified analyses indicated that rs4646440 significantly enhanced the susceptibility of NSCLC in BMI > 24 kg/m 2 , non-smokers and non-drinkers (OR 14.29, p = .012; OR 1.56, p = .023; OR 1.67, p = .031, respectively). Besides, we observed that rs3735451 exhibited an increased risk of NSCLC in BMI > 24 kg/m 2 (OR 2.47, p = .030), whereas rs4646437 had a reduced risk of NSCLC in BMI ≤ 24 kg/m 2 (OR 0.47, p = 5.17 × 10 -5 ). We also found that rs35564277 was considered as a protective factor of NSCLC in non-smokers (OR 0.50, p = .032)., Conclusion: Our study indicated that CYP3A4 genetic variants were associated with NSCLC susceptibility in a Shaanxi Han population., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Inc.)

Background: Anaplastic lymphoma kinase (ALK) rearrangement is a common driver gene of non-small cell lung cancer (NSCLC). Ceritinib is a second-generation ALK inhibitor, which can bring survival benefits to ALK-positive metastatic NSCLC. However, few studies focus on the safety and efficacy of ceritinib in China. Therefore, this study intends to investigate the safety and preliminary efficacy of ceritinib 450 mg with meals in Chinese patients with ALK-positive NSCLC through a real world study., Methods: From October 2018 to December 2019, patients with ALK-positive NSCLC from 8 medical centers in Sichuan province were recruited in this study. All of these participants received ceritinib 450 mg/d with food. The basic characteristics, adverse effects (AEs) and responses were collected and analyzed in order to evaluate the safety and efficacy of ceritinib., Results: A total of 109 patients were included in this study. Data cutoff was January 23, 2020. The median duration of treatment exposure was 5.87 mon (range: 0.4 mon-15.7 mon). Total AEs were reported in 98 (89.9%) of 109 patients and grade 3 or 4 AEs were reported in 22.9% of patients. Most common AEs (mainly grade 1 or 2) were diarrhea (60.6%), elevated alanine aminotransferase (ALT)(38.5%) and aspartate aminotransferase (AST)(37.6%). As of data cutoff, 45 patients discontinued ceritinib. The overall response rate (ORR) was 37.6% (95%CI: 28.5%-47.4%) and disease control rate (DCR) was 86.2% (95%CI: 78.3%-92.1%)., Conclusions: The treatment of ceritinib 450 mg with food for Chinese ALK-positive NSCLC patients had a good safety profile and favorable DCR in real-world setting. However, this conclusion needs to be further verified by large sample, prospective trials.

Objective Apatinib is an oral small molecule anti-angiogenic drug. This phase I study aimed to establish the feasible dose of apatinib in combination with pemetrexed plus carboplatin as first-line therapy for epidermal growth factor receptor (EGFR) and anaplasticlymphoma kinase (ALK) negative stage IV non-squamous non-small cell lung cancer (NSCLC). Methods Using a 3 + 3 dose-reduction design, patients received oral apatinib at four dose levels: 750 mg qd, 500 mg qd, 500 mg/day two weeks on/one week off schedule (500 mg schedule 2/1) or 250 mg qd. Pemetrexed (500 mg/m 2 ) plus carboplatin (AUG = 5) was administered every three weeks. Maintenance therapy by apatinib or pemetrexed could be carried on until disease progression or unacceptable toxicity. The feasible dose was determined based on cycle 1 dose-limiting toxicities (DLT); other assessments included safety and antitumor activity according to response evaluation criteria in solid tumors. Result A total of twelve patients were enrolled and cycle 1 DLTs were observed in two patients at 750 mg qd dosage of apatinib (both Grade 3 hypertension), two patients at 500 mg qd (Grade 3 hypertension and Grade 3 hand-foot syndrome), and only one of six patients at 500 mg/day schedule 2/1 (Grade 3 hypertension). The most frequently drug-related adverse events (AEs) were hematological toxicity, hypertension, hand-foot syndrome, and hepatic transaminases elevation. Partial response was observed in four patients of eleven evaluable patients (objective response rate 36.4%), and six patients exhibited stable disease (disease control rate 90.9%). Conclusion In patients with advanced non-squamous NSCLC, the feasible dose of apatinib given with standard-dose pemetrexed and carboplatin was 500 mg/day schedule 2/1. The schedule was generally well tolerated and demonstrated promising clinical benefit in NSCLC.

Toll-like receptor (TLR) signaling is an emerging pathway in tumor cell invasion and metastasis. Myeloid differentiation protein-2 (MD2) contributes to ligand recognition and activation of TLRs in response to exogenous microbial insults or endogenous agents. We hypothesized that blocking MD2 using a specific inhibitor would prevent TLR4-mediated inflammatory responses and metastatic cancer growth. Here, we report that a MD2 inhibitor, L6H21, inhibited migration and invasion of LPS-activated colon cancer CT26.WT cells. These activities were accompanied by inhibition of nuclear factor-κB (NF-κB) activation, and thereby inhibition of the production of pro-inflammatory cytokines and adhesive molecules in colon cancer cells. Furthermore, L6H21 inhibited CT26.WT metastasis to the lung in BALB/c mice as well as suppressed colitis-induced colon cancer induced by azoxymethane/dextran sulfate sodium (AOM/DSS). Taken together, our results demonstrated that L6H21 suppressed tumor invasion and metastasis through blocking TLR4-MD2/NF-κB signaling axis. These findings reveal that inhibition of MD2 may be an important target for the development of colon cancer therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

To achieve accurate and fast deformable image registration (DIR) for pulmonary CT, we proposed a Multi-scale DIR framework with unsupervised Joint training of Convolutional Neural Network (MJ-CNN). MJ-CNN contains three models at multi-scale levels for a coarse-to-fine DIR to avoid being trapped in a local minimum. It is trained based on image similarity and deformation vector field (DVF) smoothness, requiring no supervision of ground-truth DVF. The three models are first trained sequentially and separately for their own registration tasks, and then are trained jointly for an end-to-end optimization under the multi-scale framework. In this study, MJ-CNN was trained using public SPARE 4D-CT data. The trained MJ-CNN was then evaluated on public DIR-LAB 4D-CT dataset as well as clinical CT-to-CBCT and CBCT-to-CBCT registration. For 4D-CT inter-phase registration, MJ-CNN achieved comparable accuracy to conventional iteration optimization-based methods, and showed the smallest registration errors compared to recently published deep learning-based DIR methods, demonstrating the efficacy of the proposed multi-scale joint training scheme. Besides, MJ-CNN trained using one dataset (SPARE) could generalize to a different dataset (DIR-LAB) acquired by different scanners and imaging protocols. Furthermore, MJ-CNN trained on 4D-CTs also performed well on CT-to-CBCT and CBCT-to-CBCT registration without any re-training or fine-tuning, demonstrating MJ-CNN's robustness against applications and imaging techniques. MJ-CNN took about 1.4 s for DVF estimation and required no manual-tuning of parameters during the evaluation. MJ-CNN is able to perform accurate DIR for pulmonary CT with nearly real-time speed, making it very applicable for clinical tasks.

Aim: To assess the cost-effectiveness of crizotinib verses platinum-based doublet chemotherapy as the first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in the real-world setting. Methods: Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China). They were categorized into two groups as treated with crizotinib (n = 83) or chemotherapy (n = 80) as a first-line therapy. The progression-free survival (PFS) as the primary clinical outcome, and the direct medical costs were collected from hospital information systems. Incremental cost-effectiveness ratio (ICER) was calculated with costs, quality-adjusted life-years, as well as the costs discounted at 3% annually. Additionally, two different kinds of medical insurance (MI) for pharma-economic assessment were considered. Results: Crizotinib improved PFS versus chemotherapy in ALK positive patients (median PFS 19.67 m vs 5.47 m; p < 0.001). Moreover, crizotinib obtained an ICER of US$36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than the willingness to pay threshold (three-times of gross domestic product per capita in mainland China or Sichuan Province). However, ICER was US$7321.16, which is less than willingness to pay, when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anticancer drugs were MI covered. One-way sensitivity analysis for the reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased. Conclusion: Crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC with the MI coverage currently available in Chengdu, Sichuan Province, China.

Objectives: Small cell lung carcinoma (SCLC) is a highly malignant tumor characterized by early metastasis even at the time of diagnosis. Although pancreatic metastasis occurring in SCLC is a common observation in the literatures, there is currently very limited experience with the metastasis-induced acute pancreatitis in SCLC patients., Methods: Here we retrospectively analyzed patients with metastasis-induced acute pancreatitis and SCLC in West China Hospital between 2009 and 2017. The patients were diagnosed as having SCLC by bronchoscopic biopsy or computed tomography-guided percutaneous biopsy. Metastasis-induced pancreatitis was established by clinical symptoms, radiologic surveillance, serum amylase, and lipase level. The series included 14 patients, 4 women and 10 men, with a mean age of 54 years (range, 29-76 years). The patients underwent chemotherapy plus palliative treatment (n = 8) or palliative care alone (n = 6)., Results: Compared with patients receiving palliative treatment alone, a trend toward improved survival was observed in patients who underwent chemotherapy., Conclusion: Our personal experience indicated that chemotherapy might provide a survival benefit in SCLC patients with metastasis-induced pancreatitis, especially those with good performance status.

Background: Inflammation is crucial for lung cancer development. Variants of multiple genes in inflammation pathways may lead to susceptibility to lung cancer. In the present study, we aimed to assess the influence of polymorphisms in inflammation-related genes (IL2RA and IL2RB) on lung cancer risk., Methods: A total of 507 patients with lung cancer and 503 healthy controls were genotyped for seven polymorphisms of IL2RA and IL2RB using the Agena MassARRAY platform. We evaluated the relationship of the genotypes with lung cancer susceptibility using odds ratio (OR), 95% confidence interval (95% CI) and chi square test., Results: We found that IL2RA rs12722498 was significantly associated with a decreased risk of lung cancer in dominant (p = 0.040, OR = 0.71, 95% CI = 0.51-0.98), additive (p = 0.016, OR = 0.68, 95% CI = 0.50-0.93) and allele (p = 0.019, OR = 0.69, 95% CI = 0.51-0.94) models. After stratification analysis, the results showed that IL2RA rs12569923 (non-smokers), IL2RA rs791588 (≤60 years old, non-drinkers, BMI < 24 kg/m 2 ), IL2RA rs12722498 (≤60 years old, non-drinkers, BMI < 24 kg/m 2 , female) and IL2RB rs2281089 (female, stage) significantly decreased the risk of lung cancer. Additionally, the haplotypes of rs12569923 and rs791588 in IL2RA had strong relationships with lung cancer in the subgroups of BMI < 24 kg/m 2 , age ≤ 60 years old, non-smokers and non-drinkers., Conclusion: Our results showed that the IL2RA and IL2RB polymorphisms were associated with lung cancer risk in the Chinese Han population, which suggests roles for IL2RA and IL2RB polymorphisms in lung cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The limited-angle intrafractional verification (LIVE) system was developed to track tumor movement during stereotactic body radiation therapy (SBRT). However, the four-dimensional (4D) MV/kV imaging procedure results in additional radiation dose to patients. This study is to quantify imaging radiation dose from optimized MV/kV image acquisition in the LIVE system and to determine if it exceeds the American Association of Physicists in Medicine Task Group Report 180 image dose threshold., Methods: TrueBeam™ platform with a fully integrated system for image guidance was studied. Monte Carlo-simulated kV and MV beams were calibrated and then used as incident sources in an EGSnrc Monte Carlo dose calculation in a CT image-based patient model. In three representative lung SBRT treatments evaluated in this study, tumors were located in the patient's posterior left lung, mid-left lung, and right upper lung. The optimized imaging sequence comprised of arcs ranging from 2 to 7, acquired between adjacent three-dimensional (3D)/IMRT beams, with multiple simultaneous kV (125 kVp) and MV (6 MV) image projections in each arc, for different optimization scenarios. The MV imaging fields were generally confined to the treatment target while kV images were acquired with a normal open field size with a full bow-tie filter., Results: In a seven-arc acquisitions case (highest imaging dose scenario), the maximum kV imaging doses to 50% of the tissue volume (D50 from DVHs), for spinal cord, right lung, heart, left lung, and the target, were 0.4, 0.4, 0.6, 0.7, and 1.4 cGy, respectively. The corresponding MV imaging doses were 0.1 cGy to spinal cord, right lung, heart, and left lung, and 11 cGy to target. In contrast, the maximum radiation dose from two cases treated with two Volumetric-Modulated Arc Therapy (VMAT) fields and two-arc image acquisitions is approximately 30% of that of the seven-arc acquisition., Conclusions: We have evaluated the additional radiation dose resulting from optimized LIVE system MV/kV image acquisitions in two best (least imaging dose) and one worst (highest imaging dose) lung SBRT treatment scenarios. The results show that these MV/kV imaging doses are comparable to those resulting from current imaging procedures used in Image-Guided Radiation Therapy (IGRT) and are within the dose threshold of 5% target dose as recommended by the AAPM TG-180 report., (© 2019 American Association of Physicists in Medicine.)

To clinically investigate the limited-projection CBCT (LP-CBCT) technology for daily positioning of patients receiving breath-hold lung SBRT radiation treatment and to investigate the feasibility of reconstructing fast 4D-CBCT from 1 min 3D-CBCT scan. Eleven patients who underwent breath-hold lung SBRT radiation treatment were scanned daily with on-board full-projection CBCT (CBCT) using half-fan scan. A subset of the CBCT projections and the prior planning CT were used to estimate the LP-CBCT images using the weighted free-form deformation method. The limited projections are clusteringly sampled within fifteen sub-angles in 360° in order to simulate the fast 1 min scan for 4D-CBCT. The estimated LP-CBCTs were rigidly registered to the planning CT to determine the clinical shifts needed for patient setup corrections, which were compared with shifts determined by the CBCT for evaluation. Both manual and automatic registrations were performed in order to compare the systematic registration errors. Fifty CBCT volumes were obtained from the eleven patients in fifty fractions for this pilot clinical study. For the CBCT images, the mean (±standard deviation) shifts between CBCT and planning CT from manual registration in left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions are 1.1  ±  1.2 mm, 2.1  ±  1.9 mm, 5.2  ±  3.6 mm, respectively. The mean deviation difference between shifts determined by CBCT and LP-CBCT images are 0.3  ±  0.5 mm, 0.5  ±  0.8 mm, 0.4  ±  0.3 mm, in LR, AP, and SI directions, respectively. The mean vector length of CBCT shift for all fractions is 6.1  ±  3.6 mm, and the mean vector length difference between CBCT and LP-CBCT for all fractions studied is 1.0  ±  0.9 mm. The automatic registrations yield similar results as manual registrations. The pilot clinical study shows that LP-CBCT localization offers comparable accuracy to CBCT localization for daily tumor positioning while reducing the projection number to 1/10 for patients receiving breath hold lung radiation treatment. The cluster projection sampling in this study also shows the feasibility of reconstructing fast 4D-CBCT from 1 min 3D-CBCT scan.

Objective: MicroRNAs (miRNAs) are endogenous, non-coding small RNAs, which play an important part in regulating organismal and pathological processes. Previous studies have shown that miRNA-199 acts as a tumor suppressor gene. However, we aimed to explore the characteristics and function of miRNA-199 in lung cancer (LCa), so as to further study its relationship with clinicopathological parameters and prognosis., Patients and Methods: Quantitative Real-time polymerase chain reaction (qRT-PCR) was used to detect miRNA-199 expression in 75 pairs of LCa tissues and normal adjacent tissues. In addition, the relationship between miRNA-199 expression and pathological features along with the prognosis of LCa patients were investigated. Besides, the expression level of miRNA-199 in LCa cells was further validated by qRT-PCR. In addition, miRNA-199 overexpression expression model was constructed in LCa cell lines H1299 and SPCA1. Cell counting kit-8 (CCK-8), cell cloning experiments, transwell invasion and migration assays were performed to analyze the effect of miRNA-199 on the biological function of LCa cells. Finally, the potential mechanism was explored using Western blot., Results: qRT-PCR results displayed that the expression level of miRNA-199 in LCa tissues was significantly lower than that of the normal tissues. Compared with patients with high miRNA-199 expression, patients with lowly-expressed miRNA-199 had higher rates of lymph node metastases and distant metastases, and their overall survival rates were lower. In addition, the proliferation, invasion and metastasis of the miRNA-199 overexpression group were significantly increased than that in the negative control group. Western Blot results showed that the expression of key proteins in the EMT pathway, such as N-cadherin, Vimentin, β-catenin and MMP9 significantly increased in miRNA-199 overexpression group. Moreover, we also found that miRNA-199 and RGS17 have mutual regulation, which inhibited the malignant progression of LCa., Conclusions: miRNA-199 expression was down-regulated in LCa and was significantly associated with LCa stage, distant metastasis, and poor prognosis. Besides, miRNA-199 may inhibit the malignant progression of LCa by interacting with RGS17.

Background and Purpose: Postoperative radiotherapy (PORT) can potentially lead to radiation pneumonitis. We aim to develop a nomogram predicting the severe acute radiation pneumonitis (SARP, grade ≥3) in patients with non-small cell lung cancer (NSCLC) receiving PORT., Materials and Methods: Clinical and dose-volume histogram (DVH) factors were collected from 109 patients between 2006 and 2017. The endpoint was the development of SARP within 3 months after PORT. Logistic regression was used to evaluate the prognostic value of each factor in predicting SARP. Nomogram was generated based on multivariate regression coefficients. Area under the ROC curve (AUC), calibration curves, and decision curve analyses (DCA) were conducted to validate the model., Results: Univariate and multivariate analysis indicated that total lung mean dose (tlMD) (OR: 1.003, 95%CI: 1.001-1.006, p = 0.013), percentage of ipsilateral lung volume receiving ≥5 Gy (ilV 5 ) (OR: 1.084, 95%CI: 1.020-1.151, p = 0.009), and concurrent chemoradiotherapy (CCRT) (OR: 4.091, 95%CI: 1.331-12.572, p = 0.014) were independent prognosticators of SARP and were included in the nomogram. ROC curves revealed the AUC of the nomogram was 0.842, which was much higher than any factor alone (tlMD: 0.769; ilV 5 : 0.744; CCRT: 0.661). Calibration curves showed favorable consistency between the predicted SARP and the actual observation. DCA showed satisfactory positive net benefits of the model among most of the threshold probabilities, indicating great clinical effect., Conclusion: We identified that the tlMD (>10.8 Gy), ilV 5 (>64.9%), and CCRT could predict SARP among patients with NSCLC receiving PORT. Combining clinical and DVH parameters, a nomogram was first built and validated, showing its potential value in practice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

Lung adenocarcinoma (LAD) is one of the most common malignancies that threats human health worldwide. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in tumorigenesis and might be novel biomarkers and targets for diagnosis and treatment of cancers. TP73-AS1 is a newly discovered lncRNA involved in the tumorigenesis and development of several cancers. However, its role in LAD has not been investigated yet. In the present study, we first found that TP73-AS1 expression was markedly increased in LAD tissues and cell lines and its overexpression was strongly associated with poor clinical outcomes. Then the loss/gain-of-function assays elucidated that TP73-AS1 contributed to cell proliferation, migration, and invasion in vitro , and the in vivo experiments illustrated that its knockdown inhibited tumor growth and metastasis. What was more, we discovered that phosphoinositide 3-kinase and AKT (PI3K/AKT) pathway was activated both in LAD tissues and cell lines but inactivated under TP73-AS1 silence. Moreover, the activation of this pathway could rescue the inhibitory effects of TP73-AS1 suppression on LAD cellular processes partially. These data suggested that TP73-AS1 served as an oncogene in LAD partially through activating PI3K/AKT pathway and it could be a potential target for diagnosis and treatment of LAD., (© 2019 The Author(s).)

Central nervous system (CNS) progression is frequently detected in patients with favorable initial responses to first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), but data are incomplete with respect to clinical features and prognostic factors of CNS failure in this population. We retrospectively evaluated 420 advanced nonsmall cell lung cancer (NSCLC) patients treated with first-generation EGFR-TKI for over 3 months. We analyzed CNS progression of these patients, defining as newly developed CNS metastases or progression of preexisting brain lesions after EGFR-TKI treatment. Of the 420 patients, 99 (23.6%) with CNS progression after EGFR-TKI initiation were identified. The median time to CNS progression was 12 months (95% confidence interval [CI] 10.5-13.5). Patients with L858R mutation were more likely to experience CNS failure than those with exon 19 deletion ( p  = 0.008). For patients with previous brain metastases (BM), the median time to CNS progression of patients with EGFR-TKI and local CNS therapy was significantly longer than those treated with EGFR-TKI alone (14.0 months vs. 11.2 months; p  = 0.016). The median survival time after CNS progression was 11.2 months (95% CI 8.8-13.5). L858R mutation, multiple BM progression and CNS with other site failures were negative prognostic factor, while localized CNS therapy was the only significant favorable prognostic factor for overall survival after CNS progression. For advanced NSCLC patients treated successfully with first-generation EGFR-TKI, careful monitoring for CNS progression should be considered, especially for those with L858R mutation. Localized CNS therapy should be considered for CNS progression.

Background: This study compared the differences between the estimated glomerular filtration rate (eGFR) calculated by several equations based on serum creatinine (Scr) and cystatin C (CysC) concentrations for monitoring renal function in patients with small-cell lung cancer (SCLC) during chemotherapy., Methods: Seventy-one patients with SCLC were retrospectively analyzed. The eGFR before and after each chemotherapy cycle was calculated by the following equations: the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, the modification of diet in renal disease (MDRD) equation, the Cockcroft-Gault (CG) equation, and five CysC-based equations. The patients were compared among the different eGFR groups., Results: The mean decreases in eGFR CKD-EPI (-2.25 ± 9.89 ml/min/1.73 m 2 ) between each treatment cycle were more significant than the decreases in eGFR CG (-0.46 ± 10.17 ml/min/1.73 m 2 ), eGFR MDRD (-0.48 ± 9.79 ml/min/1.73 m 2 ), and five calculated eGFR CysC (p < 0.05). Single-/multiparameter analyses showed that patients with a higher body mass index (BMI >23) and receiving more treatment cycles (>3) were at increased risk for developing renal impairment with an eGFR less than 60 ml/min/1.73 m 2 during chemotherapy., Conclusions: The eGFR calculated by the CKD-EPI equation changed more significantly between each chemotherapy cycle than did the eGFR from the other equations based on Scr or CysC in patients with SCLC. Oncologists should pay more attention to the renal function of specific patient groups during treatment.

Background/aims: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11's role in NSCLC and the detailed mechanism behind it., Methods: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial-mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression., Results: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial-mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells., Conclusions: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Limited-angle intrafraction verification (LIVE) has been previously developed for four-dimensional (4D) intrafraction target verification either during arc delivery or between three-dimensional (3D)/IMRT beams. Preliminary studies showed that LIVE can accurately estimate the target volume using kV/MV projections acquired over orthogonal view 30° scan angles. Currently, the LIVE imaging acquisition requires slow gantry rotation and is not clinically optimized. The goal of this study is to optimize the image acquisition parameters of LIVE for different patient respiratory periods and gantry rotation speeds for the effective clinical implementation of the system., Method: Limited-angle intrafraction verification imaging acquisition was optimized using a digital anthropomorphic phantom (XCAT) with simulated respiratory periods varying from 3 s to 6 s and gantry rotation speeds varying from 1°/s to 6°/s. LIVE scanning time was optimized by minimizing the number of respiratory cycles needed for the four-dimensional scan, and imaging dose was optimized by minimizing the number of kV and MV projections needed for four-dimensional estimation. The estimation accuracy was evaluated by calculating both the center-of-mass-shift (COMS) and three-dimensional volume-percentage-difference (VPD) between the tumor in estimated images and the ground truth images. The robustness of LIVE was evaluated with varied respiratory patterns, tumor sizes, and tumor locations in XCAT simulation. A dynamic thoracic phantom (CIRS) was used to further validate the optimized imaging schemes from XCAT study with changes of respiratory patterns, tumor sizes, and imaging scanning directions., Results: Respiratory periods, gantry rotation speeds, number of respiratory cycles scanned and number of kV/MV projections acquired were all positively correlated with the estimation accuracy of LIVE. Faster gantry rotation speed or longer respiratory period allowed less respiratory cycles to be scanned and less kV/MV projections to be acquired to estimate the target volume accurately. Regarding the scanning time minimization, for patient respiratory periods of 3-4 s, gantry rotation speeds of 1°/s, 2°/s, 3-6°/s required scanning of five, four, and three respiratory cycles, respectively. For patient respiratory periods of 5-6 s, the corresponding respiratory cycles required in the scan changed to four, three, and two cycles, respectively. Regarding the imaging dose minimization, for patient respiratory periods of 3-4 s, gantry rotation speeds of 1°/s, 2-4°/s, 5-6°/s required acquiring of 7, 5, 4 kV and MV projections, respectively. For patient respiratory periods of 5-6 s, 5 kV and 5 MV projections are sufficient for all gantry rotation speeds. The optimized LIVE system was robust against breathing pattern, tumor size and tumor location changes. In the CIRS study, the optimized LIVE system achieved the average center-of-mass-shift (COMS)/volume-percentage-difference (VPD) of 0.3 ± 0.1 mm/7.7 ± 2.0% for the scanning time priority case, 0.2 ± 0.1 mm/6.1 ± 1.2% for the imaging dose priority case, respectively, among all gantry rotation speeds tested. LIVE was robust against different scanning directions investigated., Conclusion: The LIVE system has been preliminarily optimized for different patient respiratory periods and treatment gantry rotation speeds using digital and physical phantoms. The optimized imaging parameters, including number of respiratory cycles scanned and kV/MV projection numbers acquired, provide guidelines for optimizing the scanning time and imaging dose of the LIVE system for its future evaluations and clinical implementations through patient studies., (© 2017 American Association of Physicists in Medicine.)

Purpose: To accelerate volumetric cine MRI (VC-MRI) using undersampled 2D-cine MRI to provide real-time 3D guidance for gating/target tracking in radiotherapy., Methods: 4D-MRI is acquired during patient simulation. One phase of the prior 4D-MRI is selected as the prior images, designated as MRI prior . The on-board VC-MRI at each time-step is considered a deformation of the MRI prior . The deformation field map is represented as a linear combination of the motion components extracted by principal component analysis from the prior 4D-MRI. The weighting coefficients of the motion components are solved by matching the corresponding 2D-slice of the VC-MRI with the on-board undersampled 2D-cine MRI acquired. Undersampled Cartesian and radial k-space acquisition strategies were investigated. The effects of k-space sampling percentage (SP) and distribution, tumor sizes and noise on the VC-MRI estimation were studied. The VC-MRI estimation was evaluated using XCAT simulation of lung cancer patients and data from liver cancer patients. Volume percent difference (VPD) and Center of Mass Shift (COMS) of the tumor volumes and tumor tracking errors were calculated., Results: For XCAT, VPD/COMS were 11.93  ±  2.37%/0.90  ±  0.27 mm and 11.53  ±  1.47%/0.85  ±  0.20 mm among all scenarios with Cartesian sampling (SP  =  10%) and radial sampling (21 spokes, SP  =  5.2%), respectively. When tumor size decreased, higher sampling rate achieved more accurate VC-MRI than lower sampling rate. VC-MRI was robust against noise levels up to SNR  =  20. For patient data, the tumor tracking errors in superior-inferior, anterior-posterior and lateral (LAT) directions were 0.46  ±  0.20 mm, 0.56  ±  0.17 mm and 0.23  ±  0.16 mm, respectively, for Cartesian-based sampling with SP  =  20% and 0.60  ±  0.19 mm, 0.56  ±  0.22 mm and 0.42  ±  0.15 mm, respectively, for radial-based sampling with SP  =  8% (32 spokes)., Conclusions: It is feasible to estimate VC-MRI from a single undersampled on-board 2D cine MRI. Phantom and patient studies showed that the temporal resolution of VC-MRI can potentially be improved by 5-10 times using a 2D cine image acquired with 10-20% k-space sampling.

Objective: The objective of this study is to theoretically and experimentally evaluate the dosimetry in the microscopic disease regions surrounding the tumor under stereotactic body radiation therapy of lung cancer., Methods: For simplicity, the tumor was considered moving along 1 dimension with a periodic function. The probability distribution function of the tumor position was generated according to the motion pattern and was used to estimate the delivered dose in the microscopic disease region. An experimental measurement was conducted to validate both the estimated dose with a probability function and the calculated dose from 4-dimensional computed tomography data using a dynamic thorax phantom. Four tumor motion patterns were simulated with cos 4 (x) and sin(x), each with 2 different amplitudes: 10 mm and 5 mm. A 7-field conformal plan was created for treatment delivery. Both films (EBT2) and optically stimulated luminescence detectors were inserted in and around the target of the phantom to measure the delivered doses. Dose differences were evaluated using gamma analysis with 3%/3 mm., Results: The average gamma index between measured doses using film and calculated doses using average intensity projection simulation computed tomography was 80.8% ± 0.9%. In contrast, between measured doses using film and calculated doses accumulated from 10 sets of 4-dimensional computed tomography data, it was 98.7% ± 0.6%. The measured doses using optically stimulated luminescence detectors matched very well (within 5% of the measurement uncertainty) with the theoretically calculated doses using probability distribution function at the corresponding position. Respiratory movement caused inadvertent irradiation exposure, with 70% to 80% of the dose line wrapped around the 10 mm region outside the target., Conclusion: The use of static dose calculation in the treatment planning system could substantially underestimate the actual delivered dose in the microscopic disease region for a moving target. The margin for microscopic disease may be substantially reduced or even eliminated for lung stereotactic body radiation therapy.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (ADC) but rare in squamous cell carcinoma (SQC). The efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for SQC with EGFR mutations is unclear. The aim of this study was to evaluate the efficacy of EGFR-TKIs for these patients. We performed a retrospective matched-pair case-control study from 3 cancer centers, including 44 SQC and 44 ADC patients with EGFR mutation who were treated with EGFR-TKI. Subsequently, we performed a pooled analysis on the efficacy of EGFR-TKIs for EGFR-mutant SQC in 115 patients, including 71 patients selected from 25 published reports. In our multicenter study, EGFR-mutant SQC and ADC patients had similar objective response rate (ORR) (43.2% vs. 54.5%, p = 0.290), but SQC patients had lower disease control rate (DCR) (71.3% vs. 100%, p = 0.001), significant shorter median progression free survival (PFS) (5.1 vs. 13.0 months, p = 0.000) and median overall survival (OS) (17.2 vs. 23.6 months, p = 0.027). In pooled analysis, the ORR, DCR, PFS and OS of SQC patients were 39.1%, 71.3%, 5.6 months and 15.0 months, respectively. Performance status was the only independent predictor of PFS and erlotinib treatment was associated with a better survival. In conclusion, EGFR-TKI was less effective in EGFR-mutant SQC than in ADC but still has clinical benefit for SQC patients. Further study is need to evaluate the using of EGFR-TKIs in these SQC patients.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic receptors have been identified as highly promising antitumor agents preferentially eliminating cancer cells with minimal damage, the emergence of TRAIL resistance in most cancers may contribute to therapeutic failure. Thus, there is an urgent need for new approaches to overcome TRAIL resistance. Gold nanoparticles (AuNPs) are one of the most promising nanomaterials that show immense antitumor potential via targeting various cellular and molecular processes; however, the effects of AuNPs on TRAIL sensitivity in cancer cells remain unclear. In this study, we found that AuNPs combined with TRAIL exhibited a greater potency in promoting apoptosis in non-small-cell lung cancer (NSCLC) cells compared with TRAIL alone, suggesting that AuNPs sensitize cancer cells to TRAIL. Further experiments demonstrated that the combination of TRAIL and AuNPs was more effective in causing excessive mitochondrial fragmentation in cancer cells accompanied by a dramatic increase in mitochondrial recruitment of dynamin-related protein 1 (Drp1), mitochondrial dysfunctions, and enhancement of autophagy induction. Small interfering RNA (siRNA) silencing of Drp1 or inhibition of autophagy could effectively alleviate apoptosis in cells exposed to TRAIL combined with AuNPs. In vivo studies revealed that AuNPs augmented TRAIL sensitivity in tumor-bearing mice. Our data indicated that AuNPs potentiate apoptotic response to TRAIL in NSCLC cells through Drp1-dependent mitochondrial fission, and TRAIL combined with AuNPs can be a potential chemotherapeutic strategy for the treatment of NSCLC., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: To investigate the feasibility of using structural-based principal component analysis (PCA) motion-modeling and weighted free-form deformation to estimate on-board 4D-CBCT using prior information and extremely limited angle projections for potential 4D target verification of lung radiotherapy., Methods: A technique for lung 4D-CBCT reconstruction has been previously developed using a deformation field map (DFM)-based strategy. In the previous method, each phase of the 4D-CBCT was generated by deforming a prior CT volume. The DFM was solved by a motion model extracted by a global PCA and free-form deformation (GMM-FD) technique, using a data fidelity constraint and deformation energy minimization. In this study, a new structural PCA method was developed to build a structural motion model (SMM) by accounting for potential relative motion pattern changes between different anatomical structures from simulation to treatment. The motion model extracted from planning 4DCT was divided into two structures: tumor and body excluding tumor, and the parameters of both structures were optimized together. Weighted free-form deformation (WFD) was employed afterwards to introduce flexibility in adjusting the weightings of different structures in the data fidelity constraint based on clinical interests. XCAT (computerized patient model) simulation with a 30 mm diameter lesion was simulated with various anatomical and respiratory changes from planning 4D-CT to on-board volume to evaluate the method. The estimation accuracy was evaluated by the volume percent difference (VPD)/center-of-mass-shift (COMS) between lesions in the estimated and "ground-truth" on-board 4D-CBCT. Different on-board projection acquisition scenarios and projection noise levels were simulated to investigate their effects on the estimation accuracy. The method was also evaluated against three lung patients., Results: The SMM-WFD method achieved substantially better accuracy than the GMM-FD method for CBCT estimation using extremely small scan angles or projections. Using orthogonal 15° scanning angles, the VPD/COMS were 3.47 ± 2.94% and 0.23 ± 0.22 mm for SMM-WFD and 25.23 ± 19.01% and 2.58 ± 2.54 mm for GMM-FD among all eight XCAT scenarios. Compared to GMM-FD, SMM-WFD was more robust against reduction of the scanning angles down to orthogonal 10° with VPD/COMS of 6.21 ± 5.61% and 0.39 ± 0.49 mm, and more robust against reduction of projection numbers down to only 8 projections in total for both orthogonal-view 30° and orthogonal-view 15° scan angles. SMM-WFD method was also more robust than the GMM-FD method against increasing levels of noise in the projection images. Additionally, the SMM-WFD technique provided better tumor estimation for all three lung patients compared to the GMM-FD technique., Conclusion: Compared to the GMM-FD technique, the SMM-WFD technique can substantially improve the 4D-CBCT estimation accuracy using extremely small scan angles and low number of projections to provide fast low dose 4D target verification., (© 2017 American Association of Physicists in Medicine.)

Purpose: The purpose of this study was to develop a techique to generate on-board volumetric cine-magnetic resonance imaging (VC-MRI) using patient prior images, motion modeling, and on-board 2-dimensional cine MRI., Methods and Materials: One phase of a 4-dimensional MRI acquired during patient simulation is used as patient prior images. Three major respiratory deformation patterns of the patient are extracted from 4-dimensional MRI based on principal-component analysis. The on-board VC-MRI at any instant is considered as a deformation of the prior MRI. The deformation field is represented as a linear combination of the 3 major deformation patterns. The coefficients of the deformation patterns are solved by the data fidelity constraint using the acquired on-board single 2-dimensional cine MRI. The method was evaluated using both digital extended-cardiac torso (XCAT) simulation of lung cancer patients and MRI data from 4 real liver cancer patients. The accuracy of the estimated VC-MRI was quantitatively evaluated using volume-percent-difference (VPD), center-of-mass-shift (COMS), and target tracking errors. Effects of acquisition orientation, region-of-interest (ROI) selection, patient breathing pattern change, and noise on the estimation accuracy were also evaluated., Results: Image subtraction of ground-truth with estimated on-board VC-MRI shows fewer differences than image subtraction of ground-truth with prior image. Agreement between normalized profiles in the estimated and ground-truth VC-MRI was achieved with less than 6% error for both XCAT and patient data. Among all XCAT scenarios, the VPD between ground-truth and estimated lesion volumes was, on average, 8.43 ± 1.52% and the COMS was, on average, 0.93 ± 0.58 mm across all time steps for estimation based on the ROI region in the sagittal cine images. Matching to ROI in the sagittal view achieved better accuracy when there was substantial breathing pattern change. The technique was robust against noise levels up to SNR = 20. For patient data, average tracking errors were less than 2 mm in all directions for all patients., Conclusions: Preliminary studies demonstrated the feasibility of generating real-time VC-MRI for on-board localization of moving targets in radiation therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear., Materials and Methods: EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed., Results: Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months., Conclusions: WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)