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ObjectivesThe tyrosine kinase inhibitor (TKI)-sensitive mutations of the epidermal growth factor receptor (EGFR) gene is essential in the treatment of lung adenocarcinoma. To overcome the difficulty of EGFR gene test in situations where surgery and biopsy samples are too risky to obtain, we tried a noninvasive imaging method using radiomics features and random forest models.MethodsFive hundred three lung adenocarcinoma patients who received surgery-based treatment were included in this study. The diagnosis and EGFR gene test were based on resections. TKI-sensitive mutations were found in 60.8% of the patients. CT scans before any invasive operation were gathered and analyzed to extract quantitative radiomics features and build random forest classifiers to identify EGFR mutants from wild types. Clinical features (sex and smoking history) were added to the image-based model. The model was trained on a set of 345 patients and validated on an independent test group (n = 158) using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity.ResultsThe performance of the random forest model with 94 radiomics features reached an AUC of 0.802. Its AUC was further improved to 0.828 by adding sex and smoking history. The sensitivity and specificity are 60.6% and 85.1% at the best diagnostic decision point.ConclusionOur results showed that radiomics could not only reflect the genetic differences among tumors but also have diagnostic value and the potential to be a diagnostic tool.Key Points• Radiomics provides a potential noninvasive method for the prediction of EGFR mutation status.• In situations where surgeries and biopsy are not available, CT image-based radiomics models could help to make treatment decisions.• The accuracy, sensitivity, and specificity still need to be improved before the image-based EGFR identifier could be used in clinics.

ObjectiveNeutrophils are prominent components of solid tumours and exhibit distinct phenotypes in different tumour microenvironments. However, the nature, regulation, function and clinical relevance of neutrophils in human gastric cancer (GC) are presently unknown.DesignFlow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 105 patients with GC. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro and in vivo regulation and function assays.ResultsPatients with GC showed a significantly higher neutrophil infiltration in tumours. These tumour-infiltrating neutrophils showed an activated CD54+ phenotype and expressed high level immunosuppressive molecule programmed death-ligand 1 (PD-L1). Neutrophils activated by tumours prolonged their lifespan and strongly expressed PD-L1 proteins with similar phenotype to their status in GC, and significant correlations were found between the levels of PD-L1 and CD54 on tumour-infiltrating neutrophils. Moreover, these PD-L1+ neutrophils in tumours were associated with disease progression and reduced GC patient survival. Tumour-derived GM-CSF activated neutrophils and induced neutrophil PD-L1 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signalling pathway. The activated PD-L1+ neutrophils effectively suppressed normal T-cell immunity in vitro and contributed to the growth and progression of human GC in vivo; the effect could be reversed by blocking PD-L1 on these neutrophils.ConclusionsOur results illuminate a novel mechanism of PD-L1 expression on tumour-activated neutrophils in GC, and also provide functional evidence for these novel GM-CSF-PD-L1 pathways to prevent, and to treat this immune tolerance feature of GC.

Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163 + CD206 + M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163 + CD206 + M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10 high TGF-β high IL-12 p35 low ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.

Organoids have certain cellular composition and physiological features in common with real organs, making them promising models of organ formation, function, and diseases. However, Matrigel, the commonly used animal‐derived matrices in which they are developed, has limitations in mechanical adjustability and providing complex physicochemical signals. Here, the incorporation of Ti3C2TxMXene nanomaterial into Matrigel regulates the properties of Matrigel and exhibits satisfactory biocompatibility. The Ti3C2TxMXene Matrigel composites (MXene‐Matrigel) regulate the development of Cochlear Organoids (Cochlea‐Orgs), particularly in promoting the formation and maturation of organoid hair cells. Additionally, regenerated hair cells in MXene‐Matrigel are functional and exhibit better electrophysiological properties compared to hair cells in Matrigel. MXene‐Matrigel potentiates the amycin (mTOR) signaling pathway to promote hair cell differentiation, and mTOR signaling inhibition restrains hair cell differentiation. Moreover, MXene‐Matrigel facilitates innervation establishment between regenerated hair cells and spiral ganglion neurons (SGNs) growing from the Cochlea modiolus in a co‐culture system, as well as promotes synapse formation efficiency. The approach overcomes some limitations of the Matrigel‐dependent culture system and greatly accelerates the application of nanomaterials in organoid development and research on therapies for hearing loss. 3D Ti3C2TxMXene composited Matrigel (MXene‐Matrigel) has biocompatibility to Cochlear Organoids (Cochlea‐Orgs) and potentiates rapamycin activity to promote differentiation and maturation of Cochlea‐Orgs. Regenerated organoid hair cells are functional and comparable to postnatal day 2 native auditory hair cells. Ti3C2TxMXene also benefits the formation of synapse‐like contacts between regenerated hair cells and sensory neurons.

This study evaluated patterns of treatment failure (especially locoregional failure; LRF) after radical esophagectomy and proposes a clinical target volume (CTV) for postoperative radiotherapy (PORT) among patients with thoracic esophageal squamous cell carcinoma (SCC). All patients who were followed up in our center after radical esophagectomy between 2007 and 2011 were retrospectively enrolled. The patterns of first discovered failure were assessed, and LRFs (including anastomotic and regional lymph node recurrences) were evaluated to determine whether our proposed PORT CTV encompassed these areas. The clinicopathologic factors predictive of lymphatic recurrence type were analyzed. Of the 414 patients who underwent surgery and were followed up over the study, 207 experienced recurrent or metastatic diseases. The median time to progression was 11.0 months. Of the 173 patients with locoregional recurrence, nodal failure recurred in 160; supraclavicular and superior mediastinal lymph nodes had the highest metastasis rates. All 233 recurrent sites across the 160 patients were located in a standard CTV area, including the bilateral supraclavicular areas, the entire mediastinum, and the left gastric lymphatic drainage region. A total of 203 sites (87.2%) were located in either the bilateral supraclavicular areas or the entire mediastinum, and 185 sites (79.4%) were located in either the bilateral supraclavicular areas or the upper mediastinum. A multivariate analysis revealed the lymph node metastatic ratio (LNMR) and tumor differentiation were risk factors for nodal failure. Locoregional recurrence (especially lymph node recurrence) was the most common and potentially preventable type of initial treatment failure after curative surgery among patients with thoracic esophageal SCC. The proposed PORT CTV covered most LRF sites. The lymphatic drainage regions for PORT are selective, and the supraclavicular and superior mediastinal areas should be considered. However, the value of PORT and the extent of CTV should be investigated in further prospective studies.

Background To explore the maximum tolerated dose (MTD) and evaluate the safety of dose escalation using hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) concurrent with chemotherapy for unresectable stage III non-small cell lung cancer (NSCLC). Methods Four escalating radiation dose levels were used. This study included 25 patients with previously untreated NSCLC who received six concurrent weekly chemotherapy cycles comprising cisplatin and docetaxel. Dose-limiting toxicity (DLT) was defined as any acute toxicity that interrupted radiotherapy for more than 1 week. MTD was defined as the highest dose level that didn’t induce DLT or grade 5 toxicity in two patients. Results All 25 patients received the prescribed escalating radiation dose from the start dose up to LEVEL 4. Two patients experienced DLT at dose LEVEL 4. One patient died because of upper gastrointestinal hemorrhage within 6 months after radiotherapy, whereas another patient among the additional five patients died because of grade 5 radiation pneumonitis within 2 months after radiotherapy. Dose LEVEL 3 was defined as MTD. The 1- and 2-year local controls were 82.8 and 67.8%, respectively. The median progression-free survival was 15.4 months, whereas the median overall survival was 27.3 months. Conclusions Dose escalation was safely achieved up to LEVEL 3 [the planning gross target volume (PTVG) 60.5 Gy/22 Fx, 2.75 Gy/Fx; the planning clinical target volume (PTVC) 49.5 Gy/22 Fx] using SIB-IMRT concurrently with chemotherapy for unresectable stage III NSCLC, and the acute toxicities were generally well tolerated. Further prospective studies on long-term outcomes and late toxicities are warranted. Trial registration Retrospective registration, ChiCTR1900027290 (08/11/2019).

The aim of the present study was to explore the potential role of cluster of differentiation CD68+ tumor-associated macrophages (TAMs) induced by interleukin (IL)-6 in the progression of gastric cancer (GC) and patient prognosis. The expression levels of IL-6 and CD68 were detected by immunohistochemical staining in 60 samples of tumor and non-tumor gastric tissues. CD14+ monocytes were isolated from peripheral blood mononuclear cells and stimulated with macrophage colony stimulation factor (M-CSF) and IL-6, and the expression levels of IL-10, IL-12, vascular endothelial growth factor (VEGF)-C and transforming growth factor (TGF)-β were measured by reverse transcription polymerase chain reaction and ELISA. The GC MGC-803 cell line was co-cultured with monocytes stimulated by M-CSF and IL-6 and the invasion ability of the MGC-803 was evaluated by Transwell analysis. The levels of STAT3, P-STAT3 and interferon-regulatory factor 4 (IRF4) in the monocytes stimulated by M-CSF and IL-6 were detected by western blotting. The results demonstrated that the frequencies of IL-6+ macrophages (Mφs) and CD68+ Mφs were significantly higher in tumor regions compared with the corresponding non-tumor regions of GC tissues. Kaplan-Meier analysis revealed that the densities of tumor-infiltrating CD68+ or IL-6+ Mφs were inversely associated with the overall survival rates of the patients. In vitro, the expression levels of IL-10, VEGF-C and TGF-β significantly increased in CD14+ monocytes subsequent to M-CSF and IL-6 stimulation. The invasion abilities of MGC-803 were increased by the monocytes stimulated with M-CSF and IL-6. The levels of STAT3, P-STAT3 and IRF4 proteins increased in the monocytes stimulated by M-CSF and IL-6. In conclusion, the results from the present study suggest that a high density of CD68+ TAMs predicts a poor prognosis in GC. IL-6 may polarize the Mφs and promote tumor invasion through the IL-6/STAT3/IRF4 signaling pathway.

Background Cumulative preclinical and clinical evidences showed radiotherapy might augment systemic antitumoral responses to immunotherapy for metastatic non-small cell lung cancer, but the optimal timing of combination is still unclear. The overall infiltration and exhausted subpopulations of tumor-infiltrating CD8 + T cells might be a potential biomarker indicating the response to immune checkpoint inhibitors (ICI), the alteration of which is previously uncharacterized during peri-irradiation period, while dynamic monitoring is unavailable via repeated biopsies in clinical practice. Methods Basing on tumor-bearing mice model, we investigated the dynamics of overall infiltration and exhausted subpopulations of CD8 + T cells after ablative irradiation. With the understanding of distinct metabolic characteristics accompanied with T cell exhaustion, we developed a PET radiomics approach to identify and visualize T cell exhaustion status. Results CD8 + T cell infiltration increased from 3 to 14 days after ablative irradiation while terminally exhausted populations significantly predominated CD8 + T cells during late course of this infiltrating period, indicating that 3–7 days post-irradiation might be a potential appropriate window for delivering ICI treatment. A PET radiomics approach was established to differentiate T cell exhaustion status, which fitted well in both ICI and irradiation settings. We also visualized the underlying association of more heterogeneous texture on PET images with progressed T cell exhaustion. Conclusions We proposed a non-invasive imaging predictor which accurately assessed heterogeneous T cell exhaustion status relevant to ICI treatment and irradiation, and might serve as a promising solution to timely estimate immune-responsiveness of tumor microenvironment and the optimal timing of combined therapy.

To develop accurate and accessible prediction methods for assessing pathologic response following NICT prior to surgery, we conducted a retrospective study including 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after two cycles of NICT between January 2019 and March 2022 at our center. We collected clinical parameters to evaluate the dynamic changes in the primary tumor. Univariate and multivariate analyses were performed to determine the correlations between these parameters and the pathologic response of the primary tumor. Subsequently, we constructed prediction models for pCR and MPR using multivariate logistic regression. The MPR prediction Model 2 was internally validated using bootstrapping and externally validated using an independent cohort from our center. The univariate logistic analysis revealed significant differences in clinical parameters reflecting tumor regression among patients with varying pathologic responses. The clinical models based on these assessments demonstrated excellent predictive performance, with the training cohort achieving a C-index of 0.879 for pCR and 0.912 for MPR, while the testing cohort also achieved a C-index of 0.912 for MPR. Notably, the MPR prediction Model 2, with a threshold cut-off of 0.74, exhibited 92.7% specificity and greater than 70% sensitivity, indicating a low rate of underestimating residual tumors. In conclusion, our study demonstrated the high accuracy of clinical assessment-based models in pathologic response prediction, aiding in decision-making regarding organ preservation and radiotherapy adjustments after induction immunochemotherapy.

There are no optimal regimens for advanced thymic epithelial tumors (TETs) when frontline chemotherapy fails. In this study, we aimed to assess the activity of Bevacizumab in combination with a routine chemotherapeutic regimen. Patients with advanced TETs who had failed after previous chemotherapy were enrolled in this study. Paclitaxel (160 mg/m 2 ) and cisplatin (70 mg/m 2 ) or carboplatin (area under the curve, 6) plus Bevacizumab (7.5 mg/kg) were intravenously injected on day 1.The treatment was repeated every 3 weeks until the disease progressed or intolerable toxicities occurred. Between March 2018 and August 2020, a total of 49 patients (21 thymoma and 28 thymic carcinoma) received the new treatment. There were 28 men and 21 women with a median age of 50 years (range: 21–73 years). The median number of cycles was 3 (range: 1–6) per patient. The objective response rate (ORR) for all patients was 43% (21/49). The ORRs for thymoma and thymic carcinoma were 24% and 57%, respectively. The median progression-free survival for thymoma and thymic carcinoma was 6 and 8 months, respectively. Hematological toxicities were the main side effects. Paclitaxel and platinum plus Bevacizumab showed promising effects in refractory or relapsed advanced TETs without severe toxicity. Even when applied as salvage therapy, this regimen resulted in a better ORR than frontline chemotherapy.