Background: There was no study investigating real-world utilization and outcome of LCT in Osimertinib-treated NSCLC with oligo-residual disease. This study was to analyze the clinical value of local consolidative therapy (LCT) in Osimertinib-treated non-small cell lung cancer (NSCLC) patients with oligo-residual disease.Methods: Patients receiving standard Osimertinib treatment and developing oligo-residual disease (five or fewer residual metastatic lesions) were retrospectively reviewed. Local therapies performed to the oligo-residual tumor lesions or primary lung site before Osimertinib treatment failure were considered as LCT.Results: Of 108 patients recruited, first-line and second-line Osimertinib were administered in 25 and 83 patients, respectively, while LCT was performed in 14 patients. With a median follow-up of 43.6 months, 69 patients developed progressive disease. LCT significantly improved progression-free survival (PFS) (NR vs 12.8 months,p = 0.01) and was independently associated with prolonged PFS (HR = 0.29, 95%CI 0.12 to 0.68,p = 0.004). Patients receiving LCT had a numerically longer overall survival (OS) (85.8 vs 77.1 months,p = 0.58) and after adjusting for potentially confounding factors, LCT was associated with a non-significantly prolonged OS (HR = 0.37, 95%CI 0.12–1.16,p = 0.089). Pattern of failure analyses indicated that progressive disease developed at the originally existed oligo-residual lesions in 76.2% of the 63 patients who didn’t receive LCT and had Osimertinib treatment failure. Of note, 7 (70%) of the 10 patients who had oligo-residual cranial disease but didn’t receive LCT, developed more than five progressive lesions in the brain, which were no longer suitable for stereotactic radiosurgery.Conclusion: Among Osimertinib-treated NSCLC patients having oligo-residual lesions, LCT could improve local control and significantly increase PFS, which need to be verified by further investigations.

Background: Brain metastasis (BM) is most common in non-small cell lung cancer (NSCLC) patients. This study aims to enhance BM risk prediction within three years for advanced NSCLC patients by using a deep learning-based segmentation and computed tomography (CT) radiomics-based ensemble learning model. Methods: This retrospective study included 602 stage IIIA-IVB NSCLC patients, 309 BM patients and 293 non-BM patients, from two centers. Patients were divided into a training cohort (N = 376), an internal validation cohort (N = 161) and an external validation cohort (N = 65). Lung tumors were first segmented by using a three-dimensional (3D) deep residual U-Net network. Then, a total of 1106 radiomics features were computed by using pretreatment lung CT images to decode the imaging phenotypes of primary lung cancer. To reduce the dimensionality of the radiomics features, recursive feature elimination configured with the least absolute shrinkage and selection operator (LASSO) regularization method was applied to select the optimal image features after removing the low-variance features. An ensemble learning algorithm of the extreme gradient boosting (XGBoost) classifier was used to train and build a prediction model by fusing radiomics features and clinical features. Finally, Kaplan‒Meier (KM) survival analysis was used to evaluate the prognostic value of the prediction score generated by the radiomics–clinical model. Results: The fused model achieved area under the receiver operating characteristic curve values of 0.91 ± 0.01, 0.89 ± 0.02 and 0.85 ± 0.05 on the training and two validation cohorts, respectively. Through KM survival analysis, the risk score generated by our model achieved a significant prognostic value for BM-free survival (BMFS) and overall survival (OS) in the two cohorts (P < 0.05). Conclusions: Our results demonstrated that (1) the fusion of radiomics and clinical features can improve the prediction performance in predicting BM risk, (2) the radiomics model generates higher performance than the clinical model, and (3) the radiomics-clinical fusion model has prognostic value in predicting the BMFS and OS of NSCLC patients.

The invasiveness of Salmonella enterica serovar Typhimurium (S. Typhimurium) is closely associated with the Salmonella pathogenicity island (SPI)‐encoded type Ⅲ secretion system (T3SS), which can directly inject a series of effector proteins into eukaryotic cells to enable bacterial infection. In this study, syringaldehyde was identified as an effective inhibitor of the S. Typhimurium T3SS using an effector protein‐lactamase fusion reporter system. Syringaldehyde treatment could inhibit the expression of important effector proteins (SipA, SipB and SipC) at a concentration of 0.18 mM without affecting bacterial growth. Additionally, significant inhibition of bacterial invasion and cellular injury was observed following the syringaldehyde treatment in the co‐infection system of HeLa cells and S. Typhimurium. Furthermore, treatment with syringaldehyde provided systemic protection to mice infected with S. Typhimurium, reducing mortality (40.00%) and bacterial loads and relieving caecal damage and systemic inflammation. The results presented in this study indicate that syringaldehyde significantly affects T3SS activity and is a potential leading compound for treating S. Typhimurium infections.

Evidence suggests that fatty acid receptor FFAR4 plays a tumor-promoting role in adipose tissue-adjacent malignancies, but its clinical relevance remains unexplored. Here, we investigated the clinical significance and underlying mechanisms of FFAR4 in hormone receptor-positive breast cancer (HRPBC). FFAR4 expression was assessed by immunohistochemistry in an exploration cohort of 307 breast cancer cases collected from two independent institutes. Two public breast cancer microarray datasets served as validation cohorts. Gas chromatography-mass spectrometry was employed to identify FFAR4 ligands in normal and cancerous breast tissues. Survival analyses were performed in all cohorts and designated molecular subgroups. Mechanistic studies were performed in vitro in hormone receptor-positive breast cancer cell lines MCF-7 and T-47D. Aberrant FFAR4 expression and endogenous FFAR4 ligands were identified in breast cancer tissues, five FFAR4 ligands showed significantly elevated proportions in cancerous versus normal tissues. In the exploration cohort, FFAR4 was demonstrated as an independent prognostic factor for recurrences (HR: 2.183, 95% CI: 1.360–3.504, P = 0.001) and breast cancer-specific deaths (HR: 2.102, 95% CI: 1.173–3.766, P = 0.013) in HRPBC cases. In contrast, FFAR4 expression was not associated with prognosis in hormone receptor-negative cases. In the validation cohorts, FFAR4 mRNA levels were also observed to be associated with disease recurrence in estrogen receptor-positive cases, but not so in estrogen receptor-negative cases. FFAR4 activation by endogenous ligands and a synthetic ligand TUG891 significantly dampened tamoxifen’s efficacy on HRPBC cells, whereas FFAR4 knockdown or antagonist AH7614 abrogated this effect. Furthermore, FFAR4-induced tamoxifen resistance was dependent on ERK and AKT pathways in HRPBC. Our results establish a novel role of FFAR4 and its ligands in the complicated interactions between tissue lipid profile and cancer biology. FFAR4 signaling confers tamoxifen resistance in HRPBC cell line and FFAR4 expression can serve as a prognostic biomarker for tamoxifen-treated HRPBC patients. FFAR4 may serve as a potential target for anti-breast cancer therapies, especially in endocrine resistant cases.

Background: Despite the emergence of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs), knowledge gaps remain regarding the impact and timing of cranial radiotherapy for patients receiving anti-PD-1/PD-L1 therapy. Methods: Data were collected from 461 consecutive patients who received anti-PD-1/PD-L1 therapy for metastatic NSCLC at three institutions between June 2017 and September 2020. Intracranial progressive disease (PD) at the original disease sites, new sites, or both sites were classified as original-site PD (OPD), new-site PD (NPD), and original-and-new-site PD (ONPD), respectively. Patients with baseline BMs were categorized based on whether they received upfront cranial radiotherapy (uCRT) at any time point between the introduction of anti-PD-1/PD-L1 therapy and the first subsequent progression. Results: Of the 461 patients enrolled, 110 (23.9%) had BMs at baseline. The presence of BMs did not show independent prognostic value for progression-free survival (PFS) or overall survival (OS). During a median follow-up of 13.2 months, 96 patients with BMs developed PD, of whom 53 (55.2%) experienced intracranial PD. OPD, NPD, and ONPD were observed in 50.9%, 18.9%, and 30.2% of patients, respectively. Patients who received uCRT exhibited a longer median OS than those with BMs who did not receive uCRT (25.4 vs. 14.6 months, HR: 0.52, 95% CI: 0.29–0.91, P=0.041); this survival advantage was more prominent in patients with 1–4 BMs (median OS, 25.4 vs. 17.0 months, HR: 0.42, 95% CI: 0.22–0.81, P=0.024), and uCRT was independently associated with OS among these patients. Conclusions: The presence of BMs at baseline was not associated with poorer OS in patients with metastatic NSCLC treated with anti-PD-1/PD-L1 therapy. Intracranial progression on PD-l/PD-L1 inhibitors predominately occurred at the original BM sites. The use of uCRT may improve OS, especially in NSCLC patients with 1–4 BMs.

Background: Prophylactic cranial irradiation (PCI) is indicated for limited-stage small cell lung cancer (LS-SCLC) with good response to chemoradiotherapy (CRT). However, brain metastasis (BM) developed in LS-SCLC before PCI is not rare. In this study, we comprehensively investigated the features of pre-PCI BMs, aiming to explore the potential of PCI optimization for LS-SCLC. Methods: One-hundred-ten LS-SCLC patients achieving clinical complete remission after definitive CRT with contrast-enhanced cranial magnetic resonance imaging (MRI) at baseline and immediately before PCI were included. The time trend and risk factors for pre-PCI BM were evaluated. Several radiological features, including numbers, sizes, and locations of pre-PCI BMs, were investigated to explore the technical feasibility of stereotactic radiotherapy and hippocampal-avoidance (HA) PCI. Results: Twenty-four (21.8%) of the LS-SCLC patients harbored pre-PCI BM, all except one were asymptomatic. CRT duration (CRT-D) was the only independent risk factor for pre-PCI BM. The pre-PCI BM rate gradually increased in line with a growing time interval between treatment initiation and pre-PCI MRI. Pre-PCI BM and prolonged CRT-D were both correlated with worse overall survival. Of 129 pre-PCI intracranial lesions, 2 (1.5%) were in the HA region. Eight of the 24 (33.3%) pre-PCI BM patients were ineligible for stereotactic radiotherapy. Conclusion: Our findings suggest that PCI is still of importance in LS-SCLC, and MRI evaluation before PCI is indispensable. Investigations are warranted to explore the possibility of moving PCI up to before CRT completion in LS-SCLC patients with prolonged CRT-D. HA-PCI could be considered to reduce neurotoxicity.