Unraveling CCL20's role by regulating Th17 cell chemotaxis in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.

Navigating first-line therapies for extensive-stage small-cell lung cancer: a frequentist network meta-analysis and systematic review.

Aim: To identify the optimal first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Materials & methods: We conducted a network meta-analysis (CRD42023486863) to systematically evaluate the efficacy and safety of eight first-line treatment regimens for ES-SCLC, including 15 clinical trials. Results: Our analysis showed that the PD-1/PD-L1 + etoposide combined with platinum (EP) and PD-L1 + vascular endothelial growth factor (VEGF) + EP regimens significantly enhanced overall survival and progression-free survival, with subgroup analysis revealing that serplulimab ranked as the most promising option for improving overall survival. Integrating anti-angiogenesis drugs into immunochemotherapy presents potential benefits, with an increased incidence of adverse events necessitating further investigation. Conclusion: Our findings offer valuable insights for future research and for developing more effective treatment strategies for ES-SCLC, underscoring the critical need for continued innovation in this therapeutic area.

[Box: see text].

A novel multi-target tyrosine kinase inhibitor anlotinib combined with irinotecan has in-vitro anti-tumor activity against human small-cell lung cancer.

Anlotinib is a multi-target tyrosine kinase inhibitor developed independently in China. Its biological effects remain unclear in small-cell lung cancer (SCLC). The current study aimed to evaluate the effects of anlotinib in combination with irinotecan on H446 and H2227 SCLC cell lines and provide new treatment strategy for SCLC. Cell growth of two cell lines was inhibited by anlotinib, irinotecan and the combination in a dose-dependent manner. After 72 h incubation, the inhibition rate was greater in the combination group than all single drug group. A similar result was found when apoptosis was assessed after 12 h, but not after 6 h of treatment. Compared with single drug, combination drug suppressed the migration and invasion abilities in two cell lines; however, there was no difference between individual anlotinib or irinotecan. The colony formation rate was obviously lower in the combination group. Vascular endothelial growth factor receptor, fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor were expressed in two cell lines after treatment regardless single or combination, but FGFR was expressed more after combination treatment than anlotinib. The expression of phosphorylated (p) ERK was decreased with anlotinib alone or combination treatment and pAKT expression was impaired with combination treatment, but not with anlotinib or irinotecan alone. The biological function of anlotinib and irinotecan may be mediated through the AKT/ERK signaling pathway. Additional investigations on biomarker-guided patient-stratification and elucidating individualized targets in patients anlotinib are urgently needed.

Plasma YKL-40 and NGAL are useful in distinguishing ACO from asthma and COPD.

BACKGROUND: Asthma-chronic obstructive pulmonary disorder (COPD) overlap (ACO) is characterized by the coexistence of features of both asthma and COPD and is associated with rapid progress and a poor prognosis. Thus, the early recognition of ACO is crucial. OBJECTIVES: We sought to explore the plasma levels of biomarkers associated with asthma (periostin, TSLP and YKL-40), COPD (NGAL) and their possible correlation with lung function, the bronchodilator response and radiographic imaging in patients with asthma, COPD and with features of ACO. METHODS: We enrolled 423 subjects from 6 clinical centers. All participants underwent blood collection, lung function measurements, bronchodilator response tests and high-resolution CT. Correlations of the plasma biomarkers with lung function, the bronchodilator response and percentemphysema were calculated by Spearman's rank correlation and multivariate stepwise regressionanalysis. RESULTS: 1) Patients with features of ACO had lower plasma YKL-40 than COPD patients and a moderate elevated plasma level of NGAL compared with asthma patients. 2) Patients with features of ACO had an intermediate degree of airflow obstruction, the bronchodilator response and emphysema between patients with COPD and asthma. 3) Plasma YKL-40 was negatively correlated with lung function and with the bronchodilator response, and plasma NGAL was positively correlated with the extent of emphysema. CONCLUSIONS: Plasma YKL-40 is a promising candidate for distinguishing between patients with features of ACO and COPD patients, while plasma NGAL may be a valuable biomarker for differentiating between patients with features of ACO and asthma patients. CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-16009221.

Circulating tumor cell counts/change for outcome prediction in patients with extensive-stage small-cell lung cancer.

AIMS: As data on the use of circulating tumor cells (CTCs) to predict patient outcomes in extensive-stage small-cell lung cancer (ES-SCLC) remain inconclusive, we investigated the clinical value of CTC determination in an open-label, multicenter study of 91 patients with newly diagnosed ES-SCLC. MATERIALS & METHODS: Blood CTC counts were determined using the CellSearch® system at baseline, after the second cycle of chemotherapy, and on disease progression. RESULTS & CONCLUSION: Following the second cycle of treatment, CTC numbers and the change in CTCs were strong, significant and independent indicators for both progression-free survival and overall survival in ES-SCLC. The CTC change was associated with both refractory disease (response to initial therapy ≤3 months) and sensitive disease (response to initial therapy >3 months).

[Identification and clinical significance of myeloid-derived suppressor cells in peripheral blood of small-cell lung cancer patients].

OBJECTIVE: To explore the presence, frequency and clinical value of myeloid-derived suppressor cells (MDSCs) in peripheral blood of patients with small cell lung cancer (SCLC). METHODS: Flow cytometry using antibodies against CD11b, CD33, CD14 or HLA-DR was conducted to explore the unique cell surface markers of MDSCs and statistical analysis was performed to explore the correlation of MDSCs and clinical features. RESULTS: MDSCs were present in 36 patients with SCLC and uniquely marked by CD11b and CD33-positive, but HLA-DR-negative on cell surfaces and possessed mononuclear phenotype. The levels of CD11b(+)CD33(+)HLA-DR(-)cells (MDSCs) in the SCLC patients and healthy controls were (26.87 ± 6.87)% and (11.04 ± 3.76)%, respectively, with a statistically significant difference (P < 0.001). MDSCs level was significantly associated with clinical stage and tumor distant metastasis (P < 0.05) , but not with age, sex, smoking status and performance status. The later was the clinical stage, the higher was the MDSCs level (r = 0.665, P < 0.001). The level of MDSCs was higher in SCLC patients with distant metastasis than in those without metastasis (r = 0.489, P = 0.003). The level of MDSCs was higher before treatment than after treatment and the difference was statistically significant (P = 0.003). CONCLUSIONS: The results of our study demonstrate the existence of MDSCs in SCLC patients and the MDSCs level is associated with SCLC stage, metastasis and treatments. MDSCs might be a novel biomarker for early diagnosis and prognosis for SCLC patients.

Association of systemic inflammation response index with all-cause mortality as well as cardiovascular mortality in patients with chronic kidney disease.

Background: Chronic Kidney Disease (CKD) stands as a formidable health challenge, recognized not only for its growing prevalence but also for its association with elevated mortality rates. Emerging evidence suggests that CKD is inherently linked to inflammatory processes, marking it as an inflammatory disorder. In this landscape, the systemic inflammatory response index (SIRI) emerges as a novel inflammation marker, yet to be applied for assessing the risk of mortality in CKD patients. Objective: This study aims to investigate the prognostic significance of the SIRI in all-cause and cardiovascular disease (CVD) mortality among patients with CKD. Method: This study conducted a retrospective observational study using the National Health and Nutrition Examination Survey (NHANES) database, encompassing data from 1999 to 2018. This analysis included 9,115 CKD patients, categorized based on SIRI quartiles. Key outcomes were all-cause and CVD mortality, analyzed using Kaplan-Meier survival curves, restricted cube splines (RCS) and cox proportional hazards models. Result: In this study of 9,115 CKD patients, the Kaplan-Meier survival analysis revealed a greater incidence of all-cause death among groups with higher SIRI (P-log rank <0.001). In the fully adjusted model (Model 3), each unit increase in SIRI led to a 20% increase in the risk of all-cause mortality. Additionally, higher SIRI quartiles (Q3 and Q4) were associated with increased risk compared to the lowest quartile (Q1) (Q3: HR: 1.16, 95% CI: 1.01-1.34; Q4: HR: 1.63, 95% CI: 1.40-1.90; P for trend <0.001). Similarly, for CVD mortality, each unit increase in SIRI in Model 3 increased the risk by 33%, with Q3 and Q4 showing higher risk than Q1 (Q3: HR: 1.39, 95% CI: 1.11-1.70; Q4: HR: 2.26, 95% CI: 1.72-2.98; P for trend <0.001). Conclusion: SIRI was positively associated with all-cause and CVD mortality in patients with CKD.

NLRP3-mediated IL-1ß in regulating the imbalance between Th17 and Treg in experimental autoimmune prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a urinary disorder that affects youthful to middle-aged men most frequently. It has been revealed that Th17/Treg imbalance is a crucial factor in the pathophysiological mechanisms behind this disease. However, this imbalance's mechanisms are unknown. In the experimental autoimmune prostatitis (EAP) mouse model, the NLRP3 inflammasome was turned on, IL-1ß levels went up. Moreover, there exists a discernible positive association between the upsurge in IL-1ß and the perturbation of Th17/Treg equilibrium. Additionally, we have revealed that IL-1ß plays a vital role in promoting the differentiation of Naïve CD4+ T cells into the Th17 cells and enhances the conversion of Treg cells into Th17 cells. Further studies revealed that IL-1ß promotes STAT3 phosphorylation, which is what causes Treg cells to become Th17 cells. All data strongly suggest that the NLRP3 inflammatory influence Th17 cell development and the conversion of Treg cells into Th17 cells through IL-1ß, disrupting the Th17/Treg balance and exacerbating EAP inflammation. In this article, we provide new theories for the pathogenesis of CP/CPPS and propose new prevention and therapy methods.

Alcohol intake exacerbates experimental autoimmune prostatitis through gut microbiota driving cholesterol biosynthesis-mediated Th17 differentiation.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is very common worldwide, and alcohol consumption is a notable contributing factor. Researches have shown that gut microbiota can be influenced by alcohol consumption and is an important mediator in regulating Th17 cell immunity. However, it is still unclear the exact mechanism by which alcohol exacerbates the CP/CPPS and the role of gut microbiota in this process. METHOD: We first constructed the most-commonly used animal model for CP/CPPS, the experimental autoimmune prostatitis (EAP) model, through immunoassay. Based on this, mice were divided into EAP group and alcohol-consuming EAP group. By 16S rRNA sequencing and non-targeted metabolomics analysis, differential gut microbiota and their metabolites between the two groups were identified. Subsequently, metabolomics detection targeting cholesterols was carried out to identify the exact difference in cholesterol. Furthermore, multiple methods such as flow cytometry and immunohistochemistry were used to detect the differentiation status of Th17 cells and severity of prostatitis treated with 27-hydroxycholesterol (the differential cholesterol) and its upstream regulatory factor-sterol regulatory element-binding protein 2 (SREBP2). Lastly, fecal transplantation was conducted to preliminary study on whether alcohol intake exacerbates EAP in immune receptor mice. RESULTS: Alcohol intake increased the proportion of Th17 cells and levels of related inflammatory factors. It also led to an altered gut bacterial richness and increased gut permeability. Further metabolomic analysis showed that there were significant differences in a variety of metabolites between EAP and alcohol-fed EAP mice. Metabolic pathway enrichment analysis showed that the pathways related to cholesterol synthesis and metabolism were significantly enriched, which was subsequently confirmed by detecting the expression of metabolic enzymes. By targeting cholesterol synthesis, 27-hydroxycholesterol was significantly increased in alcohol-fed EAP mice. Subsequent mechanistic research showed that supplementation with 27-hydroxycholesterol could aggravate EAP and promote Th17 cell differentiation both in vivo and in vitro, which is regulated by SREBP2. In addition, we observed that fecal transplantation from mice with alcohol intake aggravated EAP in immunized recipient mice fed a normal diet. CONCLUSION: Our study is the first to show that alcohol intake promotes Th17 cell differentiation and exacerbates EAP through microbiota-derived cholesterol biosynthesis.

Anti-MDA5 antibody dermatomyositis-associated rapidly progressive interstitial lung disease patient complicated with mixed connective tissue disease: A case report.

Anti-MDA5 antibody dermatomyositis (DM) is a special type of myositis, which can potentially cause rapidly progressive interstitial lung disease (RP-ILD). Mixed connective tissue disease (MCTD) is a complex disease with different characteristics of autoimmune connective tissue disease, associated with ILD. Both are rare diseases, and few patients with both diseases have been reported. A 71-year-old woman complained of palpitations, with a 2 months history of rash around her hands, extensor surface of right elbow, and the nape of her neck. Subsequently, the patient had acute exacerbation of dyspnea and tachypnea. Anti-Ro52, U1 RNP and MDA5 antibodies were positive; the presenting evidence was suggestive of anti-MDA5+ DM-RP-ILD complicated with MCTD. Our patient deteriorated rapidly and had a fatal outcome, despite "triple therapy" for RP-ILD. This case illustrates that patients with coexisting anti-MDA5+ DM and MCTD have the former's typical clinical manifestations, and may develop ILD quickly rather than slowly as in MCTD, especially with the coexistence of anti-Ro52 antibodies.

BLCA prognostic model creation and validation based on immune gene-metabolic gene combination.

BACKGROUND: Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. METHODS: Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. RESULTS: We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. CONCLUSIONS: The model in our work is a novel assessment tool to measure immunotherapy's effectiveness and anticipate BLCA patients' prognosis, offering new avenues for immunological biomarkers and targeted treatments.

The Prevalence and Concurrent Pathogenic Mutations of KRAS G12C in Northeast Chinese Non-small-cell Lung Cancer Patients.

OBJECTIVE: KRAS mutation is one of important driver genes in non-small-cell lung cancer (NSCLC) and the patients with KRAS G12C mutations benefit from the inhibitor AMG510. However, the frequency, concurrent pathogenic mutations, and clinical characteristic of KRAS G12C is unknown in the NSCLC population of Northeast China. METHODS: The retrospective analysis was derived from 431 NSCLC patients in Jilin Cancer Hospital between January 2018 and June 2019. The mutation frequency and concurrent mutations of KRAS G12C in tumor or peripheral blood was detected by next-generation sequencing (NGS). RESULTS: The RAS mutant rate was observed in 10.7% (46/431) of this cohort. All RAS-driver cancers are caused by mutations in the KRAS isoform, while the NRAS and HRAS isoforms were not detected. Among KRAS-mutant patients, 42 (91.3%) showed exon 2 mutation in 12 codon and 13 codon. KRAS G12C showed a 4.6% (20/431) mutation rate in this cohort and the highest frequency (43.5%, 20/46) in KRAS-mutant-positive patients. There was no difference between tumor tissue and plasma in terms of either KRAS or KRAS G12C mutation. The most frequent co-occurrence mutations with KRAS G12C were TP53, followed by PTEN. Furthermore, KRAS G12C was exclusive with STK11 mutation. KRAS G12C mutation was associated with age, disease stage, and smoking status (P=0.024; P=0.02; P=0.006), smoking remained an independent factor for KRAS G12C mutation (P=0.037), and higher mutation frequency in patients older than 60, stage I-III, or smoking in NSCLC (P=0.0151, P=0.0343, P=0.0046, respectively). CONCLUSION: KRAS mutation was the only isoforms of RAS family, of these 43.5% harbored the KRAS G12C subtype in northeastern Chinese NSCLC patients. KRAS G12C is associated with age, pathological stage and smoking status, more commonly harbored TP53/PTEN mutations, and providing more genome profile for targeted therapy in local clinical practice.

Construction and validation a nomogram to predict overall survival for colorectal signet ring cell carcinoma.

To construct and validate a nomogram to predict the overall survival (OS) of colorectal signet ring cell carcinoma (SRCC). The potentially eligible cases were obtained against the SEER database from 2004 to 2015. Log-rank test and Cox analysis were conducted to identify the independent prognostic factors for predicting OS. The identified prognostic factors were later integrated for the construction of an OS prediction nomogram. Altogether 2904 eligible cases were identified, and the median survival time was 18 (range: 0-155) months. As suggested by multivariate analysis, age, primary site, grade, tumor size, T stage, N stage, M stage, surgery, lymph node dissection and chemotherapy were identified as the independent factors for predicting OS. Afterwards, the above variables were incorporated into the nomogram. The C-index indicated better discriminatory ability of the nomogram than AJCC 8th TNM staging and SEER summary stage systems (both P < 0.001). Calibration plots further showed good consistency between the nomogram prediction and actual observation. The time independent area under the curves (tAUCs) for 3-year and 5-year OS in nomogram were larger than AJCC and SEER summary stage system. The constructed nomogram could potentially predict the survival of colorectal SRCC individuals.

The Relationship Between Interleukin-4 Levels and Cardiovascular Events in Patients with Chronic Kidney Disease.

BACKGROUND: Cardiovascular diseases (CVDs) are the main cause of death in patients with chronic kidney disease (CKD). Interleukin-4 (IL-4) is considered an inflammatory cytokine. However, few studies have investigated the association between serum IL-4 and cardiovascular events in CKD. This study investigated whether serum IL-4 levels were associated with an increased risk of cardiovascular (CV) events in patients with CKD. PATIENTS AND METHODS: A total of 302 patients with stage 1-5 CKD were followed up for a mean of 32 (range=4-36) months for end points (CV events). Serum IL-4 levels were measured at baseline. The independent relationship between serum IL-4 and the risk of CV events was assessed with multivariate Cox regression analysis. RESULTS: The average age of this cohort (N=302) was 65.4 years. A total of 69.9% of them were male. CV events numbered 41 (13.6%) during the follow-up period. The Kaplan-Meier analysis showed that the rate of CV events was higher in patients with CKD with IL-4 levels above the mean (126.2 pg/mL) than in those with IL-4 levels below the mean. The multivariate Cox proportional hazard analysis revealed that serum IL-4 (HR=1.650, 95% CI 1.266-2.210, P<0.001) was associated with CV events in these patients with CKD. Sensitivity analysis showed that the association between serum IL-4 and CV events was not affected by the use of anti-inflammatory medication. The significant association between higher IL-4 levels and increased risk of CV events existed in patients with CKD3-5 but not in patients with CKD1-2 by using the stratified analysis. CONCLUSION: Higher serum IL-4 levels were associated with an increased risk of CV events during follow-up. Elevated serum IL-4 levels may help clinicians predict early CV events in patients with CKD.

Analysis of NTRK mutation and clinicopathologic factors in lung cancer patients in northeast China.

OBJECTIVE: NTRK mutations and clinicopathological factors in patients with lung cancer in northeast China were analyzed by next-generation sequencing (NGS), and references were provided for patients with NTRK mutations undergoing targeted therapy in northeast China. METHODS: A total of 224 specimens in 173 patients with lung cancer were collected. This included 51 patients with matched tissue and whole blood samples,133 tissue samples, 84 whole blood samples, and 7 pleural effusion samples. NGS (520 genes) was used to detected NTRK mutations and clinicopathologic factors. RESULTS: NTRK mutation was detected in eight patients (8/173, 4.6%), including four NTRK missense mutations (4/173, 2.3%), two NTRK fusion gene mutations (2/173, 1.2%), and two NTRK copy number deletions (2/173, 1.2%). Among the eight patients with NTRK mutations, four were associated with lung cancer driver gene mutations (3/4 EGFR, 1/4ALK); NTRK in two patients was inconsistent in tissue and paired whole blood testing; NTRK missense mutation was detected in one patient, and NTRK copy number deletion was detected in the other; and NTRK wild type was detected in two patients. There was no correlation between NTRK mutation and clinicopathologic factors (including gender, age, pathological type, smoking status, metastasis site). CONCLUSION: NTRK mutation was only 4.6%, effective fusion gene mutation was 1.2%, and common driver gene mutation in lung cancer was evident in 50% of patients. The results of NTRK were inconsistent with matched tissues and whole blood. Therefore, patients with NTRK mutation should use a variety of specimen types and large target area sequencing (panel) analysis method to provide individualized treatment.

Long Noncoding RNA LINC01426 Sequesters microRNA-519d-5p to Promote Non-Small Cell Lung Cancer Progression by Increasing ETS1 Expression.

PURPOSE: Recent studies have identified important roles for long intergenic non-protein coding RNA 1426 (LINC01426) in glioma and clear cell renal cell carcinoma. The present study evaluated the expression profile of LINC01426 in non-small cell lung cancer (NSCLC) tissues and cell lines. Furthermore, the function of LINC01426 in NSCLC and the molecular mechanisms involved were extensively studied. METHODS: The abundance of LINC01426 in NSCLC tissues and cell lines was determined using quantitative reverse transcription-polymerase chain reaction. The cell counting kit-8 assay, flow cytometry, transwell experiments for migration and invasion, and xenograft tumor model were used to assess the function of LINC01426 in NSCLC cells. Mechanistic studies were performed using the luciferase reporter assay and RNA immunoprecipitation. RESULTS: Significant LINC01426 upregulation was observed in NSCLC tissues and cell lines. Silencing LINC01426 inhibited proliferation, migration, and invasion of NSCLC cells and facilitated cell apoptosis in vitro. Furthermore, interference of LINC01426 restricted tumor growth of NSCLC cells in vivo. In addition, LINC01426 showed the ability to directly bind to microRNA-519d-5p (miR-519d-5p) and act as a molecular sponge for miR-519d-5p in NSCLC cells. Furthermore, the ETS proto-oncogene 1 (ETS1) was identified as a direct target of miR-519d-5p and LINC01426 could indirectly upregulate ETS1 expression by sponging miR-519d-5p. Moreover, the cancer-inhibiting activities of LINC01426 knockdown in NSCLC cells were partially offset by miR-519d-5p inhibition. CONCLUSION: LINC01426 increases ETS1 expression by sequestering miR-519d-5p, thereby aggravating the malignant progression of NSCLC. The LINC01426/miR-519d-5p/ETS1 competing endogenous RNA pathway may provide a target for designing therapeutic agents for NSCLC treatment.

Factors related to rapid progression of non-small cell lung cancer in Chinese patients treated using single-agent immune checkpoint inhibitor treatment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). While rapid progression (RP) has been proposed as a non-negligible pattern of response to ICIs, its definition and related factors remain unclear. This study aimed to develop a clinical definition of RP and to identify related factors. METHODS: We retrospectively evaluated Chinese patients who had received an ICI as second-line or later treatment for locally advanced or metastatic NSCLC at a single center. We defined RP as radiological progression at the first response assessment (<2 months after starting the ICI), as well as confirmation of progressive disease or cancer-related death occurring at <3 months. The clinical outcomes were compared for patients with RP or non-RP to identify prognostic factors. RESULTS: The study evaluated 74 eligible patients with detailed records regarding their ICI therapy, including 25 patients (33.8%) who had experienced RP. Relative to patients with non-RP, patients with RP had significantly shorter median progression-free survival (1.7 months [95% CI: 1.4-2.0 months] vs. 6.3 months [95% CI 5.2-7.3 months], P < 0.001; hazard ratio: 0.14, 95% CI: 0.08-0.25) and significantly shorter median overall survival (8.2 months [95% CI 3.0-13.4 months] vs. 22.6 months [95% CI 17.0-28.1 months], P < 0.001; hazard ratio: 0.27, 95% CI: 0.15-0.49). Multivariate analysis revealed that RP was independently predicted by the presence of ≥3 metastatic sites (P = 0.039) and a neutrophil-to-lymphocyte ratio of ≥3 (P = 0.044). CONCLUSIONS: Among NSCLC patients, RP was a common response to ICI monotherapy and was associated with dramatically reduced progression-free and overall survival. Care is needed when selecting ICI monotherapy for these patients, especially if they have ≥3 metastatic sites or a neutrophil-to-lymphocyte ratio of ≥3. KEY POINTS: Significant findings of the study: Patients with rapid progression after immune checkpoint inhibitor monotherapy had poor survival outcomes. The number of metastatic sites and the neutrophil-to-lymphocyte ratio may independently predict treatment response in this setting. WHAT THIS STUDY ADDS: This is the first study to evaluate rapid progression after second-line or later single-agent immunotherapy in a Chinese population. Our findings may help establish effective immunotherapy strategies for NSCLC.

Protections against toxicity in the brains of rat with chronic fluorosis and primary neurons exposed to fluoride by resveratrol involves nicotinic acetylcholine receptors.

Protection of Resveratrol (RSV) against the neurotoxicity induced by high level of fluoride was investigated. Sprague-Dawley (SD) rats and their offspring, as well as cultures of primary neurons were divided randomly into four groups: untreated (control); treated with 50 mg RSV/kg/ (once daily by gavage) or (20 M in the cultured medium); exposed to 50 ppm F- in drinking water or 4 mmol/l in the cultured medium; and exposed to fluoride then RSV as above. The adult rats were treated for 7 months and the offspring sacrificed at 28 days of age; the cultured neurons for 48 h. For general characterization, dental fluorosis was assessed and the fluoride content of the urine measured (by fluoride-electrode) in the rates and the survival of cultured neurons monitored with the CCK-8 test. The spatial learning and memory of rats were assessed with the Morris water maze test. The levels of α7 and α4 nicotinic acetylcholine receptors (nAChRs) were quantified by Western blotting; and the activities of superoxide dismutase (SOD) and catalase (CAT), and the levels of malondialdehyde (MDA) and H2O2 assayed biochemically. The results showed that chronic fluorosis resulted in the impaired learning and memory in rats and their offspring, and more oxidative stress in both rat brains and cultured neurons, which may be associated the lower levels of α7 and α4 nAChR subunits. Interestingly, RSV attenuated all of these toxic effects by fluorosis, indicating that protection against the neurotoxicity of fluoride by RSV might be in mechanism involved enhancing the expressions of these nAChRs.

Comprehensive characterization and clinical impact of concomitant genomic alterations in EGFR-mutant NSCLCs treated with EGFR kinase inhibitors.

OBJECTIVES: Although the majority of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients respond to EGFR tyrosine kinase inhibitors (TKIs), significant heterogeneity in clinical response is observed which might be attributed to the distinct sub-molecular characteristics. The present study aims to identify genetic alterations correlated with clinical outcomes and treatment response to different EGFR-TKI inhibitors. MATERIALS AND METHODS: We integrated the genomic data and clinical outcomes including progression-free survival (PFS) and overall survival (OS) in 179 patients with advanced EGFR-mutant NSCLC who were treated with EGFR-TKI as 1st line of treatment. RESULTS: We found that EGFR-mutant patients harboring concomitant TP53 mutation (OS: 21 vs. 40 months, P = 0.05), ERBB2 amplification (PFS: 6.1 vs. 12.5 months, P = 0.01) or FGF19 amplification (OS: 11.2 vs. 27.1 months, P = 0.01) were significantly associated with a poorer clinical prognosis after treated with 1st generation EGFR-TKI. In contrast, the presence of TP53 mutation did not affect the PFS nor OS of patients treated with 2nd generation EGFR-TKI. Furthermore, EGFR-mutant and TP53-wild type (WT) patients benefited more from a combinatorial treatment consisting of EGFR-TKI and bevacizumab comparing to EGFR-TKI as a single agent (PFS: 21.7 vs. 9.3 months, P < 0.01). Copy number variation (CNV) (PFS: 4.6 vs.9.4 months, p = 0.018) was identified as an unfavorable predictive factor to 3rd-generation TKI. We also revealed distinct resistance mechanisms associated with different EGFR-TKIs. CONCLUSION: Our study highlights the heterogeneity both in the primary molecular landscape and acquired alterations in EGFR-mutated NSCLCs, which might play a role in determining the clinical efficacy of EGFR-TKIs. We also revealed the differential prognostic role of TP53 mutation in patients treated with the 1st or 2nd generation of EGFR-TKI. Our study also suggests that EGFR-mutant and TP53-WT patients may benefit more from combinatorial treatment consisting of EGFR-TKI and bevacizumab, highlighting the importance of further stratifying EGFR-mutant patients.

[Disparities of EGFR mutations between Biopsy and Rebiopsy in Non-small Cell Lung Cancer Patients].

BACKGROUND: Epidermal growth factor receptor (EGFR)-based targeted therapy improves the survival of patients with advanced lung adenocarcinoma harboring EGFR mutations. However, factors including treatment or heterogeneity partly contribute to EGFR genetic status alteration between baseline and disease progresses (PD). The aim of this study is to compare difference of EGFR mutations between biopsy and rebiopsy in real world. METHODS: Data from 61 paired specimens performed EGFR testing in Jilin Provincial Cancer Hospital between January 2015 and December 2017 were collected and analyzed. The specimens were collected at baseline and PD, confirmed by histology or cytology and categorized as tumor tissue, malignant pleural effusion or plasma. All patients were naive and received chemotherapy or targeted therapy as first-line treatment. Amplification Refractory Mutation System (ARMS) was used to detect EGFR mutations. RESULTS: EGFR mutation rate in tumor tissue, pleural effusion or blood was 90.2% vs 88.5%, 6.6% vs 6.6% and 3.2% vs 4.9% at baseline or PD respectively and discrepancy was 72% and 36.3% for the same (n=50) or different (n=11) type of specimens. The EGFR mutation rate was 95.1% and 91.8% in patients before and after treatment, and the discrepancy was 63.9%, among which, 69.2% and 92.3% in chemotherapy-treated patients (n=13) with discrepancy to 46.1% (6/13), and 100.0% and 91.7% in EGFR-TKI-treated patients (n=48) with discrepancy to 70.8%. There were four types of alterations in terms of EGFR mutations: wild type turned into mutation (4.9%), mutation disappeared (8.2%), sensitive mutations transformed (1.6%), and new mutations appeared (49.1%). CONCLUSIONS: In real world, the EGFR mutation status in advanced non-small cell lung cancer (NSCLC) patients altered significantly, due to tissue resources and therapeutic approaches, implying the importance of rebiopsy and real-time detection of EGFR mutation, in order to provide data to guide precise strategy in the following treatment.