Purpose Prognosis for patients with EGFR- mutant non-small-cell lung cancer and leptomeningeal metastasis is highly uncertain, complicating treatment decisions. We aimed to develop and validate a multimodal risk score for predicting overall survival to enable risk-stratified management. Methods In this retrospective, multicenter study, a derivation cohort (n = 350) and an independent external validation cohort (n = 302) were used. Independent prognostic factors were identified via Cox regression and integrated into an integer-based risk score. Model performance was evaluated by the C-index, calibration, and decision curve analysis. Results Multivariate analysis identified five independent predictors of poorer OS: ECOG PS ≥ 3, brain metastasis, meningeal enhancement on MRI, positive Cerebrospinal Fluid cytology (CSFC) and intracranial pressure > 220 mmH2O. The resulting risk score stratified patients into low-risk and high-risk groups, with median OS of 22.6 months versus 9.9 months, respectively (p < 0.001). The model demonstrated good discrimination, with a bias-corrected C-index of 0.73. In the external validation cohort, all factors remained significant, and the model maintained consistent performance (C-index = 0.71). The model showed good calibration and positive net benefit. Conclusion We developed and validated a robust, clinically accessible risk score that accurately stratifies OS in patients with EGFR- mutant NSCLC and LM. This practical tool facilitates risk‑stratified patient counseling and may aid in the design of future clinical trials.

Background and objective Leptomeningeal metastasis (LM) is a severe complication of non-small cell lung cancer (NSCLC). Although intrathecal Pemetrexed chemotherapy can effectively prolong patient survival, a high incidence of neurotoxicity has emerged as a critical factor limiting its clinical application. This study aims to investigate the efficacy and safety of Huangqi Guizhi Wuwu decoction (HGWD) in mitigating neurotoxicity induced by intrathecal Pemetrexed chemotherapy in NSCLC patients with LM. Methods In a prospective, randomized, double-blind, controlled trial, 220 NSCLC patients with LM were enrolled and randomly assigned to either the treatment group (HGWD+intrathecal chemotherapy) or the control group (placebo+intrathecal chemotherapy), with 110 patients in each group. The incidence and grade of neurotoxicity, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life, and adverse reactions were observed and compared between the two groups. Results The incidence of neurotoxicity in the treatment group was 29.1%, significantly lower than that in the control group (51.8%)(P<0.001). The incidences of both grade 1-2 and grade 3-4 neurotoxicity were lower in the treatment group than in the control group (P<0.010). Nerve conduction studies showed that the sensory nerve action potential amplitude of the sural nerve was significantly higher in the treatment group than in the control group (P=0.012), and the conduction velocities of the median and ulnar nerves showed a trend toward improvement. The DCR was 76.4% in the treatment group, higher than 69.1% in the control group (P=0.045). Both median PFS (7.8 vs 6.1 mon, P<0.001) and median OS (10.5 vs 8.9 mon, P=0.007) were significantly prolonged in the treatment group. Improvements in quality of life and traditional Chinese medicine syndrome scores were superior in the treatment group (P<0.05). No significant difference in adverse reactions were observed. Conclusion HGWD can significantly reduce the incidence of neurotoxicity induced by Pemetrexed intrathecal chemotherapy, improve chemotherapy tolerance and survival benefits, with a good safety profile in NSCLC patients with LM.

Background:Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality due to frequent metastasis, despite therapeutic advances. This study aims to identify novel drivers of NSCLC metastasis to facilitate the development of prognostic biomarkers and therapeutic targets. Methods:We analyzed single-cell RNA-seq data (GSE121907) to identify differentially expressed genes (DEGs) in epithelial cells from metastatic NSCLC. Functional enrichment was performed. Based on bioinformatic findings, we investigated the role of zinc finger protein 528 (ZNF528) through gain- and loss-of-function studies in NSCLC cell lines. Cellular proliferation, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays, respectively. Epithelial-mesenchymal transition (EMT) markers were analyzed by immunoblotting. A cell-derived xenograft (CDX) model was established to evaluate tumor growth and metastasis in vivo. Results:Single-cell analysis revealed an expanded epithelial compartment in metastatic samples. Among the DEGs identified in these epithelial cells, ZNF528 was significantly upregulated. Pathway analysis indicated enrichment of ZNF528-correlated genes in proliferation and invasion-related pathways (e.g., NF-κB, MAPK). Consistently, functional assays demonstrated that ZNF528 knockdown suppressed, while its overexpression enhanced, NSCLC cell proliferation, migration, invasion, and EMT in vitro. Moreover, ZNF528 overexpression promoted tumor growth and metastasis in mouse xenograft models. Conclusions:ZNF528 acts as a novel promoter of NSCLC metastasis, representing a potential prognostic biomarker and therapeutic target.

Abstract Leptomeningeal metastasis is driven by rare cerebrospinal fluid circulating tumor cells (CSF-CTCs). However, the mechanisms underlying their adaptation to chemotherapeutic stress remain elusive, primarily because transcriptomics alone poorly predicts functional protein states. Here, we present scMAPS, a single-cell multi-omics method that employs magnetic-assisted partitioning cell lysates to enable unbiased transcriptome-proteome co-profiling without loss-prone physical splitting and precision device. By coupling scMAPS with our custom CLEAP (CTC Label-free Enrichment and Accurate Picking) system, we performed the first deep multi-omics profiling of rare clinical CSF-CTCs before and after localized chemotherapy, detecting an average of 2,547 proteins and 7,821 genes per cell. The integrated CLEAP-scMAPS pipeline reveals a coordinated prioritizing survival over proliferation malignant dormancy phenotype and identified post-transcriptional buffering as the primary driver of treatment resistance. Our platform enables the comprehensive molecular phenotyping of rare clinical specimens, providing a highly versatile framework for decoding complex post-transcriptional regulatory networks.

Diagnosing and monitoring leptomeningeal metastasis (LM) presents a significant clinical challenge. This study evaluated cerebrospinal fluid (CSF) Human Epididymis Protein 4 (HE4) as a novel diagnostic and monitoring biomarker for LM in non-small cell lung cancer (NSCLC). A prospective cohort study enrolled 117 participants (including 61 NSCLC patients with LM and 56 controls without central nervous system malignancies) from March 2023 to December 2024. Paired CSF and serum levels of HE4, carcinoembryonic antigen (CEA), and Cytokeratin 19 Fragment (CYFRA21-1) were measured using electrochemiluminescence immunoassay. Multivariable binary logistic regression, adjusting for clinical covariates (KPS, ICP, and symptom-to-diagnosis interval), was employed to identify independent diagnostic predictors. Diagnostic performance was quantified using receiver operating characteristic (ROC) curve analysis and compared via the DeLong test. Serial CSF HE4 monitoring was performed in a subset of patients to assess treatment response. CSF HE4 levels were markedly elevated in LM patients compared to controls (median 807.00 vs. 99.35 pmol/L, P < 0.001). Multivariable logistic regression revealed that CSF HE4 was a robust, independent diagnostic factor for LM (Adjusted OR = 1.027; 95

BackgroundNon-small cell lung cancer (NSCLC) represents approximately 85% of all lung malignancies, with lung adenocarcinoma (LUAD) being the predominant histologic subtype. Epidermal growth factor receptor (EGFR) mutations serve as critical therapeutic targets in NSCLC; however, resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) remains a major clinical challenge. Recent studies highlight the need to identify molecular drivers of resistance to improve therapeutic outcomes.MethodThis study analyzed tumor tissue datasets to investigate the role of the assembly factor for spindle microtubules (ASPM) in NSCLC progression and drug resistance. Bioinformatics methods revealed high expression of ASPM in tumor tissues and its association with low patient survival. Functional validation was performed using the EGFR-TKI-resistant cell line PC9 osimertinib-resistant (PC-9 OR), with ASPM-silenced models. Cellular proliferation, invasion, and EGFR protein stability analyses were conducted. Additionally, the therapeutic impact of ASPM silencing and overexpression combined with the third-generation TKI osimertinib was evaluated.ResultsASPM is significantly upregulated in NSCLC tumor tissues and is strongly associated with reduced patient survival. ASPM silencing attenuates PC-9 and PC-9 OR malignant phenotypes, including proliferation and invasion, and sensitizes resistant cells to osimertinib. In addition, inhibiting the expression of ASPM effectively reduces damage to the cell cycle and protein stability of drug-resistant cells, thereby restoring the expression and function of EGFR.ConclusionThis study identified ASPM as a novel regulator of EGFR-TKI resistance in NSCLC, with dual roles in promoting tumor aggressiveness and stabilizing EGFR signaling. Targeting ASPM may represent a promising therapeutic strategy to overcome EGFR-TKI resistance, enhance osimertinib efficacy, and expand treatment options for refractory NSCLC patients. These findings provide a foundation for developing ASPM-directed therapies in precision oncology.

Background and objective Leptomeningeal metastasis (LM) is a devastating complication of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), with a poor prognosis. While high-dose third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can enhance drug concentrations in the central nervous system, their efficacy as monotherapy remains limited. Intrathecal Pemetrexed (IP) offers a promising local treatment approach by bypassing the blood-brain barrier and acting directly within the cerebrospinal fluid. However, clinical data on the efficacy and safety of combining high-dose third-generation EGFR-TKIs Furmonertinib (160 mg/d) with IP in EGFR-mutant NSCLC-LM patients are still scarce. Therefore, this study aims to evaluate the efficacy and safety of this combination regimen in this population to provide real-world data support for clinical practice. Methods In this retrospective study, 40 patients with EGFR-mutant NSCLC-LM were enrolled at Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University between June 2021 and December 2024. All patients received oral Furmonertinib (160 mg/d) combined with IP. Primary endpoints were intracranial progression-free survival (iPFS), overall survival (OS), overall response rate (ORR) and adverse events. Survival analysis was performed using the Kaplan-Meier method, and prognostic factors were assessed via Cox proportional hazards regression by collecting the clinical data and follow-up information of the patients. Results After a median follow-up of 20.0 months, the combination therapy demonstrated significant efficacy. The ORR was 85.0%, with a median iPFS of 9.6 months and a median OS of 12.6 months. The 6-, 12- and 24-month OS rates were 79.9%, 53.9% and 27.0%, respectively. Multivariate analysis identified combination therapy with Bevacizumab as an independent protective factor [hazard ratio (HR)=0.283, 95%CI: 0.114-0.702, P=0.006], while a poor baseline Karnofsky performance status (KPS) score was an independent risk factor (HR=3.069, 95%CI: 1.313-7.170, P=0.010). Adverse events were primarily grade 1-2, including myelosuppression (42.5%), elevated transaminases (22.5%), and gastrointestinal reactions (nausea and/or vomiting, 20.0%). Only one case of grade 4 myelosuppression was reported and resolved after supportive care. Conclusion High-dose Furmonertinib combined with IP is an effective and well-tolerated regimen for EGFR-mutant NSCLC-LM. The addition of Bevacizumab may further improve outcomes, offering a promising strategy for refractory patients.

Proinflammatory repolarization of tumor‐associated macrophages (TAMs) positively correlates with improved therapeutic outcomes in non‐small cell lung cancer (NSCLC), positioning TAM‐targeted immunotherapy as a promising strategy. Here, porous silicon nanoparticles (PSiNPs) are reported that enhance macrophage internalization of manganese@albumin nanocomplexes (M‐BSA), driving an endocytic shift from phagocytosis to clathrin‐mediated endocytosis. This endocytic programming facilitates the trafficking and endosomal aggregation of membrane‐anchored toll‐like receptor 4 (TLR4), redirecting downstream signaling toward the toll/interleukin‐1 receptor domain‐containing adaptor‐inducing interferon‐β (TRIF)‐biased pathway to trigger robust proinflammatory responses. Compared to free M‐BSA, M‐BSA@PSiNPs significantly elevate macrophage secretion of tumor necrosis factor‐α (TNF‐α), enhancing cytotoxicity against NSCLC cells in vitro. Combined with immune checkpoint blockade therapy, M‐BSA@PSiNPs synergistically repolarize TAM and remodel the immunosuppressive tumor microenvironment, resulting in potent eradication of established NSCLC tumors in vivo. These findings highlight the potential of M‐BSA@PSiNPs as a TLR4 nanoagonist platform for TAM‐mediated immunotherapy against NSCLC.

Non-small-cell lung cancer (NSCLC) has a terrible consequence called leptomeningeal metastases (LM). It is crucial to look for novel biomarkers because none of the known biomarkers could effectively reflect the oncogenesis, progression and therapeutic responses of LM. Exosomal miRNAs from plasma have a critical function in lung cancer, according to growing data. However, unique biomarkers of cerebrospinal fluid (CSF) are more representative for patients with LM, which have not been reported. Here, we explore the possibility of using CSF-derived exosomal microRNAs as potential biomarkers for NSCLC-LM. Nine NSCLC-LM patients who received regular intrathecal chemotherapy with permetexed were divided into a partial response (PR) group and a progressive disease (PD) group. CSF samples were taken from all patients before and after intrathecal treatment and five non-cancerous controls. Using the size exclusion chromatography (SEC) method, the exosome microRNAs were isolated and profiled. Between LM patients and controls, 56 differentially expressed genes (DEGs) were found, of which three highly elevated diagnostic biomarkers (hsa-miR-183-5p, hsa-miR-96-5p and hsa-miR-182-5p) were ruled out. The two most significant DEGs between the untreated PR group and the PD group were determined to be upregulated hsa-miR-509-3p and downregulated hsa-miR-449a, and they may serve as potential indicators of intrathecal anti-pemetrexed treatment. Hsa-miR-1-3p increased gradually with the intrathecal chemotherapy in the PR group, which might offer a new approach to screen optimal patients and estimate the efficacy. This study revealed specific CSF exosomal miRNAs profile and dynamic changes of patients with NSCLC-LM for the first time and identified several potential exosomal miRNA biomarkers in diagnosis, drug resistance and prognosis.

The immunomodulatory effect of divalent manganese cations (Mn 2+ ), such as activation of the cGAS−STING pathway or NLRP3 inflammasomes, positions them as adjuvants for cancer immunotherapy. In this study, it is found that trace Mn 2+ ions, bound to bovine serum albumin (BSA) to form Mn@BSA nanocomplexes, stimulate pro‐inflammatory responses in human‐ or murine‐derived macrophages through TLR4‐mediated signaling cascades. Building on this, the assembly of Mn@BSA nanocomplexes to obtain nanowire structures enables stronger and longer‐lasting immunostimulation of macrophages by regulating phagocytosis. Furthermore, Mn@BSA nanocomplexes and their nanowires efficiently activate peritoneal macrophages, reprogramme tumor‐associated macrophages, and inhibit the growth of melanoma tumors in vivo. They also show better biosafety for potential clinical applications compared to typical TLR4 agonists such as lipopolysaccharides. Accordingly, the findings provide insights into the mechanism of metalloalbumin complexes as potential TLR agonists that activate macrophage polarization and highlight the importance of their nanostructures in regulating macrophage‐mediated innate immunity.

Objective:To evaluate the effects of intrathecal infusion chemotherapy on intracranial pressure (ICP) in non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM) by ultrasound measurement of the optic nerve beside the bed of optic nerve sheath diameter (ONSD) .Methods:A total of 31 NSCLC-LM patients who underwent intrathecal infusion chemotherapy at Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School from June 10, 2021 to December 25, 2022 were collected. The ONSD values were measured before and after the first lumbar puncture by bedside optic nerve ultrasound, and measured dynamically 30 min before intrathecal infusion chemotherapy (T0) , 30 min (T1) , 1 h (T2) , 2 h (T3) , 4 h (T4) , 6 h (T5) , and 24 h (T6) after intrathecal infusion chemotherapy. ICP ONSD was calculated, with differences between ICP LP and ICP ONSD, and differences between ONSD and ICP ONSD series at different time being compared separately. Mean arterial pressure (MAP) , heart rate, and headache score were assessed and compared respectively at T0, T1, T2, T3, T4, T5 and T6. Spearman analysis was used to evaluate the correlation between the response assessment in neuro-oncology (RANO) score and ICP. Results:Before the first lumbar puncture for cerebrospinal fluid drainage, ICP LP was (218.55±63.83) mmH 2O, left eye, right eye, and binocular eyes ICP ONSD were (217.28±57.17) mmH 2O, (223.64±51.13) mmH 2O, and (220.46±52.50) mmH 2O respectively, in NSCLC-LM patients, with no statistically significant difference ( F=0.77, P=0.463) . After first lumbar puncture for cerebrospinal fluid drainage, ICP LP was (214.68±58.01) mmH 2O, left eye, right eye, and binocular eyes ICP ONSD were (216.71±48.96) mmH 2O, (216.62±47.18) mmH 2O, and (216.67±47.86) mmH 2O respectively, with no statistically significant difference ( F=0.12, P=0.757) . At T0, T1, T2, T3, T4, T5, and T6, the MAP during intrathecal infusion chemotherapy was 89.80 (83.40, 93.67) mmHg, 95.00 (80.83, 99.37) mmHg, 91.86 (79.88, 100.14) mmHg, 90.15 (79.04, 100.55) mmHg, 105.14 (88.55, 114.74) mmHg, 98.96 (81.72, 111.81) mmHg, and 89.29 (85.45, 100.38) mmHg, with a statistically significant difference ( χ2=16.11, P=0.013) ; heart rates were 80.00 (75.00, 84.50) times/min, 80.00 (72.50, 87.50) times/min, 74.00 (66.00, 87.50) times/min, 82.00 (72.00, 90.00) times/min, 80.00 (70.50, 90.00) times/min, 77.00 (68.00, 91.00) times/min, 77.00 (71.50, 88.50) times/min, with no statistically significant difference ( χ2=2.18, P=0.902) ; headache scores were 2.00 (0.50, 3.00) score, 2.00 (1.00, 3.00) score, 2.00 (2.00, 3.00) score, 2.00 (1.00, 3.00) score, 2.00 (1.00, 2.00) score, 2.00 (1.00, 2.00) score, and 2.00 (0.00, 2.00) score, with no statistically significant difference ( χ2=11.64, P=0.071) . At T0, T1, T2, T3, T4, T5, and T6, left eye, right eye, and binocular ONSD were (5.85±0.64) mm, (5.72±0.68) mm, (7.11±1.11) mm, (6.42±0.78) mm, (5.69±0.63) mm, (5.61±0.64) mm, (5.65±0.88) mm, (5.85±0.12) mm, (5.89±0.12) mm, (6.93±0.20) mm, (6.40±0.14) mm, (5.71±0.12) mm, (5.66±0.12) mm, (5.33±0.14) mm, (5.85±0.64) mm, (5.81±0.64) mm, (7.02±1.03) mm, (6.41±0.75) mm, (5.70±0.63) mm, (5.64±0.63) mm, (5.49±0.76) mm, with statistically significant differences ( F=58.48, P<0.001; F=49.34, P<0.001; F=78.05, P<0.001) ; ICP ONSD were (222.81±56.81) mmH 2O, (211.89±60.29) mmH 2O, (335.12±98.32) mmH 2O, (274.17±68.87) mmH 2O, (208.77±56.12) mmH 2O, (201.75±56.79) mmH 2O, (205.59±78.36) mmH 2O, (223.26±58.33) mmH 2O, (227.08±61.68) mmH 2O, (319.36±101.10) mmH 2O, (272.33±69.61) mmH 2O, (211.21±57.73) mmH 2O, (206.51±57.22) mmH 2O, (177.22±68.98) mmH 2O, (223.03±57.24) mmH 2O, (219.49±57.24) mmH 2O, (327.24±91.56) mmH 2O, (273.25±67.04) mmH 2O, (209.99±56.26) mmH 2O, (204.13±56.29) mmH 2O, (191.40±67.95) mmH 2O, with statistically significant differences ( F=58.48, P<0.001; F=49.34, P<0.001; F=78.13, P<0.001) . The ONSD of the left eye, right eye, and binocular eyes and the corresponding ICP ONSD increased significantly at T2 compared with T0, T1, T3, T4, T5, and T6, with statistically significant differences (all P<0.05) . Pre- and post-treatment RANO scores were 4.00 (3.00, 7.00) score and 3.00 (2.00, 6.00) score respectively. Pre- and post-treatment RANO scores were positively correlated with ICP ONSD in the left eye ( r=0.55, P=0.001; r=0.60, P<0.001) , right eye ( r=0.54, P=0.001; r=0.46, P=0.009) and binocular eyes ICP ONSD ( r=0.45, P=0.010; r=0.37, P=0.043) . Conclusion:Intrathecal infusion chemotherapy for NSCLC-LM patients can cause a transient increase in ONSD and ICP, with the greatest effect at 1 hour after intrathecal infusion chemotherapy. RANO score is positively correlated with ICP ONSD before and after treatment, which can provide an important reference for evaluating the efficacy of intrathecal infusion chemotherapy.

Objectives: To explore the diagnostic accuracy of ultrasound measurement of optic nerve sheath diameter (ONSD) and optic disc height (ODH) in detecting intracranial hypertension in non-small-cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM). Methods: Seventy-two patients with NSCLC-LM and 65 patients with NSCLC were enrolled. The ONSD, ODH, eyeball transverse diameter (ETD), and eyeball vertical diameter (EVD) were measured by ultrasound. Subsequently, lumbar puncture was performed in NSCLC-LM patients to measure cerebrospinal fluid pressure (CSFP), and intrathecal chemotherapy was regularly implemented. Pearson's correlation analysis was used to analyze the relationship between CSFP and ultrasound findings. The diagnostic accuracy of ONSD, ODH, and combined ONSD and ODH was evaluated by receiver operating characteristic (ROC) curve analysis and the corresponding area under the ROC curve (AUC). Results: The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were higher in the NSCLC-LM group (all p < 0.05). The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were all elevated in the abnormally elevated CSFP group (all p < 0.05). ONSD, ODH, ONSD/ETD, and ONSD/EVD were positively correlated with CSFP (r = 0.531, 0.383, 0.534, and 0.535, all p < 0.0001). The AUCs for ONSD, ODH, ONSD/ETD, and ONSD/EVD to detect CSFP > 280 mmH2O were 0.787 (95% CI: 0.64-0.93, sensitivity 68.75%, specificity 91.07%), 0.885 (95% CI: 0.81-0.96, sensitivity 100%, specificity 69.64%), 0.765 (95% CI: 0.64-0.89, sensitivity 81.25%, specificity 64.29%), and 0.788 (95% CI: 0.64-0.93, sensitivity 56.25%, specificity 91.07%), respectively. When ONSD was combined with ODH, the AUC was 0.913 (95% CI: 0.83-0.99, sensitivity 87.85%, specificity 85.70%). Furthermore, intrathecal chemotherapy was associated with a downtrend in CSFP and ultrasound findings. Conclusion: There are important advantages of using bedside ultrasonography for detecting elevated CSFP in NSCLC-LM patients. Further research should be performed to evaluate the clinical significance of an enlarged ONSD and increased ODH in NSCLC-LM.

Intrathecal pemetrexed is a potential therapeutic strategy for Leptomeningeal metastasis (LM) from lung adenocarcinoma (LUAD), but still faces many obstacles caused by repeated lumbar puncture. In this study, we administered intrathecal pemetrexed via Ommaya reservoir in refractory LUAD-LM patients. This provides the realworld evidence of the safety, pharmacokinetic and clinical activity of intrathecal pemetrexed via Ommaya reservoir in resistant LUAD-LM for the first time. Introduction: Leptomeningeal metastasis (LM) is a highly fatal and debilitating complication of lung adenocarcinoma (LUAD) with limited therapeutic options. This study aimed to evaluate the efficacy and toxicities of intrathecal chemotherapy (IC) with pemetrexed via Ommaya reservoir in LUAD with refractory LM. Methods: In this prospective, single-arm, phase I trial (ChiCTR2000028936), LUAD-LM patients who had progressed after at least two prior treatments were recruited. Pemetrexed from 30 mg to 50 mg was administered on Days 1 and 8 every 3 weeks via Ommaya reservoir. Serial samples of cerebrospinal fluid (CSF) and plasma were obtained for pharmacokinetic studies. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and therapeutic toxicities. Results: Twenty-three patients were enrolled and analyzed, revealing an ORR of 43.5% (95% CI, 23.2%-63.8%) and DCR of 82.6% (95% CI, 61.2%-95.0%). The median PFS and OS were 6.3 and 9.5 months, respectively. Dose-limiting toxicity was only observed in 2 patients (2/23, 8.7%), and 30 mg pemetrexed was considered as the recommended dose for IC. Pharmacokinetic analysis showed that using Ommaya reservoirs, higher pemetrexed concentrations and prolonged half-lives were achieved in

Objective:To investigate the pharmacokinetics of cerebrospinal fluid pemetrexed following intrathecal injection chemotherapy in patients with leptomeningeal metastasis (LM) from lung adenocarcinoma and provide a basis for clinical intrathecal injection chemotherapy.Methods:A total of 21 patients with lung adenocarcinoma LM who underwent pemetrexed intrathecal injection chemotherapy via Ommaya capsule at Nanjing Drum Tower Hospital, Aiffilitated Hospital of Nanjing University Medical School from November 2019 to November 2022 were collected, and divided into 30, 40 and 50 mg groups ( n=10, n=4, n=7) according to pemetrexed dose. Cerebrospinal fluid was collected at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy, and day 8 of each cycle for three groups. Reversed phase high performance liquid chromatography was used to determine the drug concentration in cerebrospinal fluid, to clarify the drug-related pharmacokinetic parameters, and to compare the differences in pemetrexed concentration among groups. Finally, cerebrospinal fluid pemetrexed concentration changes were observed and compared after different intrathecal injection chemotherapy cycles. Results:There were statistically significant differences in cerebrospinal fluid drug concentrations of patients in three groups at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy (30 mg group: F=20.56, P<0.001; 40 mg group: F=27.06, P<0.001; 50 mg group: F=28.63, P<0.001), and there were statistically significant differences in the concentration of cerebrospinal fluid drugs in each dose group at 0.5, 1, 2, 4, 6 and 12 h compared to 0 h after intrathecal injection chemotherapy (all P<0.05). Compared to the 30 mg group, cerebrospinal fluid drug concentrations in the 50 mg group increased at 1, 2, 4, 6, 12 and 24 h after intrathecal injection chemotherapy, with statistically significant differences (all P<0.05). Pharmacokinetic analysis of cerebrospinal fluid pemetrexed showed that area under the concentration-time curve (AUC) 0-∞ of the 30, 40 and 50 mg groups were (5 696.12±283.32), (7 886.29±396.57), and (14 202.70±440.19) h·mg/L, respectively, with a statistically significant difference ( F=1 159.00, P<0.001) ; AUC 0-∞ increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; AUC 0-∞ increased in the 40 mg group compared to the 30 mg group ( P<0.05). The half-lives of three groups were (8.75±0.23), (11.29±0.59) and (16.42±1.23) h, respectively, with a statistically significant difference ( F=206.80, P<0.001) ; half-life was longer in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; half-life was longer in the 40 mg group compared to the 30 mg group ( P<0.05). The peak time of three groups were (1.55±0.10), (1.00±0.01), (1.43±0.11) h, respectively, with a statistically significant difference ( F=48.11, P<0.001) ; the peak time was shorter in the 40 and 50 mg groups compared to the 30 mg group (both P<0.05). Clearance of three groups were (7.02±2.46), (5.80±1.25) and (3.66±1.32) L/h, respectively, with a statistically significant difference ( F=6.02, P=0.009) ; clearance was decreased in the 50 mg group compared to the 30 mg group ( P<0.05). The peak concentration of three groups were (540.45±32.25), (820.75±46.47) and (1 014.78±64.96) mg/L, respectively, with a statistically significant difference ( F=207.70, P<0.001) ; peak concentration increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; peak concentration increased in the 40 mg group compared to the 30 mg group ( P<0.05). Cerebrospinal fluid drug concentrations were dynamically monitored after 4 cycles of intrathecal injection chemotherapy, in which cerebrospinal fluid pemetrexed concentrations in 30 mg group were (13.76±4.79), (11.41±7.08), (9.41±2.59) and (7.86±4.02) mg/L, respectively; 40 mg group were (14.45±6.59), (12.87±15.73), (11.24±2.48) and (9.09±3.38) mg/L, respectively; 50 mg group were (12.94±10.34), (9.72±7.62), (8.15±8.17) and (4.34±4.21) mg/L, respectively. There was a statistically significant difference in cerebrospinal fluid drug concentrations among different intrathecal injection chemotherapy cycles in 30 mg group ( F=4.04, P=0.016), and the cerebrospinal fluid drug concentration decreased in cycles 3 and 4 compared to cycle 1 (both P<0.05). There were no statistically significant differences in cerebrospinal fluid drug concentrations among different treatment cycles in 40 and 50 mg groups ( F=0.28, P=0.837; F=3.57, P=0.066) . Conclusion:Reversed phase high performance liquid chromatography method can effectively detect the pemetrexed concentration in cerebrospinal fluid; dynamic monitoring of cerebrospinal fluid pemetrexed concentration can provide a basis for the dosage and the treatment cycle of intrathecal injection chemotherapy in LM patients with lung adenocarcinoma.

目的 探讨LUAD伴LM患者CSF中的DKK1与LM发病、耐药性、预后的相关性.方法 筛选就诊于南京鼓楼医院进行规律的培美曲塞鞘内化疗的LUAD伴LM患者20例,依据RANO疗效评价标准分为:疾病控制(disease control,DC)组,疾病进展(progressive disease,PD)组.收集入组患者及10例非瘤对照者脑脊液样本.其中DC组样本按治疗周期分为:DC-0C组(鞘内化疗前),DC-2C组(两周期鞘内化疗后),DC-4C组(四周期鞘内化疗后).使用ELISA检测样本DKK1表达情况,分析其与患者临床特征、疗效、无进展生存期(progression-free survival,PFS)相关性.结果 LUAD患者CSF中DKKl表达较非瘤对照升高(P<0.05),PD组上调更为显著(P<0.05).DC组DKKl表达水平不断下降,DC-4C组较DC-0C组显著下降(P<0.05).依据ROC曲线,CSF中DKK1最佳诊断截断点为139.36pg/mL(敏感性70％,特异性80％,AUC=0.745).DC组与PD组患者PFS存在显著差异(P<0.01).以截断点为界,DKK1高表达组(16/20)与低表达组(4/20)PFS之间差异明显(P<0.05).相关性分析显示,DKK1和PFS显著相关(Pearson相关系数为-0.528,P=0.017).结论 LUAD伴LM患者CSF中DKK1表达及动态变化可能与LM的发生、发展及耐药密切相关.

Adenoid cystic carcinoma (ACC) is a rare salivary glands tumor and often displays aggressive behavior with frequent relapse and metastasis. The terminal ACC lacks standard treatment guidelines and is always accompanied by poor prognosis. Here, we report a case of rare perianal ACC who received resection and palliative adjuvant radiation. Five years later, PET-computed tomography (CT) showed perianal recurrence and multiple pulmonary metastases. Combined chemotherapy with doxorubicin, carboplatin and cyclophosphamide was applied for two cycles but ineffective. Further next-generation sequencing analysis of perianal tissue demonstrated the v-myb avian myelobastosis viral oncogene homolog and nuclear factor I/B fusion gene and two novel BCL-6 corepressor (BCOR) mutations (p.F1106Tfs*5 and p.L1524Hfs*8). The therapy was switched to eribulin and anlotinib and has been performed for eight cycles. At recent follow-ups, MRI and CT examinations revealed the diminishing perianal and pulmonary lesions. This study presented the first case of perianal ACC with multiple pulmonary metastases and particular BCOR mutations, who presented a durable response to eribulin and anlotinib, providing a potential therapeutic option for advanced refractory ACC.

Objective:To analyze the diagnostic value of metabolic makers in cerebrospinal fluid in advanced lung adenocarcinoma patients with leptomeningeal metastases (LM) .Methods:A total of 46 cerebrospinal fluid samples (LM group) from lung adenocarcinoma patients with LM admitted to Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School from December 2019 to December 2021 were collected, and 48 cerebrospinal fluid samples (control group) from patients with benign neurological diseases during the same period were collected. Metabolomics analysis of cerebrospinal fluid was carried out by high-performance liquid chromatography-mass spectrometry. Principle component analysis (PCA) and orthogonal to partial least squares discriminant analysis (OPLS-DA) were used for modeling. Multi-criteria assessment was used to identify the different metabolites between the two groups. Receiver operating characteristic (ROC) curve, pathway enrichment analysis and other methods were used to screen metabolites and pathways related to LM from lung adenocarcinoma.Results:There were no statistically significant differences in the proportions of age ( Z=-0.41, P=0.210) , gender ( χ2=1.19, P=0.275) , history of smoking ( χ2=2.86, P=0.091) , Karnofsky performance status score ( χ2=0.65, P=0.419) and increased intracranial pressure ( χ2=0.65, P=0.419) between the LM group and control group. The models of PCA (R2X was 0.608 and 0.583, Q2 was 0.462 and 0.513 in electrospray ion positive and negative modes, respectively) and OPLS-DA (R2Y was 0.967 and 0.889, Q2 was 0.959 and 0.852 in electrospray ion positive and negative modes, respectively) showed that the overall data quality was good. Meanwhile, the model interpretation rate and prediction rate were effective. The permutation tests duplicated for 200 times and showed no over-fitting of the established model. The metabolic profiles of the two groups were significantly different. A total of 30 endogenously differential metabolites were screened by using multi-criteria assessment. Six potential biomarkers with larger area under the curve (AUC) were identified through ROC curve analysis, including tyrosine (AUC=0.967, 95% CI: 0.906-1.000) , phenylalanine (AUC=0.992, 95% CI: 0.973-1.000) , pyruvate (AUC=0.976, 95% CI: 0.935-1.000) , tryptophan (AUC=0.935, 95% CI: 0.880-0.973) , glucose (AUC=0.932, 95% CI: 0.880-0.975) and adenosine monophosphate (AUC=0.993, 95% CI: 0.987-1.000) . The 30 selected differential metabolites were enriched and analyzed for metabolic pathways, and 20 relevant metabolic pathways were matched. Among them, the four metabolic pathways most likely to cause changes in metabolites were glycolysis and glucose metabolic synthesis, pyruvate metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis. Conclusion:Untargeted metabolomics analysis can effectively screen specific cerebrospinal fluid metabolites in lung adenocarcinoma patients with LM. Six potential metabolites such as tyrosine, phenylalanine, pyruvate, tryptophan, adenosine monophosphate, glucose and their metabolic pathways may be involved in the pathogenesis of LM from lung adenocarcinoma.

The development of nanocarrier-based drug delivery systems is essential to fight against multidrug-resistant (MDR) breast cancer. Herein, we firstly conjugated bovine serum albumin (BSA) with triphenylphosphonium (TPP), and then encapsulated model anticancer drug (doxorubicin, DOX) and photothermal reagent (IR820) via one-pot synthesis of glutathione reduction, to obtain BSA-TPP@(IR820/DOX) nanocomposites. Compared to BSA@(IR820/DOX) with no TPP modifications as a control, BSA-TPP@(IR820/DOX) nanocomposites could be internalized by MDR breast cancer cells with higher efficiency, and rapidly escape from the intracellular endo-/ lysosomes into cytoplasms. Moreover, they also had a good behavior of dual pH/NIR light-controlled release of DOX molecules. On this basis, BSA-TPP@(IR820/DOX) nanocomposites exhibited an enhanced inhibitive activity against the proliferation of MDR breast cancer cells via combined chemo-photothermal therapy. Considering the excellent biosafty of BSA, we suggested that this delivery nanosystem developed here has a great promise to overcome MDR of breast cancer in future clinic.

我国是肺癌大国,发病率和死亡率都很高,其中非小细胞肺癌(non-small cell lung cancer,NSCLC)占绝大部分.表皮生长因子受体(EGFR)突变型肺癌属于NSCLC,第一代表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKIs)(如吉非替尼及厄洛替尼)为其首选治疗方案.但有学者报道,尽管接受EGFR-TKIs治疗的病人在初期反应显著,但由于获得性耐药,常在接受治疗后9～13个月内发生疾病进展,超过60％进展病人的肿瘤细胞中可检测到T790M突变,是EGFR-TKIs最常见的耐药机制[1].奥希替尼(Osimertinib)是一种口服的高选择性EGFR-TKIs,作为首先应用于临床的第三代EGFR-TKI,因其高选择性地对T790M不可逆结合,减轻了第一、二代EGFR-TKIs的不良反应[2-3],从而克服了第一、二代EGFR-TKIs对T790M突变的耐药性和选择性问题,相关研究均呈现了该药良好的安全性及有效性[1,3-6].但随着其逐步应用于病人,相关药物不良反应虽不多见,可一旦出现却能产生严重后果,甚至威胁病人生命.

海藻希瓦菌( Shewanella algae,S. algae)是人畜共患疾病的重要致病菌之一,广泛分布于自然界尤其是海洋环境中,对人类的健康危害极大.海藻希瓦菌可引起败血症、皮肤及软组织感染、腹部及肝胆感染、呼吸道感染、耳部及眼部感染、骨骼感染、脑膜炎、心内膜炎等.随着免疫功能低下人群的增多,经济发展导致滨海城市旅游业的推广,抗生素广泛应用致使细菌耐药性的增强,这一条件致病菌引起的机会性感染日益增多.本文对近年来国内外海藻希瓦菌所致感染性疾病的相关研究报道做一综述,分析其生物学特点、易感因素和诊疗方案,以期为临床实践及未来的相关研究提供依据.