[This corrects the article DOI: 10.3892/etm.2018.6955.].

Precise regulation of the activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development but is frequently disrupted in cancer. Among the polycomb group (PCGF) family members, which are key components of polycomb repressive complex 1 (PRC1), PCGF1 emerged as the factor most strongly associated with poor prognosis in non-small cell lung cancer (NSCLC) based on analyses of The Cancer Genome Atlas (TCGA) cohort. In lung cancer cells, PCGF1 upregulation enhanced the deposition of H2AK119ub and H3K27me3 at chromatin. These depositions inhibit the cytokine-cytokine receptor interaction pathway, especially CCL5, CXCL10, CD40, and FAS. Single-cell RNA sequencing further indicated that PCGF1 acts as a negative regulator of natural killer (NK) cell effector function. When NK cell-derived cytokines attempted to activate the cytokine-cytokine receptor interaction pathway in tumor cells, this repressive chromatin state attenuated pathway activation. Consequently, reduced expression of these genes weakened NK cell recruitment and cytotoxic responses. Collectively, this study uncovers a previously unrecognized mechanism by which PCGF1-driven disruption of bivalent promoter balance silences immune signaling cascades, enabling tumor cells to evade NK cell-mediated immunity in NSCLC. These findings highlight bivalent chromatin as a critical regulatory node in tumor immune escape and establish PCGF1 as a promising epigenetic target for immunotherapeutic intervention.PCGF1 promotes immune evasion in NSCLC by suppressing cytokine-cytokine receptor interaction pathway. Upregulation of PCGF1 in NSCLC cells enhances the deposition of the repressive histone modifications H2AK119ub and H3K27me3 while reducing the enrichment of the transcriptionally active histone modification H3K4me3 at target chromatin regions, thereby suppressing cytokine-cytokine receptor interaction pathway. This epigenetic repression reduces the expression of immune-related genes, including CCL5, CXCL10, CD40, and FAS. Consequently, tumor-cell responses to NK cell-derived cytokines are attenuated, leading to impaired NK cell recruitment and cytotoxicity. The schematic diagram was created using BioRender.

Lung cancer is still one of the most common malignant tumors in the world. With the increase of its incidence and the development of medical technology, the overall survival of lung cancer patients has significantly extended compared to before. The incidence of brain and meningeal metastases from lung cancer has also been rising year by year, but patients with brain and meningeal metastases from lung cancer have a poor prognosis and a very high mortality rate, and the diagnosis is mainly based on computed tomography (CT), magnetic resonance imaging (MRI) and other imaging examinations. However, the imaging features are diverse and the specificity is low, which makes it easy to be misdiagnosed and missed. Therefore, accurately identifying brain and meningeal metastases and timely targeted treatment is crucial for improving patient prognosis. This paper analyzed the diagnosis and treatment of a case of lung cancer with no obvious recurrence and metastasis in nearly 7-year long-term follow-up after radical lung cancer surgery, but the patient with abnormal behavior, impaired consciousness and epilepsy in the past 5 months, and multiple punctate calcifications in the brain found by head CT and MRI. This paper consider that the patient's mental and behavioral symptoms were caused by brain and meningeal metastasis of lung cancer after excluding infectious disease and ineffective treatment of autoimmune encephalitis, and further pathological biopsy and genetic detection confirmed the diagnosis of metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) L858R gene mutation, and the patient's symptoms were significantly improved after targeted therapy by Osimertinib. This paper also searched the relevant literatures of brain calcifications in databases such as China National Knowledge Infrastructure (CNKI), Wanfang, UpToDate, PubMed, etc., and found that intracerebral calcifications exist in a variety of diseases, including infectious, genetic and neurodegenerative diseases, vascular diseases, metabolic diseases and tumors. However, brain calcification in brain and meningeal metastases are often underestimated, and the consequent risk is misdiagnosis and delayed treatment. Therefore, brain and meningeal metastases manifested as brain calcification should not be ignored in patients with a history of previous tumors.

Background CMG901 is a novel first-in-class antibody-drug conjugate with a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the antitumour activity and safety of CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer and other solid tumours. Methods KYM901 is a multicentre, open-label, single-arm, phase 1 trial consisting of dose-escalation and dose- expansion stages. Patients with advanced solid tumours, including gastric or gastro-oesophageal junction and pancreatic cancers, were recruited from 31 hospital sites in China. Eligible patients were aged 18 years or older, were refractory to standard therapy or had no available standard-of-care regimen, and had an Eastern Cooperative Oncology Group performance status score of 0-1, a life expectancy of at least 3 months, and at least one measurable lesion. Patients received intravenous CMG901 every 3 weeks (03-34 mg/kg in dose escalation and 22-30 mg/kg in dose expansion) until disease progression, unacceptable toxic effects, initiation of new antitumour therapy, study withdrawal, or death. Primary endpoints were adverse events and dose-limiting toxic effects in the dose-escalation phase, and objective response rate and recommended phase 2 dose in the dose-expansion phase. Confirmed objective response was defined as a partial or complete response that was verified by follow-up imaging at least 4 weeks after the initial assessment. Safety was assessed in all patients who received at least one dose of CMG901 with at least one post-dose safety evaluation. Antitumour activity was assessed in all patients who received at least one dose of CMG901 (full analysis set) and in all CMG901-treated patients with at least one post-dose imaging evaluation and no major protocol deviations (efficacy analysis set). Dose-expansion data for patients with pancreatic cancer will be published separately. Due to small sample sizes, results in patients with other solid tumours (n=2) are not planned for publication. This ongoing trial is registered with ClinicalTrials.gov, NCT04805307. Findings Between Dec 24, 2020, and Feb 23, 2023, 27 patients were enrolled in the dose-escalation phase (median age 570 years [IQR 480-630]; 14 [52%] male, 13 [48%] female) and 107 patients with gastric or gastro-oesophageal junction cancer in the dose-expansion phase (median age 560 years [440-640]; 57 [53%] male, 50 [47%] female). As of Feb 24, 2024, one dose-limiting toxic effect (grade 3 pancreatitis) occurred at 22 mg/kg, and the maximum tolerated dose was not reached in the dose-escalation phase. All 27 patients reported at least one treatment-emergent adverse event, most frequently vomiting (19 [70%]), decreased appetite (16 [59%]), proteinuria (16 [59%]), and anaemia (15 [56%]), and five (19%) had drug-related grade 3 or worse treatment-emergent adverse events. In 107 patients, grade 3 or worse treatment-emergent adverse events occurred in 73 (68%) patients and serious adverse events occurred in 54 (50%) patients in dose expansion. The most common grade 3-4 adverse events were neutrophil count decreased (22 [21%]), anaemia (15 [14%]), and vomiting (11 [10%]). One treatment-related death was reported. At median follow-up of 90 months (IQR 44-129), among 113 patients with gastric or gastro-oesophageal junction cancer in the 22-30 mg/kg cohort full analysis set across both the dose-escalation and dose-expansion phases, the confirmed objective response rate was 28% (95% CI 20-38; 32 of 113 patients). In the 109 patients included in the efficacy analysis set, the confirmed objective response rate was 29% (95% CI 21-39; 32 of 109 patients). Based on overall safety, activity, and pharmacokinetics of CMG901, 22 mg/kg was the proposed recommended phase 2 dose. Interpretation CMG901 showed a manageable safety profile and had promising antitumour activity in patients with advanced gastric or gastro-oesophageal junction cancer. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

This phase II study aims to evaluate the efficacy and safety of the combination therapy of osimertinib and bevacizumab in treatment-na & iuml;ve recurrent or metastatic NSCLC patients with EGFR exon 21 L858R mutation. The enrollment of 90 patients has been successfully completed. Upon data readout, it will provide additional evidence for clinical practice. Introduction: Osimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatmentna & iuml;ve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. Materials and Methods: FLAIR is a prospective, multicenter, randomized, open label study, which is initiated by Chinese Thoracic Oncology Group (CTONG2002). Patients age >= 18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-na & iuml;ve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. Results: FLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate). Conclusions: This study will offer better perspectives on the efficacy and safety of osimertinib plus bevacizumab combination therapy in treatment-na & iuml;ve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation, providing valuable guidance for clinical practice.

e16004 Background: Chemotherapy and PD-1 inhibitor have shown significant clinical benefits in first-line treatment of metastatic gastric and esophagogastric junction adenocarcinoma. The prospective, open-lable, single-arm, single-center clinical trial was designed to assess efficacy and safety of Toripalimab plus docetaxel, oxaliplatin and capecitabine. Methods: Eligible criteria were treatment histopathologically confirmed stage IV(AJCC8) and ECOG 0-2, HER2 negative, regardless of CPS expression of untreated metastatic gastric and esophagogastric junction adenocarcinoma. Patients were given with Docetaxel (75mg/m2, iv,d1), Oxaliplatin(130mg/m2, iv,d1), Capecitabine (750mg/m2 bid, po,d1-d14) combined with Toripalimab (240mg, iv,d4), every 3 weeks. Dexamethasone 4.5mg, q12h, po. started at the night before docetaxel administrated for 3 days. Tumor response was assessed every 2/4 cycles by radiologic imaging. After 4 cycles, MDT was employed to determine subsequent treatment plan. Primary endpoints were ORR (investigator-assessed RECIST 1.1) and safety. The secondary endpoints were progression-free survival and overall survival. Results: 30 patients were enrolled up to 6/1/2025. The median follow-up was 11.7month (range 1.1-61.4). The median age was 57 years (range 32-78), male was 53.3%.The proportion of ECOG 1 patients accounted for 60%, ECOG 2 for 23.3%. A total of 22 patients completed 4 cycles treatment, and 26 patients were eligible for efficacy assessment. Confirmed ORRs were 73.1% (95% CI: 53.9,86.3) and DCR were 96.2% (95%CI: 81.1, 99.3). 57.7% of patients had a disease response depth greater than 50%. Median PFS was 8.5 month (95% CI: 6.76-10.19), the 6-month and 12-month PFS rate was 72.4% and 29.0%, respectively. Median OS was 11.03 month (95% CI: 9.45,12.63) , the 6-month and 12-month OS rate was 80.0% and 43.3%, respectively. The OS of patients completed 4 cycles could reach 18 monthsThe overall incidence of adverse events is 86.7%, Gr ≥3 AEs were seen in 46.7% of patients, Gr 5 AEs were not observed. The most common treated-related AEs were Diarrhea (26.7%) and Platelet count decreased (26.7%). The most common immune-related AEs were Rash (10%). Conclusions: These results showed favorable tumor response, higher ORR, DCR, tumor response depth. The possible reasons were the use of immunotherapy on the 4 th day and the combination with docetaxel. Compared to other GC immunotherapy-related studies, there was no advantage in OS for all patients, while PFS and completed 4 cycles patients' OS were superior to others. The safety of Toripalimab plus docetaxel, oxaliplatin and capecitabine was consistent with each agents known safety profile; no new safety signals were identified. Clinical trial information: ChiCTR2000030877 .

Background:The incidence of meningeal metastasis in lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations is rising annually. Refractory meningeal metastasis following EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance presents a significant clinical challenge, lacking effective treatments and often leading to fatal outcomes. This study aims to evaluate the antitumor efficacy and safety of intrathecal pemetrexed in patients with EGFR-TKI-resistant meningeal metastasis. Methods:From November 1, 2020 to November 1, 2022, a total of 10 patients were enrolled. All underwent next-generation sequencing (NGS) and carcino-embryonic antigen (CEA) testing of cerebrospinal fluid (CSF). These patients had previously experienced symptomatic and supportive treatment, EGFR-TKI resistance, systemic intravenous chemotherapy, and bevacizumab therapy. Intrathecal pemetrexed was administered at doses of 20 or 40 mg once weekly and was well-tolerated. Results:The disease control rate (DCR) was 88.8% (8/9), with 10% (1/10) showing negative CSF cytology. Quality of life (QoL) scores improved, and CSF CEA levels decreased. The median progression-free survival (PFS) was 5 months, and the median overall survival (OS) was 8.15 months. Adverse events occurred in 90% of patients, with nausea, vomiting, and myelosuppression being the most common. Grade 3 or higher adverse events were observed in 40% (4/10) of patients, primarily myelosuppression, which improved with systemic treatment. No treatment-related deaths occurred. Conclusions:This study suggests that intrathecal pemetrexed can be a viable salvage treatment for refractory meningeal metastasis in EGFR-TKI-resistant lung adenocarcinoma.

BackgroundLung cancer stands as the second most prevalent malignant neoplasm worldwide. Addressing the underlying mechanisms propelling the progression of non-small cell lung cancer is of paramount importance. In this study, we have elucidated the pivotal role of PHF12 in this context.Materials and methodsWe harnessed clinical lung cancer tissue samples and non-small cell lung cancer cell lines to discern the expression pattern of PHF12. In vitro assays probing cell proliferation were conducted to substantiate the functional impact of PHF12. Furthermore, an in vivo Xenograft model was employed to dissect the role of PHF12. Employing ChIP assays and qRT-PCR, we delved into the intricate binding dynamics between PHF12 and HDAC1. Mechanistic insights into the PHF12-HDAC1 axis in lung cancer progression were pursued via RNA-seq and GSEA analyses.ResultsNotably, PHF12 exhibited a substantial upregulation within tumor tissue, concomitant with its correlation to HDAC1. The trilogy of cell proliferation assays, transwell assays, and the Xenograft model collectively underscored the promoting influence of PHF12 on lung cancer proliferation, both in vitro and in vivo. The ChIP assay unveiled the transcriptional regulatory role of PHF12 in governing HDAC1 expression. This correlation extended to both mRNA and protein levels. PHF12 promotes NSCLC progression through regulating HDCA1 expression. Intriguingly, the rescue of function within NSCLC cell lines post PHF12 knockdown was achievable through HDAC1 overexpression. Additionally, our findings unveiled the capacity of the PHF12-HDAC1 axis to activate the EGFR/AKT signaling pathway, thereby further corroborating its significance in lung cancer progression.ConclusionOur study identified PHF12 as an oncogenic role in lung cancer proliferation and migration for the first time. PHF12 transcriptionally regulate HDAC1 and activate EGFR/AKT signaling pathway in NSCLC progression. PHF12 may serve as an important target in lung cancer therapy.

2635 Background: Immune checkpoint inhibitors (ICIs) have shown significant efficacy in metastatic gastric cancer, but some patients may not respond to them because of immune resistance. Recombinant Human Adenovirus Type 5 (H101), the world’s first oncolytic virus antitumor drug in China, can induce cell death, expose tumor antigens, provide adjuvants for anti-tumor immune priming, and potentially increase responsiveness to immunotherapies. Here, we presented the efficacy and safety of H101 combined with immune checkpoint inhibitors (ICIs) in patients with liver metastatic gastric cancer. Methods: In this multi-center, phase II trial (the TROJAN 021 study, ChiCTR1900027922), patients with liver metastatic gastric cancer received 2 cycles of H101 ultrasound guided injections into liver lesions, bi-weekly in combination with anti-PD-1 antibodies and chemotherapy bi-weekly until progression or intolerable toxicity. The primary objective was safety and objective response rate (ORR). Secondary objective included progression-free survival (PFS), overall survival (OS) and disease control rate (DCR). Efficacy assessments were performed every 4 weeks following RECIST v1.1 criteria. PFS and OS were estimated using the Kaplan-Meier method. Results: From September 2020 to September 2022, 21 patients were enrolled. Of them, 18 were males, median age was 66 years (range: 36-71) and ECOG performance status was either 0 (n=15) or 1 (n=6). 10 patients (47.6%) received as first-line therapy, 1 (4.8%) as second-line and 5 (23.8%) as third line and above therapy. The primary endpoint was met with a median PFS of 4.8 months. The median OS was 13.2 months. Objective tumor responses were CR (n=0), PR (n=7), SD (n=12) and PD (n=2). ORR was 33.3% (7/21), and DCR was 90.5% (19/21). Treatment related adverse events (TRAE) occurred in 12 patients (57.1%). The most frequently observed TRAEs were injection site pain (48.1%), fever (57.1%) and fatigue (23.8%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included neutropenia (2/21, 9.5%) and hypertension (1/21, 4.8%). Conclusions: These promising results show that combination of Recombinant Human Adenovirus Type 5 (H101) and ICIs demonstrated acceptable toxicity and promising antitumor efficacy in patients with liver metastatic gastric cancer. Further validation of the efficacy in a randomized prospective trial is warranted. Clinical trial information: ChiCTR1900027922.

INTRODUCTION:Osimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. MATERIALS AND METHODS:FLAIR is a prospective, multicenter, randomized, open label study, which is initiated by Chinese Thoracic Oncology Group (CTONG2002). Patients age ≥18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-naïve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. RESULTS:FLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate). CONCLUSIONS:This study will offer better perspectives on the efficacy and safety of osimertinib plus bevacizumab combination therapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation, providing valuable guidance for clinical practice.

We aimed to investigate the prognostic role of genetic variants of VEGF in advanced NSCLC patients treated with platinum-based chemotherapy. A total of 196 patients with advanced NSCLC treated with first-line platinum-based chemotherapy were enrolled. We evaluated the relationship between VEGF polymorphisms and efficacy outcomes and chemotherapy toxicity. We found that rs699947, rs833061 and rs1005230 were in full linkage disequilibrium. Patients with CC genotype of rs833061 had a significant longer PFS than TT genotype (CC vs TT, HR = 1.67, 95%CI = 1.01-2.76, P = 0.043). Patients harbouring CC genotype had longer PFS compared with CT genotype (P < 0.001). Moreover, CC genotypes conferred a significantly increased PFS compared to CT and TT genotype in dominant model (CC vs CT + TT, HR = 1.95, 95%CI = 1.23-3.10, P = 0.005). Patients carrying TT genotype of rs833061 had improved both ORR (HR = 0.54, 95%CI = 0.30-0.98, P = 0.041) and DCR (HR = 0.37, 95%CI = 0.20-0.66, P = 0.001) than non-TT patients. Furthermore, no association was found between any rs833061 alleles and adverse events (P = 0.425), but patients carrying rs1570360 AA genotype were more likely to experience grade 3-4 toxicities (P = 0.004) (GG vs AA, HR = 3.16, 95%CI = 1.26-7.94, P = 0.015). In conclusion, the variant homozygote CC of rs833061 exhibited a better prognosis based on association analysis. The present study provides reference for the future study of platinum-based chemotherapy response and toxicity.

Central nervous system metastasis of malignant tumors includes parenchymal metastasis and leptomeneneal metastasis. The optimal treatment of patients with central nervous system metastases involves a multidisciplinary approach, including supportive care, local treatments such as surgery, stereotactic radiation therapy and whole brain radiotherapy, and systemic therapy. In this paper, the choice of drugs, the selection of radiotherapy, the diagnosis of meningeal metastasis and Ventriculoperitoneal shunts were reviewed.

The incidence of meningeal metastasis in lung adenocarcinoma with EGFR mutation is increasing annually. Refractory meningeal metastasis following EGFR-TKI resistance has no effective treatment and a lethal complication of tumors. The purpose of this study was to evaluate the potential antitumor efficacy and safety of intrathecal pemetrexed in patients with EGFR-TKI resistance refractory meningeal metastasis. From November 1, 2020 to November 1 2022, a total of 10 patients were enrolled in the study, and all patients underwent NGS and CEA testing of cerebrospinal fluid. The patients had entered the stage of symptomatic and supportive treatment before intrathecal pemetrexed, experienced EGFR-TKI resistance, systemic intravenous chemotherapy and bevacizumab treatment previously. Intrathecal pemetrexed was well-effective and tolerated, occurring at the 20mg or 40mg once a week dose. The disease control rate of intrathecal injection was 88.8% (8/9); 10% (1/10) had negative cerebrospinal fluid cytology; concurrently, the quality of life (QoL)score improved, and cerebrospinal fluid CEA decreased. The median PFS of intrathecal injection was five months, and the median OS was 8.15 months. Ninety percent of patients experienced adverse events of varying degrees, with nausea, vomiting, and myelosuppression being the most common. The incidence of grade three or higher adverse events was 40% (4/10), primarily myelosuppression, which improved after systemic treatment; no treatment-related deaths occurred.This study suggests intrathecal pemetrexed can be used for salvage treatment of refractory meningeal metastatic in EGFR-TKI resistant lung adenocarcinoma.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients.METHODS: We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment ap-proaches, LM progression-free survival (LMPFS) and overall survival (OS) after the diagnosis of LM (OSLM) were analyzed. RESULTS: The median OSLM was 16.0 months and the 3 -year OS rate was 22.5%. The PFSLM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was signifi-cantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P = 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P = 0.024). Better Eastern Cooperative Oncology Group perfor-mance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS.CONCLUSIONS: The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive.

Lung cancer with Leptomeningeal metastasis has a poor prognosis, and for epidermal growth factor receptor(EGFR) mutation-positive patients with T790M negative after first-generation tyrosine kinase inhibitors resistance, guidelines recommend chemotherapy combined with anti-angiogenesis therapy. This article presented a female patient with EGFR L858R mutation and Iressa-resistant T790M negative leptomeningeal metastasis of lung cancer, who refused chemotherapy because of senior and could not tolerate the gastrointestinal reaction of chemotherapy. According to the multidisciplinary consultation and discussion opinions of the adiologist, neurosurgeon,radiotherapist and medical oncologist, the best curative effect of Osimertinib followed ventriculoperitoneal shunt was disease stability, and the overall survival time after diagnosis of leptomeningeal metastasis was more than 3 years.

Background Although numerous measures have been used to improve the outcome of lung cancer patients, lung cancer, as the second most common diagnosed cancer, is still the main cause of cancer death. It becomes increasingly urgent for us to deeply deplore the molecular mechanism of lung cancer and to discover the potential therapeutic targets. In our study, we are dedicated to discovering the role of MIB2 in lung cancer development. Methods The public databases were used to compare the expression level of MIB2 in cancer and non-cancer tissue. We analyzed the expression of MIB2 in lung cancer samples by performing Rt-PCR and western blot. We carried out CCK8 and clone assays to study the influence of MIB2 in lung cancer proliferation. The transwell assays and wound healing assays were implemented to study the function of MIB2 in metastasis and invasion. Proteins of cell cycle control pathways are detected to verify the potential mechanism of MIB2 in lung cancer progression. Results MIB2 is up regulated in lung cancer tissue compared to adjacent normal lung tissue according to both public databases and our clinical lung cancer samples. Knockdown of MIB2 inhibits proliferation, metastasis, and invasion of lung cancer cell lines. Cyclins and cyclin dependent kinases (CDK) including CDK2, CDK4, and cyclinB1 were down regulated in MIB2 knockdown cells. Conclusion Our results prove that MIB2 acts as a driver in NSCLC tumorigenesis by regulating cell cycle control pathways.

Objective:Focusing on the dynamic changes of B cells in the development and progression of lung adenocarcinoma, the role of B cells in the tumor microenvironment of lung adenocarcinoma was preliminarily elucidated by analyzing the single-cell data of lung adenocarcinoma.Methods:Single-cell data of lung adenocarcinoma were analyzed, raw read counts were normalized using the NormalizeData function, and cell-to-cell differences in gene expression were eliminated using the ScaleData function. Use "FindVariableFeatures" to calculate high-expression genes between groups. After cell clustering, SingleR-assisted cell class annotation was performed, 10 B-cell subclass cells were time-quasi-sequence analysis using monocle2, differences between genes in different states were calculated and heat maps were drawn, differentially expressed genes were enriched by GO pathway.Results:B cells are rarely distributed in normal lung tissue, and relatively more in tumor tissue. Among them, the number of memory B cells and plasma cells in the lung primary lesion increased significantly, in brain metastases, plasma cells were significant, and the differential genes in various tissues were enriched and analyzed, and it was found that immune B cells in the primary tumor of lung cancer produced a strong immune response to cancer cells, and when the tumor cells metastasized, the role of plasma cells in brain metastases was mainly to inhibit cell growth, ensure the stability of cells and tissues, and alleviate the damage of tumor cells invading other tissues to a certain extent.Conclusion:Based on single-cell analysis, the mechanism of action of B cells in the pathogenesis and brain metastasis of lung adenocarcinoma can be further understood, and the clinical application of immunity to lung adenocarcinoma brain metastasis can be further understood.

(1) Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been the first line therapy for EGFR-mutant lung adenocarcinoma (LAC) patients with brain metastases (BMs). However, the role and the optimal time of brain radiotherapy remains controversial. We aimed to investigate the role of upfront brain stereotactic radiotherapy (SRS) and the impact of deferral radiotherapy on patients’ clinical outcomes. (2) Methods: We retrospectively studied 53 EGFR-mutant LAC patients with limited synchronous BMs between 2014 and 2020 at our institute. The limited BMs was defined with one to four BM lesions, with a maximal size of ≤4 cm. Patients were categorized into two groups: upfront brain SRS (upfront RT) and upfront TKIs. The intracranial progression-free survival (iPFS), progression-free survival (PFS), and overall survival (OS) between groups were analyzed. (3) Results: The median iPFS (21.0 vs. 12.0 months, p = 0.002) and PFS (20.0 vs. 11.0 months, p = 0.004) of the upfront RT group was longer than that of the upfront TKI group. There were no significant differences in median OS (30.0 vs. 26.0 months, p = 0.552) between the two groups. The upfront RT group is less likely to suffer from intracranial progression of the original sites than that of upfront TKIs during the disease course (36.1% vs. 0.0%, p = 0.025). Multivariate analysis showed that the Karnofsky Performance Scale and the presence of synchronous meningeal metastases were associated with overall survival. (4) Conclusions: Compared with upfront TKI, the combination of upfront SRS with TKIs can improve the iPFS and PFS in EGFR-mutant LAC with synchronous BMs. The addition of upfront brain SRS was useful for the original intracranial metastatic lesions.

BackgroundLung is the most common primary site of brain metastases (BMs). For different pathological types of BMs have some similar characteristics, it is still a challenge to confirm the origin based on their characteristics directly. BMs of small cell lung cancer (SCLC) have favorable therapeutic expectations due to their high sensitivity to radiotherapy. This study sought to identify unique characteristics of BMs in SCLC, aiming to assist in clinical decision-making.MethodsPatients diagnosed with BMs of lung cancer who received radiotherapy from January 2017 to January 2022 were reviewed (N = 284). Definitive diagnosis of BMs of SCLC was reached for 36 patients. All patients underwent head examination using magnetic resonance imaging. The number, size, location, and signal characteristics of lesions were analyzed.ResultsThere were 7 and 29 patients with single focus and non-single focus, respectively. Ten patients had diffuse lesions, and the remaining 26 patients had a total of 90 lesions. These lesions were divided into three groups according to size: <1, 1-3, and >3 cm (43.33%, 53.34%, and 3.33%, respectively). Sixty-six lesions were located in the supratentorial area, primarily including cortical and subcortical lesions (55.56%) and deep brain lesions (20%). Moreover, 22 lesions were located in the infratentorial area. According to diffusion-weighted imaging and T1-weighted contrast enhancement, the imaging characteristics were classified into six patterns. Hyperintensity in diffusion-weighted imaging and homogeneous enhancement was the most common pattern of BMs in SCLC (46.67%), while partial lesions showed hyperintensity in diffusion-weighted imaging without enhancement (7.78%).ConclusionsThe manifestations of BMs in SCLC were multiple lesions (diameter: 1-3 cm), hyperintensity in diffusion-weighted imaging, and homogeneous enhancement. Interestingly, hyperintensity in diffusion-weighted imaging without enhancement was also one of the characteristics.

434420 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced gastric/gastroesophageal junction (G/GEJ) cancer. CMG901, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E (MMAE), has demonstrated potent anti-tumor activity in preclinical studies. Methods: This phase 1 trial included a dose-escalation phase (part A; 0.3-3.4 mg/kg) and a dose-expansion phase (part B; 2.2, 2.6, and 3.0 mg/kg) to evaluate safety, tolerability, and anti-tumor activity of CMG901 in patients (pts) with advanced G/GEJ cancer and other solid tumors. CLDN18.2 expression was not required for study entry in part A, but CLDN18.2 expression of ≥2+ membrane staining intensity in ≥5% tumor cells was required for G/GEJ cancer in part B. CMG901 was administrated intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety/tolerability and maximum tolerated dose (MTD) for part A, and objective response rate (ORR, per RECIST v1.1) and recommended phase 2 dose in part B. Here we present the G/GEJ cancer data from this ongoing trial. Results: MTD was not reached during dose escalation. As of July 24, 2023, 113 G/GEJ cancer pts received CMG901 at doses of 2.2-3.0 mg/kg (6 pts from part A and 107 pts from part B). The median prior lines of systemic therapy were 2 (range 1-6). Most common TEAEs were anaemia (62.8%), vomiting (57.5%), and hypoalbuminaemia (57.5%). Neutrophil count decreased (18.6%) and anaemia (13.3%) were the most frequent grade ≥3 TEAEs. Of 89 evaluable (≥1 post-treatment scan) CLDN18.2-positive pts, confirmed ORR was 32.6% (Table). For all 93 CLDN18.2-positive pts, the median progression-free survival was 4.76 months (95%CI 3.35-6.14) after a median follow-up of 5.98 months. The median overall survival (OS) was not reached, with an OS rate of 56.4% at 9 months. Conclusions: CMG901 demonstrated promising clinical efficacy in CLDN18.2-positive G/GEJ cancer pts, with a manageable safety profile. These results support further evaluation of CMG901 in CLDN18.2-positive G/GEJ cancer. Clinical trial information: NCT04805307 .[Table: see text]