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Objective This retrospective study aimed to investigate the clinical features of lung cancer patients with leptomeningeal metastasis (LM) and explore the clinical efficacy and tolerance of intrathecal pemetrexed (IP) combined with systemic antitumor therapy. Methods Thirty-four lung cancer patients (11 men, 23 women) with LM receiving IP at our hospital were retrospectively reviewed between August 2018 and December 2019. Identified cases showed either positive cerebrospinal fluid cytology or typical findings (leptomeningeal enhancement or ventricle broadening) upon imaging examination. Results Before the diagnosis of LM, 24 (70.6%) patients received EGFR-TKI therapy with or without other agents (antivascular therapy, or chemotherapy), 5 (14.7%) patients received chemotherapy, 1 (2.9%) patient received antivascular therapy, and 3 (8.8%) patients received ALK inhibitors. Fourteen (41.2%) patients did not change the systematic regimen at the beginning of IP, while 20 (58.8%) patients changed to antitumor agents. IP was administered for a median of 3 times (range, 1-12 times). The IP dose was 15, 20, 25, 30, and 40 mg in 8 (23.5%), 21 (58.8%), 2 (5.9%), 2 (5.9%), and 1 (5.9%) patient, respectively. In all IP dose levels, the major adverse events were myelosuppression and elevation of hepatic aminotransferases (EHA). Grade 1/2 myelosuppression occurred in 4 (11.8%) patients. Grade 1/2 EHA also occurred in 4 (11.8%) patients. Grades 3/4 adverse events were not observed. After IP and systematic therapy, the clinical manifestations related to LM in 26 (76.5%) patients improved. In the whole cohort, the median overall survival was 20 months. The median time from the initial IP administration until death or the last follow-up was 3.5 months. Conclusions IP showed controllable toxicity and good efficacy, prolonged the survival time, and improved the quality of life when combined with tailored systemic antitumor therapy in lung cancer patients.

Hepatoblastoma (HB), a leading primary hepatic malignancy in children, originates from primitive hepatic stem cells. This study aimed to uncover the genetic variants that are responsible for HB oncogenesis. One family, which includes the healthy parents, and two brothers affected by HB, was recruited. Whole-genome sequencing (WGS) of germline DNA from all the family members identified two maternal variants, located within APC gene and X-linked WAS gene, which were harbored by the two brothers. The mutation of APC (rs137854573, c.C1606T, p.R536X) could result in HB carcinogenesis by activating Wnt signaling. The WAS variant (c.G3T, p.M1-P5del) could promote HB cell proliferation and inhibit T-cell-based immunity by activating PLK1 signaling and inactivating TCR signaling. Further analysis reflected that WAS deficiency might affect the antitumor activity of natural killer and dendritic cells. In summary, the obtained results imply that an APC mutant together with an X-linked WAS mutant, could lead to HB tumorigenesis by activating Wnt and PLK1 signaling, inhibiting TCR signaling, and reducing the antitumor activity of natural killer and dendritic cells.

Background Long non-coding RNAs (lncRNAs) have been reported to exert crucial functions in regulating the progression of human cancers. However, the function and mechanism of long intergenic non-protein coding RNA 01089 (LINC01089) in non-small cell lung cancer (NSCLC) have not been revealed. Methods The expression level of LINC01089, microRNA (miRNA, miR)-152-3p and phosphatase and tensin homolog deleted onc hromosome ten (PTEN) mRNA was detected by quantitative real-time PCR (qRT-PCR). After gain-of-function and loss-of-function models were established with NSCLC cell lines, the proliferation, migration and invasion of NSCLC cells were detected by cell counting kit-8 (CCK-8) assay, scratch healing assay, Transwell assay, respectively. Dual luciferase reporter assay was employed to validate the binding relationship between miR-152-3p and LINC01089 or the 3’UTR of PTEN. Western blot was used to detect PTEN expression in NSCLC cells after LINC01089 and miR-152-3p were selectively modulated. Results LINC01089 was down-regulated in NSCLC tissues and cells. Functional experiments showed that knockdown of LINC01089 could promote the proliferation, migration and invasion of NSCLC cells, while over-expression of LINC01089 had the opposite effects. miR-152-3p was identified as a functional target for LIN01089, and miR-152-3p could reverse the function of LINC01089. Additionally, LINC01089 could up-regulate the expression level of PTEN via repressing miR-152-3p. Conclusions Down-regulation of LINC01089 promoted the progression of NSCLC through regulating miR-152-3p/PTEN axis.

Immune checkpoint inhibitors (ICIs) have greatly transformed the treatment and improved the prognosis for patients with non-small cell lung cancer (NSCLC) without driver gene alterations. However, the effects of ICI combination therapy in ROS1 fusion-positive NSCLC remains unclear. Herein, we present a case with ROS1 fusion-positive NSCLC treated with ICI plus chemotherapy. The patient achieved a continuous partial response (PR) to ICI plus chemotherapy and a more than 35 months progression free survival. This case demonstrates that ICI plus chemotherapy is a promising option for patients with ROS1 fusion-positive NSCLC.

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Background: Leptomeningeal metastasis (LM) is a detrimental complication of advanced lung cancer, more frequently occurring in patients harboring epidermal growth factor receptor (EGFR) mutation. Due to limited access to the leptomeningeal lesion, we explored the potential role of cerebrospinal fluid (CSF) as a source for liquid biopsy in LM patients with EGFR mutation.Materials and methods: The CSF samples from Lung cancer patients with LM were collected between June 2021 and August 2018 at First Affiliated Hospital of Zhengzhou University. Next-generation sequencing was performed to detect the mutations in EGFR genes, overall 38 patients detected with EGFR mutations were finally enrolled in further retrospectively clinical analyses.Results: CSF samples of 38 lung patients with LM harboring EGFR mutation were enrolled in this study.we found 20 cases of L858R of exon 21 and 14 cases of exon 19 deletion.Other EGFR mutations included EGFR exon 20 insertion(n=1),EGFR G719A of exon 18 (n=1) ,EGFR G719S of exon 18 (n=1), EGFR S768I of exon 20 and G719C of exon 18(n=1).CSF samples from 6 patients were collected before prescribing them TKIs.The most frequently detected concurrent genes in CSF was TP53 missense mutation(50%).CSF of 10 patients were obtained after failure to 1st TKI.The most frequently detected concurrent genes in CSF were TP53 missense mutation(40%,n=4),EGFR copy number amplification (40%,n=4) and NKX2-1 copy number gain(30.0%,n=3).Acquired resistance to 1st TKI of T790M mutation was detected in two patients. Similarly, the CSF samples from 22 patients were collected during their 3rd TKI therapy and the TP53 missense mutation was detected in 31.8% of patients followed by EGFR amplification (22.7%), STK11 deletions (18.2%) and MYC amplification (18.2%), while two patients harbored T790M mutation. Known mechanisms of acquired resistance to EGFR- 3rd TKIs were identified in 31.8% of cases. C797S and C797G mutation was found in three patients.Possible EGFR-independent resistant mechanism included PIK3CA missense mutation(4.5%),MET amplification(4.5%),CDK4 amplification(4.5%) and RET gene fusion(4.5%).In the 38 cases , average TMB was 8.4mutations/Mb (median 6.9 , range 1.1-23.83mutations/Mb) ,12 cases with more than 10 mutations/Mb. There were no significant difference of CSF TMB among the three group of patients who hadn’t received TKI, progressed on 1st TKI and progressed on 3rd TKI.Conclusion: CSF cfDNA provided comprehensive profiles of driver and resistance genes of lung cancer with LM harboring EGFR mutation, supporting the importance of CSF cfDNA as a liquid biopsy medium and guiding the choice of anti-tumor drugs.

Background Anaplastic lymphoma kinase (ALK) fusion is a prognostic indicator for patients with non‐small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitors (TKIs). The real‐world data of ALK TKIs remain a major concern. Methods Patients with ALK‐positive advanced NSCLC, who received crizotinib or alectinib treatment in first line, were retrospectively reviewed. ALK status was detected using immunohistochemistry (IHC) or next‐generation sequencing (NGS). Clinical outcomes have been comprehensively analyzed between TKIs, ALK fusions, EML4‐ALK variants, and next‐generation TKIs after crizotinib failure. Results One hundred sixty‐eight patients were successively enrolled (crizotinib, n = 109; alctinib, n = 59). Alectinib showed consistent superiority in progressive‐free survival (PFS) over crizotinib (hazard ratio [HR]: 0.43, 95% confidential interval [CI]: 0.24–0.77, p = 0.004). Multivariate Cox regression showed chemotherapy (CT) prior to TKIs or synchronous chemotherapy seemed not to improve PFS compared to ALK inhibitors alone (p > 0.05). And, alectinib was superior to crizotinib in prolonging intracranial PFS (HR 0.12, 95% CI: 0.03–0.49, p = 0.003). Patients in EML4 group had a better prognosis than those in non‐EML4 group after alectinib administration (HR 0.13, 95% CI: 0.03–0.60, p = 0.009). TP53 co‐mutations were relatively common (34.0%) and associated with adverse outcome in ALK‐positive patients (adjusted HR 2.22, 95% CI: 1.00–4.92, p = 0.049). After crizotinib failure, 33 patients received a sequential application of next‐generation ALK TKIs. Compared to ceritinib and brigatinib, alectinib might have better PFS (p = 0.043). Conclusion Our results revealed alectinib had better PFS and higher intracranial efficacy compared to crizotinib in ALK‐positive NSCLC, and might improve PFS by comparison with ceritinib and brigatinib after crizotinib failure.