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Background: Thymic epithelial tumors (TETs) are rare thoracic malignancies with no standard second-line treatment. Tumor angiogenesis is closely associated with the pathogenesis and invasiveness of TETs. Anlotinib is a small-molecule multitarget tyrosine kinase inhibitor (TKI) which inhibits tumor angiogenesis and tumor cell proliferation. Published studies have demonstrated the promising clinical effect of multitarget TKIs sunitinib and lenvatinib in previously treated TETs. However, TKIs have a high incidence of adverse events (AEs). Objective: In this study, we investigated the clinical efficacy and safety of anlotinib in previously treated TET patients. Methods: We collected clinical data of 22 patients from Shandong Cancer Hospital and Institute between October 2018 and March 2022. These patients were diagnosed with advanced TETs and received at least the first-line (1st-line) treatment. We analyzed the clinical effects between anlotinib monotherapy and anlotinib combination therapy in the second-line (2nd-line) or anlotinib treatment in different lines. Results: These 22 patients included 18 cases of thymic carcinoma (TC) and 4 cases of thymoma (T). 68.2% of patients were males, and the median age was 53 years. Fourteen patients (63.6%) received anlotinib monotherapy and 8 patients (36.4%) received anlotinib combination therapy. The objective response rate (ORR) was 9.1% in the overall patients. The median progression-free survival (PFS) in the overall population was 12 months (14 months for T and 9 months for TC), and the median overall survival (OS) was 24 months (survival was not reached for T and was 24 months for TC). The incidence of AEs was 50%, most of them were grades I and II, and the incidence of grades III and IV AEs was 9%. Conclusion: This is the first study reporting the clinical effect of anlotinib in previously treated TETs patients. The survival data indicate that the efficacy of anlotinib is superior to sunitinib and lenvatinib. Our results suggest that anlotinib is a promising treatment option for previously treated TET patients and its toxicity is tolerable. More research and patents are needed in the future to explore better options for the diagnosis and treatment of TETs.

Glioblastoma (GBM) is the most common primary brain tumor, and patients with GBM have a universally poor prognosis. Genomic profiling has detected epidermal growth factor receptor (EGFR) gene alterations in more than half of GBMs. Major genetic events include amplification and mutation of EGFR. Interestingly, we identified an EGFR p.L858R mutation in a patient with recurrent GBM for the first time. Based on the genetic testing results, almonertinib combined with anlotinib and temozolomide was administered and obtained 12 months of progression-free survival after the diagnosis of recurrence as the fourth-line treatment. This is the first report that an EGFR p.L858R mutation was identified in a patient with recurrent GBM. Furthermore, this case report represents the first study applying the third-generation TKI inhibitor almonertinib in the treatment of recurrent GBM. The results of this study indicate that EGFR might be a new marker for the treatment of GBM with almonertinib.

Leptomeningeal metastases (LMs) are highly invasive which leads to poor prognosis, but the accurate diagnosis of LM is challenging. It is necessary to investigate more advanced diagnostic methods to realize precision medicine. The main purpose of this study was to select a more effective method for the auxiliary diagnosis of LM by comparing various detection methods. The secondary purpose was to explore the value of cerebrospinal fluid (CSF) tumor markers (TMs) and circulating tumor DNA (ctDNA) testing in guiding clinical treatment.TMs in serum and CSF of patients were detected by chemiluminescence. The ctDNA of CSF and plasma were detected by the next-generation sequencing (NGS) technology.In total, 54 tumor patients participated in this study, in which 39 with LM and 15 without LM (8 with parenchymal tumor and 7 without brain metastasis). The results showed that the sensitivity and accuracy of CSF cytology isolated during the first lumbar puncture were 0.31 (95% CI 0.17-0.48) and 0.50 (95% CI 0.36-0.64), respectively. The sensitivity and accuracy of CSF_CEA were 0.71 (95% CI 0.54-0.85) and 0.78 (95% CI 0.64-0.89), which were better than those of CSF_NSE and CSF_CFRA-211. The sensitivity and accuracy of CSF_ctDNA were 0.92 (95% CI 0.79-0.98) and 0.91 (95% CI 0.80-0.97), significantly higher than that of CSF cytology (P 0.01). The sensitivity and accuracy of CSF_CEA combined with CSF_ctDNA were 0.97 (95% CI, 0.87-1.00) and 0.94 (95% CI 0.85-0.99), which were significantly higher than the traditional methods CSF cytology (P 0.01). For LM patients with hydrocephalus, the sensitivity of CSF ctDNA even achieved 100% (14/14).CSF_CEA combined with CSF_ctDNA could be used to accurately distinguish patients with LM from those with no brain metastasis and from those with parenchymal tumors. CSF_ctDNA testing reveals a unique mutation profile for patients with LM. Dynamic detection of CSF TM and ctDNA can better predict the efficacy and reveal the cause of drug resistance to guide subsequent treatment.Clinical trial registration number: NCT03029065.

Purpose Our previous study has shown that PTPRZ1-MET (ZM) fusion is a viable target for MET inhibitors in gliomas. However, the diversity and prevalence of somatic MET alterations in diffuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets. Methods Totally, 1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas (CGGA) and published data. All kinds of MET fusions and/or splicing variants (MET F/SVs) were identified by bioinformatical methods. Single-cell RNA sequencing (scRNA-seq) were used for validation. In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment. Results MET F/SVs but not genomic amplification, were highly enriched in the secondary glioblastomas (sGBM) and marked worse prognosis. Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression. Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors. Conclusion Our findings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may benefit from MET-targeted therapy.

Diffuse midline gliomas (DMGs), which are malignant, fast-growing and entail a poor prognosis, are a rare subtype of glial tumor. DMGs harboring H3 K27-mutation are a novel entity with a poorer prognosis than the H3 wildtype and are categorized as a grade IV glioma. Histone-mutated DMGs characterized by a midline location occur more commonly in children and less frequently in adults. Considering the DMG treatment is limited, there is an urgent need for effective therapeutic strategies. Olaparib is a poly-adenosine diphosphate-ribose polymerase inhibitor, which has been reported to inhibit glioma in preclinical and clinical trials. Olaparib plus bevacizumab has been successfully used in ovarian cancer. However, the application of olaparib in DMGs has not been reported yet. Herein, we firstly reported that an adult DMG patient benefited from olaparib combined with bevacizumab and achieved complete remission. The duration of response and overall survival was 8 months and 16 months respectively. This report provides a promising treatment option for patients with DMG.

We describe a case of recurrent glioblastoma treated with anlotinib in this report. The patient was administered anlotinib 12 mg p.o. once every day (days 1–14, with a 21-day cycle) (anlotinib clinical study NCT04004975) and oral temozolomide chemotherapy 100 mg/m2 (days 1–7, days 15–21, 28-day cycle; 12 cycles). After 2 months of therapy, the patient achieved a partial response that has been maintained for >17 months of follow-up. Molecular characterization confirmed the presence of a TERT promoter mutation, wild-type IDH1/2, an FGFR3-TACC3 fusion, and FGFR3 amplification in the patient. Anlotinib is a multitarget tyrosine kinase inhibitor that was originally designed to inhibit VEGFR2/3, FGFR1–4, PDGFRα/β, and c-Kit. Patients with TERT promoter mutations and high-grade IDH-wild-type glioma have shorter overall survival than patients with IDH-wild-type glioma without TERT promoter mutations. However, this patient had a favorable clinic outcome, and FGFR3-TACC3 fusion may be a new marker for treatment of glioma with anlotinib. Key Points This case study is believed to be the first report that FGFR3-TACC3 fusion could be a novel indication to treat recurrent glioblastoma with the drug anlotinib. This case exhibited an exceptional response (maintained partial response >17 months) after 2-month combined therapy of anlotinib and oral temozolomide chemotherapy. This case also underscores the importance of molecular diagnosis for clinically complex cases. Tumor tissue-based assessment of molecular biomarkers in brain tumors has been successfully translated into clinical application.

Background Neurofibromatosis type 1 (NF1), a dysregulated neurocutaneous disorder, is an autosomal dominant genetic disease caused by mutations in the NF1 gene. Anaplastic astrocytoma is rare in NF1 patients, and research has proposed that high-grade astrocytomas could be due to larger germ-line mutations in NF1.We present a clinical and molecular study of a Chinese family with NF1. Case Description A 28-year-old male patient with NF1 presents with headache, vertigo, and dizziness. Histopathologic examination and molecular features identified a cerebellar anaplastic astrocytoma, IDH-wildtype. The patient underwent gross total resection of the lesion and received radiotherapy and chemotherapy. A rare splice error mutation (c.4110+945A>G) in intron 23–2 of NF1 was identified by next-generation sequencing in the proband. Sanger sequencing identified and confirmed it in some affected family members. CONCLUSIONS We present a unique case of NF1 with anaplastic astrocytoma that revealed a rare splice error mutation in the NF1 gene in the family.

Objective This study aimed to determine the efficacy and tolerability of apatinib plus dose-dense temozolomide (TMZ) as first-line treatment for recurrent glioblastoma (rGBM). Methods Patients with rGBM were enrolled in this study. Patients were subjected to concurrent treatment of apatinib (500 mg qd) and dose-dense TMZ (100 mg/m2, 7 days on with 7 days off) until disease progression or intolerable toxicity. Efficacy was evaluated using Response Assessment in Neuro-Oncology criteria for high-grade glioma. Safety was assessed using NCI-CTCAE 4.0. Survival was estimated with Kaplan-Meier curve and log rank test. Results From March 2016 to January 2018, 20 eligible patients who had relapsed from the standard chemoradiotherapy regimen (TMZ and radiotherapy) were enrolled in this study. The median follow-up time was 12 months. All patients were eligible for efficacy analysis. The objective response rate (ORR) was 45%. The disease control rate (DCR) was 90%. The median progress-free survival time was 6 months (95% CI, 5.3 to 7.8 months). The 6-month progression-free survival rate was 50%. The median overall survival was 9 months (95% CI, 8.2 to 12.2 months). The most common treatment-related adverse events were hypertension (21%), hand-foot syndrome (16%), leukopenia (14%), and thrombocytopenia (12%). Conclusion Apatinib combined with dose-dense TMZ was effective in terms of PFS, ORR, and DCR and was well tolerated after appropriate dose reduction in the Chinese population tested. Further randomized controlled clinical studies are needed to confirm the efficacy of apatinib combined with TMZ for treatment of rGBM.

Clear cell meningioma (CCM), an unusual subtype of World Health Organization (WHO) grade II meningioma, represents only 0.2– 0.8% of meningiomas. Spinal CCMs are even rarer with unique clinical features: more common in younger patients; more likely to appear in lumbar spine; high recurrence rate. Although surgery and radiotherapy are the most common treatment for primary tumors and disease recurrence, there are lack of treatment options for recurrent or metastasis disease. It is urgent need to explore new effective treatment method. In our case, we firstly reported a rare spinal CCM patient with PD-L1 positive and multiple metastases benefiting from PD-1 inhibitor plus anti- angiogenesis therapy. This treatment program is effective, safe, and has a strong therapeutic reference value, which provides promising treatment options and the direction of future clinical trials for spinal CCMs.

Background Invasive pituitary adenomas often recurred after postoperative radiotherapy and are difficult to treat. Temozolomide is an alkylating cytostaticum and has been reported to reduce pituitary tumor size and hormone hypersecretion. However, this is far from enough. Pituitary adenomas have relatively high expression of vascular endothelial growth factor. Therefore an antiangiogenic agent has been used in a small number of aggressive or malignant pituitary tumors after recurrence. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2 and also mildly inhibits c-Kit and c-Src tyrosine kinases, abundant in invasive pituitary adenomas. Case Description We present a 41-year-old female with a growth hormone (GH)-secreting invasive pituitary adenoma causing menstrual disorder and headache symptoms. Over 3 years, she underwent 4 surgeries and a stereotactic radiosurgery, but the results were poor. Two months after the fourth operation, she started treatment with temozolomide (200 mg/m2, days 1−5, 28 days, orally) and apatinib (0.425 g, daily, orally). Her GH level dropped to normal with a >90% decrease in tumor size, after 1-year treatment. There was no evidence of recurrence by imaging or by serum GH levels over 31.5 months of follow-up. Conclusions We successfully treated this patient with recurrent invasive pituitary adenoma with temozolomide and apatinib for 31.5 months without recurrence. Angiogenesis is an active process in the cases of invasive pituitary adenomas that cannot be controlled by conventional therapy.

e14028 Background: Epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase, consists of an extracellular ligand-binding domain (ECD), a single transmembrane domain (STMD) and an intracellular kinase domain (ICD). Glioma is the most common primary brain tumor, and variations of EGFR are frequently reported in glioma patients. This study aimed to analysis the landscape of EGFR mutation subtype in Chinese patients with glioma. Methods: We retrospectively collected 1779 patients with glioma. In all patients enrolled, the comprehensive genomic profiling containing EGFR gene was detected using tumor tissue, including WES, 539 tumor related-gene panel or 131+4 gene panel (Simceredx). And the somatic mutations including SNV, INDEL, CNV, fusion were analyzed correspondingly. Results: Among 1779 patients with glioma, EGFR mutations were identified in 392 (22.03%) patients. The age was significantly higher in patients with EGFR-mutant group than in patients without EGFR-mutant group, with median age 54 vs. 45 (p = 4.81e-19). The sex didn’t reach statistical significance in two group. The incidence rate of different EGFR mutation types among all patients with EGFR-mutant were amplification (314,80.10%), SNV(198,50.51%), Indel(24,6.12%) and fusion(44,11.22%) respectively. 162 (46.69%) had two or more mutation types simultaneously. The main partner gene of EGFR fusion was LOC100996654, followed by ELDR and SEC61G, and the main EGFR breakpoints were in intron24, intron7, exon7. Within 347 SNV and Indel mutations, exon7, 15, 20, 6 and 8 were detected in 103(29.68%), 50(14.41%), 28 (8.07%), 25(7.20%) and 18 (5.19%) respectively. The top three mutaton subtypes within exon7 were account for 19.31%, which included p.A289V,p.A289T,p.T263P. Meanwhile, the mutation frequency within ICD encoded by exons 18-24 was 17.00%, in which exon20 mostly distributed (8%). In exon20, the most common mutation subtypes were p.V774M,p.H773dup,p.T790M, while in the second proportion exon18 (3.46%), the main subtype were p.G719A/D. Conclusions: EGFR amplification was the most common mutation type. There were 122 SNV and Indel subtypes altogether and occurred throughout almost the entire exon region, in which exon7 contained maximum 21 different subtypes and the p.A289V was the main type. The distribution of subtypes in ECD were much more than in ICD. The relationship between subtypes occurrence and cancer will be further studied in the future.

Diffuse midline gliomas (DMGs), characterized by malignant, fast growing and carrying a poor prognosis, are a rare subtype of glial tumor. Majority of DMGs harboring H3 K27-mutation are a novel entity with a worse prognosis and are categorized as a grade IV glioma. Histone-mutated DMGs characterized by a midline location occur more commonly in children and less frequently in adults. Considering the treatment is limited in DMG, the need for effective therapeutic strategies is urgent. Olaparib is one of Poly-ADP-Ribose Polymerase (PARP) inhibitors and has been reported in inhibiting glioma in some preclinical trials and clinical trial in glioblastoma. Olaparib plus bevacizumab have been successfully used in ovarian cancer. However, the olaparib application in DMGs has not been reported yet. Herein, we firstly reported that an adult DMG patient benefited from olaparib combined with bevacizumab. This report provides a promising treatment option for DMG patients.

Activating alterations of the MET gene are well-characterized oncogenic drivers, and MET inhibitors could successfully treat several tumor types with MET alterations, including gliomas with PTPRZ1-MET fusion. However, the full diversity and prevalence of MET alterations in gliomas are still lacking to accurately identify a subset of patients likely to benefit from MET inhibitor treatment. Here, we interrogated genomic profiles of 1,351 gliomas, and further identify 60 cases harboring MET alterations, including MET fusions and various MET exon skipping events. MET RNA alterations, but not MET amplification, are highly enriched in the secondary glioblastomas (sGBM) with significantly worse prognosis. Further molecular analysis has shown that MET RNA alterations acting an additive effects of MET overexpression are induced in the course of glioma evolution. In vitro and clinical studies indicate cells and patients harboring MET alterations have better response to MET inhibitors. Collectively, these data suggest that a subgroup of gliomas harboring MET alterations likely to have benefit from MET-targeted therapy.

Up to now, no proven effective medical therapy for surgery and radiation-refractory anaplastic meningioma (AM) exists. Patients with vascular endothelial growth factor receptor 2 (VEGFR-2) positive meningiomas showed significantly shorter progression-free survival. Apatinib is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2. We report three cases of recurrent AM (VEGFR-2 positive) treated with apatinib. After apatinib treatment, the best outcome for all three patients was the partial response. The Progression-free survival was 17.3 months, 10.3 months, and 14+ months, respectively. The third patient lost follow-up after the last review. The overall survival was 28.5 months and 18 months, respectively. The main adverse events were hypertension, hand-foot syndrome, and myelosuppression. Apatinib is active in recurrent AM patients and this is the first report in the world. It is promising to launch a Phase II clinical trial of apatinib to further evaluate its efficacy on AM. BACKGROUND: Anaplastic meningioma (AM) are rare and aggressive tumors with high recurrence rates despite optimal surgical or medical management. Up to now, no proven effective medical therapy, surgery, or radiation-refractory for AM exist. The progression-free survival (PFS) of patients with vascular endothelial growth factor receptor 2 (VEGFR-2)-positive meningiomas was significantly low. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2. CASE PRESENTATION: CASE #1: A 47-year-old Asian female patient with malignant meningioma underwent four operations and three radiotherapies. She was given a 500 mg apatinib daily oral treatment, and the dosage was halved to 250 mg 3 months into the treatment. According to the Response Assessment in Neuro-Oncology (RANO) evaluation criteria, the best outcome during treatment was the partial response (PR) 6 months after the treatment. The PFS was 17.3 months, whereas the overall survival (OS) was 28.5 months. The best change in the Karnofsky performance scale (KPS) was a 10-point increase. The main adverse events included anemia (grade II), thrombocytopenia (grade II), and proteinuria (grade I). CASE #2: A 71-year-old Asian woman with AM underwent two operations and two gamma knife stereotactic radiotherapies. She was given a 500 mg apatinib daily oral treatment with a follow-up period of 18 months. apatinib was taken orally for 10 months. According to the RANO evaluation criteria, the best outcome during treatment was PR. The PFS was 10.3 months, whereas the OS was 18 months. The best change in KPS was a 20-point increase. The main adverse events included hypertension (grade II), hand–foot syndrome (grade II), and fecal ocular blood (grade II). Case #3: A 16-year-old Asian girl with AM underwent two operations and two radiotherapies. She was given a 250 mg apatinib daily oral treatment with a follow-up period of 16 months. Apatinib was taken orally for 8 months. The patient did not follow-up after the last review of the brain-enhanced magnetic resonance imaging. According to the RANO evaluation criteria, the best outcome during treatment was PR. The PFS was 14+ months, and the best change in KPS was a 10-point increase. The main adverse events included hypertension (grade I) and hand–foot syndrome (grade I). CONCLUSION: Apatinib is actively used in treating patients with recurrent AM. A randomized trial and phase II clinical trial of this inhibitor should be performed to further evaluate its efficacy in treating malignant meningioma.

Yi Sun,1–3,* Yong Wang,2,* Shaolong Han,3 Bo Xing,3 Hong Li,4 Yufang Zhu,2 Shizhen Zhou,2 Xiuhua Wang,2 Jun Xu,2 Rongjie Tao2 1School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, 2Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, 3Department of Neurosurgery, The Sixth People’s Hospital of Jinan, 4Department of Ophthalmology and Otolaryngology, The Sixth People’s Hospital of Jinan, Jinan City, Shandong Province, People’s Republic of China *These authors contributed equally tothis work Background: Pemetrexed, a new and novel agent for primary central nervous system lymphomas (PCNSLs), has shown to be efficient as a savage therapy for recurrent PCNSLs. However, more studies are needed. A prospective study was performed on 17 recurrent PCNSL patients with pemetrexed at Shandong Tumor Hospital in China to assess the efficacy and safety of pemetrexed for recurrent PCNSL patients. Materials and methods: The medical records and imaging data on all the cases of recurrent PCNSL patients with pemetrexed in our study were collected during August 2012 and April 2015. Folic acid, B12, and dexamethasone were used to induce toxicities related to pemetrexed. Patients were treated with pemetrexed at a dose of 900 mg/m2 intravenously every 3 weeks, and one cycle consists of 6 weeks. Results: A total of 17 cases of recurrent PCNSL patients were enrolled in our study, including 10 males and 7 females with a median age of 66.2 years (ranging from 35 to 81). After the treatment, five cases had complete remission, with partial remission in five cases, stable disease infour cases, and progressive disease in three cases. Consequently, the overall response rate was 58.8%, and the disease control rate was 82.4%. The median overall survival was 7.8 months (95% confidence interval: 5.9–9.6 months) in the study of recurrent PCNSL patients. Conclusion: This study has been the first clinical trial that applied pemetrexed to treat recurrent PCNSL patients in China, and results indicated that chemotherapy using large pemetrexed may become an effective treatment for PCNSL recurrence with modest toxicity. Keywords: primary central nervous system lymphomas, efficacy, safety, recurrence

524 Objectives Tumor microvesicles, known as exosomes, are emerging mediators of tumorigenesis and metastatic progression. It has been shown that exosomes from lung-, liver- and brain- tropic tumor cells (both human and mouse) fuse preferentially with resident cells at their predicted destination (Hoshino et al. Nature 2015). Non-invasive imaging techniques, such as SPECT or PET, offer an opportunity to study exosome distribution in vivo and thus detect/predict pre-metastatic niches for future metastasis detection. In the current study, we describe a rapid and reliable method of radioiodination of exosomes using the highly efficient succinimidyl p-131I-phenylpropanoate reagent (131I-BH). The in vivo distribution profile of 131I-exosomes is studied in “naive” nude mice. Methods Exosomes from highly metastatic lung-tropic MDA-MB-231 breast cancer cells (4175-LuT) were collected by sequential centrifugation of 3-4 day cell conditioned media. Radiolabeling proceeded in physiological conditions (PBS pH 7.4; RT) by combining 131I-BH (200-250 MBq) and purified exosomes (300ug in PBS) and gently shaking for 1h. Unreacted 131I-BH was removed by size exclusion chromatography with PBS (PD-10 column). To characterize the integrity of 131I-exosomes, mock-labeled exosomes, prepared with equivalent volumes of carrier matching buffer (no radioactivity), were compared with natural ones using electron microscopy. Purified 131I-exosomes were injected into the tail vein of naive female nude mice (1-3MBq). Animals (4-5/group) were euthanized at 1, 6, 24 and 48h post injection (pi). Blood and tissues were collected and assayed for radioactivity to calculate the %ID/g tissue. Results Chemically and radiochemically pure (>99%) 131I-exosomes were obtained in >60% yields (n=5). PD-10 collected fractions F7-F9 contained the highest concentrations of pure 131I-exosomes. No effect of the radioiodination method on exosome integrity was evident as revealed by comparing mock-labeled exosomes with natural ones under the electron microscope. Following i.v. injection in mice, 131I-exosomes cleared rapidly from the circulation ( liver>>>spleen). No significant differences in pharmacokinetics was observed whether pooled F7-F9 or each fraction separately was injected in mice. Conclusions 4175-LuT-derived exosomes were efficiently labeled with high yield using the succinimidyl p-131I-phenylpropanoate reagent. In naive nude mice, 131I-exosomes injections showed fast blood and background tissue clearance with specific accumulation in the lungs (4175-LuT metastatic organ). These findings suggest that radiolabeled exosomes can be used to determine the specificity and the dynamics of the distribution of exosomes in vivo and help to define their role in tumor progression and pre-metastatic niche formation

Certain microRNAs (miRs) regulate the progression and metastasis of various cancer types. In the present study, the role of miR-370 in the progression and proliferation of human astrocytoma and glioblastoma cells was assessed and the underlying molecular mechanism was investigated. miR-370 levels in clinical specimens of human glioma and peritumoral tissues were determined by reverse-transcription quantitative PCR. Oligonucleotide mimics and inhibitors were transfected into the U-251MG human astrocytoma cell line and the and U-87MG glioblastoma cell line and the cell viability of was determined by an MTT assay. The expression of β-catenin and forkhead box protein (FOX)O3a was determined by western blot analysis. The results revealed that the expression of miR-370 in human glioma tissues was significantly decreased compared with that in peritumoral tissues. The miR-370 levels in patients with grade III/IV gliomas were significantly decreased compared with those in grade I/II. Transfection with miR-370 mimics inhibited the proliferation of U-251MG and U-87MG cells. Furthermore, the miR-370 levels were negatively correlated with β-catenin and positively correlated with nuclear FOXO3a. In conclusion, miR-370 inhibited the proliferation of human glioma cells by regulating the levels of β-catenin and the activation of FOXO3a, suggesting that miR-370 was a tumor suppressor in the progression of human astrocytoma and glioblastoma cells.

The aim of this study was to explore the efficacy and safety of high-dose pemetrexed with cisplatin versus combination with temozolomide in patients with brain metastases (BM) of lung adenocarcinoma. After standard whole-brain radiotherapy (WBRT, 30 Gy/10 fractions), patients with BM of non-small cell lung cancer (NSCLC) were given high-dose pemetrexed (900 mg/m2) on day 1 of each cycle (3 weeks), and cisplatin was administered on days 1-3 in the cisplatin-treated group. The temozolomide-treated group was treated as follows: 75 mg/m2 temozolomide orally with concurrent WBRT followed by 150 mg/m2 temozolomide on days 1-5 with high-dose pemetrexed (900 mg/m2) on day 1 of each cycle (3 weeks). Six cycles later, high-dose pemetrexed (900 mg/m2) monotherapy or the best available supportive therapy was administered to both groups. An evaluation was carried out every 2-3 cycles. The primary end-points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Secondary end-points included safety and tolerability. Thirty-two patients in the pemetrexed plus cisplatin (PC) group and 28 patients in the pemetrexed plus temozolomide (PT) group were enrolled from November 2013 to October 2015. The ORR was 68.8% and 75%, in the PC and PT groups, respectively, and there was no statistically significant difference between the two groups (p=0.711). The median PFS rates of the PC and PT groups were 13.6 months and 16.9 months, respectively, and the median OS rates of the PC and PT groups were 18.9 months and 19.3 months, respectively. There were no differences in PFS and OS between the two groups. There were no grade 4 or higher side-effects in either group, but grade 3 side-effects such as leucopenia (2/32, 6.3%), nausea/vomiting (2/32, 6.3%), alopecia (1/32, 3.1%), rash (3/32, 9.4%) and renal insufficiency (1/32, 3.1%) were observed in the PC group, whereas the PT-group-only showed the following grade 3 side-effects: leucopenia (1/28, 3.6%) and nausea/vomiting (2/28, 7.1%). The data showed that the PT group achieved the same efficacy in PFS and OS as the PC group but with fewer toxicities. Therefore, high-dose pemetrexed plus temozolomide may be a better regimen for treating NSCLC with BM due to its better safety.

The aim of this study was to explore the efficacy and safety of high-dose pemetrexed with cisplatin versus combination with temozolomide in patients with brain metastases (BM) of lung adenocarcinoma. After standard whole-brain radiotherapy (WBRT, 30 Gy/10 fractions), patients with BM of non-small cell lung cancer (NSCLC) were given high-dose pemetrexed (900 mg/m

Background Brain metastases (BMs) occur in up to 40% of patients with nonsmall-cell lung cancer (NSCLC). When surgery or radiosurgery is not possible, whole-brain radiotherapy (WBRT) is the standard treatment, with a cerebral response rate of approximately 30%. Pemetrexed-based chemotherapy presents an approximately 40% response rate on brain lesions of NSCLC with brain metastases. Methods This trial assessed the efficacy and safety of high-dose pemetrexed plus cisplatin in NSCLC with BMs after WBRT. Thirty-two patients with Karnofsky Performance Status ≥70 were enrolled. Patients of NSCLC with brain metastases were eligible for WBRT, which was administered at 30 Gy/10f. Thereafter, high-dose pemetrexed plus cisplatin was given up to 6 cycles. Primary end point was objective response rate (RR) and progression-free survival on BM. Secondary end points included extracerebral and overall RR, safety profile, and survival. Results The objective cerebral RR (complete and partial response) was 68.8 % (22 of 32 patients). Extracerebral and globe RR was 37.5% and 31.3%, respectively. The median progression-free survival of BM was 13.6 months, and median overall survival was 19.1 months. Conclusions This modality of treatment appears to a better efficacy and a good safety of BM, as well as extracerebral. Further clinical studies are warranted.

Objective We report 18 cases of facial nerve schwannomas in which stripping surgery was attempted to preserve facial nerve integrity and favorable facial nerve function. Methods We attempted stripping surgery on 18 cases of facial nerve schwannomas. Postoperative facial nerve function was evaluated. Results Stripping surgery was successfully achieved in 11 cases, and facial nerve decompression was performed on the remaining 7 cases in which stripping surgery was impossible. Favorable facial nerve function was successfully maintained in all cases who underwent stripping surgery and 5 of 7 cases who underwent facial nerve decompression. Conclusions It was possible to accomplish stripping surgery in most cases with favorable facial nerve function, which maintained good facial nerve function after total tumor removal.

To explore the efficacy and safety of pemetrexed in the treatment of relapsed primary central nervous system lymphoma (PCNSL).Seven cases with relapsed PCNSL admitted in our hospital between August 2012 and August 2013 were retrospectively reviewed.Of the 7 relapsed cases, ectopic recurrence occurred in 3, in situ recurrence in 3 and leptomeningeal metastasis in 1. Patients with relapsed PCNSL were administered with high-dose pemetrexed (900 mg/m²) once for every 3 weeks and supplemented with folic acid and vitamin B₁₂. Complete remission was obtained in 2 patients, partial remission in 3 patients and progressive disease in 2. The overall response rate was 71.4% (5/7). The main adverse reactions were myelosuppression and gastrointestinal reaction.Treatment of relapsed PCNSL is difficult, and its prognosis is very poor. Pemetrexed therapy is a meaningful trial.

To investigate the alteration of T-lymphocyte subsets and NK activity in patients with squamous cell carcinoma of pharynx and larynx.T-lymphocyte subsets and NK activity were determined by flow cytometry in 123 patients with squamous cell carcinoma of pharynx and larynx. Blood samples of 36 nontumor patients were used as control.The total T lymphocytes were lower in patients with squamous cell carcinoma of pharynx and larynx than control group significantly (P0.05). The levels of helper lymphocyte subsets were little lower than those in control group(P0.05). On the other hand, the levels of suppressor lymphocytes in patients were higher than those in the control group (P0.05). Therefore, the CD4/CD8 ratios in patients were lower than those of the control group statistically (P0.05). There was no statistical difference in activated T lymphocytes and total B lymphocytes (P0.05), but NK activity in patients were lower than those in control group significantly (P0.01). There was no statistical difference in total T lymphocytes between stage I-II and stage III--IV (P0.05). The levels of helper lymphocyte subsets in stage I-II patients were little higher than in stage III-IV patients (P0.05), but the levels of suppressor lymphocytes in stage I-II patients were lower than in stage III-IV patients (P0.01). The CD4/CD8 ratios in stage I-II patients were significantly higher than in stage III-IV patients (P0.01). The levels of total B lymphocytes in stage I-II patients were significantly higher than in stage III-IV patients (P0.05). The activated T lymphocytes and NK activity did not changed statistically (P0.05).The immune function in patients with squamous cell carcinoma of pharynx and larynx is disordered and lower. With advanced stage disease, not only the cellular immune function in patients decrease gradually, but also the humoral immunity is lower. Analyzing T-lymphocyte subsets and NK activity determined by flow cytometry would be easy and helpful to evaluate the immunologic condition of every patient.

MicroRNAs (miRNAs) are endogenously small non-coding RNAs which are key post-transcriptional regulators of gene expression. Deregulation of miRNAs is common in human tumorigenesis. We report that miRNA-205 is significantly down-regulated in glioma cell lines and tissue specimens. Ectopic expression of miRNA-205 induces apoptosis, cell cycle arrest, impairs cell viability, clonability and invasive properties of glioma cells. We further demonstrate that miRNA-205 can specifically suppress expression of VEGF-A by directly interacting with the putative miRNA-205 binding site at the 3'-UTR. Identification of VEGF-A as a direct target for miRNA-205 may imply that miRNA-205 is a novel target for glioma therapy. Taken together, the present study for the first time provides evidence that miRNA-205 is a glioma-specific tumor suppressor by targeting VEGF-A.