Zanubrutinib delays selinexor resistance evolution in biopsy sample-derived primary central nervous system lymphoma models.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma of the brain with poor prognosis. The scarcity of cell lines established using PCNSL makes it difficult to conduct preclinical studies on new drugs. We aimed to explore the effect of selinexor combined with zanubrutinib in PCNSL using established PCNSL cells and an orthotopic PCNSL model. Primary PCNSL cells were successfully cultured. Selinexor inhibited proliferation, induced G1 phase arrest, and promoted apoptosis, however, induced drug resistance in PCNSL. Selinexor combined with zanubrutinib had a synergistic effect on PCNSL and prevented the onset of selinexor resistance in PCNSL by inhibiting AKT signaling. Moreover, selinexor combined with zanubrutinib notably slowed tumor growth and prolonged survival compared to that of the control. Overall, the addition of zanubrutinib to selinexor monotreatment had a synergistic effect in vitro and prolonged survival in vivo.

Outcomes, responses, and prognostic analyses of intrathecal combined treatment for leptomeningeal metastasis from lung adenocarcinoma.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic therapy has shown promise as a treatment approach for LM. Thus, this study aimed to evaluate the features and responses to IT combined therapy and identify determinants affecting patients with leptomeningeal metastasis resulting from lung adenocarcinoma (LM-LA). METHODS: A retrospective analysis of medical records from our hospital database was performed, covering from April 2018 to August 2022, for 37 patients diagnosed with LM-LA and treated with IT combined therapy. Patients who received IT combined therapy for LM-LA were evaluated for demographic characteristics, treatment efficacy, survival, and variables that impacted them. RESULTS: The median overall survival (mOS) of 37 patients was 16.0 months, and the survival rates at 6 and 12 months were 75.7% and 35.1%, respectively. Among the 21 patients with LM-LA who received IT combined with tyrosine kinase inhibitors (TKIs), the mOS was 17.0 months, which was significantly longer than that of patients treated with IT combined with chemotherapy (7.0 months, P = 0.010) and the best supportive care (6.0 months, P = 0.001). However, no significant survival benefit was observed in patients treated with IT combined with TKIs when compared with those treated with IT combined with PD-1 (5.0 months, P = 0.249). Multivariate analysis indicated that the combination of TKIs was an independent favorable prognostic factor for patients with LM-LA. CONCLUSION: Combination treatment is regarded as an additional option for patients with LM-LA. Compared with other combination therapies in our study, IT combined with TKI therapy provided a better survival outcome for patients with LM-LA.

Healthy and Unhealthy Plant-Based Diets and Glioma in the Chinese Population.

Plant-based diets have been suggested to help prevent various chronic diseases, including cancer. However, there are few reports on central nervous system tumors, and data on dose-response relationships are lacking. This individual-matched case-control study included 506 cases and 506 controls. The overall plant-based diet index (PDI), the healthy plant-based diet index (hPDI), and the unhealthy plant-based diet index (uPDI) were calculated using dietary information collected through a food frequency questionnaire, with higher scores indicating better adherence. We analyzed the relationship of plant-based diets with glioma. After adequate adjustment for confounders, PDI was associated with a reduced glioma risk (OR = 0.42, 95% CI: 0.24-0.72). Conversely, uPDI was associated with an elevated glioma risk (OR = 8.04, 95% CI: 4.15-15.60). However, hPDI was not significantly associated with glioma risk (OR = 0.83, 95% CI: 0.48-1.45). For subgroups, PDI was not significant in analyzing young age, BMI, or any pathological subtypes. The restricted cubic spline function showed a significant dose-response relationship between PDI (p-nonlinearity< 0.0001) and uPDI (p-nonlinearity= 0.0711) and glioma. Further analysis found that refined grains had the greatest effect on gliomas in the less healthy plant-based food group. Therefore, following a plant-based diet was linked to a lower risk of glioma, especially when consuming fewer unhealthy plant-based foods.

Chinese Dietary Indices and Glioma: New Insights of a Case-Control Study in the Chinese Population.

Identifying modifiable factors in primary prevention strategies is a typical goal of glioma epidemiology. Among many glioma risk factors, diet was always considered as one. Most of the relevant studies thus far were concentrated on the West. It was crucial to investigate the connection between the Chinese diet and gliomas given the stark variations between western and eastern diets. A food frequency questionnaire including 114 items was used to investigate the food intake of the study subjects. The Chinese Dietary Quality Index (CDQI), the Chinese Dietary Balance Index (CDBI), the Dietary Antioxidant Index (DAI), the Dietary Inflammation Index (DII), and the Chinese Healthy Eating Index (CHEI) were calculated based on the data provided by the food frequency questionnaire to evaluate dietary quality, dietary balance, dietary antioxidants, dietary inflammation and adherence to the Chinese dietary guidelines in 506 glioma patients and 506 controls, respectively. After adjusting covariates, CHEI (OR = 0.90, 95% CI: 0.88-0.93) and DAI (OR = 0.61, 95% CI: 0.54-0.70) were correlated to a reduced glioma risk, and CDBI-based undernutrition (OR = 1.08, 95% CI: 1.06-1.12) and overnutrition (OR = 1.14, 95% CI: 1.09-1.20) and DII (OR = 2.20, 95% CI: 1.81-2.68) were correlated to an elevated glioma risk. Moreover, restrictive cubic spline analysis showed that there were significant nonlinear dose-response relationships between CHEI, CDBI, DAI, DII, and glioma. Therefore, adhering to the Chinese dietary guidelines was connected with a lower glioma risk, and undernutrition and overnutrition in the Chinese diet were associated with an increased risk of glioma.

Phase I study of chlorogenic acid injection for recurrent high-grade glioma with long-term follow-up.

OBJECTIVE: This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid (CGA) in patients with recurrent high-grade glioma after standard of care treatments, through a first-in-human, open-label, dose-escalation phase I trial. METHODS: A total of 26 eligible patients were enrolled, received intramuscular CGA injections at 5 dose levels, and were followed up for 5 years. CGA was well tolerated, and the maximum tolerated dose was 5.5 mg/kg. RESULTS: The most common treatment-related adverse events occurred at the sites of injection. No grade 3 or 4 adverse events (e.g., drug allergy) were reported for these patients except for induration at the injection sites. A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma, with a t1/2 of 0.95-1.27 h on day 1 and 1.19-1.39 h on day 30, and no detectable CGA was observed on days 9, 11, 13, 23, 25, 27, and 29 before CGA administration. After the first treatment cycle, 52.2% of patients (12 of 23) achieved stable disease. Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients. Of the 18 patients with grade 3 glioma, the median overall survival was 9.5 months. Two patients remained alive at the cutoff day. CONCLUSIONS: This phase I study demonstrated that CGA has a favorable safety profile (with no severe toxicity), and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies, thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.

Dietary B vitamins and glioma: A case-control study based on Chinese population.

Background: Dietary antioxidants have long been thought to be likely to prevent the development of gliomas. Previous studies have reported vitamin A, C, and E protective effects against gliomas. B vitamins, one of the main vitamins in the diet, are closely related to human health, but the association with gliomas has rarely been reported. Objective: This study aimed to evaluate the relationship between five B vitamins and glioma. Methods: In this Chinese population-based case-control study, 506 glioma cases and 506 matched (age and sex) controls were included. The dietary intake of study participants was assessed using a valid 111-item food frequency questionnaire. The intake of five B vitamins was calculated based on participants' dietary information from the food frequency questionnaire. The logistic regression model was used to examine the association between B vitamins and glioma, and the restriction cubic spline evaluated the dose-response relationship between the two. Results: After adjusting for confounding factors, thiamine (OR = 0.09, 95%CI: 0.05-0.20), riboflavin (OR = 0.12, 95%CI: 0.06-0.25), nicotinic acid (OR = 0.24, 95%CI: 0.12-0.47), folate (OR = 0.07, 95%CI: 0.03-0.15) and biotin (OR = 0.14, 95%CI: 0.07-0.30) in the highest tertile were associated with a significantly decreased risk of glioma compared with the lowest tertile. The results of thiamine and biotin in glioma with different pathological types and grades were different. The restricted cubic spline function showed significant dose-response relationships between the intake of five B vitamins and the risk of glioma. When B vitamins exceeded a specific intake, the risk of glioma did not change. Conclusion: Our study suggests that higher dietary intake of thiamine, riboflavin, nicotinic acid, and folate are associated with a decreased risk of glioma, but the results of biotin are not consistent among different populations. In the future, prospective studies should be conducted better to validate the effects of B vitamins on gliomas.

Association between dietary minerals and glioma: A case-control study based on Chinese population.

Background: As one of the essential nutrients for the human body, minerals participate in various physiological activities of the body and are closely related to many cancers. However, the population study on glioma is not sufficient. Objective: The purpose of this study was to evaluate the relationship between five dietary minerals and glioma. Methods: A total of 506 adult patients with glioma and 506 healthy controls were matched 1:1 according to age (±5 years) and sex. The food intake of the subjects in the past year was collected through the food frequency questionnaire, and the intakes of calcium, magnesium, iron, zinc, and copper in the diet were calculated. The logistic regression model was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for dietary minerals to gliomas. Results: After adjusting for confounders, higher intakes of calcium (OR = 0.65, 95% CI: 0.57-0.74), magnesium (OR = 0.18, 95% CI: 0.11-0.29), iron (OR = 0.04, 95% CI: 0.02-0.11), zinc (OR = 0.62, 95% CI: 0.54-0.73), and copper (OR = 0.22, 95% CI: 0.13-0.39) were associated with a significantly decreased risk of glioma. Similar results were observed in gliomas of different pathological types and pathological grades. The restriction cubic spline function suggested significant linear dose-response relationships between intakes of five minerals and the risk of glioma. When the dietary minerals exceeded a particular intake, the risk of glioma stabilized. Conclusion: Our study suggests that higher dietary intakes of calcium, magnesium, iron, zinc, and copper are associated with a decreased risk of glioma. However, the results of this study require further exploration of potential mechanisms in the future better to elucidate the effects of mineral intake on gliomas.

PHF6 promotes the progression of endometrial carcinoma by increasing cancer cells growth and decreasing T-cell infiltration.

Uterine corpus endometrial carcinoma (UCEC) is the most common cancer of the female reproductive tract. The overall survival of advanced and recurrent UCEC patients is still unfavourable nowadays. It is urgent to find a predictive biomarker and block tumorgenesis at an early stage. Plant homeodomain finger protein 6 (PHF6) is a key player in epigenetic regulation, and its alterations lead to various diseases, including tumours. Here, we found that PHF6 expression was upregulated in UCEC tissues compared with normal tissues. The UCEC patients with high PHF6 expression had poor survival than UCEC patients with low PHF6 expression. PHF6 mutation occurred in 12% of UCEC patients, and PHF6 mutation predicted favourable clinical outcome in UCEC patients. Depletion of PHF6 effectively inhibited HEC-1-A and KLE cell proliferation in vitro and decreased HEC-1-A cell growth in vivo. Furthermore, high PHF6 level indicated a subtype of UCECs characterized by low immune infiltration, such as CD3+ T-cell infiltration. While knockdown of PHF6 in endometrial carcinoma cells increased T-cell migration by promoting IL32 production and secretion. Taken together, our findings suggested that PHF6 might play an oncogenic role in UCEC patients. Thus, PHF6 could be a potential biomarker in predicting the prognosis of UCEC patients. Depletion of PHF6 may be a novel therapeutic strategy for UCEC patients.

HSP90 facilitates stemness and enhances glycolysis in glioma cells.

BACKGROUND: Glioma is one of the most commonly occurring malignant brain cancers with high recurrence and mortality. Glioma stem cells (SCs) are a rare sub-group of glioma cells that play a critical role in tumor progression. Heat shock protein 90 (HSP90) is known to promote the stemness of glioma SCs. Here, we investigated the role of HSP90 in glioma SC metabolism, to reveal its potential as a novel therapeutic target. METHODS: Self-renewal assays were used to assess stemness. Cell migration, invasion and viability were measured using Transwell and CCK-8 assays, respectively. Tumor growth was evaluated in xenograft nude mouse models. The expression of known markers of stemness including CD44, A2B5, Oct4, Nestin, Lgr5, Sox2, CD24 were assessed by western blotting. HSP90 expression was assessed by western blotting and immunohistochemistry (IHC). Glucose consumption, lactic acid production and ATP levels were measured using commercially available kits. Extracellular acidification rates (ECAR) were measured using the Seahorse XFe/XF analyzer. RESULTS: HSP90 was upregulated in spheroid cells compared to parental cells. HSP90 facilitated the characteristics of SCs through enhancing self-renewal capacity, glucose consumption, lactic acid production, total ATP, ECAR and glycolysis. 2-DG, an inhibitor of glycolysis, reduced HSP90 expression and inhibited the stemness of glioma cells. CONCLUSIONS: We show that HSP90 accelerates stemness and enhances glycolysis in glioma cells. Inhibition of glycolysis with 2DG prevented stemness. This reveals new roles for HSP90 during glioma progression and highlights this protein as a potential target for much-needed anti-glioma therapeutics.

Intrathecal methotrexate in combination with systemic chemotherapy in glioblastoma patients with leptomeningeal dissemination: A retrospective analysis.

BACKGROUND: Glioblastoma (GBM) is one of the most common and aggressive primary malignant brain tumors with severe symptoms and a poor prognosis. Leptomeningeal dissemination (LMD) is a serious complication of GBM that often results in dire outcomes. There is currently no effective treatment. AIM: To estimate the clinical outcomes of combination therapy in GBM patients with LMD. METHODS: A retrospective analysis was conducted using data collected from GBM patients diagnosed with LMD from January 2012 to December 2019 at our institution. All these patients had received at least one cycle of a combination therapy consisting of intrathecal methotrexate (MTX) and systemic chemotherapy. Clinical and pathological data were analyzed to explore the outcome of GBM patients with LMD and to determine the most effective treatment. RESULTS: Twenty-six patients were enrolled in this study. The median time from GBM diagnosis to LMD development was 9.3 mo (range: 2-59 mo). The median overall survival of LMD patients from diagnosis to after receiving systemic chemotherapy in combination with intrathecal MTX was 10.5 mo (range: 2-59 mo). In the Cox univariate analysis, gross resection of tumor (P = 0.022), Karnofsky performance status (KPS) > 60 (P = 0.002), and Ommaya reservoir implant (P < 0.001) were correlated with survival. Multivariate analysis showed that KPS > 60 (P = 0.037) and Ommaya reservoir implant (P = 0.014) were positive factors correlated with survival. Myelotoxicity and gastrointestinal reactions were the common toxicities of this combination therapy. According to Common Terminology Criteria of Adverse Events 4.03, most of the patients presented with toxicity less than grade 3. CONCLUSION: Intrathecal MTX administration combined with systemic chemotherapy is a potentially effective treatment for patients with GBM and LMD, with mild treatment-related side effects.

Targeting visualization of malignant tumor based on the alteration of DWI signal generated by hTERT promoter-driven AQP1 overexpression.

PURPOSE: To specifically diagnose malignant tumors in DWI using the human telomerase reverse transcriptase (hTERT) promoter-driven AQP1 expression. METHODS: The human telomerase reverse transcriptase (hTERT) promoter-driven AQP1 gene overexpression lentivirus system (hTERT-AQP1) and cytomegalovirus (CMV) promoter-driven AQP1 gene overexpression lentivirus system (CMV-AQP1) were prepared, and transduced into telomerase-positive and -negative cells. The AQP1 expression and DWI signal intensity (SI) change in transduced cells were analyzed. Balb/C nude mice subcutaneous xenograft models derived from lentivirus-transduced telomerase-positive and -negative cells were used to evaluate AQP1 expression and DWI SI change in vivo. We further established another group of subcutaneous xenograft model using pristine telomerase-positive and -negative cells, followed by injecting the lentiviral vectors intratumorally or intravenously, to determine the malignant tumor-targeted imaging of hTERT-AQP1. RESULTS: The hTERT-AQP1 and CMV-AQP1 were successfully prepared. After transduction, hTERT-AQP1 could induce the specific overexpression of AQP1 in telomerase-positive cells. Compared with untransduced cells, all CMV-AQP1-pretransduced cells and hTERT-AQP1-pretransduced telomerase-positive cells showed decreased SI and increased apparent diffusion coefficient (ADC) in DWI, while hTERT-AQP1-pretransduced telomerase-negative cells showed no obvious SI and ADC change. Correspondingly, hTERT-AQP1-transduced telomerase-positive tumors and CMV-AQP1-transduced telomerase-positive and -negative tumors showed decreased DWI SI and increased ADC, while hTERT-AQP1-transduced telomerase-negative tumor had no SI and ADC changes. After intratumoral or intravenous injection, CMV-AQP1 could upregulate AQP1 expression and induce DWI SI and ADC alteration in both telomerase-positive and -negative tumors, while hTERT-AQP1 worked in telomerase-positive tumors specifically. CONCLUSION: Cancers can be specifically visualized based on the DWI signal alteration which triggered by hTERT-AQP1 lentivirus system that combined AQP1 gene and hTERT promoter.

Case report: The treatment for olfactory neuroblastoma combined with leptomeningeal carcinomatosis via an ommaya reservoir.

Olfactory neuroblastoma is a rare neoplasm that usually presents in the upper nasal cavity. Although its prognosis is highly unfavorable, effective treatment options are still lacking. Moreover, there is no standard treatment for patients with olfactory neuroblastoma that progressed to leptomeningeal carcinomatosis. Here we report an uncommon case of a 59-year-old woman who was diagnosed with olfactory neuroblastoma and leptomeningeal carcinomatosis. For a direct delivery of the drugs to the tumor, and to avoid the impact of lumbar puncture on the patient's quality of life, the intravenous chemotherapy plus intrathecal administration of MTX via an Ommaya reservoir was chosen. The results were striking, with the disappearance of tumor cells in the cerebrospinal fluid and the relief of the patient's symptoms with PR. Our result indicates that chemotherapy via an Ommaya reservoir offers a new potential therapy for patients with meningeal metastases.

N,Cl-Codoped Carbon Dots from Impatiens balsamina L. Stems and a Deep Eutectic Solvent and Their Applications for Gram-Positive Bacteria Identification, Antibacterial Activity, Cell Imaging, and ClO- Sensing.

In this study, we first synthesized metal-free N,Cl-doped carbon dots (N,Cl-CDs) using Impatiens balsamina L. stems as green precursors in a deep eutectic solvent (DES). The obtained N,Cl-CDs were characterized through transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, fluorescence (FL) spectroscopy, and ultraviolet (UV) spectroscopy. In addition to the common features of carbon dots (CDs), such as high light stability, small size, low toxicity, good aqueous solubility, and favorable biocompatibility, these N,Cl-CDs exhibited excellent recognition and selectivity for Gram-positive bacteria by doping with N and Cl elements using DES. The N,Cl-CDs with positive charge cannot only differentiate Gram-positive bacteria by selective fluorescence imaging but also have antibacterial effects on Gram-positive bacteria. Through potential, ROS, and morphological analyses of bacteria before and after treatment with N,Cl-CDs, the antibacterial mechanisms of bacteriostasis, Enterococcus faecium, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Salmonella were explored. In addition, N,Cl-CDs demonstrated low cytotoxicity and good cell imaging ability in cancer and normal cells. Moreover, they can be used as a fluorescence sensor for the detection of ClO- with a detection range from 100 nM to 40 µM and a limit of detection (LOD) of 30 nM. In summary, the prepared N,Cl-CDs could be applied as environmentally friendly Gram-positive bacterial identification and antibacterial agents. Additionally, their cell imaging and ClO- detection abilities were outstanding.

Synergistic Theranostics of Magnetic Resonance Imaging and Photothermal Therapy of Breast Cancer Based on the Janus Nanostructures Fe3O4-Aushell-PEG.

BACKGROUND: Satisfactory prognosis of breast cancer (BC) is limited by difficulty in early diagnosis and insufficient treatment. The combination of molecular imaging and photothermal therapy (PTT) may provide a solution. METHODS: Fe3O4-Aushell nanoparticles (NPs) were prepared by thermal decomposition, seeded growth and galvanic replacement and were comprehensively characterized. After conjugated to PEG, NPs were used as MRI and PTT agents in vitro and in vivo. RESULTS: Fe3O4-Aushell NPs which had uniform Janus-like morphology were successfully synthesized. The Fe3O4 had a size of 18 ± 2.2 nm, and the Aushell had an outer diameter of 25 ± 3.3 nm and an inner diameter of 20 ± 2.9 nm. The NPs showed superparamagnetism, a saturation magnetization of 36 emu/g, and an optical absorption plateau from 700 to 808 nm. The Fe3O4-Aushell NPs were determined to possess good biocompatibility. After PEG coating, the zeta potential of NPs was changed from -23.75 ± 1.37 mV to -13.93 ± 0.55 mV, and the FTIR showed the characteristic C-O stretching vibration at 1113 cm-1. The NPs' MR imaging implied that the T2 can be shortened by Fe3O4-Aushell NPs in a concentration-dependent manner, and the Fe3O4-Aushell NPs coated with PEG at the molar ratio of 160 (PEG: NPs) showed the highest transverse relaxivity (r 2) of 216 mM-1s-1. After irradiation at 0.65 W/cm2 for 5 min, all cells incubated with the Fe3O4-Aushell-PEG160 NPs (Fe: 30 ppm, Au: 70 ppm) died. After administrated intratumorally, Fe3O4-Aushell-PEG160 notably decreased the signal intensity of tumor in T2WI images. Under the same irradiation, the temperature of tumors injected with Fe3O4-Aushell-PEG160 quickly rose to 54.6°C, and the tumors shrank rapidly and were ablated in 6 days. CONCLUSION: Fe3O4-Aushell-PEG NPs show good r 2 and PTT performance and are promising synergistic theranostic agents of MRI and PTT for BC.

Antitumor activity of the third generation EphA2 CAR-T cells against glioblastoma is associated with interferon gamma induced PD-L1.

Glioblastoma (GBM) is the most common and aggressive brain malignancy in adults and is currently incurable with conventional therapies. The use of chimeric antigen receptor (CAR) modified T cells has been successful in clinical treatment of blood cancers, except solid tumors such as GBM. This study generated two third-generation CARs targeting different epitopes of ephrin type-A receptor 2 (EphA2) and examined their anti-GBM efficacy in vitro and in tumor-bearing mice. We observed that these two types of T cells expressing CAR (CAR-T) targeting EphA2 could be activated and expanded by EphA2 positive tumor cells in vitro. The survival of tumor-bearing mice after EphA2 CAR-T cell treatment was significantly improved. T cells transduced with one of the two EphA2 CARs exhibited better anti-tumor activity, which is related to the upregulation of CXCR-1/2 and appropriate interferon-γ (IFN-γ) production. CAR-T cells expressed excessively high level of IFN-γ exhibited poor anti-tumor activity resulting from inducing the upregulation of PD-L1 in GBM cells. The combination of CAR-T cells with poor anti-tumor activity and PD1 blockade improved the efficacy in tumor-bearing mice. In conclusion, both types of EphA2 CAR-T cells eliminated 20%-50% of GBM in xenograft mouse models. The appropriate combination of IFN-γ and CXCR-1/2 levels is a key factor for evaluating the antitumor efficiency of CAR-T cells.

Fluorine-mediated synthesis of anisotropic iron oxide nanostructures for efficient T2-weighted magnetic resonance imaging.

Herein, we developed a novel strategy for the shape-controlled synthesis of iron oxide nanostructures with superior r2 values through the introduction of fluoride ions as a morphology controlling agent and dopant. The selective adsorption of fluoride ions onto the specified crystal planes of iron oxide nanocrystals leads to the formation of octapod nanoparticles (ONPs) and cubic nanocrystal clusters (CNCs). Both ONPs and CNCs present high r2 values (526.5 and 462.2 mM-1 s-1, respectively) due to the synergistic effect of a larger effective radius, clustering and fluorine doping. The in vivo MRI results show significant enhancement in T2-weighted images of the liver after the intravenous injection of ONPs and CNCs, suggesting their great potential as efficient T2-weighted MRI contrast agents. This new approach of achieving anisotropic fluorine-doped iron oxide nanostructures with high r2 relaxivity provides an alternative strategy for the development of highly sensitive T2 contrast agents for MRI.

Effect of BRAF/MEK Inhibition on Epithelioid Glioblastoma with BRAFV600E Mutation: a Case Report and Review of the Literature.

BACKGROUND: To explore the effect of BRAF inhibitor on epithelioid glioblastoma (Ep-GBM) with BRAFV600E mutation. METHODS: A patient of Ep-GBM with BRAFV600E mutation underwent BRAF inhibition therapy. The rationale behind combined BRAF and MEK inhibition in Ep-GBM was reviewed. RESULTS: Vemurafenib can initially inhibit the progression of Ep-GBM with BRAFV600E mutation. However, the tumor may become resistant to vemurafenib and then progress. CONCLUSIONS: BRAF inhibition therapy can inhibit the progression of Ep-GBM with BRAFV600E mutation, but the subsequent resistance development leads to a poor outcome.

EFEMP2 indicates assembly of M0 macrophage and more malignant phenotypes of glioma.

Immune response mediated by macrophages is critical in tumor progression and implicates new targets in potential efficient immunotherapies. Tumor associated macrophages (TAM) are divided into either polarized M1 or M2 phenotype depending on different regulators of polarization and pro- or anti-oncogenic roles they play. Glioma-infiltrated TAMs have been newly reported contrary to the current polarization dogma. Instead, macrophages in glioma exhibit a continuum phenotype between the M1- and M2-like TAM that resembling M0 macrophage. Here we proposed an OS (overall survival)-correlated gene EFEMP2 (EGF containing fibulin-like extracellular matrix protein 2) via screening with transcriptional expression levels and methylation data in two glioma databases. EFEMP2 was found highly expressed in glioma of higher WHO grade and Mesenchymal subtype glioma, and its transcriptional level could predict OS efficiently in validation datasets. EFEMP2 exhibited a remarkable preference of intercellular expression. In vitro assay showed that EFEMP2's level in medium was closely related to glioma cells' growth. Moreover, EFEMP2 expression level was remarkably correlated with immunological responses. M0-like macrophage as a feature of malignancy of glioblastoma revealed distinct assembly in glioma with high level of EFEMP2. These results revealed EFEMP2's role as a potential characteristic marker of malignant glioma, which are enriched of M0 macrophage.

[Efficacy and Safety of Crizotinib in Advanced or Recurrent 
ALK-positive Non-small Cell Lung Cancer].

BACKGROUND: Anaplastic lymphoma kinase (ALK) positive in non-small cell lung cancer (NSCLC) was about 5%-7% and ALK tyrosine kinase inhibitor (TKI) was the standard treatment in NSCLC. The aim of this study is to evaluate the efficacy and safety of crizotinib in patients with advanced ALK gene-positive or recurrent NSCLC. METHODS: Three methods were used to screen patients with advanced or recurrent NSCLC harboring ALK gene fusion/translocation. The patients with ALK positive tested by flourescence in situ hybridization (FISH) was given orally crizotinib, 250 mg, bid. The objective response rate (ORR), progression-free survival (PFS) and safety were evaluated. RESULTS: A total of 226 patients were screened, 39 of whom had ALK fusion or translocation, and 37 were enrolled in the study. 35 patients were evaluated for objective response, ORR was 70.3%, and disease control rate (DCR) was 94.6%, and median PFS was 11.8 mon. The main adverse reactions were elevated transaminase (Grade 1, 91.7%), elevated transaminases (Grade 2, 23.4%), nausea (Grade 1, 75.6%), anemia (Grade 1-2, 62.3%), visual impairment (Grade 1, 21.8%), weight loss (Grade 1, 31.4%), pneumonia (Grade 2, 3.5%). CONCLUSIONS: Crizotinib can be used for the treatment of advanced NSCLC with ALK fusion/translocation. It is highly effective and well tolerated.

[Clinical Characteristics, Treatment and Prognosis of 47 Non-small Cell Lung Cancer with Neuroendocrine Differentiation Patients].

BACKGROUND: Non-small cell lung cancer (NSCLC) with neuroendocrine differentiation (NED) was a new pathologic type and uncommon in clinics. The aim of this study is to observe the relationship between clinical pathologic characteristics, imagination, biological behavior and prognosis in NSCLC-NED. METHODS: The clinical data of 47 patients with NSCLC-NED admitted from January 2009 to November 2017 in the Fifth Medical Center of General Hospital of People's Liberation Army were collected. The demographic data and imaging characteristics were summarized. Pathological features, treatment and prognosis, analysis of the correlation between different factors and prognosis. RESULTS: Of the 47 patients with NSCLC-NED, the median age was 61 years (45 years-78 years), 38 males and 9 females; 37 were poorly differentiated cancer with NED, and 10 were middle differentiated cancer with NED; 2 cases of driving gene positive (1 case of EGFR sensitive mutation, 1 case of ALK fusion), objective response rate (ORR) of first-line chemotherapy was 34.5%, and median progression-free survival (PFS) was 4 months; the median overall survival (OS) was 11 months, and only 2 cases (4.2%, 2/47) of OS were over 2 years. CONCLUSIONS: NSCLC-NED is different from simple NSCLC or pulmonary neuroendocrine tumors. Males, ≤70 years old, severely smoking, and patients with lower tumor differentiation often have NED, and most of them are stage IV. This type of patient-driven gene positive proportion is lower than the general adenocarcinoma population, less sensitive to chemotherapy, and the overall survival is shorter, indicating a poor prognosis.