Publications by authors named "Mingxiao Li"

65 Publications

Combining MGMT promoter pyrosequencing and protein expression to optimize prognosis stratification in glioblastoma.

Cancer Sci 2021 Jun 11. Epub 2021 Jun 11.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Pyrosequencing (PSQ) represents the golden standard for MGMT promoter status determination. Binary interpretation of results based on the threshold from the average of several CpGs tested would neglect the existence of the "gray zone". How to define the gray zone and reclassify patients in this subgroup remains to be elucidated. A consecutive cohort of 312 primary glioblastoma patients were enrolled. CpGs 74-81 in the promoter region of MGMT were tested by PSQ and the protein expression was assessed by immunohistochemistry (IHC). Receiver operating characteristic curves were constructed to calculate the area under the curves (AUC). Kaplan-Meier plots were used to estimate the survival rate of patients compared by the log-rank test. The optimal threshold of each individual CpG differed from 5% to 11%. Patients could be separated into the hypomethylated subgroup (all CpGs tested below the corresponding optimal thresholds, n = 126, 40.4%), hypermethylated subgroup (all CpGs tested above the corresponding optimal thresholds, n = 108, 34.6%), and the gray zone subgroup (remaining patients, n = 78, 25.0%). Patients in the gray zone harbored an intermediate prognosis. The IHC score instead of the average methylation levels could successfully predict the prognosis for the gray zone (AUC for overall survival, 0.653 and 0.519, respectively). Combining PSQ and IHC significantly improved the efficiency of survival prediction (AUC: 0.662, 0.648, and 0.720 for PSQ, IHC, and combined, respectively). Immunohistochemistry is a robust method to predict prognosis for patients in the gray zone defined by PSQ. Combining PSQ and IHC could significantly improve the predictive ability for clinical outcomes.
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http://dx.doi.org/10.1111/cas.15024DOI Listing
June 2021

Corrigendum: Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological and Molecular Features.

Front Oncol 2021 19;11:700599. Epub 2021 May 19.

Department of Neurosurgery, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

[This corrects the article DOI: 10.3389/fonc.2021.627325.].
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http://dx.doi.org/10.3389/fonc.2021.700599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171117PMC
May 2021

Differential Predictors and Clinical Implications Associated With Long-Term Survivors in IDH Wildtype and Mutant Glioblastoma.

Front Oncol 2021 13;11:632663. Epub 2021 May 13.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Glioblastoma (GBM) is the most aggressive intracranial tumor which can be divided into two subtypes based on status of isocitrate dehydrogenase (IDH). A small fraction of patients after receiving standard treatment can be long-term survivors (LTS). This study was designed to disclose the predictors and clinical implications associated with LTS in IDH wildtype and mutant GBM.

Methods: Patients who survived beyond five years after diagnosis of GBM were defined as LTS, while those with a survival less than one year were defined as short-term survivors (STS). A total of 211 patients with diagnosis of GBM in Beijing Tiantan Hospital from January 2007 to January 2015 were enrolled, including 44 (20.9%) LTS and 167 (79.1%) STS. The clinical, radiological and molecular features between groups were systematically compared.

Results: Compared with STS, LTS were a subgroup of patients with a younger age at diagnosis (=0.006), a higher KPS score (=0.011), higher rates of cystic change (=0.037), O-methylguanine-DNA methyltransferase (MGMT) promoter methylation (=0.007), and IDH mutation (=0.049), and more likely to have undergone gross total resection (<0.001). Survival analysis demonstrated that LTS with wildtype IDH conferred a longer progression-free survival (66.0 27.0 months, =0.04), but a shorter post-progression survival (46.5 months not reached, =0.0001) than those of LTS with mutant IDH. LTS with mutant IDH showed a trend towards increased survival after receiving re-operation (=0.155) and reirradiation (=0.127), while this clinical benefit disappeared in the subset of LTS with wildtype IDH (>0.05).

Conclusion: The prognostic value and therapeutic implications associated with LTS in GBM population significantly differed on the basis of IDH status. Our findings provide a new approach for physicians to better understand the two subtypes of GBM, which may assist in making more tailored treatment decisions for patients.
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http://dx.doi.org/10.3389/fonc.2021.632663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155513PMC
May 2021

Combination of Immunotherapy and Radiotherapy for Recurrent Malignant Gliomas: Results From a Prospective Study.

Front Immunol 2021 7;12:632547. Epub 2021 May 7.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients.

Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545.

Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (<0.05).

Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen.
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http://dx.doi.org/10.3389/fimmu.2021.632547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138184PMC
May 2021

Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features.

Front Oncol 2021 20;11:627325. Epub 2021 Apr 20.

Department of Neurosurgery, National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Pseudoprogression (PsP) mimics true early progression (TeP) in conventional imaging, which poses a diagnostic challenge in glioblastoma (GBM) patients who undergo standard concurrent chemoradiation (CCRT). This study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in isocitrate dehydrogenase (IDH) wild-type GBM patients. New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date). Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (: 2.161, = 0.026), gross total removal (GTR) of the tumor (: 6.571, < 001), located in the frontal lobe (: 2.561, = 0.008), non-subventricular zone (SVZ) infringement (: 10.937, < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (: 9.737, < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve. Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging.
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http://dx.doi.org/10.3389/fonc.2021.627325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093388PMC
April 2021

Role of circulating tumor cell detection in differentiating tumor recurrence from treatment necrosis of brain gliomas.

Biosci Trends 2021 May 29;15(2):107-117. Epub 2021 Apr 29.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Differentiating treatment necrosis from tumor recurrence poses a diagnostic conundrum for many clinicians in neuro-oncology. To investigate the potential role of circulating tumor cells (CTCs) detection in differentiating tumor recurrence and treatment necrosis in brain gliomas, we retrospectively analyzed the data of 22 consecutive patients with tumor totally removed and new enhancing mass lesion(s) showed on MRI after initial radiotherapy. The 22 patients were finally classified into tumor recurrence group (n = 10) and treatment necrosis group (n = 12), according to evidence from the clinical course (n = 11) and histological confirmation (n = 11). All 22 patients received CTCs detection, and DSC-MRP and 11C-MET-PET were performed on 20 patients (90.9%) and 17patients (77.3%) respectively. The data of the diagnosis efficacy to differentiate the two lesions by CTC detection, MPR and PET were analyzed by ROC analysis. The mean CTCs counts were significantly higher in the tumor recurrence group (6.10 ± 3.28) compared to the treatment necrosis group (1.08 ± 2.54, p < 0.001). The ROC curve showed that an optimized cell count threshold of 2 had 100% sensitivity and 91.2% specificity with AUC = 0.933 to declare tumor recurrence. The diagnostic efficacy of CTC detection was superior to rCBV of DSC-MRP and rSUV in MET-PET. Furthermore, we observed that CTCs detection could have a potential role in predicting tumor recurrence in one patient. Our research results preliminarily showed the potential value of CTC detection in differentiating treatment necrosis from tumor recurrence in brain gliomas, and is worthy of further confirmation with large samples involved.
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http://dx.doi.org/10.5582/bst.2021.01017DOI Listing
May 2021

Synthesis of Polymer Brushes Via SI-PET-RAFT for Photodynamic Inactivation of Bacteria.

Macromol Rapid Commun 2021 Apr 8:e2100106. Epub 2021 Apr 8.

School of Chemical Engineering, Australian Centre for NanoMedicine, Cluster for Advanced Macromolecular Design, The University of New South Wales, Sydney, New South Wales, 2052, Australia.

Biofilms are a persistent issue in healthcare and industry. Once formed, the eradication of biofilms is challenging as the extracellular polymeric matrix provides protection against harsh environmental conditions and physically enhances resistance to antimicrobials. The fabrication of polymer brush coatings provides a versatile approach to modify the surface to resist the formation of biofilms. Herein, the authors report a facile synthetic route for the preparation of surface-tethered polymeric brushes with antifouling and visible light activated bactericidal properties using surface-initiated photoinduced electron transfer-reversible addition-fragmentation chain transfer polymerization (SI-PET-RAFT). Bactericidal property via the generation of singlet oxygen, which can be temporally and spatially controlled, is investigated against both Gram-positive and Gram-negative bacteria. In addition, the antibacterial properties of the surface can be recycled. This work paves the way for the preparation of polymer films that can resist and kill bacterial biofilms.
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http://dx.doi.org/10.1002/marc.202100106DOI Listing
April 2021

Construction of Bone Metastasis-Specific Regulation Network Based on Prognostic Stemness-Related Signatures in Breast Invasive Carcinoma.

Front Oncol 2020 27;10:613333. Epub 2021 Jan 27.

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Bone is the most common metastatic site of Breast invasive carcinoma (BRCA). In this study, the bone metastasis-specific regulation network of BRCA was constructed based on prognostic stemness-related signatures (PSRSs), their upstream transcription factors (TFs) and downstream pathways.

Methods: Clinical information and RNA-seq data of 1,080 primary BRCA samples (1,048 samples without bone metastasis and 32 samples with bone metastasis) were downloaded from The Cancer Genome Atlas (TCGA). The edgeR method was performed to identify differential expressed genes (DEGs). Next, mRNA stemness index (mRNAsi) was calculated by one-class logistic regression (OCLR). To analyze DEGs by classification, similar genes were integrated into the same module by weighted gene co-expression network analysis (WGCNA). Then, univariate and multivariate Cox proportional hazard regression were applied to find the PSRSs. Furthermore, PSRSs, 318 TFs obtained from Cistrome database and 50 hallmark pathways quantified by GSVA were integrated into co-expression analysis. Significant co-expression patterns were used to construct the bone metastasis-specific regulation network. Finally, spatial single-cell RNA-seq and chromatin immunoprecipitation sequence (ChIP-seq) data and multi-omics databases were applied to validate the key scientific hypothesis in the regulation network. Additionally, Connectivity Map (CMap) was utilized to select the potential inhibitors of bone metastasis-specific regulation network in BRCA.

Results: Based on edgeR and WGCNA method, 43 PSRSs were identified. In the bone metastasis-specific regulation network, MAF positively regulated CD248 (R = 0.435, P < 0.001), and hallmark apical junction was the potential pathway of CD248 (R = 0.353, P < 0.001). This regulatory pattern was supported by spatial single-cell RNA sequence, ChIP-seq data and multi-omics online databases. Additionally, alexidine was identified as the possible inhibitor for bone metastasis of BRCA by CMap analysis.

Conclusion: PSRSs played important roles in bone metastasis of BRCA, and the prognostic model based on PSRSs showed good performance. Especially, we proposed that CD248 was the most significant PSRS, which was positively regulated by MAF, influenced bone metastasis apical junction pathway. And this axis might be inhibited by alexidine, which providing a potential treatment strategy for bone metastasis of BRCA.
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http://dx.doi.org/10.3389/fonc.2020.613333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875018PMC
January 2021

Convex-Meniscus-Assisted Self-Assembly at the Air/Water Interface to Prepare a Wafer-Scale Colloidal Monolayer Without Overlap.

Langmuir 2021 Jan 23;37(1):249-256. Epub 2020 Dec 23.

R&D Center of Healthcare Electronics, Institute of Microelectronics, Chinese Academy of Sciences, Beijing 100029, China.

Self-assembly at the air/water interface (AWI) has proven to be an efficient strategy for fabricating two-dimensional (2D) colloidal monolayers, which was widely used as the template for nanosphere lithography in nanophononics, optofluidics, and solar cell studies. However, the monolayers fabricated at the AWI usually suffer from a small domain area and quasi-double layer structure caused by submerged particles. To overcome this, we proposed an improved protocol to prepare 2D colloidal monolayers free of overlapping nanospheres at the AWI. Utilizing the stable suspension infusion to the water surface, a convex meniscus, whose height is related to viscous force, was formed adjoining the three-phase boundary. As a result of the resistance of the convex meniscus, the polystyrene nanospheres in the initial suspension directly self-assembled into a preliminary monolayer, which proved effective in preventing nanospheres' sinking and increasing the colloidal crystal domain size. An optimal parameter for transferring the monolayer was also developed based on the numerical simulation results. Finally, a wafer-scale monolayer, covered with less than one nanosphere per 100 μm × 100 μm area, was achieved on the desired substrate with an average domain size attaining centimeter scale. The high-quality 2D colloidal crystal may further promote the application of nanosphere lithography, especially in the fields that require a defect-free template.
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http://dx.doi.org/10.1021/acs.langmuir.0c02851DOI Listing
January 2021

Classification of Progression Patterns in Glioblastoma: Analysis of Predictive Factors and Clinical Implications.

Front Oncol 2020 3;10:590648. Epub 2020 Nov 3.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: This study was designed to explore the progression patterns of IDH-wildtype glioblastoma (GBM) at first recurrence after chemoradiotherapy.

Methods: Records from 247 patients who underwent progression after diagnosis of IDH-wildtype GBM was retrospectively reviewed. Progression patterns were classified as either local, distant, subependymal or leptomeningeal dissemination based on the preoperative and serial postoperative radiographic images. The clinical and molecular characteristics of different progression patterns were analyzed.

Results: A total of 186 (75.3%) patients had local progression, 15 (6.1%) patients had distant progression, 33 (13.3%) patients had subependymal dissemination, and 13 (5.3%) patients had leptomeningeal dissemination. The most favorable survival occurred in patients with local progression, while no significant difference of survival was found among patients with distant progression, subependymal or leptomeningeal dissemination who were thereby reclassified into non-local group. Multivariable analysis showed that chemotherapy was a protective factor for non-local progression, while gender of male, subventricular zone (SVZ) involvement and O-methylguanine-DNA-methyltransferase (MGMT) promoter methylation were confirmed as risk factors for non-local progression ( < 0.05). Based on the factors screened by multivariable analysis, a nomogram was constructed which conferred high accuracy in predicting non-local progression. Patients in non-local group could be divided into long- and short-term survivors who differed in the rates of SVZ involvement, MGMT promoter methylation and reirradiation ( < 0.05), and a nomogram integrating these factors showed high accuracy in predicting long-term survivors.

Conclusion: Patients harboring different progression patterns conferred distinct clinical and molecular characteristics. Our nomograms could provide theoretical references for physicians to make more personalized and precise treatment decisions.
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http://dx.doi.org/10.3389/fonc.2020.590648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673412PMC
November 2020

Benchtop Preparation of Polymer Brushes by SI-PET-RAFT: The Effect of the Polymer Composition and Structure on Inhibition of a Biofilm.

ACS Appl Mater Interfaces 2020 Dec 24;12(49):55243-55254. Epub 2020 Nov 24.

Centre for Advanced Macromolecular Design and Australian Centre for NanoMedicine, School of Chemical Engineering, The University of New South Wales, Sydney, New South Wales 2052 Australia.

We report a high-throughput method for producing surface-tethered polymeric brushes on glass substrates via surface-initiated photoinduced electron transfer-reversible addition-fragmentation chain transfer polymerization (SI-PET-RAFT). Due to its excellent oxygen tolerance, SI-PET-RAFT allows brush growth using low reagent volumes (30 μL) without prior degassing. An initial 28 homopolymer brush library was successfully prepared and screened with respect to their antifouling performance. The high-throughput approach was further exploited to expand the library to encompass statistical, gradient, and block architectures to investigate the effect of monomer composition and distribution using two monomers of disparate performance. In this manner, the degree of attachment from Gram-negative (PA) bacterial biofilms could be tuned between the bounds set by the homopolymer brushes.
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http://dx.doi.org/10.1021/acsami.0c15221DOI Listing
December 2020

Multiscale dynamic human mobility flow dataset in the U.S. during the COVID-19 epidemic.

Sci Data 2020 11 12;7(1):390. Epub 2020 Nov 12.

GeoDS Lab, Department of Geography, University of Wisconsin-Madison, Madison, WI, 53706, United States.

Understanding dynamic human mobility changes and spatial interaction patterns at different geographic scales is crucial for assessing the impacts of non-pharmaceutical interventions (such as stay-at-home orders) during the COVID-19 pandemic. In this data descriptor, we introduce a regularly-updated multiscale dynamic human mobility flow dataset across the United States, with data starting from March 1st, 2020. By analysing millions of anonymous mobile phone users' visits to various places provided by SafeGraph, the daily and weekly dynamic origin-to-destination (O-D) population flows are computed, aggregated, and inferred at three geographic scales: census tract, county, and state. There is high correlation between our mobility flow dataset and openly available data sources, which shows the reliability of the produced data. Such a high spatiotemporal resolution human mobility flow dataset at different geographic scales over time may help monitor epidemic spreading dynamics, inform public health policy, and deepen our understanding of human behaviour changes under the unprecedented public health crisis. This up-to-date O-D flow open data can support many other social sensing and transportation applications.
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http://dx.doi.org/10.1038/s41597-020-00734-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661515PMC
November 2020

Characterization of hydrogen production and microbial community shifts in microbial electrolysis cells with L-cysteine.

Sci Total Environ 2021 Mar 29;760:143353. Epub 2020 Oct 29.

State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.

L-cysteine is used to improve efficiency in anaerobic biological systems as an oxygen scavenger, electron shuttle and substrate source. The performance of MEC by addition of L-cysteine was investigated during start-up and operation phases, respectively. Results showed that the maximum current density of 6.36 ± 0.14 A/m, hydrogen yield of 1.08 ± 0.05 m/m and energy efficiency of 130% were achieved with L-cysteine adding during operation phase. By contrast, the addition of L-cysteine during the start-up phase reduced the energy efficiency by more than 30%. The microbial community analysis revealed that a higher microbial community richness and diversity were achieved, the enrichment of Sulfuricurvum, Sulfurospirillum, Desulfovibrio and other electroactive microorganisms indicated their relative abundance could be regulated by L-cysteine during start-up phase when L-cysteine was added. This study provided an alternative method to enhanced hydrogen production and a better understanding of the mechanism of L-cysteine action in MEC performance.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143353DOI Listing
March 2021

The Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Pan-Cancer.

PPAR Res 2020 22;2020:6527564. Epub 2020 Sep 22.

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, China.

Peroxisome proliferator-activated receptors (PPARs) are members of nuclear transcription factors. The functions of the PPAR family (PPARA, PPARD, and PPARG) and their coactivators (PPARGC1A and PPARGC1B) in maintenance of lipid and glucose homeostasis have been unveiled. However, the roles of PPARs in cancer development remain elusive. In this work, we made use of 11,057 samples across 33 TCGA tumor types to analyze the relationship between PPAR transcriptional expression and tumorigenesis as well as drug sensitivity. We performed multidimensional analyses on PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B, including differential expression analysis in pan-cancer, immune subtype analysis, clinical analysis, tumor purity analysis, stemness correlation analysis, and drug responses. PPARs and their coactivators expressed differently in different types of cancers, in different immune subtypes. This analysis reveals various expression patterns of the PPAR family at a level of pan-cancer and provides new clues for the therapeutic strategies of cancer.
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http://dx.doi.org/10.1155/2020/6527564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528029PMC
September 2020

Single-Cell Electroporation with Real-Time Impedance Assessment Using a Constriction Microchannel.

Micromachines (Basel) 2020 Sep 16;11(9). Epub 2020 Sep 16.

R&D Center of Healthcare Electronics, Institute of Microelectronics, Chinese Academy of Sciences, Beijing 100029, China.

The electroporation system can serve as a tool for the intracellular delivery of foreign cargos. However, this technique is presently limited by the inaccurate electric field applied to the single cells and lack of a real-time electroporation metrics subsystem. Here, we reported a microfluidic system for precise and rapid single-cell electroporation and simultaneous impedance monitoring in a constriction microchannel. When single cells (A549) were continuously passing through the constriction microchannel, a localized high electric field was applied on the cell membrane, which resulted in highly efficient (up to 96.6%) electroporation. During a single cell entering the constriction channel, an abrupt impedance drop was noticed and demonstrated to be correlated with the occurrence of electroporation. Besides, while the cell was moving in the constriction channel, the stabilized impedance showed the capability to quantify the electroporation extent. The correspondence of the impedance variation and electroporation was validated by the intracellular delivery of the fluorescence indicator (propidium iodide). Based on the obtained results, this system is capable of precise control of electroporation and real-time, label-free impedance assessment, providing a potential tool for intracellular delivery and other biomedical applications.
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http://dx.doi.org/10.3390/mi11090856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570009PMC
September 2020

Lithium niobate photonic-crystal electro-optic modulator.

Nat Commun 2020 Aug 17;11(1):4123. Epub 2020 Aug 17.

Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, 14627, USA.

Modern advanced photonic integrated circuits require dense integration of high-speed electro-optic functional elements on a compact chip that consumes only moderate power. Energy efficiency, operation speed, and device dimension are thus crucial metrics underlying almost all current developments of photonic signal processing units. Recently, thin-film lithium niobate (LN) emerges as a promising platform for photonic integrated circuits. Here, we make an important step towards miniaturizing functional components on this platform, reporting high-speed LN electro-optic modulators, based upon photonic crystal nanobeam resonators. The devices exhibit a significant tuning efficiency up to 1.98 GHz V, a broad modulation bandwidth of 17.5 GHz, while with a tiny electro-optic modal volume of only 0.58 μm. The modulators enable efficient electro-optic driving of high-Q photonic cavity modes in both adiabatic and non-adiabatic regimes, and allow us to achieve electro-optic switching at 11 Gb s with a bit-switching energy as low as 22 fJ. The demonstration of energy efficient and high-speed electro-optic modulation at the wavelength scale paves a crucial foundation for realizing large-scale LN photonic integrated circuits that are of immense importance for broad applications in data communication, microwave photonics, and quantum photonics.
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http://dx.doi.org/10.1038/s41467-020-17950-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431411PMC
August 2020

Comparison of Long-Term Stability of Initiating Monolayers in Surface-Initiated Controlled Radical Polymerizations.

Macromol Rapid Commun 2020 Sep 6;41(17):e2000337. Epub 2020 Aug 6.

Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA.

The reproducibility of polymer brush synthesis via surface-initiated controlled radical polymerization is interrogated. Experiments compare the stability of initiating monolayers for surface-initiated (SI) reversible addition-fragmentation chain transfer polymerization (SI-RAFT) and SI atom transfer radical polymerization (SI-ATRP). Initiator-functionalized substrates are stored under various conditions and grafting densities of the resulting polymer brush films are determined via in situ ellipsometry. Decomposition of one of the examined SI-RAFT initiators results in limited reproducibility for polymer brush surface modification. In contrast, initiators for SI-ATRP show excellent stability and reproducibility. While both techniques bring inherent benefits and limitations, the described findings will help scientists choose the most efficient technique for their goals in chemical and topographical surface modification.
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http://dx.doi.org/10.1002/marc.202000337DOI Listing
September 2020

Athermal lithium niobate microresonator.

Opt Express 2020 Jul;28(15):21682-21691

Lithium niobate (LN), possessing wide transparent window, strong electro-optic effect, and large optical nonlinearity, is an ideal material platform for integrated photonics application. Microring resonators are particularly suitable as integrated photonic components, given their flexibility of device engineering and their potential for large-scale integration. However, the susceptibility to temperature fluctuation has become a major challenge for their implementation in a practical environment. Here, we demonstrate an athermal LN microring resonator. By cladding an x-cut LN microring resonator with a thin layer of titanium oxide, we are able to completely eliminate the first-order thermo-optic coefficient (TOC) of cavity resonance right at room temperature (20C), leaving only a small residual quadratic temperature dependence with a second-order TOC of only 0.37 pm/K. It corresponds to a temperature-induced resonance wavelength shift within 0.33 nm over a large operating temperature range of (-10 - 50)C that is one order of magnitude smaller than a bare LN microring resonator. Moreover, the TiO-cladded LN microring resonator is able to preserve high optical quality, with an intrinsic optical Q of 5.8 × 10 that is only about 11% smaller than that of a bare LN resonator. The flexibility of thermo-optic engineering, high optical quality, and device fabrication compatibility show great promise of athermal LN/TiO hybrid devices for practical applications, elevating the potential importance of LN photonic integrated circuits for future communication, sensing, nonlinear and quantum photonics.
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http://dx.doi.org/10.1364/OE.398363DOI Listing
July 2020

Surface Engineering with Polymer Brush Photolithography.

Macromol Rapid Commun 2020 Sep 19;41(18):e2000177. Epub 2020 Jul 19.

Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA.

Surface-tethered macromolecules, or polymer brushes, offer a unique platform for coating surfaces for a wide variety of applications. Surface-initiated polymerization (SI-P), through which polymer brushes can be grown directly from an initiator-functionalized surface, offers a facile, highly customizable approach that is synergistic with photolithography. Using a variety of photolithography devices and SI-Ps, complex polymer brush architectures can be fabricated with great spatial and temporal control. This article not only addresses techniques, advancements, applications, and possible future directions within the field of polymer brush photolithography, but it also provides resources to assist the reader in selecting the polymerization technique and photolithography device most conducive to a given endeavor.
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http://dx.doi.org/10.1002/marc.202000177DOI Listing
September 2020

Shallow-etched thin-film lithium niobate waveguides for highly-efficient second-harmonic generation.

Opt Express 2020 Jun;28(13):19669-19682

High-fidelity periodic poling over long lengths is required for robust, quasi-phase-matched second-harmonic generation using the fundamental, quasi-TE polarized waveguide modes in a thin-film lithium niobate (TFLN) waveguide. Here, a shallow-etched ridge waveguide is fabricated in x-cut magnesium oxide doped TFLN and is poled accurately over 5 mm. The high fidelity of the poling is demonstrated over long lengths using a non-destructive technique of confocal scanning second-harmonic microscopy. We report a second-harmonic conversion efficiency of up to 939 %.W (length-normalized conversion efficiency 3757 %.W.cm), measured at telecommunications wavelengths. The device demonstrates a narrow spectral linewidth (1 nm) and can be tuned precisely with a tuning characteristic of 0.1 nm/°C, over at least 40 °C without measurable loss of efficiency.
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http://dx.doi.org/10.1364/OE.395545DOI Listing
June 2020

Mixed Polymer Brushes for "Smart" Surfaces.

Polymers (Basel) 2020 Jul 13;12(7). Epub 2020 Jul 13.

Department of Chemical Engineering, The Pennsylvania State University, University Park, PA 16802, USA.

Mixed polymer brushes (MPBs) are composed of two or more disparate polymers covalently tethered to a substrate. The resulting phase segregated morphologies have been extensively studied as responsive "smart" materials, as they can be reversible tuned and switched by external stimuli. Both computational and experimental work has attempted to establish an understanding of the resulting nanostructures that vary as a function of many factors. This contribution highlights state-of-the-art MPBs studies, covering synthetic approaches, phase behavior, responsiveness to external stimuli as well as novel applications of MPBs. Current limitations are recognized and possible directions for future studies are identified.
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http://dx.doi.org/10.3390/polym12071553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408536PMC
July 2020

Microfluidic devices for neutrophil chemotaxis studies.

J Transl Med 2020 04 15;18(1):168. Epub 2020 Apr 15.

Institute of Microelectronics, Chinese Academy of Sciences, 3 Beitucheng West Road, Beijing, 100029, China.

Neutrophil chemotaxis plays a vital role in human immune system. Compared with traditional cell migration assays, the emergence of microfluidics provides a new research platform of cell chemotaxis study due to the advantages of visualization, precise control of chemical gradient, and small consumption of reagents. A series of microfluidic devices have been fabricated to study the behavior of neutrophils exposed on controlled, stable, and complex profiles of chemical concentration gradients. In addition, microfluidic technology offers a promising way to integrate the other functions, such as cell culture, separation and analysis into a single chip. Therefore, an overview of recent developments in microfluidic-based neutrophil chemotaxis studies is presented. Meanwhile, the strength and drawbacks of these devices are compared.
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http://dx.doi.org/10.1186/s12967-020-02335-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158383PMC
April 2020

Wafer-level fabrication of 3D nanoparticles assembled nanopillars and click chemistry modification for sensitive SERS detection of trace carbonyl compounds.

Nanotechnology 2020 Apr 24;31(26):265301. Epub 2020 Mar 24.

Institute of Microelectronics, Chinese Academy of Sciences, Beijing, People's Republic of China. School of Future Technology, University of Chinese Academy of Sciences, Beijing, People's Republic of China.

In this work, we develop a new method for fabricating wafer-level gold nanoparticles covered silicon nanopillars (SNPs) combined with surface chemical modification to detect trace level carbonyl compounds based on surface-enhanced Raman scattering (SERS) technique. The SNPs are fabricated with an etching process using nano masks synthesized in oxygen-plasma bombardment of photoresist, and further deposited with gold nanoparticles on the surface, thus forming a 3D 'particles on pillars' nanostructure for sensitive SERS detection. The enhancement factor (EF) of the devices for R6G detection can achieve 1.56 × 10 times compared with a flat Si substrate. We also developed an oximation click chemistry reaction procedure by chemically modifying the nanostructures with aminooxy dodecane thiol (ADT) self-assemble modification. The chip is further integrated with a polydimethylsiloxane (PDMS) microfluidic chamber, which allows fast and convenient detection of trace carbonyl compounds in liquid samples. The SERS detection capability was demonstrated by the dropwise addition of fluorescent carbonyl compounds before and after elution. Furthermore, the device was proved with high surface consistency(<70%) for repeated measurement, which has the potential for ppb(parts per billion) level concentration of carbonyl compounds detection.
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http://dx.doi.org/10.1088/1361-6528/ab82d5DOI Listing
April 2020

Dynamic Estimation of Individual Exposure Levels to Air Pollution Using Trajectories Reconstructed from Mobile Phone Data.

Int J Environ Res Public Health 2019 11 15;16(22). Epub 2019 Nov 15.

State Key Laboratory of Resources and Environmental Information System, Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences, Beijing 100101, China.

The spatiotemporal variability in air pollutant concentrations raises challenges in linking air pollution exposure to individual health outcomes. Thus, understanding the spatiotemporal patterns of human mobility plays an important role in air pollution epidemiology and health studies. With the advantages of massive users, wide spatial coverage and passive acquisition capability, mobile phone data have become an emerging data source for compiling exposure estimates. However, compared with air pollution monitoring data, the temporal granularity of mobile phone data is not high enough, which limits the performance of individual exposure estimation. To mitigate this problem, we present a novel method of estimating dynamic individual air pollution exposure levels using trajectories reconstructed from mobile phone data. Using the city of Shanghai as a case study, we compared three different types of exposure estimates using (1) reconstructed mobile phone trajectories, (2) recorded mobile phone trajectories, and (3) residential locations. The results demonstrate the necessity of trajectory reconstruction in exposure and health risk assessment. Additionally, we measure the potential health effects of air pollution from both individual and geographical perspectives. This helped reveal the temporal variations in individual exposures and the spatial distribution of residential areas with high exposure levels. The proposed method allows us to perform large-area and long-term exposure estimations for a large number of residents at a high spatiotemporal resolution, which helps support policy-driven environmental actions and reduce potential health risks.
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http://dx.doi.org/10.3390/ijerph16224522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888556PMC
November 2019

Diffuse midline glioma with H3 K27M mutation: a comparison integrating the clinical, radiological, and molecular features between adult and pediatric patients.

Neuro Oncol 2020 05;22(5):e1-e9

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background: Diffuse midline glioma (DMG), H3 K27M mutant, occurs in both adult and pediatric populations. The characteristics of the 2 DMG groups were systematically explored in this study.

Methods: H3 K27M-mutant DMG was diagnosed in 116 patients at Beijing Tiantan Hospital from May 2016 to December 2018 who were included in our study. Patients were classified into an adult group (n = 57; 49.1%) and a pediatric group (n = 59; 50.9%). Clinical, radiological, and molecular features were compared between the groups. Univariate and multivariate analyses were performed to identify prognostic factors.

Results: Compared with the adult group, pediatric patients had a younger age (8.9 ± 4.1 y vs 35.1 ± 11.8 y, P < 0.001), a lower preoperative Karnofsky performance scale score (62.9 ± 15.5 vs 72.1 ± 16.5, P = 0.004), a lower rate of total resection (5.7% vs 26.8%, P = 0.009), a larger tumor size (4.4 ± 0.9 vs 3.9 ± 1.5 cm, P = 0.045), a higher Ki-67 index (63.0% vs 37.8%, P = 0.047), and higher rates of postoperative cranial nerve palsy (61.0% vs 36.8%, P = 0.009) and ataxia (45.8% vs 26.3%, P = 0.029). Adult DMG was located predominantly in the thalamus, while the predilection site for pediatric DMG was brainstem (P < 0.001). Kaplan-Meier plot showed that the median survival of adult and pediatric DMG was 16.0 (9.7-22.3) months and 10.0 (8.3-11.7) months, respectively, which imparted a significant difference (P = 0.008). Age at diagnosis, radiotherapy, and motor deficit were confirmed as independent prognostic factors according to the multivariate analysis (P < 0.05).

Conclusion: Compared with adult patients, children with H3 K27M-mutant DMG confer distinct clinical, radiological, and molecular characteristics and have a dismal prognosis. Radiotherapy is an independent factor associated with prolonged survival.
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http://dx.doi.org/10.1093/neuonc/noz152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962140PMC
May 2020

Super-early initiation of temozolomide prolongs the survival of glioblastoma patients without gross-total resection: a retrospective cohort study.

J Neurooncol 2019 Aug 7;144(1):127-135. Epub 2019 Jun 7.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Brain Tumor, #119 Fanyang Road, Fengtai District, Beijing, 100070, China.

Objective: The optimal timing of chemoradiotherapy in patients with newly diagnosed glioblastoma (GBM) remains unclear. In this study, we explored the clinical efficacy of super-early initiation of temozolomide (TMZ) in the treatment interval from surgery to radiotherapy.

Methods: We retrospectively reviewed the clinical data of 375 patients with GBM in our institution from 2012 to 2018. One hundred and sixty-three patients received super-early TMZ within 7 days after craniotomy based on standard Stupp protocol (super-early group, SEG), while two hundred and twelve patients underwent standard Stupp protocol alone (control group, CG). We performed propensity score matching (PSM) to reduce patient selection bias between the two groups.

Results: Before PSM, both median progression-free survival (PFS) and overall survival (OS) of patients in SEG were longer than those in CG (PFS 11.5 vs. 9.0 months, P = 0.0384 and OS 23.0 vs. 17.0 months, P = 0.0014). After PSM, the clinical efficacy of super-early initiation of TMZ only remained significant in term of OS, which was further validated in Cox hazard proportional model (HR = 0.583, 95% CI 0.384-0.884, P = 0.011). In the subgroup analysis, patients without gross total resection (GTR) or with O-methylguanine DNA methyltransferase promoter methylation could benefit from super-early initiation of TMZ in both PFS and OS (P < 0.05). No significant difference of treatment emerging adverse events was observed between the two groups (P > 0.05).

Conclusions: This retrospective study highlights that super-early initiation of TMZ in newly diagnosed GBM may confer to survival benefit, especially for those without GTR.
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http://dx.doi.org/10.1007/s11060-019-03211-1DOI Listing
August 2019

Prognostic implications of epidermal growth factor receptor variant III expression and nuclear translocation in Chinese human gliomas.

Chin J Cancer Res 2019 Feb;31(1):188-202

Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.

Objective: To determine the prognostic implications and clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression and EGFRvIII nuclear translocation in Chinese human gliomas.

Methods: We retrospectively examined EGFRvIII expression and EGFRvIII nuclear translocation using immunohistochemistry in specimens of 240 Chinese patients with glioma, including 84 World Health Organization (WHO) II gliomas, 84 WHO III gliomas and 72 glioblastomas (WHO IV). Factors that correlated with EGFRvIII and EGFRvIII nuclear translocation expression were analyzed by the Chi-square test. Kaplan-Meier methodology and Cox regression were used for the survival analysis.

Results: Log-rank tests showed that patient age, Karnofsky performance scale (KPS) score, tumor grade, EGFRvIII expression, EGFRvIII nuclear translocation, 1p/19q codeletion, isocitrate dehydrogenase (IDH) mutation, Ki-67 labeling index and O6-methylguanine-DNA methyltransferase (MGMT) status (P<0.05) were significantly correlated with overall survival (OS) time. Multivariate Cox regression analysis revealed that patient age, tumor grade, EGFRvIII nuclear translocation, 1p/19q codeletion, and IDH mutation (P<0.05) were significantly correlated with OS. Patients with a high level of EGFRvIII nuclear translocation (≥7%) had both significantly shorter OS [hazard ratio (HR): 1.920, 95% confidence interval (95% CI): 1.228-3.003, P=0.004] and progression-free survival (PFS) times (HR: 1.661, 95% CI: 1.116-2.471, P=0.012) than those with a low level of EGFRvIII nuclear translocation (<7%).

Conclusions: A high level of EGFRvIII nuclear translocation in glioma is an independent factor indicating a poor prognosis, but EGFRvIII expression is not an independent clinical prognostic factor. The level of EGFRvIII nuclear translocation maybe a novel and crucial prognostic biomarker in glioma.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2019.01.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433583PMC
February 2019

Proliferation-dominant high-grade astrocytoma: survival benefit associated with extensive resection of FLAIR abnormality region.

J Neurosurg 2019 Mar 22;132(4):998-1005. Epub 2019 Mar 22.

1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, and China National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China; and.

Objective: The aim of this study was to investigate the relationship between extent of resection (EOR) and survival in terms of clinical, molecular, and radiological factors in high-grade astrocytoma (HGA).

Methods: Clinical and radiological data from 585 cases of molecularly defined HGA were reviewed. In each case, the EOR was evaluated twice: once according to contrast-enhanced T1-weighted images (CE-T1WI) and once according to fluid attenuated inversion recovery (FLAIR) images. The ratio of the volume of the region of abnormality in CE-T1WI to that in FLAIR images (VFLAIR/VCE-T1WI) was calculated and a receiver operating characteristic curve was used to determine the optimal cutoff value for that ratio. Univariate and multivariate analyses were performed to identify the prognostic value of each factor.

Results: Both the EOR evaluated from CE-T1WI and the EOR evaluated from FLAIR could divide the whole cohort into 4 subgroups with different survival outcomes (p < 0.001). Cases were stratified into 2 subtypes based on VFLAIR/VCE-T1WI with a cutoff of 10: a proliferation-dominant subtype and a diffusion-dominant subtype. Kaplan-Meier analysis showed a significant survival advantage for the proliferation-dominant subtype (p < 0.0001). The prognostic implication has been further confirmed in the Cox proportional hazards model (HR 1.105, 95% CI 1.078-1.134, p < 0.0001). The survival of patients with proliferation-dominant HGA was significantly prolonged in association with extensive resection of the FLAIR abnormality region beyond contrast-enhancing tumor (p = 0.03), while no survival benefit was observed in association with the extensive resection in the diffusion-dominant subtype (p = 0.86).

Conclusions: VFLAIR/VCE-T1WI is an important classifier that could divide the HGA into 2 subtypes with distinct invasive features. Patients with proliferation-dominant HGA can benefit from extensive resection of the FLAIR abnormality region, which provides the theoretical basis for a personalized resection strategy.
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http://dx.doi.org/10.3171/2018.12.JNS182775DOI Listing
March 2019

Supratentorial high-grade astrocytoma with leptomeningeal spread to the fourth ventricle: a lethal dissemination with dismal prognosis.

J Neurooncol 2019 Apr 2;142(2):253-261. Epub 2019 Jan 2.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Purpose: Leptomeningeal spread to the fourth ventricle (LSFV) from supratentorial high-grade astrocytoma (HGA) is rarely investigated. The incidence and prognostic merit of LSFV were analyzed in this study.

Methods: A consecutive cohort of 175 patients with pathologically diagnosed HGA according to the 2016 WHO classification of brain tumors was enrolled. LSFV was defined as radiological occupation in the fourth ventricle at the moment of initial progression. Clinical, radiological, and pathological data were analyzed to explore the difference between HGA patients with and without LSFV.

Results: There were 18 of 175 (10.3%) HGAs confirmed with LSFV. The difference of survival rate between patients with LSFV or not was significant in both overall survival (OS) (14.5 vs. 24 months, P =  0.0007) and post progression survival (PPS) (6.0 vs. 11.5 months, P = 0.0004), while no significant difference was observed in time to progression (TTP) (8.5 months vs. 9.5 months P = 0.6795). In the Cox multivariate analysis, LSFV was confirmed as an independent prognostic risk factor for OS (HR 2.06, P = 0.010). LSFV was correlated with younger age (P = 0.044), ventricle infringement of primary tumor (P < 0.001) and higher Ki-67 index (P = 0.013) in further analysis, and the latter two have been validated in the Logistic regression analysis (OR 18.16, P = 0.006; OR 4.04, P = 0.012, respectively).

Conclusion: LSFV was indicative of end-stage for supratentorial HGA patients, which shortened patients' PPS and OS instead of TTP. It's never too cautious to alert this lethal event when tumor harbored ventricle infringement and higher Ki-67 index in routine clinical course.
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http://dx.doi.org/10.1007/s11060-018-03086-8DOI Listing
April 2019
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