Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients.

Since 2005, the standard of care for patients with newly diagnosed glioblastoma (GBM) has consisted of maximal resection followed by radiotherapy plus daily temozolomide (TMZ), followed by maintenance TMZ. In patients selected for clinical trials, median overall survival (OS) and progression-free survival (PFS) with this regimen is 15-17 months and 6-7 months, respectively. There have been various, largely unsuccessful attempts to improve on this standard of care. With the FDA approval of the tumor-treating fields (TTFields) device, Optune, for recurrent GBM (2011), and the more recent EF-14 interim trial results and approval for newly diagnosed GBM patients, several questions have arisen. A roundtable of experts was convened at the 2015 ASCO meeting to engage in an open conversation and debate of the EF-14 results presented at that meeting and their implications for neuro-oncology practice and clinical research. In October 2015, subsequent to the roundtable discussion, TTFields received FDA approval for newly diagnosed GBM.

Validation of the distress and impact thermometer and the changes of mood during the first 6 months of treatment in gynecological cancer patients: a Kansai Clinical Oncology Group (KCOG)-G1103 prospective study.

PURPOSE: To verify distress and impact thermometer (DIT) for screening emotional distress in gynecological cancer patients by Hospital Anxiety and Depression Scale total (HADS-T) as gold standard and to assess emotional changes by DIT and HADS-T. METHODS: A prospective study was conducted in newly diagnosed gynecological cancer patients during the peri-treatment period after the cancer diagnosis followed by 6-month. We defined a HADS-T score of ≥11 as being indicative of emotional distress. RESULTS: 117 patients were enrolled between May 1, 2011 and March 31, 2012, and 95 were eligible. The median age was 54 years (range 31-77). (1) From the baseline to 3-month, distress (DIT-D) ≥4 with Impact (DIT-I) ≥2 exhibited sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of 0.776 [95 % confidential interval (CI) 0.688, 0.850], 0.889 (95 % CI 0.824, 0.954), 0.868 (95 % CI 0.792, 0.949), and 0.808 (95 % CI 0.731, 0.886), respectively. (2) At 6-month, DIT-D ≥2 with DIT-I ≥1 exhibited sensitivity, specificity, PPV and NPV of 0.893 (95 % CI 0.778, 1), 0.825 (95 % CI 0.707, 0.942), 0.781 (95 % CI 0.638, 0.928), and 0.917 (95 % CI 0.826, 1). (3) At 6-month, the HADS-T, DIT-D, and DIT-I scores in individual patients were significantly reduced by a mean of 4.57 (p < 0.0001), 2.34 (p < 0.0001), and 1.10 (p = 0.0031), respectively, compared with those scores of baseline (Student's paired t test), but still remained high. CONCLUSIONS: (1) On acute phase within 3-month setting, DIT; DIT-D ≥4 with DIT-I ≥2, is a reliable cut-off to screen emotional distress among gynecological cancer patients. (2) The patients' moods had improved, but not completely recovered at 6-month after the diagnosis.

Therapeutic drug monitoring of patients with psoriasis during tumour necrosis factor (TNF)-α antagonist treatment using a novel interleukin-8 reporter cell line.

BACKGROUND: Tumour necrosis factor (TNF)-α antagonist therapy is currently used for moderate and severe psoriasis. However, this treatment has several drawbacks, including interindividual variability in clinical response and secondary loss of effectiveness. OBJECTIVES: To evaluate quantitatively the TNF-α-neutralizing activity of the plasma of patients with psoriasis during TNF-α antagonist therapy and to determine poor responders objectively. METHODS: We used a human interleukin-8 reporter monocyte cell line, THP-G8, that harbours a stable luciferase orange (SLO) gene under the control of the interleukin-8 promoter. After confirming its dose-dependent response to exogenous TNF-α, we examined the suppressive activity of TNF-α antagonists and of the patients' plasma during TNF-α antagonist therapy on TNF-α-induced SLO luciferase activity (TNF-SLO-LA). RESULTS: Pretreatment of TNF-α with TNF-α antagonists or with the plasma of patients with psoriasis who achieved 75% improvement in Psoriasis Area and Severity Index (PASI 75) dose dependently suppressed TNF-SLO-LA. There was a significant correlation between change in PASI and percentage suppression (inhibitory rate of a 1 : 2 dilution of patient plasma on TNF-SLO-LA). A percentage suppression of 50·3% has a positive predictive value of 87% of achieving PASI 75, with a sensitivity of 93% and a specificity of 80%. CONCLUSIONS: Therapeutic monitoring of patients with psoriasis during TNF-α antagonist therapy using THP-G8 can provide a useful tool to determine objectively the efficacy of the administered TNF-α antagonists.

Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer.

BACKGROUND: Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA (miR)-451a, miR-144-3p, and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells. METHODS: The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan-Meier method. RESULTS: Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes (CCNE1, CCNE2, CDC25A, and PKMYT1) were identified as direct targets of miR-144-5p. The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression (P=0.025 and P=0.032). CONCLUSION: miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR-144-5p and might be good prognostic markers for survival of BC patients.

MicroRNA expression signature of oral squamous cell carcinoma: functional role of microRNA-26a/b in the modulation of novel cancer pathways.

BACKGROUND: MicroRNAs (miRNAs) have been shown to play major roles in carcinogenesis in a variety of cancers. The aim of this study was to determine the miRNA expression signature of oral squamous cell carcinoma (OSCC) and to investigate the functional roles of miR-26a and miR-26b in OSCC cells. METHODS: An OSCC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were performed to investigate cell proliferation, migration, and invasion in OSCC cells. In silico database and genome-wide gene expression analyses were performed to identify molecular targets and pathways mediated by miR-26a/b. RESULTS: miR-26a and miR-26b were significantly downregulated in OSCC. Restoration of both miR-26a and miR-26b in cancer cell lines revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Our data demonstrated that the novel transmembrane TMEM184B gene was a direct target of miR-26a/b regulation. Silencing of TMEM184B inhibited cancer cell migration and invasion, and regulated the actin cytoskeleton-pathway related genes. CONCLUSIONS: Loss of tumour-suppressive miR-26a/b enhanced cancer cell migration and invasion in OSCC through direct regulation of TMEM184B. Our data describing pathways regulated by tumour-suppressive miR-26a/b provide new insights into the potential mechanisms of OSCC oncogenesis and metastasis.

Using breast radiographers' reports as a second opinion for radiologists' readings of microcalcifications in digital mammography.

OBJECTIVE: The aim of this study was to investigate a practical method for incorporating radiographers' reports with radiologists' readings of digital mammograms. METHODS: This simulation study was conducted using data from a free-response receiver operating characteristic observer study obtained with 75 cases (25 malignant, 25 benign and 25 normal cases) of digital mammograms. Each of the rating scores obtained by six breast radiographers was utilized as a second opinion for four radiologists' readings with the radiographers' reports. A logical "OR" operation with various criteria settings was simulated for deciding an appropriate method to select a radiographer's report in all combinations of radiologists and radiographers. The average figure of merit (FOM) of the radiologists' performances was statistically analysed using a jackknife procedure (JAFROC) to verify the clinical utility of using radiographers' reports. RESULTS: Potential improvement of the average FOM of the radiologists' performances for identifying malignant microcalcifications could be expected when using radiographers' reports as a second opinion. When the threshold value of 2.6 in Breast Imaging-Reporting and Data System (BI-RADS®) assessment was applied to adopt/reject a radiographer's report, FOMs of radiologists' performances were further improved. CONCLUSION: When using breast radiographers' reports as a second opinion, radiologists' performances potentially improved when reading digital mammograms. It could be anticipated that radiologists' performances were improved further by setting a threshold value on the BI-RADS assessment provided by the radiographers. ADVANCES IN KNOWLEDGE: For the effective use of a radiographer's report as a second opinion, radiographers' rating scores and its criteria setting for adoption/rejection would be necessary.

Identification of tumour suppressive microRNA-451a in hypopharyngeal squamous cell carcinoma based on microRNA expression signature.

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HSCC) has a very poor prognosis because of its high rates of regional and distant metastasis. Identification of differentially expressed miRNAs and their regulated molecular targets in tumour cells might enhance our understanding of the molecular mechanisms of metastasis in human cancers. METHODS: A HSCC miRNA signature was constructed by array-based methods. Functional studies of microRNA-451a (miR-451a) and target genes were performed to investigate cell proliferation, migration and invasion by cancer cell lines. To identify miR-451a-regulated molecular targets, we adopted gene expression analysis and in silico database analysis. RESULTS: Our miRNA signature revealed that miR-451a was significantly downregulated in HSCC. Restoration of miR-451a in cancer cell lines revealed that this miRNA significantly inhibited cancer cell migration and invasion. Our data demonstrated that the gene coding for endothelial and smooth muscle cell-derived neuropilin-like molecule (ESDN/DCBLD2) was a direct target of miR-451a regulation. Silencing of ESDN inhibited cell migration and invasion by cancer cells. CONCLUSIONS: Loss of tumour suppressive miR-451a enhanced cancer cell migration and invasion in HSCC through direct regulation of ESDN. Our miRNA signature and functional analysis of targets regulated by tumour suppressive miR-451a provide new insights into the potential mechanisms of HSCC oncogenesis and metastasis.

Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis.

BACKGROUND: Current treatment with biologics has produced dramatic therapeutic effects in patients with psoriasis, although these agents occasionally decrease in efficacy. One of the main factors responsible for this attenuation is attributed to the development of antidrug antibodies (ADAs). OBJECTIVES: To analyse the relationship between serum drug concentrations, the presence of ADAs and treatment efficacy of adalimumab and infliximab, and to determine the optimal use of these biologics. METHODS: This was a 1-year prospective study in the dermatology departments of Kobe University Hospital and collaborating hospitals. All patients starting a regimen of adalimumab and infliximab for psoriasis were included. We measured the serum concentration of the drugs and titres of antibodies to adalimumab and infliximab, as well as the Psoriasis Area and Severity Index scores at weeks 0, 4, 12, 24 and 48 during the first year of treatment. RESULTS: We observed a 50% positive rate of ADAs to adalimumab, and a 41% positive rate of ADAs to infliximab. The titres of ADAs showed a wide range from low to high titres. In the high-titre groups, the patients exhibited a decreased clinical response, and demonstrated a negative correlation between titre and clinical response. However, an equivalent therapeutic effect was observed between the low-titre group and the group with no antibodies detected for adalimumab. For infliximab, the patients with ADAs showed decreased clinical response. An apparent negative correlation between antibody production and reduced clinical response was observed. CONCLUSIONS: Two biologics, adalimumab and infliximab, showed different therapeutic behaviour. The measurement of ADAs and drug concentrations has important implications for treatment with biologics.

Validation of a power-law noise model for simulating small-scale breast tissue.

We have validated a small-scale breast tissue model based on power-law noise. A set of 110 patient images served as truth. The statistical model parameters were determined by matching the radially averaged power-spectrum of the projected simulated tissue with that of the central tomosynthesis patient breast projections. Observer performance in a signal-known exactly detection task in simulated and actual breast backgrounds was compared. Observers included human readers, a pre-whitening observer model and a channelized Hotelling observer model. For all observers, good agreement between performance in the simulated and actual backgrounds was found, both in the tomosynthesis central projections and the reconstructed images. This tissue model can be used for breast x-ray imaging system optimization. The complete statistical description of the model is provided.

Clinical significance of serum growth-regulated oncogene alpha (GROalpha) in patients with gynecological cancer.

PURPOSE OF INVESTIGATION: To assess the clinical relevance of serum growth-regulated oncogene alpha (GROalpha) levels in gynecological cancer, we investigated its concentration in distinguishing patients with cervical cancer, endometrial cancer, ovarian cancer, benign ovarian tumor and control. METHODS: Preoperative serum GROalpha levels were measured in women with cervical cancer (n=46), endometrial cancer (n=39), ovarian cancer (n=124), benign ovarian tumors (n=52), and normal controls (n=38) using an enzyme-linked immunosorbent assay. RESULTS: Statistical analyses showed that the serum GROalpha concentration was significantly elevated in the cervical cancer, endometrial cancer and ovarian cancer patients compared with controls. Using GROalpha levels, the receiver operating characteristic (ROC) of cervical cancer (AUC approximately 0.775), endometrial cancer (AUC approximately 0.799), ovarian cancer (AUC approximately 0.749) and benign ovarian tumors (AUC approximately 0.568) vs. controls were identified. CONCLUSION: Our findings suggest that serum GROalpha measurement as a molecular marker might contribute to detection and diagnosis of gynecological cancer.

Automated detection of mass lesions in dedicated breast CT: a preliminary study.

PURPOSE: To develop an automated method to detect breast masses on dedicated breast CT (BCT) volumes and to conduct a preliminary evaluation of its performance. This method can be used in a computer-aided detection (CADe) system for noncontrast enhanced BCT. METHODS: The database included patient images, which were acquired under an IRB-approved protocol. The database in this study consisted of 132 cases. 50 cases contained 58 malignant masses, and 23 cases contained 24 benign masses. 59 cases did not contain any biopsy-proven lesions. Each case consisted of an unenhanced CT volume of a single breast. First, each breast was segmented into adipose and glandular tissues using a fuzzy c-means clustering algorithm. The glandular breast regions were then sampled at a resolution of 2 mm. At each sampling step, a 3.5-cm(3) volume-of-interest was subjected to constrained region segmentation and 17 characteristic features were extracted, yielding 17 corresponding feature volumes. Four features were selected using step-wise feature selection and merged with linear discriminant analysis trained in the task of distinguishing between normal breast glandular regions and masses. Detection performance was measured using free-response receiver operating characteristic analysis (FROC) with leave-one-case-out evaluation. RESULTS: The feature selection stage selected features that characterized the shape and margin strength of the segmented region. CADe sensitivity per case was 84% (std = 4.2%) at 2.6 (std = 0.06) false positives per volume, or 6 × 10(-3) per slice (at an average of 424 slices per volume in this data set). CONCLUSIONS: This preliminary study demonstrates the feasibility of our approach for CADe for BCT.

On the orientation of mammographic structure.

PURPOSE: Burgess et al. have shown that the power-spectral density of mammographic breast tissue P(f) follows a power-law, P(f) = c∕f(ß).(1) Due to the complexity of the breast anatomy, breast phantoms often make use of power-law backgrounds to approximate the irregular texture of breast images. However, the current methodology of estimating power-law coefficients assumes that the breast structure is isotropic. The purpose of this letter is to demonstrate that breast anatomic structure is not isotropic, but in fact has a preferred orientation. Further, we present a formalism to estimate power-law coefficients ß and c while accounting for tissue orientation in mammographic regions-of-interests (ROIs). We then show the effect of structure orientation on ß and c, as well as on the appearance of simulated power-law backgrounds. METHODS: When breast tissue exhibits a preferred orientation, the radial symmetry in the associated power spectrum is broken. The new symmetry was fit by an ellipsoidal model. Ellipse tilt angle and axis ratio were accounted for in the power-law fit. RESULTS: On average, breast structure was found to point toward the nipple: the average orientation in MLO views was 22.5 °, while it was 5 ° for CC views, and the mean orientation for left breasts was negative while it was positive for right breasts. For both power-law magnitude and exponent, the mean difference was statistically significant (<Δß > = -0.096, <Δlog(c) > =-0.192). CONCLUSIONS: A formalism for quantification of breast structure and structure orientation is provided. The difference in power-law coefficient estimates when accounting for orientation was found to be statistically significant. Examples of statistically defined backgrounds indicate that breast structure is mimicked more closely when structure orientation is accounted for.

Task-based assessment of breast tomosynthesis: effect of acquisition parameters and quantum noise.

PURPOSE: Tomosynthesis is a promising modality for breast imaging. The appearance of the tomosynthesis reconstructed image is greatly affected by the choice of acquisition and reconstruction parameters. The purpose of this study was to investigate the limitations of tomosynthesis breast imaging due to scan parameters and quantum noise. Tomosynthesis image quality was assessed based on performance of a mathematical observer model in a signal-known exactly (SKE) detection task. METHODS: SKE detectability (d') was estimated using a prewhitening observer model. Structured breast background was simulated using filtered noise. Detectability was estimated for designer nodules ranging from 0.05 to 0.8 cm in diameter. Tomosynthesis slices were reconstructed using iterative maximum-likelihood expectation-maximization. The tomosynthesis scan angle was varied between 15 degrees and 60 degrees, the number of views between 11 and 41 and the total number of x-ray quanta was infinity, 6 X 10(5), and 6 x 10(4). Detectability in tomosynthesis was compared to that in a single projection. RESULTS: For constant angular sampling distance, increasing the angular scan range increased detectability for all signal sizes. Large-scale signals were little affected by quantum noise or angular sampling. For small-scale signals, quantum noise and insufficient angular sampling degraded detectability. At high quantum noise levels, angular step size of 3 degrees or below was sufficient to avoid image degradation. At lower quantum noise levels, increased angular sampling always resulted in increased detectability. The ratio of detectability in the tomosynthesis slice to that in a single projection exhibited a peak that shifted to larger signal sizes when the angular range increased. For a given angular range, the peak shifted toward smaller signals when the number of views was increased. The ratio was greater than unity for all conditions evaluated. CONCLUSION: The effect of acquisition parameters on lesion detectability depends on signal size. Tomosynthesis scan angle had an effect on detectability for all signals sizes, while quantum noise and angular sampling only affected the detectability small-scale signals.

Scanning translucent glass-ceramic x-ray storage phosphors.

A simple benchtop apparatus has been built, to measure the x-ray imaging properties of fluorozirconate-based glass-ceramic x-ray storage phosphor materials. The MTF degradation due to stimulating light spreading in the plate is lower in comparison to optically turbid screens resulting in higher image MTF. In addition, the degree of transparency, or the amount of light scattering at the wavelength of the stimulating (laser) light is adjustable by means of the glass preparation process. The amount of stimulating exposure required for plate readout is generally higher than in previous systems, but well within the range of commercially available laser systems, for practical readout times. The effects of flare or unwanted readout due to back-reflection from the imaging plate is also less than in previous systems.A novel telecentric scanning system has been developed that is able to rapidly read out the latent image stored in the translucent imaging plates. This system features a reflective primary scan mirror to achieve telecentricity, optical correction for scan line bow, and the design should enable the construction of a relatively inexpensive scanner system for the translucent x-ray storage plates.

Spinal cord hemangioblastomas in von Hippel-Lindau disease.

STUDY DESIGN: Retrospective data analysis. OBJECTIVE: To clarify the clinical features and surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease (VHL). SETTING: Clinical VHL Research Group in Japan, Japan. METHODS: Forty-eight out of 66 patients with associated spinal cord hemangioblastoma among 142 VHL patients were retrospectively examined with respect to clinical features, accompanying lesions and outcome of surgical treatment. RESULTS: Among these 48 patients, 46 of them (95.8%) also had a central nervous system (CNS) hemangioblastoma at another site: 42 (87.5%) with cerebellar hemangioblastoma and 11 (22.9%) with brain stem hemangioblastoma. Twenty-three patients (47.9%) had more than one spinal cord hemangioblastoma. The 48 patients with spinal cord hemangioblastomas collectively had a total of 74 tumors. The tumor was accompanied with a syrinx in 64 and without it in 10 patients. Forty of the 48 patients underwent surgical treatment for their spinal cord hemangioblastomas, and 7 of these 40 underwent surgical treatment twice. When functional changes in the patients after these 47 operations were examined by postoperative evaluation by McCormick's classification, 39 of these operations (83.0%) resulted in improvement/no change and 8 (17.0%) in aggravation of symptoms. CONCLUSION: Von Hippel-Lindau disease patients bearing spinal cord hemangioblastomas mostly had a CNS hemangioblastoma at another site. These tumors can be removed in the majority of VHL patients without aggravation. In these patients, when the timing of treatment for spinal cord hemangioblastoma is determined, the probability of occurrence and treatment of other lesions should be considered.

Automated detection of microcalcification clusters for digital breast tomosynthesis using projection data only: a preliminary study.

Digital breast tomosynthesis (DBT) is a promising modality for breast imaging in which an anisotropic volume image of the breast is obtained. We present an algorithm for computerized detection of microcalcification clusters (MCCs) for DBT. This algorithm operates on the projection views only. Therefore it does not depend on reconstruction, and is computationally efficient. The algorithm was developed using a database of 30 image sets with microcalcifications, and a control group of 30 image sets without visible findings. The patient data were acquired on the first DBT prototype at Massachusetts General Hospital. Algorithm sensitivity was estimated to be 0.86 at 1.3 false positive clusters, which is below that of current MCC detection algorithms for full-field digital mammography. Because of the small number of patient cases, algorithm parameters were not optimized and one linear classifier was used. An actual limitation of our approach may be that the signal-to-noise ratio in the projection images is too low for microcalcification detection. Furthermore, the database consisted of predominantly small MCC. This may be related to the image quality obtained with this first prototype.

Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway.

Neuropilin-1 (NRP1) functions as a coreceptor through interaction with plexin A1 or vascular endothelial growth factor (VEGF) receptor during neuronal development and angiogenesis. NRP1 potentiates the signaling pathways stimulated by semaphorin 3A and VEGF-A in neuronal and endothelial cells, respectively. In this study, we investigate the role of tumor cell-expressed NRP1 in glioma progression. Analyses of human glioma specimens (WHO grade I-IV tumors) revealed a significant correlation of NRP1 expression with glioma progression. In tumor xenografts, overexpression of NRP1 by U87MG gliomas strongly promoted tumor growth and angiogenesis. Overexpression of NRP1 by U87MG cells stimulated cell survival through the enhancement of autocrine hepatocyte growth factor/scatter factor (HGF/SF)/c-Met signaling. NRP1 not only potentiated the activity of endogenous HGF/SF on glioma cell survival but also enhanced HGF/SF-promoted cell proliferation. Inhibition of HGF/SF, c-Met and NRP1 abrogated NRP1-potentiated autocrine HGF/SF stimulation. Furthermore, increased phosphorylation of c-Met correlated with glioma progression in human glioma biopsies in which NRP1 is upregulated and in U87MG NRP1-overexpressing tumors. Together, these data suggest that tumor cell-expressed NRP1 promotes glioma progression through potentiating the activity of the HGF/SF autocrine c-Met signaling pathway, in addition to enhancing angiogenesis, suggesting a novel mechanism of NRP1 in promoting human glioma progression.