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1.  A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma 
Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50–54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy.
To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma.
We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation.
Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.
Trial registration NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s40425-016-0149-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4986363  PMID: 27532020
Radiation; Fractionation; Chemotherapy; Gemcitabine; Lymphocytes; Lymphodepletion; Homeostatic repopulation; IL-7; IL-15; Immunotherapy
2.  Population-based MRI atlases of spatial distribution are specific to patient and tumor characteristics in glioblastoma 
NeuroImage : Clinical  2016;12:34-40.
Background and purpose
In treating glioblastoma (GB), surgical and chemotherapeutic treatment guidelines are, for the most part, independent of tumor location. In this work, we compiled imaging data from a large cohort of GB patients to create statistical atlases illustrating the disease spatial frequency as a function of patient demographics as well as tumor characteristics.
Materials and methods
Two-hundred-six patients with pathology-proven glioblastoma were included. Of those, 65 had pathology-proven recurrence and 113 had molecular subtype and genetic information. We used validated software to segment the tumors in all patients and map them from patient space into a common template. We then created statistical maps that described the spatial location of tumors with respect to demographics and tumor characteristics. We applied a chi-square test to determine whether pattern differences were statistically significant.
The most frequent location for glioblastoma in our patient population is the right temporal lobe. There are statistically significant differences when comparing patterns using demographic data such as gender (p = 0.0006) and age (p = 0.006). Small and large tumors tend to occur in separate locations (p = 0.0007). The tumors tend to occur in different locations according to their molecular subtypes (p < 10− 6). The classical subtype tends to spare the frontal lobes, the neural subtype tend to involve the inferior right frontal lobe. Although the sample size is limited, there was a difference in location according to EGFR VIII genotype (p < 10− 4), with a right temporal dominance for EFGR VIII negative tumors, and frontal lobe dominance in EGFR VIII positive tumors.
Spatial location of GB is an important factor that correlates with demographic factors and tumor characteristics, which should therefore be considered when evaluating a patient with GB and might assist in personalized treatment.
•Atlases of spatial distribution of glioblastoma are created.•Atlases are specific to patient characteristics such as age and gender.•Atlases are specific to tumor characteristics such as size and molecule subtype.•Atlases are specific to tumor genetics.•Spatial location should be considered when evaluating a patient with glioblastoma.
PMCID: PMC4916067  PMID: 27358767
MRI; Glioblastoma; Statistical; Atlas; Spatial
4.  Pattern Analysis of Dynamic Susceptibility Contrast-enhanced MR Imaging Demonstrates Peritumoral Tissue Heterogeneity 
Radiology  2014;273(2):502-510.
In the present study, informative features were extracted from the temporal dynamics of dynamic susceptibility contrast-enhanced MR images by using principal component analysis, and these variables were used via support vector machine classification to highlight the heterogeneity of the peritumoral region.
To augment the analysis of dynamic susceptibility contrast material–enhanced magnetic resonance (MR) images to uncover unique tissue characteristics that could potentially facilitate treatment planning through a better understanding of the peritumoral region in patients with glioblastoma.
Materials and Methods
Institutional review board approval was obtained for this study, with waiver of informed consent for retrospective review of medical records. Dynamic susceptibility contrast-enhanced MR imaging data were obtained for 79 patients, and principal component analysis was applied to the perfusion signal intensity. The first six principal components were sufficient to characterize more than 99% of variance in the temporal dynamics of blood perfusion in all regions of interest. The principal components were subsequently used in conjunction with a support vector machine classifier to create a map of heterogeneity within the peritumoral region, and the variance of this map served as the heterogeneity score.
The calculated principal components allowed near-perfect separability of tissue that was likely highly infiltrated with tumor and tissue that was unlikely infiltrated with tumor. The heterogeneity map created by using the principal components showed a clear relationship between voxels judged by the support vector machine to be highly infiltrated and subsequent recurrence. The results demonstrated a significant correlation (r = 0.46, P < .0001) between the heterogeneity score and patient survival. The hazard ratio was 2.23 (95% confidence interval: 1.4, 3.6; P < .01) between patients with high and low heterogeneity scores on the basis of the median heterogeneity score.
Analysis of dynamic susceptibility contrast-enhanced MR imaging data by using principal component analysis can help identify imaging variables that can be subsequently used to evaluate the peritumoral region in glioblastoma. These variables are potentially indicative of tumor infiltration and may become useful tools in guiding therapy, as well as individualized prognostication.
© RSNA, 2014
PMCID: PMC4208985  PMID: 24955928
5.  Evaluation of a Minimally Invasive Image-Guided Surgery System for Hepatic Ablation Procedures 
Surgical innovation  2013;21(4):419-426.
The Explorer Minimally Invasive Liver (MIL) system uses imaging to create a 3-dimensional model of the liver. Intraoperatively, the system displays the position of instruments relative to the virtual liver. A prospective clinical study compared it with intraoperative ultrasound (iUS) in laparoscopic liver ablations.
Patients undergoing ablations were accrued from 2 clinical sites. During the procedures, probes were positioned in the standard fashion using iUS. The position was synchronously recorded using the Explorer system. The distances from the probe tip to the tumor boundary and center were measured on the ultrasound image and in the corresponding virtual image captured by the Explorer system.
Data were obtained on the placement of 47 ablation probes during 27 procedures. The absolute difference between iUS and the Explorer system for the probe tip to tumor boundary distance was 5.5 ± 5.6 mm, not a statistically significant difference. The absolute difference for probe tip to tumor center distance was 8.6 ± 7.0 mm, not statistically different from 5 mm.
The initial clinical experience with the Explorer MIL system shows a strong correlation with iUS for the positioning of ablation probes. The Explorer MIL system is a promising tool to provide supplemental guidance information during laparoscopic liver ablation procedures.
PMCID: PMC4105303  PMID: 24201739
laparosopic liver surgery; ablation; image-guided surgery; laparoscopic ultrasound
6.  Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients 
Translational Oncology  2014;7(6):752-758.
The standard of care for glioblastoma (GB) is surgery followed by concurrent radiation therapy (RT) and temozolomide (TMZ) and then adjuvant TMZ. This regime is associated with increased survival but also increased occurrence of equivocal imaging findings, e.g., tumor progression (TP) versus treatment effect (TE), which is also referred to as pseudoprogression (PsP). Equivocal findings make decisions regarding further treatment difficult and often delayed. Because none of the current imaging assays have proven sensitive and specific for differentiation of TP versus TE/PsP, we investigated whether blood-derived microvesicles (MVs) would be a relevant assay. METHODS: 2.8 ml of citrated blood was collected from patients with GB at the time of their RT simulation, at the end of chemoradiation therapy (CRT), and multiple times following treatment. MVs were collected following multiple centrifugations (300g, 2500g, and 15,000g). The pellet from the final spin was analyzed using flow cytometry. A diameter of approximately 300 nm or greater and Pacific Blue–labeled Annexin V positivity were used to identify the MVs reported herein. RESULTS: We analyzed 19 blood samples from 11 patients with GB. MV counts in the patients with stable disease or TE/PsP were significantly lower than patients who developed TP (P = .014). CONCLUSION: These preliminary data suggest that blood analysis for MVs from GB patients receiving CRT may be useful to distinguish TE/PsP from TP. MVs may add clarity to standard imaging for decision making in patients with equivocal imaging findings.
PMCID: PMC4311040  PMID: 25500085
7.  Detailed characterization of tumor infiltrating lymphocytes in two distinct human solid malignancies show phenotypic similarities 
We examined the phenotype and function of lymphocytes collected from the peripheral blood (PBL) and tumor (TIL) of patients with two different solid malignancies: colorectal cancer liver metastases (CRLM) and ovarian cancer (OVC).
Tumor and corresponding peripheral blood were collected from 16 CRLM and 22 OVC patients; immediately following resection they were processed and analyzed using a multi-color flow cytometry panel. Cytokine mRNA from purified PBL and TIL CD4+ T cells were also analyzed by qPCR.
Overall, we found similar changes in the phenotypic and cytokine profiles when the TIL were compared to PBL from patients with two different malignancies. The percentage of Treg (CD4+/CD25+/FoxP3+) in PBL and TIL was similar: 8.1% versus 10.2%, respectively in CRLM patients. However, the frequency of Treg in primary OVC TIL was higher than PBL: 19.2% versus 4.5% (p <0.0001). A subpopulation of Treg expressing HLA-DR was markedly increased in TIL compared to PBL in both tumor types, CRLM: 69.0% versus 31.7% (p = 0.0002) and OVC 74.6% versus 37.0% (p <0.0001), which suggested preferential Treg activation within the tumor. The cytokine mRNA profile showed that IL-6, a cytokine known for its immunosuppressive properties through STAT3 upregulation, was increased in TIL samples in patients with OVC and CRLM. Both TIL populations also contained a significantly higher proportion of activated CD8+ T cells (HLA-DR+/CD38+) compared to PBL (CRLM: 30.2% vs 7.7%, (p = 0.0012), OVC: 57.1% vs 12.0%, (p <0.0001)).
This study demonstrates that multi-color flow cytometry of freshly digested tumor samples reveals phenotypic differences in TIL vs PBL T cell sub-populations. The TIL composition in primary and metastatic tumors from two distinct histologies were remarkably similar, showing a greater proportion of activated/suppressive Treg (HLA-DR+, CD39+, CTLA-4+ and Helios+) and activated cytotoxic T cells (CD8+/HLA-DR+/CD38+) when compared to PBL and an increase in IL-6 mRNA from CD4 TIL.
Electronic supplementary material
The online version of this article (doi:10.1186/s40425-014-0038-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4247679  PMID: 25436113
Tumor infiltrating lymphocytes; Regulatory T cells
8.  Pattern Analysis of Dynamic Susceptibility Contrast MRI Reveals Peritumoral Tissue Heterogeneity 
Radiology  2014;273(2):502-510.
The aim of this study is to augment the analysis of dynamic susceptibility contrast MRI (DSC-MRI) to uncover unique tissue characteristics that could potentially facilitate treatment planning through a better understanding of the peritumoral region of patients with glioblastoma.
Materials and Methods
IRB approval was obtained for this study with waiver of informed consent for retrospective review of medical records. DSC-MRI data was obtained for 79 patients and principal component analysis (PCA) was applied to the perfusion signal. The first six principal components (PCs) were sufficient to characterize more than 99% of variance in the temporal dynamics of blood perfusion in all regions of interest. The PCs were subsequently used in conjunction with a support vector machine (SVM) classifier to create a map of heterogeneity within the peritumoral region and the variance of this map served as the heterogeneity score.
The calculated PCs allowed near perfect separability of tissue that was likely highly infiltrated from tissue that was unlikely infiltrated with tumor. The heterogeneity map created using the PCs showed a clear relationship between voxels judged by the SVM to be highly infiltrated and subsequent recurrence. The results demonstrated a significant correlation (r=0.46, p<0.0001) between the heterogeneity score and patient survival. The hazard ratio was 2.23 (95% CI, 1.4-3.6, p <0.01) between high and low heterogeneity score patients based on the median heterogeneity score.
Analysis of DSC-MRI data using PCA can identify imaging variables that can be subsequently utilized to evaluate the peritumoral region in glioblastoma. These variables are potentially indicative of tumor infiltration and may become useful tools in guiding therapy as well as individualized prognostication.
PMCID: PMC4208985  PMID: 24955928
Perfusion; Glioblastoma; DSC-MRI; PCA
9.  The secreted protein S100A7 (psoriasin) is induced by telomere dysfunction in human keratinocytes independently of a DNA damage response and cell cycle regulators 
Replicative senescence is preceded by loss of repeat sequences of DNA from the telomeres that eventually leads to telomere dysfunction, the accumulation of irreparable DNA double strand breaks and a DNA damage response (DDR). However, we have previously reported that whilst telomere dysfunction in human keratinocytes is associated with a permanent cell cycle arrest, the DDR was very weak and transcriptional profiling also revealed several molecules normally associated with keratinocytes terminal differentiation, including S100A7 (psoriasin).
We show here that S100A7 and the closely related S100A15 (koebnerisin) are not induced by repairable or irreparable DSBs, ruling out the hypotheses that these genes are induced either by the low DDR observed or by non-specific cell cycle arrest. We next tested whether S100A7 was induced by the cell cycle effectors ARF (p14ARF), CDKN2A (p16INK4A) and TP53 (p53) and found that, although all induced a similar level of acute and permanent cell cycle arrest to telomere dysfunction, none induced S100A7 (except p53 over-expression at high levels), showing that cell cycle arrest is not sufficient for its induction. The closely related transcript S100A15 was also upregulated by telomere dysfunction, to a similar extent by p16INK4A and p53 and to a lesser extent by p14ARF.
Our results show that mere cell cycle arrest, the upregulation of senescence-associated cell cycle effectors and DNA damage are not sufficient for the induction of the S100 transcripts; they further suggest that whilst the induction of S100A15 expression is linked to both telomere-dependent and -independent senescence, S100A7 expression is specifically associated with telomere-dependent senescence in normal keratinocytes. As both S100A7 and S100A15 are secreted proteins, they may find utility in the early detection of human keratinocyte telomere dysfunction and senescence.
PMCID: PMC4304136  PMID: 25621169
Telomere; Senescence; Keratinocyte; Differentiation; SASP; S100
10.  Migraine with Aura Is Associated with an Incomplete Circle of Willis: Results of a Prospective Observational Study 
PLoS ONE  2013;8(7):e71007.
To compare the prevalence of an incomplete circle of Willis in patients with migraine with aura, migraine without aura, and control subjects, and correlate circle of Willis variations with alterations in cerebral perfusion.
Migraine with aura, migraine without aura, and control subjects were prospectively enrolled in a 1∶1∶1 ratio. Magnetic resonance angiography was performed to examine circle of Willis anatomy and arterial spin labeled perfusion magnetic resonance imaging to measure cerebral blood flow. A standardized template rating system was used to categorize circle of Willis variants. The primary pre-specified outcome measure was the frequency of an incomplete circle of Willis. The association between circle of Willis variations and cerebral blood flow was also analyzed.
170 subjects were enrolled (56 migraine with aura, 61 migraine without aura, 53 controls). An incomplete circle of Willis was significantly more common in the migraine with aura compared to control group (73% vs. 51%, p = 0.02), with a similar trend for the migraine without aura group (67% vs. 51%, p = 0.08). Using a quantitative score of the burden of circle of Willis variants, migraine with aura subjects had a higher burden of variants than controls (p = 0.02). Compared to those with a complete circle, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow (p = 0.05). Specific posterior cerebral artery variants were associated with greater asymmetries of blood flow in the posterior cerebral artery territory.
An incomplete circle of Willis is more common in migraine with aura subjects than controls, and is associated with alterations in cerebral blood flow.
PMCID: PMC3724801  PMID: 23923042
11.  S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways 
Cancer Research  2011;72(3):604-615.
S100A7/Psoriasin, a member of the epidermal differentiation complex, is widely overexpressed in invasive ER-negative (ERα-) breast cancers. However, it has not been established whether S100A7 contributes to breast cancer growth or metastasis. Here, we report the consequences of its expression on inflammatory pathways that impact breast cancer growth. Overexpression of human S100A7 or its murine homolog mS100a7a15, enhanced cell proliferation and upregulated various pro-inflammatory molecules in ERα- breast cancer cells. To examine in vivo effects, we generated mice with an inducible form of mS100a7a15 (MMTV-mS100a7a15 mice). Orthotopic implantation of MVT-1 breast tumor cells into the mammary glands of these mice enhanced tumor growth and metastasis. Compared to uninduced transgenic control mice, the mammary glands of mice where mS100a7a15 was induced exhibited increased ductal hyperplasia and expression of molecules involved in proliferation, signaling, tissue remodeling and macrophage recruitment. Furthermore, tumors and lung tissues obtained from these mice showed further increases in pro-metastatic gene expression and recruitment of tumor-associated macrophages (TAMs). Notably, in vivo depletion of TAM inhibited the effects of mS100a7a15 induction on tumor growth and angiogenesis. Further, introduction of soluble hS100A7 or mS100a7a15 enhanced chemotaxis of macrophages via activation of RAGE receptors. In summary, our work employed a powerful new model system to demonstrate that S100A7 enhances breast tumor growth and metastasis by activating proinflammatory and metastatic pathways.
PMCID: PMC3271140  PMID: 22158945
12.  Anesthetic Efficacy of Combinations of 0.5 M Mannitol and Lidocaine With Epinephrine in Inferior Alveolar Nerve Blocks: A Prospective Randomized, Single-Blind Study 
Anesthesia Progress  2011;58(4):157-165.
The purpose of this prospective, randomized, single-blind study was to determine the anesthetic efficacy of lidocaine with epinephrine compared to lidocaine with epinephrine plus 0.5 M mannitol in inferior alveolar nerve (IAN) blocks. Forty subjects randomly received an IAN block in 3 separate appointments spaced at least 1 week apart using the following formulations: a 1.8 mL solution of 36 mg lidocaine with 18 µg epinephrine (control solution); a 2.84 mL solution of 36 mg lidocaine with 18 µg epinephrine (1.80 mL) plus 0.5 M mannitol (1.04 mL); and a 5 mL solution of 63.6 mg lidocaine with 32 µg epinephrine (3.18 mL) plus 0.5 M mannitol (1.82 mL). Mandibular teeth were blindly electric pulp tested at 4-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Mean percent total pulpal anesthesia was defined as the total of all the times of pulpal anesthesia (80 readings) over the 60 minutes. Pain of solution deposition and postoperative pain were also measured. The results demonstrated that 2.84 mL of lidocaine with epinephrine plus 0.5 M mannitol was significantly better than 1.8 mL of lidocaine with epinephrine for the molars and premolars. The 5 mL of lidocaine with epinephrine plus 0.5 M mannitol was statistically better than 1.8 mL of lidocaine with epinephrine and 2.84 mL of lidocaine with epinephrine plus 0.5 M mannitol for all teeth except the central incisor. Solution deposition pain and postoperative pain were not statistically different among the mannitol formulations and the lidocaine formulation without mannitol. We concluded that adding 0.5 M mannitol to lidocaine with epinephrine formulations significantly improved effectiveness in achieving a greater percentage of total pulpal anesthesia compared with a lidocaine formulation without mannitol for IAN block.
PMCID: PMC3237325  PMID: 22168805
Inferior alveolar nerve block; Lidocaine; Mannitol
13.  Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy 
American heart journal  2009;157(4):687.e1-687.e8.
Niacin has multiple lipoprotein effects that may provide cardiovascular benefit when added to statin monotherapy.
In this randomized, placebo-controlled trial (n = 75) of magnetic resonance imaging of carotid atherosclerosis, we performed a secondary comparison of combination niacin-statin (simvastatin 20 mg/Niacin-ER 2G [S20/N]) to monotherapy with moderate (20 mg [S20]) and high-dose (80 mg [S80]) simvastatin on lipids, apolipoproteins (apo), low density lipoprotein (LDL) and high density lipoprotein (HDL) particle subclasses, and inflammatory markers.
At baseline, average age was 71, 72% were male, 62.5% used statins, and average LDL-cholesterol was 111 mg/dL. At 12 months, S20/N, compared to S80, significantly reduced apoB (−36.6% vs −11.9%; P = .05) and lipoprotein(a) (−18% vs +3.5%; P = .001) and had at least an equivalent effect on LDL-cholesterol (−39.3% vs −24.3%; P = .24). The combination reduced the proportion of subjects with atherogenic LDL pattern-B (50% to 11.5%) compared to S80 (56% to 56%) (P = .01). Despite increases in plasma free fatty acids (+62.4%; F = 5.65, P = .005 vs S20 and S80), plasma triglycerides (−29.4%; F = 6.88, P = .002 vs S20 and S80), and very-low-density lipoprotein (−44.2%; F = 7.94, P < .001 vs S20 and S80), levels were reduced by S20/N. S20/N increased HDL-cholesterol levels (+18.1%) as compared to S20 (0%) and S80 (+5.9%) (P < .001 vs both statin arms), largely due to an increase in HDL particle size (+4.6%; P = .01 vs both statin arms).
We demonstrate that full-dose niacin/moderate-dose simvastatin combination has sustained benefits on atherogenic apoB lipoproteins, at least comparable to high-dose simvastatin, while also raising HDL-cholesterol. Results of large clinical trials will inform whether niacin-statin combinations reduce cardiovascular disease events.
PMCID: PMC3088112  PMID: 19332196
14.  Noninvasive Measurement of Cerebral Blood Flow and Blood Oxygenation Using Near-Infrared and Diffuse Correlation Spectroscopies in Critically Brain-Injured Adults 
Neurocritical care  2010;12(2):173-180.
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care
15.  Classification of brain tumor type and grade using MRI texture and shape in a machine learning scheme 
The objective of this study is to investigate the use of pattern classification methods for distinguishing different types of brain tumors, such as primary gliomas from metastases, and also for grading of gliomas. The availability of an automated computer analysis tool that is more objective than human readers can potentially lead to more reliable and reproducible brain tumor diagnostic procedures. A computer-assisted classification method combining conventional MRI and perfusion MRI is developed and used for differential diagnosis. The proposed scheme consists of several steps including ROI definition, feature extraction, feature selection and classification. The extracted features include tumor shape and intensity characteristics as well as rotation invariant texture features. Feature subset selection is performed using Support Vector Machines (SVMs) with recursive feature elimination. The method was applied on a population of 102 brain tumors histologically diagnosed as metastasis (24), meningiomas (4), gliomas WHO grade 2 (22), gliomas WHO grade 3 (18), and glioblastomas (34). The binary SVM classification accuracy, sensitivity, and specificity, assessed by leave-one-out cross-validation, were respectively 85%, 87%, and 79% for discrimination of metastases from gliomas, and 88%, 85%, and 96% for discrimination of high grade (grade III and IV) from low grade (grade II) neoplasms. Multi-class classification was also performed via a one-versus-all voting scheme.
PMCID: PMC2863141  PMID: 19859947
brain tumor; MRI; classification; SVM; feature selection; texture; tumor grade
16.  Hippocampal Volumetry and Memory fMRI in Temporal Lobe Epilepsy 
Epilepsy & behavior : E&B  2009;16(1):128-138.
This study examined the utility of structural and functional MRI at 1.5 and 3 Tesla (T) in the pre-surgical evaluation and prediction of post-surgical cognitive outcome in temporal lobe epilepsy (TLE). Forty-nine patients undergoing presurgical evaluation for temporal lobe (TL) resection and twenty-five control subjects were studied. Patients completed standard pre-surgical evaluations including, intracarotid amobarbital test (IAT) and neuropsychological testing. During functional imaging, subjects performed a complex visual scene-encoding task. High-resolution structural MRI scans were used to quantify hippocampal volumes. Both structural and functional imaging successfully lateralized the seizure focus and correlated with IAT memory lateralization, with improvement for functional imaging at 3T as compared to 1.5T. Ipsilateral structural and functional MRI data was related to cognitive outcome and greater functional asymmetry was related to earlier age of onset. These findings support continued investigation of the utility of MRI and fMRI in the presurgical evaluation of TLE.
PMCID: PMC2749903  PMID: 19674939
Temporal Lobe Epilepsy; Epilepsy Surgery; fMRI; Neuropsychological Outcome; Wada; IAT
17.  Highly homologous hS100A15 and hS100A7 proteins are distinctly expressed in normal breast tissue and breast cancer 
Cancer letters  2009;277(1):101-107.
Human S100A7 (psoriasin) is considered a marker for specific stages of breast cancer. hS100A15 is almost identical to hS100A7 and difficult to discriminate. We developed specific probes to distinguish hS100A7 and hS100A15, and demonstrate their differential distribution in normal breast tissue. Further, hS100A7 and S100A15 transcripts are elevated in ER/PR negative breast cancers, but hS100A15 protein is detected in all cancer specimens while hS100A7 protein is sporadically expressed. The differential regulation, expression and distribution of hS100A7 and hS100A15 and their reported distinct functions are compelling reasons to discriminate among these proteins in normal breast and breast cancers.
PMCID: PMC2680177  PMID: 19136201
mammary cancer; calcium binding proteins; S100; psoriasis; myoepithelial cells
18.  Combination antiretroviral therapy modulates the blood oxygen level–dependent amplitude in human immunodeficiency virus–seropositive patients 
Journal of neurovirology  2008;14(5):418.
Combination antiretroviral therapy (cART) limits human immunodeficiency virus (HIV) replication in the central nervous system (CNS) and prevents progressive neurological dysfunction. We examined if the degree of CNS penetration by cART, as estimated by the CNS penetration effectiveness (CPE) score, affects brain activity as measured by the amplitude of the blood oxygen level–dependent functional magnetic resonance imaging (BOLD fMRI) response. HIV+ patients on low-CPE cART (n = 12) had a significantly greater BOLD fMRI response amplitude than HIV+ patients on high-CPE cART (n = 12) or seronegative controls (n = 10). An increase in the BOLD fMRI response in HIV patients on low-CPE cART may reflect continued HIV replication in the CNS leading to increased oxidative stress and associated metabolic demands.
PMCID: PMC2819068  PMID: 19040188
combination antiretroviral therapy (cART); functional magnetic resonance imaging; HIV-associated neurocognitive disorders
19.  Differentiation between Glioblastomas and Solitary Brain Metastases Using Diffusion Tensor Imaging 
NeuroImage  2008;44(3):653-660.
The purpose of this study is to determine whether diffusion tensor imaging (DTI) metrics including tensor shape measures such as linear and planar anisotropy coefficients (CL and CP) can help differentiate glioblastomas from solitary brain metastases. Sixty-three patients with histopathologic diagnosis of glioblastomas (22 men, 16 women, mean age 58.4 years) and brain metastases (13 men, 12 women, mean age 56.3 years) were included in this study. Contrast-enhanced T1-weighted, fluid attenuated inversion recovery (FLAIR) images, fractional anisotropy (FA), apparent diffusion coefficient (ADC), CL and CP maps were co-registered and each lesion was semi-automatically subdivided into four regions: central, enhancing, immediate peritumoral and distant peritumoral. DTI metrics as well as the normalized signal intensity from the contrast-enhanced T1-weighted images were measured from each region. Univariate and multivariate logistic regression analyses were employed to determine the best model for classification. The results demonstrated that FA, CL and CP from glioblastomas were significantly higher than those of brain metastases from all segmented regions (p < 0.05), and the differences from the enhancing regions were most significant (p < 0.001). FA and CL from the enhancing region had the highest prediction accuracy when used alone with an area under the curve of 0.90. The best logistic regression model included three parameters (ADC, FA and CP) from the enhancing part, resulting in 92% sensitivity, 100% specificity and area under the curve of 0.98. We conclude that DTI metrics, used individually or combined, have a potential as a noninvasive measure to differentiate glioblastomas from metastases.
PMCID: PMC2655208  PMID: 18951985
20.  Multi-parametric tissue characterization of brain neoplasms and their recurrence using pattern classification of MR images 
Academic radiology  2008;15(8):966-977.
Rationale and Objectives:
Treatment of brain neoplasms can greatly benefit from better delineation of bulk neoplasm boundary and the extent and degree of more subtle neoplastic infiltration. MRI is the primary imaging modality for evaluation before and after therapy, typically combining conventional sequences with more advanced techniques like perfusion-weighted imaging and diffusion tensor imaging (DTI). The purpose of this study is to quantify the multi-parametric imaging profile of neoplasms by integrating structural MRI and DTI via statistical image analysis methods, in order to potentially capture complex and subtle tissue characteristics that are not obvious from any individual image or parameter.
Materials and Methods:
Five structural MR sequences, namely, B0, Diffusion Weighted Images, FLAIR, T1-weighted, and gadolinium-enhanced T1-weighted, and two scalar maps computed from DTI, i.e., fractional anisotropy and apparent diffusion coefficient, are used to create an intensity-based tissue profile. This is incorporated into a non-linear pattern classification technique to create a multi-parametric probabilistic tissue characterization, which is applied to data from 14 patients with newly diagnosed primary high grade neoplasms who have not received any therapy prior to imaging.
Preliminary results demonstrate that this multi-parametric tissue characterization helps to better differentiate between neoplasm, edema and healthy tissue, and to identify tissue that is likely progress to neoplasm in the future. This has been validated on expert assessed tissue.
This approach has potential applications in treatment, aiding computer-assisted surgery by determining the spatial distributions of healthy and neoplastic tissue, as well as in identifying tissue that is relatively more prone to tumor recurrence.
PMCID: PMC2596598  PMID: 18620117
brain neoplasm; recurrence; pattern classification; magnetic resonance imaging (MRI); multi-parametric MRI; Diffusion Tensor Imaging; computer aided diagnosis; tumor segmentation
21.  Chemotactic activity of S100A7 (psoriasin) is mediated by RAGE and potentiates inflammation with highly homologous but functionally distinct S100A15 
Human S100A7 (psoriasin) is overexpressed in inflammatory diseases. The recently discovered, co-evolved hS100A15 is almost identical in sequence and upregulated with hS100A7 during cutaneus inflammation. The functional role of these closely related proteins for inflammation remains undefined. By generating specific antibodies, we demonstrate that hS100A7 and hS100A15 proteins are differentially expressed by specific cell types in the skin. Although highly homologous, both proteins are chemoattractants with distinct chemotactic activity for leukocyte subsets. We define RAGE (receptor of advanced glycated end products) as the hS100A7 receptor, whereas hS100A15 functions through a Gi protein coupled receptor. hS100A7-RAGE binding, signaling and chemotaxis are zinc-dependent in vitro, reflecting the previously reported zinc-mediated changes in the hS100A7 dimer structure. When combined, hS100A7 and hS100A15 potentiate inflammation in vivo. Thus, proinflammatory synergism in disease may be driven by the diverse biology of these almost identical proteins that have just recently evolved. The identified S100A7 interaction with RAGE may provide a novel therapeutic target for inflammation.
PMCID: PMC2435511  PMID: 18606705
neutrophils; cytokine; cytokine receptor; chemotaxis; inflammation
22.  Clinical Neuroimaging Using Arterial Spin-Labeled Perfusion MRI 
The two most common methods for measuring perfusion with MRI are based on dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL). Although clinical experience to date is much more extensive with DSC perfusion MRI, ASL methods offer several advantages. The primary advantages are that completely noninvasive absolute cerebral blood flow (CBF) measurements are possible with relative insensitivity to permeability, and that multiple repeated measurements can be obtained to evaluate one or more interventions or to perform perfusion-based functional MRI. ASL perfusion and perfusion-based fMRI methods have been applied in many clinical settings, including acute and chronic cerebrovascular disease, CNS neoplasms, epilepsy, aging and development, neurodegenerative disorders, and neuropsychiatric diseases. Recent technical advances have improved the sensitivity of ASL perfusion MRI, and increasing use is expected in the coming years. This review focuses on ASL perfusion MRI and applications in clinical neuroimaging.
PMCID: PMC2031222  PMID: 17599701
Magnetic resonance imaging; Arterial spin labeling; Arterial spin tagging; Perfusion; Functional MRI
23.  Purification, crystallization and preliminary X-ray diffraction of human S100A15 
S100 proteins are differentially expressed during epithelial cell maturation, tumorigenesis and inflammation. The novel human S100A15 protein has been cloned, expressed, purified and crystallized in two crystal forms, a triclinic and a monoclinic form, which diffract to 1.7 and 2.0 Å, respectively.
Human S100A15 is a novel member of the S100 family of EF-hand calcium-binding proteins and was recently identified in psoriasis, where it is significantly upregulated in lesional skin. The protein is implicated as an effector in calcium-mediated signal transduction pathways. Although its biological function is unclear, the association of the 11.2 kDa S100A15 with psoriasis suggests that it contributes to the pathogenesis of the disease and could provide a molecular target for therapy. To provide insight into the function of S100A15, the protein was crystallized to visualize its structure and to further the understanding of how the many similar calcium-binding mediator proteins in the cell distinguish their cognate target molecules. The S100A15 protein has been cloned, expressed and purified to homogeneity and produced two crystal forms. Crystals of form I are triclinic, with unit-cell parameters a = 33.5, b = 44.3, c = 44.8 Å, α = 71.2, β = 68.1, γ = 67.8° and an estimated two molecules in the asymmetric unit, and diffract to 1.7 Å resolution. Crystals of form II are monoclinic, with unit-cell parameters a = 82.1, b = 33.6, c = 52.2 Å, β = 128.2° and an estimated one molecule in the asymmetric unit, and diffract to 2.0 Å resolution. This structural analysis of the human S100A15 will further aid in the phylogenic comparison between the other members of the S100 protein family, especially the highly homologous paralog S100A7.
PMCID: PMC2219979  PMID: 16682778
S100A15; psoriasis; calcium binding; EF-hand
24.  Mineral Volume and Morphology in Carotid Plaque Specimens Using High-Resolution MRI and CT 
High-resolution MRI methods have been used to evaluate carotid artery atherosclerotic plaque content. The purpose of this study was to assess the performance of high-resolution MRI in evaluation of the quantity and pattern of mineral deposition in carotid endarterectomy (CEA) specimens, with quantitative micro-CT as the gold standard.
Methods and Results
High-resolution MRI and CT were compared in 20 CEA specimens. Linear regression comparing mineral volumes generated from CT (VCT) and MRI (VMRI) data demonstrated good correlation using simple thresholding (VMRI=-0.01+0.98VCT; R2=0.90; threshold=4×noise) and k-means clustering methods (VMRI=-0.005+1.38VCT; R2=0.93). Bone mineral density (BMD) and bone mineral content (BMC [mineral mass]) were calculated for CT data and BMC verified with ash weight. Patterns of mineralization like particles, granules, and sheets were more clearly depicted on CT.
Mineral volumes generated from MRI or CT data were highly correlated. CT provided a more detailed depiction of mineralization patterns and provided BMD and BMC in addition to mineral volume. The extent of mineralization as well as the morphology may ultimately be useful in assessing plaque stability.
PMCID: PMC1959411  PMID: 15947239
magnetic resonance imaging; computed tomography; carotid arteries; calcium

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