[Show abstract][Hide abstract] ABSTRACT: Introduction: Unlike microglia and astrocytes, neurons do not express CD4 and thus are not productively infected by HIV. The neurologic damage associated with HIV is thus thought to be mediated through multiple mechanisms, mainly neuroinflammation. This however has not been shown reliably in small animal models of HIV. The goal of this study was to image neuroinflammation in the HIV-1 transgenic (Tg) rat, a model that is known to develop neurologic dysfunction at advanced age. Imaging microglial activation as a surrogate marker for neuroinflammation can be accomplished by radiolabeling ligands that target the translocator protein (TSPO), an outer mitochondrial membrane receptor known to be overexpressed in activated microglia. Recently, an 18F labeled pyrazolopyrimidine, DPA714, was found to have higher affinity to TSPO, lower non-specific binding and increased bioavailability when compared to the prototype ligand, 11C-PK11195. In this study, we used 18F-DPA714 to image neuroinflammation in vivo in the HIV Tg rat model. Materials and Methods: Seven 9-month old rats (4 Tg and 3 Ctrl) and nine 16-month-old rats (6Tg, 3Ctrl) were imaged for 60 min on the Bio PET/CT tomograph (Bioscan, Inc.) after the administration of 18F-DPA-714 (dose: 1.75 +/-0.59 mCi, SA > 2 Ci/μmol). Dynamic images were reconstructed using OSEM-2D algorithm with scatter correction. Regional 18F-DPA714 time activity curves were generated for volumes of interest (VOI) that were drawn manually in various brain regions. As a positive control, we used the quinolinic acid (QA) unilateral striatal ablation rat model (n=3). For those rats, one VOI was selected in the left striatum at the site of QA injection, with an identical VOI drawn in the exact location in the contralateral right hemisphere as the reference region. SUV values (SUV = CPET(T) / (Injected dose / weight)) were calculated for all regions in all animals groups. Results: There were no significant differences in 18F-DPA714 SUV values of the parietal cortex, caudate, thalamus, hippocampus, pons and cerebellum between any of the four groups of animals: 9 month old Tg and controls, 16 month old Tg and controls (Fig.1). Our results were further confirmed with immunohistochemistry which did not show appreciable differential TSPO staining in the Tg compared to the ctrl animals. In the QA rat model, there was an average 1.7 fold increased 18F-DPA714 SUV in the ipsilateral VOI (lesion) compared to the contralateral VOI (range: 1.55-1.84). Discussion: We found no substantial microglial activation that can be detected using PET in the brains of HIV-Tg rats compared to age-matched controls, neither at 9 nor at 16 months of age. We validated our ligand using our positive control unilateral striatal ablation rat (with QA), which showed significant uptake corresponding to histological evidence of TSPO overexpression. Our findings suggest an alternative mechanism for neurotoxicity in this
[Show abstract][Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2013; 73(8 Supplement). DOI:10.1038/leu.2013.268 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody-antibody fragments and drug-drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent.
[Show abstract][Hide abstract] ABSTRACT: Organ shape plays an important role in clinical diagnosis, surgical planning and treatment evaluation. Shape modeling is a critical factor affecting the performance of deformable model based segmentation methods for organ shape extraction. In most existing works, shape modeling is completed in the original shape space, with the presence of outliers. In addition, the specificity of the patient was not taken into account. This paper proposes a novel target-oriented shape prior model to deal with these two problems in a unified framework. The proposed method measures the intrinsic similarity between the target shape and the training shapes on an embedded manifold by manifold learning techniques. With this approach, shapes in the training set can be selected according to their intrinsic similarity to the target image. With more accurate shape guidance, an optimized search is performed by a deformable model to minimize an energy functional for image segmentation, which is efficiently achieved by using dynamic programming. Our method has been validated on 2D prostate localization and 3D prostate segmentation in MRI scans. Compared to other existing methods, our proposed method exhibits better performance in both studies.
[Show abstract][Hide abstract] ABSTRACT: The era of stromal-based therapies is coming, and methods to image the stroma are likely to become vital to improved understanding of the intricate interrelationships of these cells. Because fibroblasts are so important for the initiation of cancer, stromal-based therapies may serve as preventive regimens in patients who are at high risk for recurrent disease. The method described by Vandsburger et al uses a reporter-gene magnetic resonance (MR) imaging- agent paradigm that withstands dilution from cell division while allowing imaging without ionizing radiation. The requirement for gene transfection makes near-term clinical translation unlikely, but the opportunities for studying cancer-associated fibroblast activity in tumor models and observing and modulating their migratory behavior is an exciting prospect, one that is hoped to bring tangible benefits to patients with cancer.
[Show abstract][Hide abstract] ABSTRACT: Patients with enlarged prostates and suspicion of prostate cancer (PCa) pose a diagnostic dilemma. PCa detection rate of systematic 12-core TRUS-guided biopsy ranges between 30-40%. For prostates >40cc this decreases to = 30%. MR-US fusion biopsy has demonstrated superior PCa detection rates. Herein, we define the detection rate of MR-US fusion biopsy in men with enlarged prostate glands.
Patients who underwent multiparametric prostate MRI (MP-MRI) followed by MR-US fusion biopsy at our institution were analyzed. Whole prostate (WP) volumes were calculated using reconstructions of the MRI. Detection rates were analyzed with respect to age, PSA, and WP volumes. Multivariable logistic regression was used to assess these as independent predictors of PCa detection.
A total of 649 patients (mean age 61.8± 7.9 years) with a median PSA of 6.65ng/ml (IQR 4.35 - 11.0ng/ml) were analyzed. Mean WP volume was 58.7± 34.3 cc. Overall detection rate of the MR-US fusion platform was 55%. For prostates <40cc the detection rate was 71.1% compared to 57.5%, 46.9%, 46.9% 33.3%, 36.4% and 30.4% for glands between 40-54.9cc, 55-69.9cc, 70-84.9cc, 85-99.9cc, 100-114.9cc and =115cc respectively (p<0.0001). Multivariable logistic regression showed significant inverse association of MRI volume with PCa detection controlling for age and PSA.
TRUS-guided and fusion biopsy cancer detection rates decrease with increasing prostate volume. However, MR-US fusion biopsy has higher PCa detection rate when compared to TRUS-guided biopsy reported in the literature. MR-US fusion biopsy represents a promising solution for patients with suspicion of PCa and enlarged prostates.
The Journal of urology 06/2013; 190(6). DOI:10.1016/j.juro.2013.05.118 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intratumor heterogeneity is often manifested by vascular compartments with
distinct pharmacokinetics that cannot be resolved directly by in vivo dynamic
imaging. We developed tissue-specific compartment modeling (TSCM), an
unsupervised computational method of deconvolving dynamic imaging series from
heterogeneous tumors that can improve vascular phenotyping in many biological
contexts. Applying TSCM to dynamic contrast-enhanced MRI of breast cancers
revealed characteristic intratumor vascular heterogeneity and therapeutic
responses that were otherwise undetectable.
[Show abstract][Hide abstract] ABSTRACT: Gleason scores from standard, 12-core prostate biopsies are upgraded historically in 25-33% of patients. Multiparametric prostate magnetic resonance imaging (MP-MRI) with ultrasound (US)-targeted fusion biopsy may better sample the true gland pathology.
The rate of Gleason score upgrading from an MRI/US-fusion-guided prostate-biopsy platform is compared with a standard 12-core biopsy regimen alone.
There were 582 subjects enrolled from August 2007 through August 2012 in a prospective trial comparing systematic, extended 12-core transrectal ultrasound biopsies to targeted MRI/US-fusion-guided prostate biopsies performed during the same biopsy session.
The highest Gleason score from each biopsy method was compared.
An MRI/US-fusion-guided platform with electromagnetic tracking was used for the performance of the fusion-guided biopsies.
A diagnosis of prostate cancer (PCa) was made in 315 (54%) of the patients. Addition of targeted biopsy led to Gleason upgrading in 81 (32%) cases. Targeted biopsy detected 67% more Gleason ≥4+3 tumors than 12-core biopsy alone and missed 36% of Gleason ≤3+4 tumors, thus mitigating the detection of lower-grade disease. Conversely, 12-core biopsy led to upgrading in 67 (26%) cases over targeted biopsy alone but only detected 8% more Gleason ≥4+3 tumors. On multivariate analysis, MP-MRI suspicion was associated with Gleason score upgrading in the targeted lesions (p<0.001). The main limitation of this study was that definitive pathology from radical prostatectomy was not available.
MRI/US-fusion-guided biopsy upgrades and detects PCa of higher Gleason score in 32% of patients compared with traditional 12-core biopsy alone. Targeted biopsy technique preferentially detects higher-grade PCa while missing lower-grade tumors.
European Urology 06/2013; 64(5). DOI:10.1016/j.eururo.2013.05.059 · 13.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology.
Materials and methods:
Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson's correlation, Student's t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post-procedural MRI, and histopathology.
MRI combined with a transurethral US-therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r(2) 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r(2) 0.89, P < 0.001, and r(2) 0.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r(2) 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student's t-test).
MRI-guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated.
BJU International 06/2013; 112(4). DOI:10.1111/bju.12126 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We determine the usefulness of multiparametric magnetic resonance imaging in detecting prostate cancer, with a specific focus on detecting higher grade prostate cancer.
Materials and methods:
Prospectively 583 patients who underwent multiparametric magnetic resonance imaging and subsequent prostate biopsy at a single institution were evaluated. On multiparametric magnetic resonance imaging, lesions were identified and scored as low, moderate or high suspicion for prostate cancer based on a validated scoring system. Magnetic resonance/ultrasound fusion guided biopsies of magnetic resonance imaging lesions in addition to systematic 12-core biopsies were performed. Correlations between the highest assigned multiparametric magnetic resonance imaging suspicion score and presence of cancer and biopsy Gleason score on the first fusion biopsy session were assessed using univariate and multivariate logistic regression models. Sensitivity, specificity, negative predictive value and positive predictive value were calculated and ROC curves were developed to assess the discriminative ability of multiparametric magnetic resonance imaging as a diagnostic tool for various biopsy Gleason score cohorts.
Significant correlations were found between age, prostate specific antigen, prostate volume, and multiparametric magnetic resonance imaging suspicion score and the presence of prostate cancer (p<0.0001). On multivariate analyses controlling for age, prostate specific antigen and prostate volume, increasing multiparametric magnetic resonance imaging suspicion was an independent prognosticator of prostate cancer detection (OR 2.2, p<0.0001). Also, incremental increases in multiparametric magnetic resonance imaging suspicion score demonstrated stronger associations with cancer detection in patients with Gleason 7 or greater (OR 3.3, p<0.001) and Gleason 8 or greater (OR 4.2, p<0.0001) prostate cancer. Assessing multiparametric magnetic resonance imaging as a diagnostic tool for all prostate cancer, biopsy Gleason score 7 or greater, and biopsy Gleason score 8 or greater separately via ROC analyses demonstrated increasing accuracy of multiparametric magnetic resonance imaging for higher grade disease (AUC 0.64, 0.69, and 0.72, respectively).
Multiparametric magnetic resonance imaging is a clinically useful modality to detect and characterize prostate cancer, particularly in men with higher grade disease.
The Journal of urology 05/2013; 190(5). DOI:10.1016/j.juro.2013.05.052 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is currently the most common solid organ cancer type among men in the Western world. Currently, all decision-making algorithms and nomograms rely on demographics, clinicopathological data and symptoms. Such an approach can easily miss significant cancers while detecting many insignificant cancers. In this review, novel functional and molecular imaging techniques used in the diagnosis and staging of localised prostate cancer and their effect on treatment decisions are discussed. Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is the most common malignancy among American men. Imaging of localized and recurrent prostate cancer is challenging since conventional imaging techniques are limited. New imaging techniques such as multiparametric MRI and PET with targeted tracers have been investigated extensively in the last decade. As a result, the role of novel imaging techniques for the detection of localized and recurrent prostate cancer has recently expanded. In this review, novel functional and molecular imaging techniques used in the management of localized and recurrent prostate cancer are discussed.
European Journal of Nuclear Medicine 05/2013; 40. DOI:10.1007/s00259-013-2419-6 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSEAlveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). PATIENTS AND METHODS
We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.ResultsOf 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. CONCLUSION
In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.
[Show abstract][Hide abstract] ABSTRACT: Tumors are characterized by a high degree of diversity and heterogeneity in receptor expression. Monoclonal antibodies (mAbs) are an established therapeutic method of targeting cell surface receptors. However, high affinity antibodies targeting highly expressed receptors are often prevented from distributing evenly throughout the tumor due to the "binding site barrier" whereby antibody is trapped peripherally before it can reach deeper into the tumor that leads inhomogeneous micro-distribution. When employing armed antibodies it is important that the toxin (in this case, phototoxin) be distributed evenly to more effectively treat the cancer. By adding an additional antibody conjugate, targeting a secondary, unsaturated receptor with lower expression, a more uniform distribution of the phototoxin can be achieved. In this study, panitumumab (Pan) and basiliximab (Bas) were conjugated with the phthalocyanine dye, IRDye700DX (IR700). Upon exposure to near infrared light, these armed antibodies produce rapid cell death only when bound to their respective receptors, a treatment termed photo-immunotherapy (PIT). ATAC4 cells which demonstrate high expression of human epidermal growth factor receptor (EGFR) and low expression of interleukin-2 receptor-alpha (CD25) were treated by PIT using a cocktail of Pan-IR700 and Bas-IR700. An in vivo study showed that the cocktail Pan-Bas-IR700 resulted in significantly reduced tumor growth and prolonged survival in ATAC4 tumor-bearing mice compared with either Pan-IR700 or Bas-IR700 alone. In conclusion, a cocktail injection of two different antibody-IR700 conjugates created a more homogeneous microdistribution of antibody-conjugates resulting in enhanced therapeutic effects after PIT, compared to the use of either antibody-IR700 conjugate.
[Show abstract][Hide abstract] ABSTRACT: The ability to switch optical imaging probes from the quenched (off) to the active state (on) has greatly improved target to background ratios. The optimal activation efficiency of an optical probe depends on complete quenching before activation and complete de-quenching after activation. For instance, monoclonal antibody-indocyanine green (mAb-ICG) conjugates, which are promising agents for clinical translation, are normally quenched but can be activated, when bound to a cell surface receptor and internalized. However, the small fraction of commonly used ICG derivative (ICG-Sulfo-OSu) can bind noncovalently to its mAb and is thus, gradually released from the mAb leading to relatively high background signal especially in the liver and the abdomen. In this study, we re-engineered a mAb-ICG conjugate, (Panitumumab-ICG) using bifunctional ICG derivatives (ICG-PEG4-Sulfo-OSu and ICG-PEG8-Sulfo-OSu) with short polyethylene glycol (PEG) linkers. Higher covalent binding (70-86%) was observed using the bifunctional ICG with short PEG linkers resulting in less in vivo non-covalent dissociation. Panitumumab-ICG conjugates with short PEG linkers were able to detect human epidermal growth factor receptor 1 (EGFR)-positive tumors with high tumor-to-background ratios (15.8 and 6.9 for EGFR positive tumor-to-negative tumor and tumor-to-liver ratios, respectively, at 3 d postinjection).
[Show abstract][Hide abstract] ABSTRACT: Active surveillance (AS) is an attempt to avoid overtreatment of clinically insignificant prostate cancer (PCa); however, patient selection remains controversial. Multiparametric prostate magnetic resonance imaging (MP-MRI) may help better select AS candidates.
We reviewed a cohort of men who underwent MP-MRI with MRI/Ultrasound fusion-guided prostate biopsy and selected potential AS patients at entry using Johns Hopkins criteria. MP-MRI findings were assessed, including number of lesions, dominant lesion diameter, total lesion volume, prostate volume, and lesion density (calculated as total lesion volume/prostate volume). Lesions were assigned a suspicion score for cancer by MRI. AS criteria were reapplied based on the confirmatory biopsy, and accuracy of MP-MRI in predicting AS candidacy was assessed. Logistic regression modeling and chi-square statistics were used to assess associations between MP-MRI interpretation and biopsy results.
Eighty-five patients qualified for AS with a mean age of 60.2 years and mean prostate-specific antigen level of 4.8 ng/mL. Of these, 25 patients (29%) were reclassified as not meeting AS criteria based on confirmatory biopsy. Number of lesions, lesion density, and highest MRI lesion suspicion were significantly associated with confirmatory biopsy AS reclassification. These MRI-based factors were combined to create a nomogram that generates a probability for confirmed AS candidacy.
As clinicians counsel patients with PCa, MP-MRI may contribute to the decision-making process when considering AS. Three MRI-based factors (number of lesions, lesion suspicion, and lesion density) were associated with confirmatory biopsy outcome and reclassification. A nomogram using these factors has promising predictive accuracy for which future validation is necessary. Cancer 2013. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Cancer 04/2013; 119(18). DOI:10.1002/cncr.28216 · 4.89 Impact Factor