Timothy D. Johnson

Vascular Targeted Nanoparticles for Imaging and Treatment of Brain Tumors

Purpose: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. Experimental Design: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. Results: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. Conclusions: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.

Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression

Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers is urgently needed to enable individualized treatment, thus improving patient outcome. We adapted the parametric response map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole-lung computed tomography (CT) scans acquired at inspiration and expiration of 194 individuals with COPD from the COPDGene study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype while providing detailed spatial information of disease distribution and location. PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients, complementing standard clinical techniques.

Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival.

PURPOSE Assessment of radiologic response (RR) for brain tumors utilizes the Macdonald criteria 8 to 10 weeks from the start of treatment. Diffusion magnetic resonance imaging (MRI) using a functional diffusion map (fDM) may provide an earlier measure to predict patient survival. PATIENTS AND METHODS Sixty patients with high-grade glioma were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both log-rank and Cox proportional hazards models were utilized to assess overall survival. RESULTS Greater increases in diffusion in response to therapy over time were observed in those patients alive at 1 year compared with those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival (52.6 v 10.9 months; log-rank, P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). Radiologic response at 10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank P < .0007; HR = 2.9; 95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A composite index of response including fDM and RR provided a robust predictor of patient survival and may identify patients in whom RR does not correlate with clinical outcome. CONCLUSION Compared with conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.

Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia

Abstract Background: Irritable bowel syndrome (IBS) and fibromyalgia (FM) are considered chronic syndromes of altered visceral and somatic perception, respectively. Because there is a significant overlap of IBS and FM, shared pathophysiological mechanisms have been suggested. Although visceral perception has been well studied in IBS, somatic perception has not. Aims: To compare hypervigilance and altered sensory perception in response to somatic stimuli in patients with IBS, IBS+FM, and healthy controls. Methods: Eleven IBS females (mean age 40), 11 IBS+FM females (mean age 46), and ten healthy female controls (mean age 39) rated pain perception in response to pressure stimuli administered to active somatic tender points, non‐tender control points and the T‐12 dermatome, delivered in a predictable ascending series, and delivered in an unpredictable randomized fashion (fixed stimulus). Results: Although IBS patients had similar pain thresholds during the ascending series compared with controls, they were found to have somatic hypoalgesia with higher pain thresholds and lower pain frequency and severity during fixed stimulus series compared with IBS+FM patients and controls (P<0.05). Patients with IBS+FM were more bothered by the somatic stimuli and had somatic hyperalgesia with lower pain thresholds and higher pain frequency and severity. Conclusions: Both hypervigilance and somatic hypoalgesia contribute to the altered somatic perception in IBS patients. Co‐morbidity with FM results in somatic hyperalgesia in IBS patients.

The parametric response map is an imaging biomarker for early cancer treatment outcome

Here we describe the parametric response map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRMrCBV and PRMrCBF) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations made on the basis of PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRMrCBV proved more predictive of overall survival.

Parametric Response Map As an Imaging Biomarker to Distinguish Progression From Pseudoprogression in High-Grade Glioma

PURPOSE To assess whether a new method of quantifying therapy-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high-grade glioma. PATIENTS AND METHODS Patients with high-grade glioma received concurrent chemoradiotherapy. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired before chemoradiotherapy and at week 3 during treatment on a prospective institutional review board-approved study. Pseudoprogression was defined as imaging changes 1 to 3 months after chemoradiotherapy that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional magnetic resonance (MR) parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. RESULTS Median radiation dose was 72 Gy (range, 60 to 78 Gy). Of 27 patients, stable disease/partial response was noted in 13 patients and apparent progression was noted in 14 patients. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in six patients. Based on PRM analysis, a significantly reduced blood volume (PRM(rCBV)) at week 3 was noted in patients with progressive disease as compared with those with pseudoprogression (P < .01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and Radiation Therapy Oncology Group recursive partitioning analysis classification did not distinguish progression from pseudoprogression. CONCLUSION PRM(rCBV) at week 3 during chemoradiotherapy is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in patients with high-grade glioma.

Meta-Analysis of Functional Neuroimaging Studies of Emotion Perception and Experience in Schizophrenia

BACKGROUND Neuroimaging studies of emotion in schizophrenia have reported abnormalities in amygdala and other regions, although divergent results and heterogeneous paradigms complicate conclusions from single experiments. To identify more consistent patterns of dysfunction, a meta-analysis of functional imaging studies of emotion was undertaken. METHODS Searching Medline and PsycINFO databases through January 2011, 88 potential articles were identified, of which 26 met inclusion criteria, comprising 450 patients with schizophrenia and 422 healthy comparison subjects. Contrasts were selected to include emotion perception and emotion experience. Foci from individual studies were subjected to a voxelwise meta-analysis using multilevel kernel density analysis. RESULTS For emotional experience, comparison subjects showed greater activation in the left occipital pole. For emotional perception, schizophrenia subjects showed reduced activation in bilateral amygdala, visual processing areas, anterior cingulate cortex, dorsolateral frontal cortex, medial frontal cortex, and subcortical structures. Schizophrenia subjects showed greater activation in the cuneus, parietal lobule, precentral gyrus, and superior temporal gyrus. Combining across studies and eliminating studies that did not balance on effort and stimulus complexity eliminated most differences in visual processing regions as well as most areas where schizophrenia subjects showed a greater signal. Reduced reactivity of the amygdala appeared primarily in implicit studies of emotion, whereas deficits in anterior cingulate cortex activity appeared throughout all contrasts. CONCLUSIONS Processing emotional stimuli, schizophrenia patients show reduced activation in areas engaged by emotional stimuli, although in some conditions, schizophrenia patients exhibit increased activation in areas outside those traditionally associated with emotion, possibly representing compensatory processing.

Diffusion MRI: A new strategy for assessment of cancer therapeutic efficacy

The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator or treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a nonvolumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

Multi-system repeatability and reproducibility of apparent diffusion coefficient measurement using an ice-water phantom

To determine quantitative quality control procedures to evaluate technical variability in multi‐center measurements of the diffusion coefficient of water as a prerequisite to use of the biomarker apparent diffusion coefficient (ADC) in multi‐center clinical trials.

Diffusion Coefficient Measurement Using a Temperature-Controlled Fluid for Quality Control in Multicenter Studies

To present the use of a quality control ice‐water phantom for diffusion‐weighted magnetic resonance imaging (DW‐MRI). DW‐MRI has emerged as an important cancer imaging biomarker candidate for diagnosis and early treatment response assessment. Validating imaging biomarkers through multicenter trials requires calibration and performance testing across sites.