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1.  Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: A phase I trial of bortezomib plus bevacizumab 
Oncotarget  2014;5(21):10280-10292.
We hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.
Experimental Design
Patients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.
Ninety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m2. Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥6 months (Total SD≥6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in Ktrans although analysis was limited by small sample size (N=12).
Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.
PMCID: PMC4279372  PMID: 25373733
bevacizumab; bortezomib; phase 1; proteasome; HIF-1α
2.  Deformable Anatomic Templates Embed Knowledge into Brain Images: Part 2. Validation Using Functional Magnetic Resonance Imaging of the Motor Hand 
This study evaluated the concordance between the Deformable Anatomical Template (DAT)-identified origin of motor hand fibers and localization of the motor cortex of the hand (MCH) by functional magnetic resonance imaging (fMRI).
Preoperative fMRI during hand motor tasks was performed on 36 hemispheres in 26 patients with gliomas in or near eloquent areas. Reformatted volume-rendered surface images were labeled with the DAT’s hand motor fibers and fMRI data. Five reviewers assessed the data for concordance.
Available fMRI data were diagnostically usable in 92% (33 of 36 analyzed hemispheres), with DAT anatomic accuracy in the remaining cases. The DAT prediction and fMRI findings were concordant in all 9 normal hemispheres and in 20 of 24 (83%) glioma-bearing hemispheres. The 4 discordant cases resulted from substantial mass effect by large frontal tumors.
This study validated DAT’s anatomical atlas and alignment process for the expected position of the MCH.
PMCID: PMC3910394  PMID: 22446375
Brain atlas; functional magnetic resonance imaging; brain mapping; mass effect; glial tumor
3.  A Practical Approach for a Wide Range of Liver Iron Quantitation Using a Magnetic Resonance Imaging Technique 
The goal of this study is to demonstrate a practical magnetic resonance imaging technique for quantifying a wide range of hepatic iron concentration (HIC) for hematologic oncology patients with transfusion iron overload in a routine clinical setting. To cover a wide range of T2* values from hematologic patients, we used a dual-acquisition method with two clinically available acquisition protocols on a 1.5T MRI scanner with different ΔTEs to acquire data in two breath-holds. An in-house image postprocessing software tool was developed to generate T2*, iron maps, and water and fat images, when fat is presented in the liver. The resulting iron maps in DICOM format are transferred to the institutional electronic medical record system for review by radiologists. The measured liver T2* values for 28 patients ranged from 0.56 ± 0.13 to 25.0 ± 2.1 milliseconds. These T2* values corresponded to HIC values ranging from 1.2 ± 0.1 mg/g to 45.0 ± 10.0 mg/g (dry weight). A moderate correlation between overall serum ferritin levels and R2* was found with a correlation coefficient of 0.83. Repeated phantom scans confirmed that the precision of this method is better than 4% for T2* measurements. The dual- acquisition method also improved the ability to quantify HIC of the patients with hepatic steatosis.
PMCID: PMC3530181  PMID: 23365743
4.  Do brain responses to emotional images and cigarette cues differ? An fMRI study in smokers 
The European journal of neuroscience  2011;34(12):2054-2063.
Chronic smoking is thought to cause changes in brain reward systems that result in overvaluation of cigarette-related stimuli and undervaluation of natural rewards. We tested the hypotheses that, in smokers, brain circuits involved in emotional processing 1) would be more active during exposure to cigarette-related than neutral pictures, and 2) would be less active to pleasant compared to cigarette-related pictures, suggesting a devaluation of intrinsically pleasant stimuli. We obtained whole brain blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) data from 35 smokers during the presentation of pleasant (erotica and romance), unpleasant (mutilations and sad), neutral, and cigarette-related pictures. Whole brain analyses showed significantly larger BOLD responses during presentation of cigarette-related pictures relative to neutral ones within the secondary visual areas, the cingulate gyrus, the frontal gyrus, the dorsal striatum, and the left insula. BOLD responses to erotic pictures exceeded responses to cigarette-related pictures in all clusters except the insula. Within the left insula we observed larger BOLD responses to cigarette-related pictures than to all other picture categories. By including intrinsically pleasant and unpleasant pictures in addition to neutral ones, we were able to conclude that the presentation of cigarette-related pictures activates brain areas supporting emotional processes, but we did not find evidence of overall reduced activation of the brain reward systems in the presence of intrinsically pleasant stimuli.
PMCID: PMC3237919  PMID: 22097928
pictures; smoking; nicotine; emotions; insula
5.  Phase 1–2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer 
The lancet oncology  2011;12(12):1109-1117.
Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population.
For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m2). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m2 intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at, number NCT00436501.
From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m2, respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3–4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1–2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%).
Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted.
US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.
PMCID: PMC3444811  PMID: 21992853
6.  Pharmacokinetics and Magnetic Resonance Imaging of Biodegradable Macromolecular Blood-Pool Contrast Agent PG-Gd in Non-Human Primates: A Pilot Study 
The purpose of this study was to evaluate poly(L-glutamic acid)-benzyl-DTPA-Gd (PG-Gd), a new biodegradable macromolecular magnetic resonance imaging contrast agent, for its pharmacokinetics and MRI enhancement in nonhuman primates. Studies were performed in rhesus monkeys at intravenous doses of 0.01, 0.02, and 0.08 mmol Gd/kg. T1-weighted MR images were acquired at 1.5T using fast spoiled gradient recalled echo and fast spin echo imaging protocols. The small-molecule contrast agent Magnevist was used as a control. PG-Gd in the monkey showed a bi-exponential disposition. The initial blood concentrations within 2 hours of PG-Gd administration were much higher than for those of Magnevist. The high blood concentration of PG-Gd was consistent with the MR imaging data, which showed prolonged circulation of PG-Gd in the blood pool. Enhancement of blood vessels and organs with a high blood perfusion (heart, liver, and kidney) was clearly visualized at 2 hours after contrast injection at the three doses used. A greater than proportional increase of the area under the blood concentration-time curve was observed when the administered single dose was increased from 0.01 mmol/kg to 0.08 mmol/kg. By 2 days after PG-Gd injection, the contrast agent was mostly cleared from all major organs, including kidney. The mean residence time was 15 hours at the 0.08 mmol/kg dose. A similar pharmacokinetic profile was observed in mice, with a mean residence time of 5.4 hours and a volume of distribution at steady-state of 85.5 mL/kg, indicating that the drug was mainly distributed in the blood compartment. Based on this pilot study, further investigations on potential systemic toxicity of PG-Gd in both rodents and large animals are needed before testing this agent in humans.
PMCID: PMC3435886  PMID: 21861289
Magnetic resonance imaging; blood pool; contrast media; polymers; non-human primate
7.  Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study 
Journal of Clinical Oncology  2011;29(19):2689-2695.
Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma.
Patients and Methods
Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle.
The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance.
Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.
PMCID: PMC3139373  PMID: 21606416
8.  Applications of Imaging Technology in Radiation Research 
Radiation Research  2012;177(4):387-397.
Imaging research and advances in systems engineering have enabled the transition of medical imaging from a means for accomplishing traditional anatomic visualization (i.e., orthopedic planar film X ray) to a means for noninvasively assessing a variety of functional measures. Perfusion imaging is one of the major highlights in functional imaging. In this work, various methods for measuring perfusion using widely-available commercial imaging modalities and contrast agents, specifically X ray and MR (magnetic resonance), will be described. The first section reviews general methods used for perfusion imaging, and the second section provides modality-specific information, focusing on the contrast mechanisms used to calculate perfusion-related parameters. The goal of these descriptions is to illustrate how perfusion imaging can be applied to radiation biology research.
PMCID: PMC3355534  PMID: 22401349
9.  Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the CNS 
To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.
Methods and Materials
Fourteen patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system (CNS) radiation necrosis. All patients were required to have radiographic or biopsy proof of CNS radiation necrosis and progressive neurological symptoms or signs. Eligible patients received irradiation for head and neck carcinomas, meningioma, or low- to mid-grade gliomas. Patients were randomized to receive IV saline or bevacizumab at 3-week intervals. MRI 3-weeks after the second treatment and clinical signs and symptoms defined response or progression.
The volumes of necrosis estimated on T2FLAIR and T1-weighted gadolinium-enhanced MRI demonstrated that, while no patient receiving placebo responded (0/7), all bevacizumab-treated patients did (5/5 randomized and 7/7 cross-over) with decreases in T2FLAIR and T1-weighted gadolinium-enhanced volumes and decrease Ktrans. All bevacizumab-treated patients – and none of the placebo-treated patients - showed improvement in neurological symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all 4 study doses, only 2 patients had experienced a recurrence of MRI changes consistent with progressive radiation necrosis, and this was the only patient to receive only 2 treatments with bevacizumab.
This class I evidence of bevacizumab efficacy in the treatment of CNS radiation necrosis justifies consideration of this treatment option for people who suffer radiation necrosis secondary to the treatment of head and neck and brain cancers.
PMCID: PMC2908725  PMID: 20399573
brain edema; magnetic resonance imaging; volumetric MRI changes; Ktrans; neurotoxicity
10.  Magnetic Resonance Assessment of Response to Therapy: Tumor Change Measurement, Truth Data and Error Sources1 
Translational Oncology  2009;2(4):211-215.
This article describes methods and issues that are specific to the assessment of change in tumor characteristics as measured using quantitative magnetic resonance (MR) techniques and how this relates to the establishment of quantitative MR imaging (MRI) biomarkers of patient response to therapy. The initial focus is on the various sources of bias and variance in the measurement of microvascular parameters and diffusion parameters as such parameters are being used relatively commonly as secondary or exploratory end points in current phase 1/2 clinical trails of conventional and targeted therapies. Several ongoing initiatives that seek to identify the magnitude of some of the sources of measurement variations are then discussed. Finally, resources being made available through the National Cancer Institute Reference Image Database to Evaluate Response (RIDER) project that might be of use in investigations of quantitative MRI biomarker change analysis are described. These resources include 1) data from phantom-based assessment of system response, including short-term (1 hour) and moderate-term (1 week) contrast response and relaxation time measurement, 2) data obtained from repeated dynamic contrast agent-enhanced MRI studies in intracranial tumors, and 3) data obtained from repeated diffusion MRI studies in both breast and brain. A concluding section briefly discusses issues that must be addressed to allow the transition of MR-based imaging biomarker measures from their current role as secondary/exploratory end points in clinical trials to primary/surrogate markers of response and, ultimately, in clinical application.
PMCID: PMC2781079  PMID: 19956380
11.  Quantitative Imaging to Assess Tumor Response to Therapy: Common Themes of Measurement, Truth Data, and Error Sources1 
Translational Oncology  2009;2(4):198-210.
RATIONALE: Early detection of tumor response to therapy is a key goal. Finding measurement algorithms capable of early detection of tumor response could individualize therapy treatment as well as reduce the cost of bringing new drugs to market. On an individual basis, the urgency arises from the desire to prevent continued treatment of the patient with a high-cost and/or high-risk regimen with no demonstrated individual benefit and rapidly switch the patient to an alternative efficacious therapy for that patient. In the context of bringing new drugs to market, such algorithms could demonstrate efficacy in much smaller populations, which would allow phase 3 trials to achieve statistically significant decisions with fewer subjects in shorter trials. MATERIALS AND METHODS: This consensus-based article describes multiple, image modality-independent means to assess the relative performance of algorithms for measuring tumor change in response to therapy. In this setting, we describe specifically the example of measurement of tumor volume change from anatomic imaging as well as provide an overview of other promising generic analytic methods that can be used to assess change in heterogeneous tumors. To support assessment of the relative performance of algorithms for measuring small tumor change, data sources of truth are required. RESULTS: Very short interval clinical imaging examinations and phantom scans provide known truth for comparative evaluation of algorithms. CONCLUSIONS: For a given category of measurement methods, the algorithm that has the smallest measurement noise and least bias on average will perform best in early detection of true tumor change.
PMCID: PMC2781075  PMID: 19956379
12.  Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme 
Neuro-Oncology  2008;10(2):216-222.
This phase II study aimed at determining the efficacy and safety of irinotecan combined with thalidomide in adults with recurrent glioblastoma multiforme (GBM) not taking enzyme-inducing anticonvulsants (EIACs). Adult patients (⩾18 years) with recurrent GBM with up to three relapses following surgery and radiation therapy were eligible for this trial. The primary end point was rate of progression-free survival at 6 months (PFS-6); secondary end points were response rate, overall survival, and toxicity. Patients were treated in 6-week cycles with 125 mg/m2 irinotecan weekly for 4 weeks followed by 2 weeks off treatment and 100 mg of thalidomide daily increased as tolerated to 400 mg/day. Of 32 evaluable patients, 8 (25%) were alive and progression free at 6 months. The median PFS was 13 weeks. One patient experienced a complete response, one a partial response, and 19 stable disease. Median overall survival time from entry into the study was 36 weeks, and the 1-year survival rate was 34%. Adverse events (grade 3 or 4) included diarrhea, abdominal cramps, lymphopenia, neutropenia, and fatigue. Two of the four deaths that occurred were possibly due to treatment-related toxicity. The combination of irinotecan, a cytotoxic agent, and thalidomide, an antiangiogenic agent, shows promising activity against recurrent GBM in patients not receiving EIACs and warrants further study. The results also provide support for similar strategies using combination therapies with newer targeted antiangiogenic agents to generate effective therapies against malignant gliomas.
PMCID: PMC2613824  PMID: 18314417
angiogenesis; combination chemotherapy; glioblastoma multiforme; progression-free survival
13.  Magnetic Resonance Imaging of Therapy-induced Necrosis Using Gadolinium-Chelated Polyglutamic Acids 
Necrosis is the most common morphological alteration found in tumors and surrounding normal tissues after radiation therapy or chemotherapy. Accurate measurement of necrosis may provide an early indication of treatment efficacy or associated toxicity. The purpose of this report is to evaluate the selective accumulation of polymeric paramagnetic magnetic resonance (MR) contrast agents—gadolinium p-aminobenzyl-diethylenetriaminepentaacetic acid-poly(glutamic acid) (L-PG-DTPA-Gd and D-PG-DTPA-Gd)—in necrotic tissue.
Methods and Materials
Two different solid tumor models, human Colo-205 xenograft and syngeneic murine OCA-1 ovarian tumors, were used in this study. Necrotic response was induced by treatment with poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL). T1-weighted spin-echo images were obtained immediately and up to 4 days after contrast injection and compared with corresponding histologic specimens. Two low-molecular-weight contrast agents, DTPA-Gd and oligomeric(L-glutamic acid)-DTPA-Gd, were used as nonspecific controls.
Initially, there was minimal tumor enhancement following injection of either L-PG-DTPA-Gd or D-PG-DTPA-Gd but rapid enhancement following injection of low-molecular-weight agents. However, polymeric contrast agents, but not low-molecular-weight contrast agents, caused sustained enhancement in regions of tumor necrosis in both tumors treated with PG-TXL and untreated tumors. These data indicate that high molecular weight, rather than in vivo biodegradation, is necessary for the specific localization of polymeric MR contrast agents to necrotic tissue. Moreover, biotinylated L-PG-DTPA-Gd co-localized with macrophages in the tumor necrotic areas, suggesting that selective accumulation of L- and D-PG-DTPA-Gd in necrotic tissue was mediated through residing macrophages.
Our data suggest that MRI with PG-DTPA-Gd may be a useful technique for noninvasive characterization of treatment-induced necrosis.
PMCID: PMC1997292  PMID: 17379450
Magnetic resonance imaging; necrosis; macrophages; polymer; treatment response
14.  Oxygenation Inhibits the Physiological Tissue-Protecting Mechanism and Thereby Exacerbates Acute Inflammatory Lung Injury 
PLoS Biology  2005;3(6):e174.
Acute respiratory distress syndrome (ARDS) usually requires symptomatic supportive therapy by intubation and mechanical ventilation with the supplemental use of high oxygen concentrations. Although oxygen therapy represents a life-saving measure, the recent discovery of a critical tissue-protecting mechanism predicts that administration of oxygen to ARDS patients with uncontrolled pulmonary inflammation also may have dangerous side effects. Oxygenation may weaken the local tissue hypoxia-driven and adenosine A2A receptor (A2AR)-mediated anti-inflammatory mechanism and thereby further exacerbate lung injury. Here we report experiments with wild-type and adenosine A2AR-deficient mice that confirm the predicted effects of oxygen. These results also suggest the possibility of iatrogenic exacerbation of acute lung injury upon oxygen administration due to the oxygenation-associated elimination of A2AR-mediated lung tissue-protecting pathway. We show that this potential complication of clinically widely used oxygenation procedures could be completely prevented by intratracheal injection of a selective A2AR agonist to compensate for the oxygenation-related loss of the lung tissue-protecting endogenous adenosine. The identification of a major iatrogenic complication of oxygen therapy in conditions of acute lung inflammation attracts attention to the need for clinical and epidemiological studies of ARDS patients who require oxygen therapy. It is proposed that oxygen therapy in patients with ARDS and other causes of lung inflammation should be combined with anti-inflammatory measures, e.g., with inhalative application of A2AR agonists. The reported observations may also answer the long-standing question as to why the lungs are the most susceptible to inflammatory injury and why lung failure usually precedes multiple organ failure.
A mouse model suggests that oxygen therapy may exacerbate lung injury by weakening the anti-inflammatory mechanisms driven by hypoxia.
PMCID: PMC1088279  PMID: 15857155
15.  Mushroom worker's lung 
Thorax  1970;25(1):25-30.
Two cases of an acute chest illness occurring in mushroom workers are described. In one patient, who was severely ill, a lung biopsy was obtained which showed a pattern of alveolitis and interstitial fibrosis. The serum of both patients gave a precipitin reaction to an extraction of mushroom compost after spawning, but no reaction occurred to a variety of hay antigens used in the diagnosis of farmer's lung. A provocation test undertaken in one patient demonstrated a reaction to the inhalation of a dilute extract of mushroom compost after spawning. The most severely ill patient made a full clinical and functional recovery without steroid therapy.
PMCID: PMC472114  PMID: 5461446

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