R.M. Koch

Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor

Purpose: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production. Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging. Results: Hypoxia enhanced HIF-1α expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition. Conclusions: The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.

Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models

Oncolytic virotherapy is a potential treatment modality under investigation for various malignancies including malignant brain tumors. Unlike some other natural or modified viruses that show oncolytic activity against cerebral neoplasms, the rodent parvovirus H-1 (H-1PV) is completely apathogenic in humans. H-1PV efficiently kills a number of tumor cells without harm to corresponding normal ones. In this study, the concept of H-1PV-based virotherapy of glioma was tested for rat (RG-2 cell-derived) and for human (U87 cell-derived) gliomas in immunocompetent and immunodeficient rat models, respectively. Large orthotopic rat and human glioma cell-derived tumors were treated with either single stereotactic intratumoral or multiple intravenous (iv) H-1PV injections. Oncolysis was monitored by magnetic resonance imaging and proven by histology. Virus distribution and replication were determined in brain and organs. In immunocompetent rats bearing RG-2-derived tumors, a single stereotactic intratumoral injection of H-1PV and multiple systemic (iv) applications of the virus were sufficient for remission of advanced and even symptomatic intracranial gliomas without damaging normal brain tissue or other organs. H-1PV therapy resulted in significantly improved survival (Kaplan-Meier analysis) in both the rat and human glioma models. Virus replication in tumors indicated a contribution of secondary infection by progeny virus to the efficiency of oncolysis. Virus replication was restricted to tumors, although H-1PV DNA could be detected transiently in adjacent or remote normal brain tissue and in noncerebral tissues. The results presented here and the innocuousness of H-1PV for humans argue for the use of H-1PV as a powerful means to perform oncolytic therapy of malignant gliomas.

Improving the Pharmacokinetic Parameter Measurement in Dynamic Contrast-Enhanced MRI by Use of the Arterial Input Function: Theory and Clinical Application

One of the most powerful features of the dynamic contrast‐enhanced (DCE) MRI technique is its capability to quantitatively measure the physiological or pathophysiological environments assessed by the passage of contrast agent by means of model‐based pharmacokinetic analysis. The widely used two‐compartment pharmacokinetic model developed by Brix and colleges fits tumor data well in most cases, but fails to explain the biexponential arterial input function. In this work, this problem has been attacked from a theoretical point of view, showing that this problem can be solved by adopting a more realistic model assumption when simplifying the general solutions of the two‐compartment pharmacokinetic equations. Pharmacokinetic parameters derived from our model were demonstrated to have comparative tissue specificity to Ktrans from Larssons model, better than those from Brixs model and the empirical area‐under‐the‐curve (AUC). Tissue‐type classifier constructed with the arterial input function–decomposed kep‐kpe pair from our model was also demonstrated to have superior performance than any other classifier based on DCE‐MRI pharmacokinetic parameters or empirical AUC. The feature that this classifier has a near‐zero false‐negative rate makes it a highly desirable tool for clinical diagnostic and response assessment applications. Magn Reson Med 59:1448–1456, 2008.

An Endovascular Canine Middle Cerebral Artery Occlusion Model for the Study of Leptomeningeal Collateral Recruitment

Objectives:This work aimed to refine a large animal in minimally invasive reversible middle cerebral artery (MCA) occlusion (MCAO) model to account for leptomeningeal collateral formation. Materials and Methods:An angiographically based methodology allowed for transient MCA and carotid terminus occlusion in 12 mongrel dogs and assessment of pial collateral recruitment. Outcome measures included 1- and 24-hour magnetic resonance imaging-based infarct volume calculation, a behavioral scale and histopathologic sections. Results:MCAO succeeded in 8 of 12 dogs (67% efficiency). One-hour postreperfusion infarct volume predicted 24-hour postreperfusion infarct volume (r2 = 0.997, P < 0.0001). Pial collateral recruitment varied with time and reproducibly assessed predicted infarct volume on 1-hour postreperfusion mean diffusivity maps (P < 0.0001; r2 = 0.946) and 24-hour fluid-attenuated inversion recovery FLAIR magnetic resonance imaging (P = 0.0033; r2 = 0.961). The canine stroke scale score correlated with infarct volumes and pial collateral score. Conclusion:This canine MCAO model produces defined cerebral infarct lesions whose volumes correlate with leptomeningeal collateral formation and canine behavior.

Clinical magnetic resonance imaging of brain tumors at ultrahigh field: a state-of-the-art review.

With the advancement of the magnetic resonance (MR) technology, the whole-body ultrahigh field MR system operated from 7 to 9.4 T becomes feasible for the routine patient imaging in clinical settings. The associated potentials and challenges from the perspectives of technology, physics, and biology as well as clinical application of the ultrahigh field MR systems are different from those systems operated at 3 T, 1.5 T, or lower field strength. In this article, we will present our initial experiences of brain tumor imaging using the 7 and 8 T whole-body MR systems at the Ohio State University Medical Center and provide a brief overview pertinent to the ultrahigh field clinical MR systems.

Multispectral Co-Occurrence With Three Random Variables in Dynamic Contrast Enhanced Magnetic Resonance Imaging of Breast Cancer

Presented is a new computer-aided multispectral image processing method which is used in three spatial dimensions and one spectral dimension where the dynamic, contrast enhanced magnetic resonance parameter maps derived from voxel-wise model-fitting represent the spectral dimension. The method is based on co-occurrence analysis using a 3-D window of observation which introduces an automated identification of suspicious lesions. The co-occurrence analysis defines 21 different statistical features, a subset of which were input to a neural network classifier where the assessments of the voxel-wise majority of a group of radiologist readings were used as the gold standard. The voxel-wise true positive fraction (TPF) and false positive fraction (FPF) results of the computer classifier were statistically indistinguishable from the TPF and FPF results of the readers using a one sample paired t-test. In order to observe the generality of the method, two different groups of studies were used with widely different image acquisition specifications.

Residual magnetism in an MRI suite after field-rampdown: what are the issues and experiences?

To investigate residual magnetization at different locations in the MRI suite at several time points prior, during and after field‐rampdown with the goal to determine if the MRI suites could be reused in a clinical environment after the field‐rampdown of MR scanners of different field strengths.

Improvement in the Reproducibility of Region of Interest Using an Auditory Feedback Loop: A Pilot Assessment Using Dynamic Contrast-Enhanced (DCE) Breast MR Images

To augment traditional visual data perception of complex multiparametric imaging data sets by adding auditory feedback to improve the delineation of regions of interest (ROIs) in tumor assessment in dynamic contrast‐enhanced (DCE) MRI.