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.

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-1aexpression 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 chemotherapyresistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.

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 postre-perfusion 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.

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Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.

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One of the most powerful features of the dynamic contrastenhanced (DCE) MRI technique is its capability to quantitatively measure the physiological or pathophysiological environments assessed by the passage of contrast agent by means of modelbased 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 K trans from Larsson's model, better than those from Brix's model and the empirical area-under-the-curve (AUC). Tissue-type classifier constructed with the arterial input function-decomposed k ep -k pe 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.

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. Keywords ultrahigh field whole-body MR; 7 and 8 Tesla clinical MR; brain tumorIn this article, ultrahigh field (UHF) is defined as the magnetic field strength (B 0 ) of 7 T or higher. Imaging systems for humans are currently used from 7 to 9.4 T. We will focus on the clinical aspects of ultrahigh-field whole-body human magnetic resonance imaging (MRI) systems.Since the introduction to clinical utility back in the 1980s, human whole-body MR scanners with various field strength have contributed significantly to patient care and became an indispensable tool for the management of most diseases of the central nerve system (CNS), including the focus of this issue, brain tumor imaging. For the past decades, the technical development for clinical MR scanners also has been making remarkable progress particularly in coil design, gradient, and radiofrequency (RF) performance as well as software development. The field strength, or B 0 , of the MR scanners increased constantly from the initial ultralow (<0.1 T) to low field (0.1-0.5 T) around the 1980s and from mid (0.5-1.5 T) to high field (3 T) during the early 1990s to 2000s. Meanwhile, the clinical experiences and applications for various CNS pathologies expand constantly as the field strength of the whole-body MR systems scanners continues to grow.Until recently, clinical MR scanners operating at field strength (B 0 ) of 1.5 T have been considered as the optimal means to evaluate neurological diseases. Just few years ago, there were many doubts about the worthiness and cost-effectiveness to develop a 3-T human system mostly because of technical challenges and cost perspectives. Fortunately, most of the technical problems have been resolved, and 3-T human scanners now become the stateof-the-art imaging modality for CNS diseases. With the improved signal-to-noise ratio (SNR) from the increased magnetic field strength, 3-T whole-body MR systems provide superior neuroimaging and functional capability as compared with those of the commonly available 1.5-T systems. Because the 3-T clinical systems have established tremendous credibility and clinical acceptance for the last few years, currently, the enthusiasm in building even higher field-strength clinical systems becomes the fastest growing segment of the MR marketplace. After the initial demonstration of feasibility at few academic ...