Multiparametric MRI of the prostate at 3 T: limited value of 3D (1)H-MR spectroscopy as a fourth parameter.

PURPOSE: The aim of our study was to assess whether multiparametric magnetic resonance imaging (MP-MRI) of the prostate with three parameters (PS3: T2-weighted, DWI, and DCE) benefits from an additional fourth parameter (PS4: including (1)H-MRSI) in the detection and grading of prostate cancer (PCa) at 3 T. METHODS: MP-MRI was performed in 64 patients (mean 66.7 years, mean PSA 13 ng/ml). Reference standard was obtained by histopathology. Two readers independently evaluated the images. A summation score of each individual parameter for three parameters (PS3) and for four parameters (PS4) was calculated. RESULTS: In 52 (81.3 %) of 64 patients, histopathology confirmed a PCa. The diagnostic performance for PCa detection of PS4 (O1: 91.7 %, O2: 91.3 %) equaled that of PS3 (O1: 92.8 %, O2: 92.2 %, P > 0.05). Prediction of high-grade PCa by PS4 (O1: 75.1 %, O2: 74.7 %) was as good as with PS3 (O1: 75.1 %, O2: 72.8 %, P > 0.05). Kappa agreement between the two readers was substantial (0.734 PS4) to moderate (0.558 PS3). CONCLUSIONS: MP-MRI with four parameters including (1)H-MRSI does not increase the detection and grading of prostate cancer at 3 T compared to MP-MRI with three parameters. A sum score accurately detects PCa at 3 T without an endorectal coil and shows potential for the prediction of tumor grade.

Novel handheld PET probes provide intraoperative localization of PET-avid lymph nodes.

INTRODUCTION: The accurate intraoperative localization of malignant nodes can pose a challenge to the surgical oncologist. Positron emission tomography (PET) scanning has significantly increased our ability to detect suspicious lesions. We investigated the ability of a novel, handheld tool to evaluate suspicious nodes intraoperatively and to correlate its findings with those seen on preoperative PET scan. METHODS: Ten nude rats were inoculated with a lymphogenic mesothelioma tumor line and followed weekly with PET scan studies. When suspicious lymph nodes were found, animals were dissected and the intraoperative amount of tissue radiation was analyzed as "tumor-to-background ratio" (TBR) using the PET probes. RESULTS: The intraoperative probe was used to guide dissections and select high-risk nodes based on their specific radiotracer uptake. A total of 52 nodes were harvested; eight of these were suspicious on preoperative PET scan studies. Using a TBR of 2.5, the intraoperative probes were able to localize all suspicious nodes previously seen on PET scan. Both gamma (sensitivity: 100%; specificity: 86%; positive predictive value (PPV): 57%; negative predictive value (NPV): 100%) and beta (sensitivity: 88%; specificity: 91%; PPV: 64%; NPV: 98%) probes showed an excellent area under the curve (AUC) in the receiver operating characteristic analysis (ROC). Both probes had an AUC of 0.95 for localizing suspicious nodes on PET scan. Furthermore, the AUC for detecting malignancy for the gamma probe was 0.90 (95% confidence interval (CI), 0.83-0.99), and for the beta probe it was 0.97 (95% CI, 0.94-1.0), suggesting a better performance of the beta probe for detecting malignancy. CONCLUSIONS: This novel tool may be used synergistically with the PET scan examination to maximize intraoperative nodal selection and sampling.

Principles and basic concepts of molecular imaging.

Advanced knowledge in molecular biology and new technological developments in imaging modalities and contrast agents calls for molecular imaging (MI) to play a major role in the near future in many human diseases (Weissleder and Mahmood Radiology 219:316-333, 2001). Imaging systems are providing higher signal-to-noise ratio and higher spatial and/or temporal resolution. New specific contrast agents offer the opportunity to drive new challenges for obtaining functional and biological information on tissue characteristics and tissue processes. All this information could be relevant for diagnosis, prognosis and treatment follow-up and to drive local therapies, enhancing local drug/gene delivery. The recent explosion of all these developments is a radical change of perspective in our imaging community because they could have a tremendous impact on our clinical practice and on teaching programs and they call for a more prominent multidisciplinary approach in this field of research.

Different strategies for reducing intestinal background radioactivity associated with imaging HSV1-tk expression using established radionucleoside probes.

One limitation of HSV1-tk reporter positron emission tomography (PET) with nucleoside analogues is the high background radioactivity in the intestine. We hypothesized that endogenous expression of thymidine kinase in bacterial flora could phosphorylate and trap such radiotracers, contributing to the high radioactivity levels in the bowel, and therefore explored different strategies to increase fecal elimination of radiotracer. Intestinal radioactivity was assessed by in vivo microPET imaging and ex vivo tissue sampling following intravenous injection of 18F-FEAU, 124I-FIAU, or 18F-FHBG in a germ-free mouse strain. We also explored the use of an osmotic laxative agent and/or a 100% enzymatically hydrolyzed liquid diet. No significant differences in intestinal radioactivity were observed between germ-free and normal mice. 18F-FHBG-derived intestinal radioactivity levels were higher than those of 18F-FEAU and 124I-FIAU; the intestine to blood ratio was more than 20-fold higher for 18F-FHBG than for 18F-FEAU and 124I-FIAU. The combination of Peptamen and Nulytely lowered intestinal radioactivity levels and increased (2.2-fold) the HSV1-tk transduced xenograft to intestine ratio for 18F-FEAU. Intestinal bacteria in germ-free mice do not contribute to the high intestinal levels of radioactivity following injection of radionucleoside analogues. The combination of Peptamen and Nulytely increased radiotracer elimination by increasing bowel motility without inducing dehydration.

Imaging a Genetically Engineered Oncolytic Vaccinia Virus (GLV-1h99) Using a Human Norepinephrine Transporter Reporter Gene.

PURPOSE: Oncolytic viral therapy continues to be investigated for the treatment of cancer, and future studies in patients would benefit greatly from a noninvasive modality for assessing virus dissemination, targeting, and persistence. The purpose of this study was to determine if a genetically modified vaccinia virus, GLV-1h99, containing a human norepinephrine transporter (hNET) reporter gene, could be sequentially monitored by [(123)I]metaiodobenzylguanidine (MIBG) gamma-camera and [(124)I]MIBG positron emission tomography (PET) imaging. EXPERIMENTAL DESIGN: GLV-1h99 was tested in human malignant mesothelioma and pancreatic cancer cell lines for cytotoxicity, expression of the hNET protein using immunoblot analysis, and [(123)I]MIBG uptake in cell culture assays. In vivo [(123)I]MIBG gamma-camera and serial [(124)I]MIBG PET imaging was done in MSTO-211H orthotopic pleural mesothelioma tumors. RESULTS: GLV-1h99 successfully infected and provided dose-dependent levels of transgene hNET expression in human malignant mesothelioma and pancreatic cancer cells. The time course of [(123)I]MIBG accumulation showed a peak of radiotracer uptake at 48 hours after virus infection in vitro. In vivo hNET expression in MSTO-211H pleural tumors could be imaged by [(123)I]MIBG scintigraphy and [(124)I]MIBG PET 48 and 72 hours after GLV-1h99 virus administration. Histologic analysis confirmed the presence of GLV-1h99 in tumors. CONCLUSION: GLV-1h99 shows high mesothelioma tumor cell infectivity and cytotoxic efficacy. The feasibility of imaging virus-targeted tumor using the hNET reporter system with [(123)I]MIBG gamma-camera and [(124)I]MIBG PET was shown in an orthotopic pleural mesothelioma tumor model. The inclusion of human reporter genes into recombinant oncolytic viruses enhances the potential for translation to clinical monitoring of oncolytic viral therapy.

Oncolytic vaccinia therapy of squamous cell carcinoma.

BACKGROUND: Novel therapies are necessary to improve outcomes for patients with squamous cell carcinomas (SCC) of the head and neck. Historically, vaccinia virus was administered widely to humans as a vaccine and led to the eradication of smallpox. We examined the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68) as an oncolytic agent against a panel of six human head and neck SCC cell lines. RESULTS: All six cell lines supported viral transgene expression (beta-galactosidase, green fluorescent protein, and luciferase) as early as 6 hours after viral exposure. Efficient transgene expression and viral replication (>150-fold titer increase over 72 hrs) were observed in four of the cell lines. At a multiplicity of infection (MOI) of 1, GLV-1h68 was highly cytotoxic to the four cell lines, resulting in > or = 90% cytotoxicity over 6 days, and the remaining two cell lines exhibited >45% cytotoxicity. Even at a very low MOI of 0.01, three cell lines still demonstrated >60% cell death over 6 days. A single injection of GLV-1h68 (5 x 10(6) pfu) intratumorally into MSKQLL2 xenografts in mice exhibited localized intratumoral luciferase activity peaking at days 2-4, with gradual resolution over 10 days and no evidence of spread to normal organs. Treated animals exhibited near-complete tumor regression over a 24-day period without any observed toxicity, while control animals demonstrated rapid tumor progression. CONCLUSION: These results demonstrate significant oncolytic efficacy by an attenuated vaccinia virus for infecting and lysing head and neck SCC both in vitro and in vivo, and support its continued investigation in future clinical trials.

Real-time intraoperative detection of melanoma lymph node metastases using recombinant vaccinia virus GLV-1h68 in an immunocompetent animal model.

There is a clinical need for improved intraoperative detection of lymph node metastases from malignant melanoma (MM). We aimed to investigate the use of recombinant vaccinia virus GLV-1h68, expressing green fluorescent protein (GFP), for real-time intraoperative detection of melanoma lymph node metastases in an immunocompetent animal model. Mice bearing foot pad tumors received intratumoral injections of GLV-1h68, and 48 hr later were evaluated for popliteal lymph node metastasis using noninvasive bioluminescence imaging and fluorescence imaging. Histologic analysis of lymph nodes was performed to determine sensitivity and specificity of virus-mediated detection. Intratumoral injection of GLV-1h68 into primary foot pad melanoma tumors resulted in viral transmission to popliteal lymph nodes, infection of lymphatic metastases, and transgene expression that was reliably and easily detected. Histologic confirmation demonstrated favorable operating characteristics of this assay (sensitivity 80%, specificity 100%, positive predictive value [PPV] 100%, negative predictive value [NPV] 91%). Detection of marker gene expression by GLV-1h68 allowed the detection of lymphatic metastases in an immunocompetent animal model of MM. This assay is rapid, sensitive, specific and easy to perform and interpret. As a candidate gene therapy virus for killing cancer, GLV-1h68 may also have significant concomitant diagnostic utility in the staging of cancer patients.

A novel recombinant vaccinia virus expressing the human norepinephrine transporter retains oncolytic potential and facilitates deep-tissue imaging.

Noninvasive and repetitive monitoring of a virus in target tissues and/or specific organs of the body is highly desirable for the development of safe and efficient cancer virotherapeutics. We have previously shown that the oncolytic vaccinia virus GLV-1h68 can target and eradicate human tumors in mice and that its therapeutic effects can be monitored by using optical imaging. Here, we report on the development of a derivative of GLV-1h68, a novel recombinant vaccinia virus (VACV) GLV-1h99, which was constructed to carry the human norepinephrine transporter gene (hNET) under the VACV synthetic early promoter placed at the F14.5L locus for deep-tissue imaging. The hNET protein was expressed at high levels on the membranes of cells infected with this virus. Expression of the hNET protein did not negatively affect virus replication, cytolytic activity in cell culture, or in vivo virotherpeutic efficacy. GLV-1h99-mediated expression of the hNET protein in infected cells resulted in specific uptake of the radiotracer [131I]-meta-iodobenzylguanidine (MIBG). In mice, GLV-1h99-infected tumors were readily imaged by [124I]-MIBG positron emission tomography. To our knowledge, GLV-1h99 is the first oncolytic virus expressing the hNET protein that can efficiently eliminate tumors and simultaneously allow deep-tissue imaging of infected tumors.

Attenuated multimutated herpes simplex virus-1 effectively treats prostate carcinomas with neural invasion while preserving nerve function.

Many cancers can cause disability and pain by invading nerves. In particular, prostate carcinoma has a high propensity for neural invasion (NI) at an early stage. Attempted surgical treatment of tumors with NI often leads to erectile dysfunction and deteriorated quality of life. Therefore, there is a need for novel modalities that will selectively target cancer cells while preserving neural function. Herpes simplex viruses (HSVs) have a natural trophism for peripheral nerves. We hypothesized that oncolytic therapy using HSV engineered to minimize neurotoxicity would be appropriate for this clinical setting. Attenuated HSV (NV1023) injected to sciatic nerves of nude mice had no toxic effect on nerve function (n=30). NV1023 had significant oncolytic effect on prostate carcinoma cells (PC3, DU145, and LNCap) in vitro. An in vivo model of NI was established by implanting prostate carcinoma cells in the sciatic nerves of nude mice. Mice were treated with NV1023 or saline 7 days after establishment of tumors. Significant reduction in tumor size and inhibition of NI was found 6-8 wk after treatment (P<0.005). All animals treated with saline developed complete paralysis <5 wk post-treatment, whereas most NV1023-treated animals had preserved nerve function >12 wk after treatment (P<0.0001). We conclude that oncolytic therapy effectively treats prostate carcinomas with NI in an in vivo murine model while preserving neural function. These findings may hold significant clinical implications for patients with prostate cancer or other neurotrophic tumors.

Escherichia coli Nissle 1917 facilitates tumor detection by positron emission tomography and optical imaging.

PURPOSE: Bacteria-based tumor-targeted therapy is a modality of growing interest in anticancer strategies. Imaging bacteria specifically targeting and replicating within tumors using radiotracer techniques and optical imaging can provide confirmation of successful colonization of malignant tissue. EXPERIMENTAL DESIGN: The uptake of radiolabeled pyrimidine nucleoside analogues and [18F]FDG by Escherichia coli Nissle 1917 (EcN) was assessed both in vitro and in vivo. The targeting of EcN to 4T1 breast tumors was monitored by positron emission tomography (PET) and optical imaging. The accumulation of radiotracer in the tumors was correlated with the number of bacteria. Optical imaging based on bioluminescence was done using EcN bacteria that encode luciferase genes under the control of an l-arabinose-inducible P(BAD) promoter system. RESULTS: We showed that EcN can be detected using radiolabeled pyrimidine nucleoside analogues, [18F]FDG and PET. Importantly, this imaging paradigm does not require transformation of the bacterium with a reporter gene. Imaging with [18F]FDG provided lower contrast than [18F]FEAU due to high FDG accumulation in control (nontreated) tumors and surrounding tissues. A linear correlation was shown between the number of viable bacteria in tumors and the accumulation of [18F]FEAU, but not [18F]FDG. The presence of EcN was also confirmed by bioluminescence imaging. CONCLUSION: EcN can be imaged by PET, based on the expression of endogenous E. coli thymidine kinase, and this imaging paradigm could be translated to patient studies for the detection of solid tumors. Bioluminescence imaging provides a low-cost alternative to PET imaging in small animals.

Oncolytic vaccinia virotherapy of anaplastic thyroid cancer in vivo.

CONTEXT: Anaplastic thyroid carcinoma (ATC) is a fatal disease with a median survival of only 6 months. Novel therapies are needed to improve dismal outcomes. OBJECTIVE: A mutated, replication-competent, vaccinia virus (GLV-1h68) has oncolytic effects on human ATC cell lines in vitro. We assessed the utility of GLV-1h68 in treating anaplastic thyroid cancer in vivo. DESIGN: Athymic nude mice with xenograft flank tumors of human ATCs (8505C and DRO90-1) were treated with a single intratumoral injection of GLV-1h68 at low dose (5x10(5) plaque-forming unit), high dose (5x10(6) plaque-forming unit), or PBS. Virus-mediated marker gene expression (luciferase, green fluorescent protein, and beta-galactosidase), viral biodistribution, and flank tumor volumes were measured. RESULTS: Luciferase expression was detected 2 d after injection. Continuous viral replication within tumors was reflected by increasing luciferase activity to d 9. At d 10, tumor viral recovery was increased more than 50-fold as compared with the injected dose, and minimal virus was recovered from the lung, liver, brain, heart, spleen, and kidneys. High-dose virus directly injected into normal tissues was undetectable at d 10. The mean volume of control 8505C tumors increased 50.8-fold by d 45, in contrast to 10.5-fold (low dose) and 2.1-fold (high dose; P=0.028) increases for treated tumors. DRO90-1 tumors also showed significant growth inhibition by high-dose virus. No virus-related toxicity was observed throughout the study. CONCLUSIONS: GLV-1h68 efficiently infects, expresses transgenes within, and inhibits the growth of ATC in vivo. These promising findings support future clinical trials for patients with ATC.

Imaging hypoxia in orthotopic rat liver tumors with iodine 124-labeled iodoazomycin galactopyranoside PET.

PURPOSE: To evaluate iodine 124 (124I)-labeled iodoazomycin galactopyranoside (IAZGP) positron emission tomography (PET) in the detection of hypoxia in an orthotopic rat liver tumor model by comparing regions of high (124)I-IAZGP uptake with independent measures of hypoxia and to determine the optimal time after injection to depict hypoxia. MATERIALS AND METHODS: The institutional animal care and use committee approved this study. Morris hepatoma tumors were established in the livers of 15 rats. Tumor oxygenation was measured in two rats with a fluorescence fiberoptic oxygen probe. (124)I-IAZGP was coadministered with the established hypoxia markers pimonidazole and EF5 in nine rats; 12-hour PET data acquisition was performed 24 hours later. Tumor cryosections were analyzed with immunofluorescence and autoradiography. In the four remaining rats, serial 20- and 60-minute PET data acquisition was peformed up to 48 hours after tracer administration. RESULTS: Oxygen probe measurements showed severe hypoxia (<1 mm Hg) distributed evenly throughout tumor tissue. Analysis of cryosections showed diffuse homogeneous uptake of (124)I-IAZGP throughout all tumors. The (124)I-IAZGP distribution correlated positively with pimonidazole (r = 0.78) and EF5 (r = 0.76) distribution. Tracer uptake in tumors was detectable with PET after 24 hours in seven of nine rats. In rats that underwent serial PET, tumor-to-liver contrast was sufficient to enable detection of hypoxia between 6 and 48 hours after tracer administration. The optimal ratio between signal intensity and tumor-to-liver contrast occurred 6 hours after tracer administration. CONCLUSION: Regions of high (124)I-IAZGP uptake in orthotopic rat liver tumors are consistent with independent measures of hypoxia; visualization of hypoxia with (124)I-IAZGP PET is optimal 6 hours after injection.

Tumor hypoxia imaging in orthotopic liver tumors and peritoneal metastasis: a comparative study featuring dynamic 18F-MISO and 124I-IAZG PET in the same study cohort.

PURPOSE: The purpose of this paper is to compare the uptake of two clinically promising positron emission tomography (PET) hypoxia targeting agents, (124)I-iodoazomycin galactopyranoside ((124)I-IAZG) and (18)F-fluoromisonidazole ((18)F-FMISO), by dynamic microPET imaging, in the same rats bearing liver tumors and peritoneal metastasis. METHODS: Morris hepatoma (RH7777) fragments were surgically implanted into the livers of four nude rats. Tumors formed in the liver and disseminated into the peritoneal cavity. Each rat had a total of two to three liver tumors and peritoneal metastasis measuring 10-15 mm in size. Animals were injected with (18)F-FMISO, followed on the next day (upon complete (18)F decay) by (124)I-IAZG. The animals were imaged in list mode on the microPET system from the time of injection of each tracer for 3 h and then again at 6 h and 24 h for the long-lived (124)I-IAZG tracer (4.2-day half-life). Micro computed tomography (CT) scans of each rat were performed for co-registration with the microPET scans acquired with a liver contrast agent, allowing tumor identification. Regions of interest (ROIs) were drawn over the heart, liver, muscle, and the hottest areas of the tumors. Time-activity curves (TACs) were drawn for each tissue ROI. RESULTS: The (18)F-FMISO signal increased in tumors over the 3-h time course of observation. In contrast, after the initial injection, the (124)I-IAZG signal slowly and continuously declined in the tumors. Nevertheless, the tumor-to-normal-tissue ratios of (124)I-IAZG increased, but more slowly than those of (18)F-FMISO and as a result of the differentially faster clearance from the surrounding normal tissues. These pharmacokinetic patterns were seen in all 11 tumors of the four animals. CONCLUSIONS: (18)F-FMISO localizes in the same intra-tumor regions as (124)I-IAZG. The contrast ratios (tumor/background) reach similar values for the two hypoxia tracers, but at later times for (124)I-IAZG than for (18)F-FMISO and, therefore, with poorer count statistics. As a consequence, the (18)F-FMISO images are of superior diagnostic image quality to the (124)I-IAZG images in the Morris hepatoma McA-R-7777 tumor model.

Value of comprehensive renal ultrasound in children with acute urinary tract infection for assessment of renal involvement: comparison with DMSA scintigraphy and final diagnosis.

The aim of this study was to evaluate the value of comprehensive renal ultrasound (US), i.e., combining greyscale US and amplitude-coded color Doppler sonography (aCDS), for assessment of urinary tract infection (UTI) in infants and children, compared to (1) (99m)Tc DMSA scintigraphy and (2) final diagnosis. Two hundred eighty-seven children with UTI underwent renal comprehensive US and DMSA scintigraphy. The results were compared with regard to their reliability to diagnose renal involvement, using (1) DMSA scintigraphy and (2) final diagnosis as the gold standard. Sixty-seven children clinically had renal involvement. Sensitivity increased from 84.1% using only aCDS to 92.1% for the combined US approach, using DMSA scintigraphy as the reference standard. When correlated with the final diagnosis, sensitivity for DMSA scintigraphy was 92.5%; sensitivity for comprehensive US was 94.0%. Our data demonstrate an increasing sensitivity using the combination of renal greyscale US supplemented by aCDS for differentiation of upper from lower UTI. Sensitivity for DMSA and comprehensive US was similar for both methods compared to the final diagnosis. Comprehensive US should gain a more important role in the imaging algorithm of children with acute UTI, thereby reducing the radiation burden.

Nerve-sparing therapy with oncolytic herpes virus for cancers with neural invasion.

PURPOSE: The invasion of cancer cells along nerves is an ominous pathologic finding associated with poor outcomes for a variety of tumors, including pancreatic and head and neck carcinomas. Peripheral nerves may serve as a conduit for these cancers to track into the central nervous system. Cancer progression within nerves and surgical resection of infiltrated nerves result in a permanent loss of neural function, potentially causing cosmetic and functional morbidity. Herpes simplex viruses (HSV) have utility for gene transfer into nerves and as oncolytic agents. We studied the use of an attenuated HSV, NV1023, as treatment for cancers with neural invasion. EXPERIMENTAL DESIGN AND RESULTS: NV1023 injection into the sciatic nerves of nude mice had no toxic effect on nerve function, whereas similar doses of wild-type HSV-1 (F' strain) caused complete nerve paralysis within 4 days and 100% mortality at day 6. NV1023 showed effective cytotoxicity in vitro on three neurotrophic human carcinoma cell lines, including pancreatic (MiaPaCa2), squamous cell (QLL2), and adenoid cystic (ACC3) carcinomas. A model of neural invasion was established by implanting human carcinoma cells in the sciatic nerves of nude mice. All control group mice developed left hind limb paralysis 5 to 7 weeks after tumor injection, whereas animals treated with NV1023 maintained intact nerve function and showed significant tumor regression (P < 0.0001). CONCLUSIONS: These results show that NV1023 oncolytic therapy may effectively treat cancers with neural invasion and preserve neural function. These findings hold significant clinical implications for patients with cancer neural invasion.

Acute pulmonary embolism: comparison of standard axial MDCT with paddlewheel technique.

PURPOSE: The purpose of this study was to evaluate the ability of rotated paddlewheel reformations for the detection of central and peripheral pulmonary embolism (PE) compared to standard axial multi detector CT (MDCT) images. MATERIAL AND METHODS: CT scans of 35 patients with PE were reviewed by three independent readers for the detection of pulmonary emboli using standard axial CT scans and reformatted paddlewheel technique. All images were evaluated in random order. MDCT examinations were performed with a collimation of 1.25 mm, a pitch of six and a reconstruction interval of 0.8mm. For each patient MIP were reformatted by using a paddlewheel arrangement with 5mm slab thickness and 5 degrees rotation. Standard of reference for PE was a consensus reading of the axial images by all three readers. RESULTS: The overall sensitivity for the axial images for the three readers ranged between 91% and 96%; for paddlewheel reformations from 78% to 83%; the specificity for both methods was 98-99%. Inter- and intraobserver agreement was also higher for axial images than for paddlewheel reformations. CONCLUSION: Comparing standard axial MDCT scans and reformatted paddlewheel images no significant difference for the detection of central PE was found, whereas for the detection of peripheral emboli standard axial images showed a significant higher percentage of detecting PE than paddlewheel reformations.

Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model.

The purpose of this study was to monitor hypoxia in an orthotopic liver tumor model using a hypoxia-sensitive reporter imaging system and to image enhanced gene expression after clamping the hepatic artery. C6 and RH7777 Morris hepatoma cells were transduced with a triple reporter gene (HSV1-tk/green fluorescent protein/firefly luciferase-triple fusion), placed under the control of a HIF-1-inducible hypoxia responsive element (HRE). The cells showed inducible luciferase activity and green fluorescent protein expression in vitro. Isolated reporter-transduced Morris hepatoma cells were used to produce tumors in livers of nude rats, and the effect of hepatic artery clamping was evaluated. Tumor hypoxia was shown by immunofluorescence microscopy with the hypoxia marker EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl acetamide)] and the fluorescent perfusion marker Hoechst 33342, and by pO(2) electrode measurements. For tumor hypoxia imaging with the HRE-responsive reporter, both luciferase bioluminescence and [(18)F]2'-fluoro-2'-deoxyarabinofuranosyl-5-ethyluracil positron emission tomography was done, and the presence of hypoxia in Morris hepatoma tumors were successfully imaged by both techniques. Transient clamping of the hepatic artery caused cessation of tumor perfusion and severe hypoxia in liver tumors, but not in adjacent liver tissue. These results show that the orthotopic reporter-transduced RH7777 Morris hepatomas are natively hypoxic and poorly perfused in this animal model, and that the magnitude of hypoxia can be monitored using a HRE-responsive reporter system for both bioluminescence and positron emission tomography imaging. However, the severity of tumor ischemia after permanent ligation of the hepatic artery limits our ability to image severe hypoxia in this animal model.

Heart rate-reducing therapy with add-on ivabradine and bisoprolol before coronary computed tomographic angiography in a fast-track ambulatory setting.

Objective This study was performed to determine whether add-on oral ivabradine in patients treated with beta blockers 1 hour before coronary computed tomographic angiography (CCTA) is effective in lowering the heart rate and thus improving CCTA quality. Methods In this single-center cohort study, the data of 294 patients referred for ambulant CCTA were retrospectively screened. Patients with an initial heart rate of ≥75 bpm (n = 112) were pretreated with either a combination of bisoprolol and ivabradine or with bisoprolol alone. Results During the scan, there was no difference in heart rate between the two groups Likewise, there was no significant difference in additionally administered intravenous bradycardic agents, the number of motion artifacts, or the radiation dose. Both drug regimens were tolerated well. Conclusion Additive oral ivabradine 1 hour before CCTA does not result in a further reduction of the heart rate. Consequently, neither movement artifacts nor radiation dose can be reduced. Therefore, pretreatment with ivabradine does not seem reasonably appropriate in an outpatient clinical setting with short patient contact.

3 Tesla breast MR imaging as a problem-solving tool: Diagnostic performance and incidental lesions.

PURPOSE: To investigate the diagnostic performance and incidental lesion yield of 3T breast MRI if used as a problem-solving tool. METHODS: This retrospective, IRB-approved, cross-sectional, single-center study comprised 302 consecutive women (mean: 50±12 years; range: 20-79 years) who were undergoing 3T breast MRI between 03/2013-12/2014 for further workup of conventional and clinical breast findings. Images were read by experienced, board-certified radiologists. The reference standard was histopathology or follow-up ≥ two years. Sensitivity, specificity, PPV, and NPV were calculated. Results were stratified by conventional and clinical breast findings. RESULTS: The reference standard revealed 53 true-positive, 243 true-negative, 20 false-positive, and two false-negative breast MRI findings, resulting in a sensitivity, specificity, PPV, and NPV of 96.4% (53/55), 92.4% (243/263), 72.6% (53/73), and 99.2% (243/245), respectively. In 5.3% (16/302) of all patients, incidental MRI lesions classified BI-RADS 3-5 were detected, 37.5% (6/16) of which were malignant. Breast composition and the imaging findings that had led to referral had no significant influence on the diagnostic performance of breast MR imaging (p>0.05). CONCLUSION: 3T breast MRI yields excellent diagnostic results if used as a problem-solving tool independent of referral reasons. The number of suspicious incidental lesions detected by MRI is low, but is associated with a substantial malignancy rate.

Multiparametric [11C]Acetate positron emission tomography-magnetic resonance imaging in the assessment and staging of prostate cancer.

BACKGROUND: The aim of this study was to evaluate whether MP [11C]Acetate PET-MRI enables an accurate differentiation of benign and malignant prostate tumors as well as local and distant staging. MATERIALS AND METHODS: Fifty-six consecutive patients fulfilling the following criteria were included in this IRB-approved prospective study: elevated PSA levels or suspicious findings at digital rectal examination or TRUS; and histopathological verification. All patients underwent MP [11C]Acetate PET-MRI of the prostate performed on separate scanners with PET/CT using [11C]Acetate and 3T MP MR imaging. Appropriate statistical tests were used to determine diagnostic accuracy, local and distant staging. RESULTS: MP imaging with two MRI parameters (T2w and DWI) achieved the highest sensitivity, specificity, and diagnostic accuracy of 95%, 68.8%, and 88%, with an AUC of 0.82 for primary PCa detection. Neither assessments with a single parameter (AUC, 0.54-0.79), nor different combinations with up to five parameters (AUC, 0.67-0.79) achieved equally good results. MP [11C]Acetate PET-MRI improved local staging with a sensitivity, specificity, and diagnostic accuracy of 100%, 96%, and 97% compared to MRI alone with 72.2%, 100%, and 95.5%. MP [11C]Acetate PET-MRI correctly detected osseous and liver metastases in five patients. CONCLUSIONS: MP [11C]Acetate PET-MRI merges morphologic with functional information, and allows insights into tumor biology. MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) yields the highest diagnostic accuracy. The addition of more parameters does not improve diagnostic accuracy of primary PCa detection. MP [11C]Acetate PET-MRI facilitates improved local and distant staging, providing "one-stop" staging in patients with primary PCa, and therefore has the potential to improve therapy. PATIENT SUMMARY: In this report we investigated MP [11C]Acetate PET-MRI for detection, local and distant staging of prostate cancer. We demonstrate that MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) achieves the best diagnostic accuracy for primary prostate cancer detection and that MP [11C]Acetate PET-MRI enables an improved local and distant staging.