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Transcriptional intermediary factor 1γ (TIF1γ; alias, TRIM33/RFG7/PTC7/ectodermin) belongs to an evolutionarily conserved family of nuclear factors that have been implicated in stem cell pluripotency, embryonic development, and tumor suppression. TIF1γexpression is markedly down-regulated in human pancreatic tumors, and Pdx1-driven Tif1γinactivation cooperates with the KrasG12Doncogene in the mouse pancreas to induce intraductal papillary mucinous neoplasms. In this study, we report that aged Pdx1-Cre; LSL-KrasG12D; Tif1γlox/loxmice develop pancreatic ductal adenocarcinomas (PDACs), an aggressive and always fatal neoplasm, demonstrating a Tif1γtumor-suppressive function in the development of pancreatic carcinogenesis. Deletion of SMAD4/DPC4(deleted in pancreatic carcinoma locus 4) occurs in approximately 50% of human cases of PDAC. We, therefore, assessed the genetic relationship between Tif1γand Smad4signaling in pancreatic tumors and found that Pdx1-Cre; LSL-KrasG12D; Smad4lox/lox; Tif1γlox/lox(alias, KSSTT) mutant mice exhibit accelerated tumor progression. Consequently, Tif1γ tumor-suppressor effects during progression from a premalignant to a malignant state in our mouse model of pancreatic cancer are independent of Smad4. These findings establish, for the first time to our knowledge, that Tif1γ and Smad4 both regulate an intraductal papillary mucinous neoplasm-to-PDAC sequence through distinct tumor-suppressor programs.

Ultrasmall gadolinium-based nanoparticles (GBNs) induce both a positive contrast for magnetic resonance imaging and a radiosentizing effect. The exploitation of these characteristics leads to a greater increase in lifespan of rats bearing brain tumors since the radiosensitizing effect of GBNs can be activated by X-ray microbeams when the gadolinium content is, at the same time, sufficiently high in the tumor and low in the surrounding healthy tissue. GBNs exhibit therefore an interesting potential for image-guided radiotherapy.

Gastro-entero-pancreatic (GEP) endocrine tumours are a heterogenous group of tumours of variable localization and prognosis. It has been suggested that positron emission tomography (PET) using 2-18Ffluoro-2-deoxy-D-glucose (18F-FDG) may have a prognostic value and help to identify patients at risk of progression. 18Ffluoro-3′-deoxy-3′-L-fluorothymidine (18F-FLT) has been recently developed as a PET proliferation tracer. At present, there are no studies investigating its role in GEP. The aim of this prospective study was to assess the value of 18F-FLT-PET for the evaluation of GEP.

Owing to their multifunctional character, nanoparticles appear well suited for combining sensing, imaging and therapy. Nanoparticles composed of a gadolinium oxide core and a polysiloxane shell were designed for the detection of biomolecules, fluorescence and MRI, and for cancer therapy. Each component (gadolinium oxide core and polysiloxane shell) of these nanoparticles plays a crucial role and enables the resulting nanoparticles to emit intense but transient light and/or long-lived and highly photostable light, to enhance the contrast of magnetic resonance images, to improve the colloidal stability, to specifically interact with biomolecules, to absorb x-ray photons and to capture thermal neutrons. The hybrid gadolinium oxide nanoparticles exhibit a great potential for sensing applications and for image-guided therapy.

We sought to assess with magnetic resonance imaging (MRI) the influence of strain type and gender on left ventricular (LV) global function and mass in 3 inbred mouse strains with a normal cardiac phenotype.

Background:Positron emission tomography (PET) is a functional imaging device that allows dynamic regional blood flow measurements. We performed a study to test whether PET could detect acute changes in renal blood flow (RBF) in patients with chronic renal failure (CRF). Methods:RBF was measured by means of PET (PET-RBF) using oxygen 15-labeled water (H215O) in eight men with hypertension and moderate CRF before and 5, 40, 80, and 120 minutes after the injection of quinaprilat (10 mg intravenously). Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured simultaneously by para-aminohippuric acid (PAH-ERPF) and inulin clearances before and 20, 60, 100, and 140 minutes after quinaprilat injection. Results:Baseline RBF and ERPF were decreased in all patients (221 ± 20 mL/min/100 g and 225 ± 38 mL/min/1.73 m2, respectively). PET-RBF increased significantly after quinaprilat injection (+15%, +26%, +19%, and +23% versus baseline; P< 0.003). PAH-ERPF did not increase significantly (−6%, +12%, +20%, and +15% versus baseline; P= 0.15). GFR (50.1 ± 8.9 mL/min/1.73 m2at baseline) did not change significantly after quinaprilat injection; however, filtration fraction (GFR-ERPF ratio) decreased significantly from 0.23% ± 0.02% to 0.20% ± 0.02% (P= 0.0004). Mean arterial pressure decreased significantly after quinaprilat injection (P< 0.005). Conclusion:This study dynamically measured RBF by means of PET in patients with CRF for the first time. It showed that RBF rapidly increased after quinaprilat injection. PET using H215O is a powerful method for the noninvasive measurement of dynamic changes in RBF that remain undetected by PAH clearance. Am J Kidney Dis40:947-954. © 2002 by the National Kidney Foundation, Inc.

To assess the respective effects of position and positive end-expiratory pressure (PEEP) on the distribution of regional pulmonary blood flow (PBF).

Evaluation of quantitative parameters such as regional myocardial blood flow (rMBF), blood volume (rMBV), and mean transit time (rMTT) by MRI is gaining acceptance for clinical applications, but still lacks robust postprocessing methods for map generation. Moreover, robustness should be preserved over the full range of myocardial flows and volumes. Using experimental data from an isolated pig heart preparation, synthetic MR kinetics were generated and four deconvolution approaches were evaluated. These methods were then applied to the first‐pass T1images of the isolated pig heart using an intravascular contrast agent and rMBF, rMBV and rMTT maps were generated. In both synthetic and experimental data, the fit between calculated and original data reached equally good results with the four techniques. rMBV was the only parameter estimated correctly in numerical experiments. Moreover, using the algebraic method ARMA, abnormal regions were well delineated on rMBV maps. At high flows, rMBF was underestimated at the experimental noise level. Finally, rMTT maps appeared noisy and highly unreliable, especially at high flows. In conclusion, over the myocardial flow range, i.e., 0–400 ml/min/100g, rMBF identification was biased in presence of noise, whereas rMBV was correctly identified. Thus, rMBV mapping could be a fast and robust way to detect abnormal myocardial regions. Magn Reson Med 48:166–179, 2002. © 2002 Wiley‐Liss, Inc.

Evaluation of quantitative parameters such as regional myocardial blood flow (rMBF), blood volume (rMBV), and mean transit time (rMTT) by MRI is gaining acceptance for clinical applications, but still lacks robust postprocessing methods for map generation. Moreover, robustness should be preserved over the full range of myocardial flows and volumes. Using experimental data from an isolated pig heart preparation, synthetic MR kinetics were generated and four deconvolution approaches were evaluated. These methods were then applied to the first-pass T1 images of the isolated pig heart using an intravascular contrast agent and rMBF, rMBV and rMTT maps were generated. In both synthetic and experimental data, the fit between calculated and original data reached equally good results with the four techniques. rMBV was the only parameter estimated correctly in numerical experiments. Moreover, using the algebraic method ARMA, abnormal regions were well delineated on rMBV maps. At high flows, rMBF was underestimated at the experimental noise level. Finally, rMTT maps appeared noisy and highly unreliable, especially at high flows. In conclusion, over the myocardial flow range, i.e., 0–400 ml/min/100g, rMBF identification was biased in presence of noise, whereas rMBV was correctly identified. Thus, rMBV mapping could be a fast and robust way to detect abnormal myocardial regions. Magn Reson Med 48:166–179, 2002. © 2002 Wiley-Liss, Inc.

Recent developments in magnetic resonance imaging (MRI) using specific contrast media allow the assessment of myocardial perfusion. The purpose of this study was to characterize the intravascular properties of a new macromolecular contrast agent, CMD‐A2‐Gd‐DOTA, to evaluate myocardial perfusion. Two groups of isolated pig hearts perfused at various controlled flows were used. To demonstrate the intravascular properties of CMD‐A2‐Gd‐DOTA, the agent was simultaneously injected with 99mTc‐labeled red blood cells in five hearts (group 1). Tracer kinetics of both compounds were assessed by coronary sinus effluent sampling, radioactivity counting and concentration determination in samples for first‐pass time curves measurements. Five other hearts (group 2) were studied using a two‐slice turboFLASH sequence on a 1.5‐T whole‐body MRI in order to evaluate first‐pass CMD‐A2‐Gd‐DOTA signal intensity (SI) versus time curves. In group 1, for the studied flows ranging from 0.8 to 3.1 ml/min−1• g−1, CMD‐A2‐Gd‐DOTA showed first‐pass concentration curves typical of an intravascular contrast agent. In group 2, MRI parameters, i.e., upslope and mean transit time of SI time curves correlated strongly with myocardial perfusion. Within the physiologic range of flows, CMD‐A2‐Gd‐DOTA was able to demonstrate tracer kinetics for in vivo assessment of myocardial perfusion using MRI. Magn Reson Med 43:403–409, 2000. © 2000 Wiley‐Liss, Inc.

This review explores the present status of contrast media available for myocardial perfusion studies, the magnetic resonance (MR) sequences adapted to multi‐slice first‐pass acquisitions, and the issue of myocardial perfusion quantification. To date, only low molecular weight paramagnetic gadolinium chelates have been used in clinical protocols for myocardial perfusion. With the availability of fast MR acquisition techniques to follow the first‐pass distribution of the contrast agent in the myocardium, the bolus tracking technique represents the more widely used protocol in MR perfusion studies. On T1‐weighted imaging, the ischemic zone appears with a delayed and lower signal enhancement compared with normally perfused myocardium. Visual analysis of the image series can be greatly improved by image post‐processing to obtain relative myocardial perfusion maps. With an intravascular tracer, myocardial kinetics are in theory easier to analyze in terms of perfusion. In experimental studies, different intravascular or blood pool MR contrast agents have been tested to measure quantitative perfusion parameters. If a simple flow‐limited kinetic model is developed with MR contrast agents, one important clinical application will be the evaluation of the functional consequence of coronary stenoses, ie, non‐invasive evaluation of the coronary reserve. J. Magn. Reson. Imaging 1999;10:423–433. © 1999 Wiley‐Liss, Inc.

This review explores the present status of contrast media available for myocardial perfusion studies, the magnetic resonance (MR) sequences adapted to multi-slice first-pass acquisitions, and the issue of myocardial perfusion quantification. To date, only low molecular weight paramagnetic gadolinium chelates have been used in clinical protocols for myocardial perfusion. With the availability of fast MR acquisition techniques to follow the first-pass distribution of the contrast agent in the myocardium, the bolus tracking technique represents the more widely used protocol in MR perfusion studies. On T1-weighted imaging, the ischemic zone appears with a delayed and lower signal enhancement compared with normally perfused myocardium. Visual analysis of the image series can be greatly improved by image post-processing to obtain relative myocardial perfusion maps. With an intravascular tracer, myocardial kinetics are in theory easier to analyze in terms of perfusion. In experimental studies, different intravascular or blood pool MR contrast agents have been tested to measure quantitative perfusion parameters. If a simple flow-limited kinetic model is developed with MR contrast agents, one important clinical application will be the evaluation of the functional consequence of coronary stenoses, ie, non-invasive evaluation of the coronary reserve. J. Magn. Reson. Imaging 1999;10:423–433. © 1999 Wiley-Liss, Inc.

Validation of new positron emission tomography (PET) tracers or magnetic (MR) imaging contrast agents is based on isolated rodent heart preparations. The use of larger animals could provide a more direct validation using the devices used for humans.

Abstract: The best test presently available to ascertain residual viability within an infarct-related area involves the use of fluorine-18 fluorodeoxyglucose (FDG) to detect the persistence of some cellular metabolism. Rest reinjection of thallium-201 is a less accurate alternative but is easy to perform. Iodinated fatty acids, which are used with standard gamma cameras, are proposed as markers of cellular metabolism. This study was performed to assess the value of 16-iodo-3-methyl-hexadecanoic acid (MIHA) as a marker of the residual cellular metabolism by comparison with FDG in patients with a recent myocardial infarction, and to evaluate its contribution compared with the201Tl stress-redistribution-reinjection technique. Stress-redistribution-reinjection201T1 imaging, rest MIHA imaging and glucoseloaded FDG imaging were performed in 22 patients with recent myocardial infarction. Out of the 628 myocardial segments obtained from the left ventricular analysis, 400 were hypoperfused (relative uptake <0.75 of maximum uptake on stress201T1 imaging), 177 of which were severely hypoperfused (relative uptake <0.50). Receiver operating characteristic (ROC) curves for predicting metabolic myocardial viability with FDG were derived from the results in respect of (a)201T1 activity during exercise, redistribution and reinjection and (b) MIHA up-take, using the two FDG thresholds most commonly considered to define metabolic viability (0.50 and 0.60). Analysis of the 400 hypoperfused segments demonstrated that201T1 reinjection was the most accurate test in predicting the presence of myocardial viability (area under the ROI curves=0.85 and 0.86 at the 0.50 and 0.60 FDG thresholds, respectively;P<0.05 vs other tests). The global predictive values of MIHA and201T1 reinjection were, respectively, 0.87 and 0.89 at the 0.50 FDG threshold (NS), and 0.82 and 0.87 at the 0.60 FDG threshold (NS). When only the 177 severely hypoperfused segments were considered,201T1 reinjection remained the most accurate test (accuracy 0.84 at the 0.50 FDG threshold and 0.82 at the 0.60 FDG threshold), while the accuracy of MIHA decreased significantly (0.78 at the 0.50 FDG threshold and 0.73 at the 0.60 FDG threshold,P<0.05 vs201T1 reinjection). In all circumstances, MIHA was less specific than201T1 reinjection for the detection of metabolic viability. In conclusion, in patients with recent myocardial infarction, MIHA accurately detects the persistence of metabolic viability, but is not superior to201T1.

Arteaga C, Canet E, Ovize M, Janier M, Revel D. Myocardial perfusion assessed by subsecond magnetic resonance imaging with a paramagnetic macromolecular contrast agent. Invest Radiol 1994;29:S54–S57.

Staging of patients with myeloma currently takes into account the number of bone lesions identified with standard X-rays. Magnetic Resonance Imaging (MRI) appears to be a more sensitive imaging technique in patients with multiple myeloma (MM) but it is not adapted to the investigation of the entire skeleton. Positron Emission Tomography (PET) imaging appears promising but this approach remains to be validated in patients with MM. Most patients with neoplasia have been performed with 18F-2-deoxy-D-glucose (FDG), a functional marker suggested to identify “active” tumor sites and useful to assess bone or extra-osseous tissue. Conversely Na18F binding is strictly limited to bone. To determine the potential usefulness of these two markers we performed a comparative analysis of these two imaging techniques in patients with MM.

Staging of patients with myeloma currently takes into account the number of bone lesions identified with standard X-rays. Magnetic Resonance Imaging (MRI) appears to be a more sensitive imaging technique in patients with multiple myeloma (MM) but it is not adapted to the investigation of the entire skeleton. Positron Emission Tomography (PET) imaging appears promising but this approach remains to be validated in patients with MM. Most patients with neoplasia have been performed with 18F-2-deoxy-D-glucose (FDG), a functional marker suggested to identify “active” tumor sites and useful to assess bone or extra-osseous tissue. Conversely Na18F binding is strictly limited to bone. To determine the potential usefulness of these two markers we performed a comparative analysis of these two imaging techniques in patients with MM. Nine patients with progressive MM, including bone lesions, underwent x-ray imaging, MRI, 18FDG and Na18F scanning. Both PET scans were performed within a one-week time frame in each patient. The number and localizations of suspect lesions identified by each type of imaging technique was assessed independently then compared. 18FDG and Na18F data were compared to X-ray/MRI data for skull, spine, pelvis and femur/humerus localizations. Localizations were considered positive in case of increased fixation with 18FDG or increased or decreased fixation with Na18F. Comparison of FDG data with X-ray/MRI showed that FDG allowed the detection of only 3 of 35 types of localizations identified by X-ray/MRI, whatever the localization (skull, femur/humerus, spine and pelvis) observed on X-ray/MRI. 18FDG showed three lesions which had not been identified by X-ray/MRI, as well as 8 costal localizations and 1 extra-osseous localization. Comparison of Na18F data with X-ray/MRI showed that Na18F allowed the detection of 17 of 35 types of localizations. In particular, Na18F identified 13 of the 19 spinal localizations observed with x-ray/MRI but only 2 of 9 skull lesions. Na18F identified 11 localizations which had not been identified by X-ray/MRI. Furthermore Na18F also identified costal localizations in all patients. Qualitative analysis of PET scans showed that background was significantly lower with Na18F imaging than with 18FDG imaging. In conclusion 18FDG and Na18F provide significantly different results in patients with progressive MM. 18FDG imaging was poorly correlated with X-rayMRI while Na18F imaging was particularly useful to identify costal and spinal lesions. PET scan could be a useful method in the staging of MM patients at diagnosis or to determine response. Figure Figure

Preconditioning (PC) is believed to be directly triggered by brief ischemia/ reperfusion. However, brief ischemia results in transient dilation (or stretching) of the heart. We sought to determine whether stretch per se, induced by rapid increase in preload, could precondition the isolated working rat heart. Thirty-four rat hearts were perfused at constant pressure with Krebs-Henselheit buffer for 30 minutes and then subjected to 30 minutes of global ischemia (37°C) followed 45 minutes of reperfusion. Prior to the 30 minute sustained ischemia, all hearts underwent a 15 minute treatment period consisting of no intervention (control; n=11), 5 minutes of zero flow global ischemia followed by 10 minutes of reperfusion (PC; n=11) or 5 minutes of transient LV stretch (ST; n=12). Transient stretch of the left ventricle was induced by raising the preload from 5 to 20cm H20 for 5 minutes, ten minutes before the sustained 30 minute global ischemia. Cumulative CPK release during reperfusion was used as an index of irreversible myocardial injury. It averaged 20±12U/g in the control group versus 1±1U/g* and 3 ±4U/g* in PC and ST groups respectively (* p&lt;0.01 vs control), indicating that PC and ST hearts experienced a dramatic reduction in infarct size. These data suggest that transient stretch of the left ventricle may precondition the globally ischemic working rat heart.

To identify viable myocardium before coronary revascularization, we prospectively submitted eleven patients (60±7 yrs; 11 M) with previous Q-wave myocardial infarction to 18FDG-Positon Emission Tomography and low-dose (5 to 10 μg/kg/min) dobutamine cine-MRI. 18FDG uptake > 60% was considered indicative of viable tissue. Ouantitation of systolic wall thickening/thinning (SW) was performed by use of a computer software allowing automatic detection of epicardial and endocardial outlines, at rest and under 5, 7.5 and 10 μg/kg/min of dobutamine. Heart slices of both 18FDG-PET scans and dobutamine cine-MRI were divided in 8 segments, matched and analyzed byobservers blinded to clinical data. Sixty-five segments were considered viable by 18FDG-PET; in this subgroup, rest SW thickening averaged 47±5% and improved by 43±8% under low-dose dobutamine. In the remaining 23 segments considered non viable by PET. rest SW thickening averaged 14±7%*(*p&lt;0.05 vs viable segment group) and further worsened by –13±8%*during low-dose dobutamine stress (*p&lt;0.05 versus viable segment group). Positive predictive value of low-dose dobutamine stress cine-MRI for assessment of myocardial viability was 84%. These data suggest that quantitative assessment of regional wall motion by dobutamine cine-MRI may help discriminate viable from non viable myocardium as defined by 18FDG-Positon Emission Tomography.