Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development.

Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.

Preoperative assessment of focal liver lesions: multidetector computed tomography challenges magnetic resonance imaging.

PURPOSE: To investigate prospectively multidetector computed tomography (CT) (MDCT) and magnetic resonance (MR) imaging (MRI) in the preoperative assessment of focal liver lesions. MATERIAL AND METHODS: Multiphasic MDCT and conventional gadolinium-enhanced MRI were performed on 31 consecutive patients prior to hepatic surgery. All images were blindly analyzed as consensus reading. Lesion counts and their relation to vascular structures and possible extrahepatic disease were determined. The data from the MDCT and MRI were compared with the results obtained by intraoperative ultrasound (IOUS) and palpation. Histopathologic verification was available. RESULTS: At surgery, IOUS and palpation revealed 45 solid liver lesions. From these, preoperative MDCT detected 43 (96%) and MRI 35 (78%) deposits. MDCT performed statistically better than MRI in lesion detection (P=0.008). Assessment of lesion vascular proximity was correctly determined by MDCT in 98% of patients and by MRI in 87%. Statistical difference was found (P=0.002). IOUS and palpation changed the preoperative surgical plan as a result of extrahepatic disease in 8/31 (26%) cases. In MDCT as well in MRI extrahepatic involvement was suspected in two cases. CONCLUSION: MDCT was superior to MRI and nearly equal to IOUS in liver lesion detection and in the determination of lesion vascular proximity. However, both techniques fail to reliably detect extrahepatic disease.

Liver tumour MRI: what do we need for lesion characterization?

BACKGROUND: Hepatic lesions constitute a daily challenge to radiology in clinical settings, and non-invasive methods are valuable in the characterization of these liver tumours. We undertook our investigation to assess the lesion characterization potential of MRI by evaluating several unenhanced MR sequences and the dynamic gadolinium (Gd)-enhanced technique. METHODS: A total of 116 focal liver lesions in 116 patients were included in our retrospective study, and histological verification was available for 107 lesions. Nine haemangiomas had a follow-up of 2 years. The 1.5-T MR system was used. T1- and T2-weighted sequences and dynamic Gd-enhanced studies were evaluated by two individual readers as separate sequences and also collectively. Lesions were classified into benign or malignant, and a specific diagnosis was proposed. The McNemar test was used in statistical analysis, and interobserver variation was measured using kappa statistics. RESULTS: Lesion classification into benign and malignant tumours (by evaluating all images in concert) was assessed in 83% and 89% of cases by readers 1 and 2, respectively. From single sequences, best lesion classification was achieved with Gd-enhanced T1 by both readers. The difference in classification was statistically significant when all sequences were evaluated in comparison with any single sequence alone (P = 0.02). Specific diagnosis was correctly determined using all sequences together in 60% and 71% of cases by readers 1 and 2, respectively. For individual sequences, correct diagnosis was most frequently proposed with a Gd-enhanced T1-weighted sequence by both readers (59% and 65% for readers 1 and 2, respectively). CONCLUSION: Multisequential MRI using Gd-enhanced imaging performs extremely well in liver lesion classification, and with moderate ability to determine a specific diagnosis.

Contrast-to-noise ratio of multiple slice spin lock technique: prospects for liver imaging.

Spin lock (SL) MRI technique has been demonstrated to provide similar lesion/liver contrast to conventional MR technique. Multiple slice SL technique allows a large number of slices to be collected within a given repetition time due to the short echo time. In addition, the short echo time reduces movement and susceptibility artefacts. In the present study, the potential of the multiple slice SL technique in liver imaging was evaluated by using tissue nuclear magnetic resonance (NMR) information and tissue NMR parameters obtained at 0.1 T. 10 healthy volunteers were imaged at 0.1 T for the measurement of tissue T1rho, T1, and T2 relaxation times. Tissue radiofrequency-attenuation information was obtained from the literature, and included in the contrast-to-noise ratio (CNR) calculations. Our results demonstrated that by increasing the number of slices the acquired liver-to-spleen CNR decreases with all locking field durations (locking time, TL). However, with small TLs, the difference is small which is important for liver MRI where a wide coverage, i.e. large number of slices, is important. Long locking pulse durations are more favourable than short TLs if large flip angles are used. With an optimal combination of a moderate amount of slices, reasonably large flip angle, and TL of the order of 20 ms, high CNR is achieved in SL MRI.

Wernicke's encephalopathy: is diffusion-weighted MRI useful?

We present the clinical and magnetic resonance imaging (MRI) findings of five patients with acute Wernicke's encephalopathy. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images demonstrated symmetrical hyperintense lesions within the dorsomedial thalami, periaqueductal white matter, and the tectum of the midbrain. None of the lesions enhanced with gadolinium. In addition to conventional MRI sequences, we performed diffusion-weighted imaging (DWI). In all patients, DWI showed symmetrical pathologic thalamic and midbrain signal hyperintensities more distinctly than did conventional T2-weighted or FLAIR sequences. The apparent diffusion coefficient (ADC) map images showed slight signal reductions in four patients, suggesting restricted diffusion within these regions. In one patient, the signal intensity within the affected thalami was isointense with the ipsilateral basal ganglia on ADC map images. For enhanced detection of pathology, we conclude that DWI should be included in the imaging protocols of patients suspected to suffer from Wernicke's encephalopathy.

Efficacy of sequential use of superparamagnetic iron oxide and gadolinium in liver MR imaging.

PURPOSE: To evaluate the efficacy of combined (double contrast) use of superparamagnetic iron particles (SPIOs) and gadolinium (Gd) in liver MR imaging. MATERIAL AND METHODS: Unenhanced, Gd-enhanced, SPIO-enhanced, and both SPIO- and Gd-enhanced images were acquired at 1.5 T. Twenty patients with previously detected liver lesions were included. Fast SE-STIR, and breath-hold true FISP, fat-suppressed T1- and T2-weighted sequences were obtained with all techniques. Lesion count was assessed by consensus reading. RESULTS: Collective evaluation of all MR sequences revealed 61 lesions in 16 patients; SPIO-enhanced MR detected lesions with a sensitivity of 95% (n=58). The sensitivity of unenhanced MR imaging was 90% (n=55). There was no statistical difference between SPIO-enhanced and unenhanced MR images. From single sequences, the greatest number of lesions was detected with the SPIO-enhanced fast SE-STIR sequence (n=56, sensitivity 92%). By using the fat-suppressed T1-weighted sequence, Gd-enhanced and both SPIO- and Gd-enhanced MR images demonstrated sensitivities of 77% (n=47) and 80% (n=49), respectively. Despite the combined use of both contrast media, this sequence was significantly less sensitive in lesion detection when compared to SPIO-enhanced imaging. CONCLUSION: SPIO-enhanced MR imaging was the most sensitive method in lesion detection. The benefit of the combined use of SPIO and Gd was negligible.

Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle.

To examine whether and how intramyocellular lipid (IMCL) content contributes to interindividual variation in insulin action, we studied 20 healthy men with no family history of type 2 diabetes. IMCL was measured as the resonance of intramyocellular CH(2) protons in lipids/resonance of CH(3) protons of total creatine (IMCL/Cr(T)), using proton magnetic resonance spectroscopy in vastus lateralis muscle. Whole-body insulin sensitivity was measured using a 120-min euglycemic-hyperinsulinemic (insulin infusion rate 40 mU/m(2). min) clamp. Muscle biopsies of the vastus lateralis muscle were taken before and 30 min after initiation of the insulin infusion to assess insulin signaling. The subjects were divided into groups with high IMCL (HiIMCL; 9.5 +/- 0.9 IMCL/Cr(T), n = 10) and low IMCL (LoIMCL; 3.0 +/- 0.5 IMCL/Cr(T), n = 10), the cut point being median IMCL (6.1 IMCL/Cr(T)). The groups were comparable with respect to age (43 +/- 3 vs. 40 +/- 3 years, NS, HiIMCL versus LoIMCL), BMI (26 +/- 1 vs. 26 +/- 1 kg/m(2), NS), and maximal oxygen consumption (33 +/- 2 vs. 36 +/- 3 ml. kg(-1). min(-1), NS). Whole-body insulin-stimulated glucose uptake was lower in the HiIMCL group (3.0 +/- 0.4 mg. kg(-1). min(-1)) than the LoIMCL group (5.1 +/- 0.5 mg. kg(-1). min(-1), P < 0.05). Serum free fatty acid concentrations were comparable basally, but during hyperinsulinemia, they were 35% higher in the HiIMCL group than the LoIMCL group (P < 0.01). Study of insulin signaling indicated that insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was blunted in HiIMCL compared with LoIMCL (57 vs. 142% above basal, P < 0.05), while protein expression of the IR was unaltered. IR substrate-1-associated phosphatidylinositol (PI) 3-kinase activation by insulin was also lower in the HiIMCL group than in the LoIMCL group (49 +/- 23 vs. 84 +/- 27% above basal, P < 0.05 between HiIMCL and LoIMCL). In conclusion, IMCL accumulation is associated with whole-body insulin resistance and with defective insulin signaling in skeletal muscle independent of body weight and physical fitness.

Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients.

To determine causes of interindividual variation in insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and insulin doses for >1 year on combination therapy with bedtime NPH insulin and metformin. Insulin absorption (increase in free and total insulin over 8 h after a subcutaneous dose of regular insulin) and actions of intravenous (6-h 0.3 mU x kg(-1) x min(-1) euglycemic insulin clamp combined with [3-3H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: insulin dose range 10-176 U (mean 42 U, fold variation 17.6x) or 0.13-1.39 U/kg (0.44 U/kg, 10.7x), absorbed insulin 10.6x, action of subcutaneous insulin to suppress FFAs 7.5 x and to stimulate glucose metabolism (M value) 11.5x, body weight 67-127 kg (91 kg, 1.9x), liver fat 2-28% (12%, 14x), and visceral fat 179-2,053 ml (1,114 ml, 11.5x). The amount of insulin absorbed, measured as either free or total insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the insulin dose per se. The actions of absorbed insulin were, on the other hand, significantly correlated with the daily insulin dose (r = 0.70 for action on FFAs, P < 0.001, and r = -0.61 for M value, P < 0.005). Actions of subcutaneous and intravenous insulin to suppress FFAs were significantly correlated (r = 0.82, P < 0.001, R2 = 67%). Of the measures of adiposity, the percent hepatic fat was the parameter best correlated with the daily insulin dose (r = 0.76, P < 0.001). The percent hepatic fat was also significantly correlated with the ability of intravenous insulin to suppress endogenous glucose production (r = 0.72, P < 0.005). We conclude that the major reason for interindividual variation in insulin requirements in type 2 diabetes is the variation in insulin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitivity of endogenous glucose production to insulin.

Perfusion CT of the brain in the assessment of flow alterations during brachytherapy of meningioma.

PURPOSE: The aim was to investigate the use of perfusion CT of the brain in the assessment of flow alterations during brachytherapy of meningiomas. MATERIAL AND METHODS: Six patients with an intracranial meningioma were investigated during brachytherapy treatment by stereotactic implantation of I-125 seeds. Cerebral blood flow (CBF) in the tumour centre and the tumour periphery as well as in the normal brain parenchyma was determined by perfusion CT. Follow-up examinations were performed during the first year after the implantation. The CBF of the normal brain parenchyma was used as control. RESULTS: In the beginning of therapy, the mean+/-SEM blood flow in the tumour centre was 231.4+/-58.1 ml/100 g/min and in the periphery 223.5+/-53.8 ml/100 g/min. Within three months after the iodine seed implantation, the tumour blood flow had decreased 41%. At the one-year follow-up, the tumour blood flow in the centre had decreased to 68.7+/-45.9 ml/100 g/min. In the periphery of the tumour, it remained nearly unchanged (199.3+/-101.0 ml/100 g/min). The CBF values obtained from normal brain parenchyma did not decrease during the treatment. Throughout the study, the mean CBF for the normal grey matter was 38.5+/-2.9 ml/100 g/min, and 22.3+/-1.2 ml/100 g/min for the normal white matter. CONCLUSION: Perfusion CT seems to enable accurate monitoring of the blood flow of meningiomas during brachytherapy, and could be used in clinical situations where blood flow changes in brain and tumours should be investigated.

On- and off-resonance spin-lock MR imaging of normal human brain at 0.1 T: possibilities to modify image contrast.

The aim of the present investigation was to determine spin lock (SL) relaxation parameters for the normal brain tissues and thus, to provide basis for optimizing the imaging contrast at 0.1 T. 68 healthy volunteers were included. On-resonance spin lock relaxation time (T1rho) and off-resonance spin lock relaxation parameters (T1rho(off), Me/Mo), MT parameters (T1sat, Ms/Mo), and T1, T2 were determined for the cortical gray matter, and for the frontal and parietal white matters. The T1rho for the frontal and parietal white matters ranged from 110 to 133 ms and from 122 to 155 ms with locking field strengths from 50 microT to 250 microT, respectively. Accordingly, the values for the gray matter ranged from 127 to 155 ms. With a locking field strength of 50 microT, T1rho(off) for the frontal and parietal white matters were from 114 to 217 ms and from 126 to 219 ms, and for the gray matter from 136 to 267 ms with the angle between the effective magnetic field (B(eff)) and the z-axis (theta) ranging from 60 degrees to 15 degrees, respectively. The T1rho of the white and gray matters increased significantly with increasing locking field amplitude (p < 0.001). The T1rho(off) decreased significantly with increasing theta (p < 0.001). T1rho and T1rho(off) with theta > or = 30 degrees were statistically significantly shorter in the frontal than in the parietal white matters (p < 0.05). The duration, amplitude and theta of the locking pulse provide additional parameters to optimize contrast in brain SL imaging.

Spin lock and magnetization transfer MR imaging of local liver lesions.

The present study was designed to evaluate tissue contrast characteristics obtained with the spin-lock (SL) technique by comparing the results with those generated with a magnetization transfer(MT)-weighted gradient echo [GRE, echo-time (TE)=40 ms] sequence. Twenty-eight patients with hepatic hemangiomas (n=14), or metastatic liver lesions (n=14) were imaged at 0.1 T by using identical imaging parameters. Gradient echo, single-slice off-resonance MT, and multiple-slice SL sequences were obtained. SL and MT-effects were measured from the focal liver lesions and from normal liver parenchyma. In addition, tissue contrast values for the liver lesions were determined. Statistically significant difference between the SL-effects of the hemangiomas and metastases, and also between the MT-effects of the lesions was observed (p < 0.02). Tissue contrast values for the lesions proved to be quite similar between the SL and MT techniques. Our results indicate that at 0.1 T multiple-slice SL imaging provides MT based tissue contrast characteristics in tissues rich in protein with good imaging efficiency and wide anatomical coverage, and with reduced motion and susceptibility artifacts.

Determination of T1rho values for head and neck tissues at 0.1 T: a comparison to T1 and T2 relaxation times.

In order to optimize head and neck magnetic resonance (MR) imaging with the spin-lock (SL) technique, the T1rho relaxation times for normal tissues were determined. Furthermore, T1rho was compared to T1 and T2 relaxation times. Ten healthy volunteers were studied with a 0.1 T clinical MR imager. T1rho values were determined by first measuring the tissue signal intensities with different locking pulse durations (TL), and then by fitting the signal intensity values to the equation with the least-squares method. The T1rho relaxation times were shortest for the muscle and tongue, intermediate for lymphatic and parotid gland tissue and longest for fat. T1rho demonstrated statistically significant differences (p < 0.05) between all tissues, except between muscle and tongue. T1rho values measured at locking field strength (B1L) of 35 microT were close to T2 values, the only exception being fat tissue, which showed T1rho values much longer than T2 values. Determination of tissue relaxation times may be utilized to optimize image contrast, and also to achieve better tissue discrimination potential, by choosing appropriate imaging parameters for the head and neck spin-lock sequences.

MnDPDP as a negative hepatic contrast agent: evaluation of STIR imaging compared with T1-weighted SE and GE techniques.

Our goal was to assess the utility of manganese dipyridoxyl diphosphate (MnDPDP) as a negative hepatic contrast agent in short inversion time IR MRI (STIR). Twenty patients with focal liver lesions (15 with metastatic disease, 5 with hemangiomas) underwent MRI (T1-weighted SE, breath-hold GE, and STIR sequences) before and after infusion of MnDPDP (5 mumol/kg). We then compared the results obtained with each sequence for hepatic parenchymal enhancement, lesion-to-liver contrast-to-noise ratio (C/N) measurements, and the number of focal liver lesions observed in pre- and postcontrast images. Hepatic enhancement values of 25.3 +/- 9.7 and 33.6 +/- 2.7% (mean +/- SEM) were obtained for the T1-weighted SE and GE sequences, respectively. The STIR sequence showed 78.9 +/- 2.1% negative enhancement (decrease of parenchymal signal intensity). Although a significant (p < 0.0001) C/N increase was seen after MnDPDP administration for all sequences, STIR showed the highest increase (149.0 +/- 25.5%) compared with T1-weighted SE (58.5 +/- 12.7%) and GE (83.3 +/- 7.2%) sequences. Similarly, more lesions for all sequences were detected, but again STIR showed the greatest postcontrast increase (29.0%). MnDPDP is an effective hepatic contrast agent. As both the negative hepatic enhancement and the increase in lesion-to-liver C/N were superior with the STIR sequence when compared with the positive enhancement and C/N values produced by the T1-weighted sequences, it should be considered for inclusion in the imaging protocol for patients with focal liver disease.

Functional CT with an experimental intravascular contrast agent in the assessment of liver vascular physiology.

RATIONALE AND OBJECTIVES: We evaluated liver vascular physiology with a functional spiral computed tomography (CT) technique and an intravascular contrast agent. METHODS: Eleven rabbits were studied by means of continuous 40-second single-section data acquisition after bolus injection of an experimental contrast agent. Sequential images were reconstructed at 200-msec intervals. Aortic, portal and hepatic venous, and liver time-HU curves were obtained. From these, hepatic blood volume and flow, tissue transit times, and arterial and portal contributions to total liver blood supply were assessed. RESULTS: The following measures were obtained: hepatic blood volume fraction, 0.33 +/- 0.03 (mean +/- standard error); total flow, 241.1 mL/min +/- 33.6 per 100 g of tissue (arterial component, 11.3 mL/min +/- 3.0 per 100 g of tissue; portal component, 226.4 mL/min +/- 30.7 per 100 g of tissue); arterial transit time, 8.7 seconds +/- 1.6; portal transit time, 8.7 seconds +/- 1.3; arterial to portal perfusion ratio, 0.06 +/- 0.01; and calculated arterial and portal perfusion indexes, 0.05 +/- 0.01 and 0.95 +/- 0.01, respectively. CONCLUSION: Functional CT is a promising, high-resolution tomographic imaging technique for evaluating liver perfusion.

Basic principles of MR contrast agents.

Although familiar for CNS enhancement, contrast agents for body MR applications are both similar and different. This short summary emphasizes the basics of tissue relaxation and the added influences of paramagnetic or superparamagnetic pharmaceuticals. An overview of safety and cost considerations is included.

Spin lock magnetic resonance imaging in the differentiation of hepatic haemangiomas and metastases.

Spin lock (SL) imaging technique, generating T1 rho-weighted images, was applied to the differentiation of hepatic haemangiomas from metastatic focal liver lesions. 17 haemangiomas and 16 metastases in 32 patients were imaged at the field-strength of 0.1 T using a multiple slice SL technique and a conventional gradient-echo (GRE) sequence with identical timing parametres. Spin lock effects of the hepatic lesions and different abdominal tissues were calculated. Images with adequate coverage of the liver and of good quality with few motion induced artefacts were acquired. A definite, statistically significant, difference was found between the SL-effects of hepatic haemangiomas and a liver metastases. Haemangiomas showed an SL effect of 46.6 +/- 3.4% and metastases of 56.2 +/- 5.8% (mean +/- SD, p < 0.0001). The multiple slice SL technique showed potential in distinguishing haemangiomas from metastatic liver lesions and should be considered as an alternative to the conventional T2 and magnetization transfer (MT) based methods.