G. van Kaick

Pathophysiologic basis of contrast enhancement in breast tumors

While the diagnostic benefits of gadolinium (Gd)‐chelate contrast agents are firmly established in magnetic resonance imaging (MRI) of tumors, the pathophysiologic basis of the enhancement observed and its histopathologic correlate remained vague. Tumor angiogenesis is fundamental for growth and metastasis and also of interest in new therapeutic concepts. By correlative analysis of a) histology; b) vascular density (CD31); and c) vascular permeability (vascular permeability factor/vascular endothelial growth factor [VPF/VEGF]), we found a) significantly (P < 0.001) faster exchange rates in malignant compared with benign breast lesions; b) distinct differences in enhancement characteristics between the histologic types (invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ); and c) dependence of enhancement kinetics on the VPF/VEGF expression. The pathophysiologic basis for the differences in contrast enhancement patterns of tumors detectable by MRI is mainly due to vascular permeability, which leads to more characteristic differences than vascular density. MRI is able to subclassify malignant breast tumors due to their different angiogenetic properties. J. Magn. Reson. Imaging 1999;10:260–266.

Evaluation of tumour metabolism and multidrug resistance in patients with treated malignant lymphomas

The management of patients with treated malignant lymphomas requires functional methods to differentiate a residual soft tissue mass. Patients with treated Hodgkins lymphoma (HL,n = 20, 68 malignant lesions, three benign lesions) or non-Hodgkins lymphoma (NHL,n = 26, 46 malignant lesions, one benign lesion) were studied with positron emission tomography (PET) and fluorine-18 deoxyglucose (FDG). Oxygen-15 labelled water was used (n = 14, 25 lesions) in addition to FDG in order to obtain information on the tissue perfusion. Long-term follow-up studies with PET and FDG were performed in nine patients up to 511 days after the initiation of second-line therapy. Fourteen patients underwent single-photon emission tomography (SPET) with technetium-99m sestamibi immediately prior to the first PET examination. PET with FDG displays a high sensitivity for the detection of viable tumour tissue, all the malignant lesions being correctly classified in this study. The possible limitations are inflammatory processes, which may obscure tumour detection due to increased FDG uptake, and malignant lesions with low FDG uptake due to reduced perfusion. Difficulties exist in the prognosis of long-term response, since the change in FDG uptake may be variable. Long-term therapy outcome was correlated with the slope values obtained from the standardized integral uptake (SIU) data, which provides a new approach for the evaluation of PET follow-up studies.99mTc-sestamibi, which should reflect the multidrug resistance, was evaluated with respect to therapy outcome. A high uptake of99m-Tc-sestamibi was observed in patients with stable disease or better. The data support the hypothesis that sestamibi may reflect multidrug resistance. Due to technical limitations of the SPET technique, the use of a positron-labelled compound would be superior to SPET for clinical application.

Cerebral arteriovenous malformations: morphologic evaluation by ultrashort 3D gadolinium-enhanced MR angiography

Abstract. The purpose of this study was to evaluate the usefulness of a new ultrashort contrast-enhanced (CE) MR angiography (MRA) for the morphologic evaluation of cerebral arteriovenous malformations (AVMs). The method was compared with conventional X-ray digital subtraction angiography (DSA) and time-of-flight (TOF) MRA in 22 patients to assess the angioarchitecture of the malformations which is essential for treatment planning and follow-up. Two experienced MR readers independently evaluated both techniques with regard to the assessment of feeding arteries, AVM nidus, and venous drainage patterns. Contrast-enhanced MRA was able to detect all AVMs seen on DSA, whereas the TOF MRA failed in 1 patient with a very small AVM. In the assessment of the different vessel components of the AVM there was no difference for the detection and delineation of feeding arteries and the AVM. The venous drainage patterns could always be clearly delineated in the CE MRA, whereas TOF MRA could demonstrate the exact venous drainage in only 9 patients. Contrast-enhanced MRA was found to be superior to conventional TOF MRA in the assessment of the angioarchitecture of cerebral AVMs especially regarding the assessment of the venous drainage patterns. The superiority is supported by the improved vessel-to-background contrast and contrast-to-noise ratios. The major limitations of this new technique consist of a low spatial resolution at the used time resolution which can be improved by further sequence modifications. Contrast-enhanced MRA is thus an important additional imaging technique for treatment planning and follow-up of AVMs.

Cerebral arteriovenous malformations: Improved nidus demarcation by means of dynamic tagging MR-angiography

Our purpose was to further improve the target volume definition for radiosurgical treatment of cerebral arteriovenous malformations (AVMs) by means of dynamic MRA (dMRA) using a blood bolus tagging sequence. We therefore compare this technique with 3D-TOF-MRA and transfemoral high resolution angiography in plain film technique. Twenty patients with angiographically proven cerebral AVMs were investigated by dMRA, TOF-MRA, and conventional angiography during the MR-assisted radiosurgical planning protocol. The patients head was fixed in an MR-compatible stereotactic device. The different angiography techniques were evaluated by consensus of two radiologists. AVMs were characterized by the number and origin of feeding arteries, the maximum diameter of the AVM nidus, and the venous drainage pattern. Dynamic MRA was able to demonstrate the complete AVM characteristics and hemodynamics in 12 out of 20 patients. In three patients with an AVM nidus smaller than 1 cm in diameter the technique could not reliably depict the malformation. Technical problems due to steel screws and pins in the initially used stereotactic frame occurred in five patients. Due to reduced vessel overlap and the lack of disturbances caused by formations with short T1 time, dMRA was superior to TOF-MRA in the detection and the exact localization of the AVM nidus in four patients. We conclude that dMRA is able to demonstrate reliably AVM characteristics and hemodynamics in AVMs with a nidus larger than 1 cm in diameter. Because of the improved demarcation of the AVM nidus, this technique may be a valuable adjunct to radiosurgery planning of cerebral AVMs.

Fluid-attenuated inversion-recovery MR imaging of gliomatosis cerebri

Abstract Magnetic resonance imaging has been shown to be the most sensitive imaging modality in the assessment of gliomatosis cerebri. Recent studies have shown that fluid-attenuated inversion-recovery (FLAIR) is a valuable MR sequence in the delineation of cerebral pathologies including intra-axial tumors. However, no data are available about the role of this novel technique in the assessment of gliomatosis lesions. The purpose of this study was therefore to evaluate the diagnostic potential of FLAIR MR imaging in patients with suspected gliomatosis cerebri. Seven patients suspected of having lesions of gliomatosis cerebri were examined by T1-weighted spin echo (SE), T2-weighted fast spin echo (FSE), and FLAIR MR imaging with identical slice parameters. T1 and FLAIR were repeated after contrast media administration. Delineation and extent of gliomatosis were the primary parameters of the image analysis. The FLAIR imaging clearly delineated the extent of gliomatosis lesions in all patients. Due to the suppression of cerebrospinal fluid, the delineation was superior to conventional T2-weighted FSE images. Especially the detection and delineation of cortical spread and the infiltration of the corpus callosum was best seen on FLAIR images. The FLAIR MR imaging is a valuable diagnostic modality in the assessment of patients with gliomatosis cerebri. Due to its better delineation of tumor spread, it was found to be the imaging method of choice and should therefore be integrated into the MR imaging protocol of these patients.

Uncoupling of 2-fluoro-2-deoxyglucose transport and phosphorylation in rat hepatoma during gene therapy with HSV thymidine kinase

This animal study investigates the application of positron emission tomography (PET) with tracers of tumour metabolism for monitoring suicide gene therapy with herpes simplex virus thymidine kinase (HSVtk). After transplantation of HSVtk-expressing Morris hepatoma cells into ACI rats, dynamic PET measurements of 18F-labeled 2-fluoro-2-deoxyglucose (FDG) uptake were performed in animals 2 days (n = 7) and 4 days (n = 5) after the onset of therapy with 100 mg ganciclovir (GCV)/kg body weight as well as after administration of sodium chloride (n = 8). The arterial FDG plasma concentration was measured dynamically in an extracorporeal loop and the rate constants for FDG transport (K1, k2) and FDG phosphorylation (k3) were calculated using a three-compartment model modified for heterogeneous tissues. Also, quantification using the metabolic rate of FDG turnover and the standardized uptake value (SUV) was done. Furthermore, the thymidine incor- poration into the tumour DNA was determined after i.v. administration of 3H-thymidine. An uncoupling of FDG transport and phosphorylation was found with enhanced K1 and k2 values and a normal k3 after 2 days of GCV treatment. The increase in FDG transport normalized after 4 days whereas the phosphorylation rate k3 increased. Quantification using the metabolic rate or the SUV showed congruent but less sensitive results compared with the modeling approach. The thymidine incorporation into the DNA of the tumours declined to 10.5% of the controls after 4 days of GCV treatment. The data indicate that PET with 18FDG and 11C-thymidine may be applied for monitoring of gene therapy with the HSVtk/GCV suicide system. Increased transport rates are evidence of stress reactions early after therapy. The measurement of thymidine incorporation into the tumour DNA can be used as an indicator of therapy efficacy.

Treatment of the Dunning Prostate Rat Tumor R3327-AT1 with Pulsed High Energy Ultrasound Shock Waves (PHEUS): Growth Delay and Histomorphologic Changes

We are interested in the interaction of pulsed high energy shock waves (PHEUS) on soft tissues treated in situ to evaluate its potential for therapeutic use. The experimental apparatus built by us was adapted from a lithotripter designed for clinical use. For the present studies we used the R3327-AT1 Dunning prostate tumor growing s.c. in the thigh of Copenhagen rats. The treatments consisted of four groups of eight animals each who received 500 or 2000 pulses at 1 or 5 Hz. Sham-treated tumor bearing animals served as controls (n = 11). During each PHEUS treatment, petechial bleeding of the skin at the point of entry and exit of sound appeared. Sonication at a repetition rate of five Hz seemed to induce more macroscopic damage in terms of hematomas and skin effects. The cytotoxic effects of PHEUS to tumor tissue were sufficient to induce a significant delay (p less than 0.05) in tumor growth but no clear-cut dose relationship was established. Histological studies revealed widespread early rupture of the fine vasculature with extravasation of erythrocytes. By 72 hr., in PHEUS treated tumors, a large necrosis was seen within the central zone which was never observed in sham-treated tumors. Our results clearly indicate that PHEUS has a cytotoxic potential. The observation of a rapid onset of hemostasis, stark hemorrhage and necrosis in the treatment field would suggest that vascular damage is an important contributing factor.

Magnetic resonance imaging of bone marrow in lymphoproliferative disorders: correlation with bone marrow biopsy

Summary. In a prospective clinical study 10 normal volunteers and 30 patients with lymphoma—11 patients with Hodgkins lymphoma and 19 patients with non‐Hodgkins lymphoma (11 low grade, 8 high grade)–were examined. Proximal femora, pelvis and lumbar spine were imaged with a 1.5 tesla superconducting MR imaging system (Siemens Magnetom). Areas of malignant infiltration in the bone marrow were clearly detected by visual and/or quantitative assessment. In most cases bone marrow involvement was demonstrated by both magnetic resonance imaging and bone marrow biopsies. However, in three of 30 patients magnetic resonance imaging showed evidence of lymphomatous involvement despite normal bone marrow histology. In one patient bone marrow cytology revealed malignant infiltration in the absence of MRI abnormalities. Thus, MRI is a sensitive method for detecting bone marrow infiltration by lymphoma.

Spiral CT vs incremental CT: Is spiral CT superior in imaging of the brain?

Abstract. The aim of this study was to evaluate image quality of spiral CT of the brain as compared with incremental CT using identical scanning parameters. Incremental or spiral cranial CT was performed on 46 consecutive, randomized patients with non-traumatic disease of the brain on a Siemens (Erlangen, Germany) Somatom Plus 4. Evaluation was done in a randomized blinded way by two experienced radiologists. Different anatomical structures, image noise, and artifacts were scaled 1 (bad) to 4 (very good). Statistical analysis was done using the F-test of variance for partial sums of squares as well as Students t-test. Incremental CT was superior to spiral CT for evaluation of the internal capsule, supratentorial artifacts, gray/white matter differentiation, and image noise. No statistically significant differences were seen for evaluation of the pons, infratentorial artifacts, and eye muscles. With identical scanning parameters incremental CT is superior to spiral CT in the assessment of small, complex structures in a low-contrast setting. No differences are seen for larger structures or small structures in a medium-contrast range. Artifacts localized close to the skull in spiral CT can easily mimic hemorrhage in traumatized patients. Spiral CT should therefore only be used for CT angiography and if 3D reconstructions are needed.

Vergleich von MultiHance® und Gadovist® zur zerebralen MR-Perfusionsmessung bei gesunden Probanden

ZusammenfassungZur Evaluierung des gering proteinbindenden MR-Kontrastmittels MultiHance® und des einmolaren MR-Kontrastmittels Gadovist® für die MR-Perfusionsmessung im Gehirn wurden in einer randomisierten, intraindividuellen Vergleichsstudie 12 gesunde männliche Probanden untersucht. Die Perfusionsmessung wurde an einem 1,5-T-MRT mit einer T2*-gewichteten GRE-EPI-Sequenz in einfacher und doppelter Kontrastmitteldosierung durchgeführt. Die Schichtposition, Sequenzparameter und Kontrastmittelapplikation waren standardisiert. Zur quantitativen Analyse wurden rCBV- und rCBF-Messungen der normalen grauen und weißen Hirnsubstanz vorgenommen. Zusätzlich wurde der prozentuale Signalverlust und die Halbwertsbreite der Signalzeitkurven ausgewertet.Die einfache Dosis wurde für beide Kontrastmittel als ausreichend für eine MR-Perfusionsmessung befunden. Der prozentuale Signalverlust (Gadovist®: 29,4% vs. MultiHance®: 28,3%) und die Halbwertsbreite des Signalverlustes (Gadovist®: 6,4 s vs. MultiHance®: 7,0 s) wie auch die errechneten Perfusionsparameter CBV und CBF waren bei beiden Kontrastmitteln in der einfachen Dosierung vergleichbar. Durch die deutlich längere Infusionszeit für MultiHance in der doppelten Dosierung war die Halbwertsbreite hier deutlich erhöht, jedoch ohne Auswirkung auf die Perfusionswerte rCBV und rCBF.Zusammengefasst hat das höher konzentrierte Gadovist® gegenüber dem stärker relaxierenden Kontrastmittel MultiHance® keine Vorteile für die MR-Perfusionsbildgebung. Beide Kontrastmittel erlauben die Berechnung qualitativ hochwertiger Perfusionsmaps in einer Dosierung von 0,1 mmol/kgbw mit identischen Qualitätsparametern.AbstractTo evaluate the weakly protein interacting MR contrast agent MultiHance® and the one-molar agent Gadovist® for cerebral perfusion MR imaging, a randomized intraindividual study was conducted in 12 healthy male volunteers. Perfusion-MRI was performed with single and double dose of each contrast agent on a 1.5T MR system using a gradient-echo EPI sequence. The imaging parameters, slice positioning and contrast media application were standardized. For the quantitative assessment rCBV and rCBF measurements of gray and white matter were performed. Additionally, the percentage of signal drop and the full width half maximum (FWHM) of ROI signal time curves were quantified. In a qualitative analysis the image quality of the rCBV and rCBF maps were assessed.Single dosage of the used new contrast agents was sufficient to achieve high quality perfusion maps. The susceptibility effect, described by percentage of signal loss (Gadovist®: 29.4% vs. MultiHance®: 28.3%) and the FWHM (Gadovist®: 6.4 s vs. Multihance®: 7.0 s) were not different between the agents for single dose.The one molar MR contrast agent Gadovist® has no advantages over MultiHance®, a MR contrast agent with a higher relaxivity in perfusion MRI. Both agents allow the calculation of high quality perfusion maps at a dosage of 0.1 mmol/kg bw with physiologic absolute values for regional CBV and CBF. The susceptibility effect is comparable for both agents and stronger than with conventional MR contrast media.