Gerhard van Kaick

Can pre-operative contrast-enhanced dynamic MR imaging for prostate cancer predict microvessel density in prostatectomy specimens?

The aim of this study was to correlate quantitative dynamic contrast-enhanced MRI (DCE MRI) parameters with microvessel density (MVD) in prostate carcinoma. Twenty-eight patients with biopsy-proven prostate carcinoma were examined by endorectal MRI including multiplanar T2- and T1-weighted spin-echo and dynamic T1-weighted turbo-FLASH MRI during and after intravenous Gd-DTPA administration. Microvessels were stained on surgical specimens using a CD31 monoclonal antibody. The MVD was quantified in hot spots by counting (MVC) and determining the area fraction by morphometry (MVAF). The DCE MRI data were analyzed using an open pharmacokinetic two-compartment model. In corresponding anatomic locations the time shift (Δt) between the beginning of signal enhancement of cancer and adjacent normal prostatic tissue, the degree of contrast enhancement and the contrast exchange rate constant (k21) were calculated. The MVC and MVAF were elevated in carcinoma (p<0.001 and p=0.002, respectively) and correlated to k21 (r=0.62, p<0.001 and r=0.80, p<0.001, respectively). k21-values of carcinoma were significantly higher compared with normal peripheral but not central zone tissue. Δt was longer in high compared with low-grade tumors (p=0.025). The DCE MRI can provide important information about individual MVD in prostate cancer, which may be helpful for guiding biopsy and assessing individual prognosis.

Stereotactic single high dose radiation therapy of benign intracranial meningiomas

Seventeen patients with intracranial meningiomas were treated with single high dose irradiation at the German Cancer Research Center in Heidelberg. Indications for radiosurgery included unresected tumors, gross disease remaining despite surgery, and recurrences. Therapy was carried out by a technique using multiple non-coplanar arc irradiations from a 15 MeV linear accelerator. This technique coupled with secondary tungsten collimators allowed a high concentration of the dose in the target volume with an extremely steep dose gradient at the field borders. The patients were treated with a single irradiation dose ranging from 10 to 50 Gy (mean of 29 Gy). Four of 17 patients died: one death was tumor-related and not attributable to the treatment, one died of a treatment related complication, and two patients died of intercurrent diseases. The remaining 13 of the 17 patients with a median follow-up time of 40 months have no evidence of tumor relapse. Late severe side effects include five patients with a large area of brain edema, three of which were concurred with tumor necrosis. We conclude from these initial data that single high doses of irradiation concentrated to the tumor volume by stereotaxic methods can achieve local tumor control. It is also clear from these data that the effective therapeutic dose range must be better defined.

ASSESSMENT OF FOCAL LIVER REACTION BY MULTIPHASIC CT AFTER STEREOTACTIC SINGLE-DOSE RADIOTHERAPY OF LIVER TUMORS

PURPOSE To characterize and quantitatively assess focal radiation reactions in the liver after stereotactic single-dose radiotherapy for liver malignancies. METHODS AND MATERIALS A total of 131 multiphasic CT scans were performed in 36 patients before and after stereotactic radiotherapy for liver tumors. The examination protocol included a nonenhanced scan and contrast-enhanced scans at different times after contrast injection. The volume of the reaction was determined in each scan and the threshold dose calculated using the dose-volume histogram of the treatment plan. RESULTS Every patient showed a focal radiation reaction on at least one follow-up examination. In 74% of the posttherapeutic scans, a sharply demarcated hypodense area surrounded the treated tumor in the nonenhanced scans. The reaction occurred at a median of 1.8 months (range 1.2-4.6) after radiotherapy. The median threshold dose was 13.7 Gy (range 8.9-19.2). The threshold dose strongly correlated with the time of detection after therapy (r = 0.7). Radiologically, three reaction types were found on the enhanced scans: type 1, portal-venous phase: hypodense and late phase: isodense; type 2, portal-venous phase: hypodense and late phase: hyperdense; and type 3, portal-venous phase: isodense/hyperdense and late phase: hyperdense. Type 1 or 2 reactions were observed significantly earlier than type 3 (p <0.05). The median threshold dose for type 1 or 2 reactions was significantly lower than for type 3 (p <0.05). The reaction volume decreased with longer follow-up (2-4 months: median 40% of initial volume). The reaction types shifted with follow-up: 58% were of type 1 at the initial manifestation and 58% were of type 3 at the next examination thereafter. CONCLUSION A focal radiation reaction occurs after stereotactic single-dose therapy in the liver. The volume of the reaction decreases and changes its radiologic appearance during follow-up. This reaction has to be differentiated from recurrent tumor.

Changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole : Assessment using T*2 and T1 measurements

The aim of this pilot‐study was to evaluate changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole (DIP) by means of MRI. Twenty healthy volunteers were examined using a multi‐echo gradient‐echo sequence. The differential myocardial signal response due to the blood oxygen level dependent (BOLD) effect was studied under variable conditions of myocardial oxygen supply caused by the vasodilator DIP. Unlike contrast agents (CA) methods, which require at least two injections of CA and DIP, the presented methods require only a single infusion of DIP. To assess changes in myocardial perfusion, a saturation recovery TurboFLASH (SRTFL) sequence with centric reordering for T1 measurements was used with global and slice‐selective spin‐preparation (five volunteers). The signal response was measured at baseline conditions and when myocardial blood flow was increased during pharmacological stress with DIP. Administration of DIP induced a 17 ± 9% increase in T*2. Enhanced perfusion resulted in a 15 ± 5% decrease of T1 after slice‐selective spin preparation and a calculated increase in absolute perfusion of about 5.1 ml/(g × min), which reflects coronary reserve.

FDG uptake, tumor proliferation and expression of glycolysis associated genes in animal tumor models

To determine the influence of tumor cell proliferation and changes in the genetic program in malignant cells on the fluorodeoxyglucose (FDG) uptake we performed PET studies in several animal tumors: spontaneous mammary fibroadenoma, chemically-induced mammary adenocarcinoma and Dunning prostate adenocarcinoma. The expression of the glucose transporter (GLUT1) and of hexokinase (Hk) was measured using 32P-labeled cDNA probes and densitometry. Furthermore the proliferative activity was determined with one-dimensional flow cytometry. The FDG uptake and the proliferation parameters were not correlated. The normalized amounts of GLUT and Hk mRNA were lower in spontaneous fibroadenomas and prostate tumors than in chemically induced mammary. The FDG uptake was correlated to GLUT1 expression with r = 0.83 and to Hk expression with r = 0.77. Multiple regression analysis revealed a relation of FDG uptake to GLUT1 and HK with r = 0.87. Our results show that the FDG uptake in our study was related not to differences in proliferation, but rather to differences in the transcription of glycolysis associated genes.

Evaluation of angiogenesis and perfusion of bone marrow lesions: Role of semiquantitative and quantitative dynamic MRI

Magnetic resonance imaging (MRI) is a noninvasive technique that complements computed tomography (CT), conventional X‐ray, and bone marrow biopsies by sampling a large volume of musculoskeletal bone and providing information that aids the diagnosis, staging, and follow‐up of various lesions. Although less sensitive to the mineral components of bones, the MRI appearance of physiologic bone marrow is mainly a reflection of the relative amounts of red marrow, yellow marrow, and trabecular bone. Therefore, use of T1‐and T2‐weighted MR sequences with or without fat suppression currently remains the most common approach to musculoskeletal bone lesion imaging. An additional imaging strategy to characterize various bone lesions is the application of contrast‐enhanced dynamic MRI. This article examines semiquantitative and quantitative dynamic imaging, evaluation, and postprocessing techniques in various benign and malignant musculoskeletal lesions. Practical guidelines for performing a dynamic contrast‐enhanced MR examination are proposed. J. Magn. Reson. Imaging 1999; 10:286–294.

The German Thorotrast Study: Recent Results and Assessment of Risks

The German Thorotrast study comprises 2,326 patients and 1,890 controls. Forty-eight Thorotrast patients and 239 controls are still alive and are invited for a follow-up examination every 2 years. In the deceased patients, the following neoplastic diseases with excess rates were registered (Thorotrast/controls): liver cancer (454/3); cancer of the bile ducts, including gallbladder (42/7); myeloid leukemia (40/7); myelodysplastic syndrome (30/4); plasmacytoma (10/2); non-Hodgkins lymphoma (15/5); bone sarcoma (4/1); malignant peritoneal or pleural mesothelioma (9/0). Dose calculations are based on results of whole-body counting, X-ray films, and data obtained from the hospital records on the volume of Thorotrast injected. For liver cancer, the cumulative risk estimate was calculated to be 40 per 10(4) person Sv (radiation weighting factor = 20). These figures are close to the results of the Danish study and are comparable to the results of the Life Span Study of A-bomb survivors after 40 years at risk with 18 to 48 liver cancers per 10(4) person Sv. For hematopoietic malignancies, the cumulative risk was calculated to be about 7 per 10(4) person Sv (radiation weighting factor = 20). This risk estimate is lower by a factor of 10 compared to the results of the Life Span Study.

Functional magnetic resonance imaging at 1.5 T: Activation pattern in schizophrenic patients receiving neuroleptic medication

Activation of the cerebral cortex during motor task performance can be visualised with functional MRI. A modified FLASH sequence (TR/TE/alpha 100/60/40 degrees, first order flow rephased, fat suppression, reduced bandwidth 28 Hz/pixel, 120 repetitions, three cycles of rest and finger movement for each hand) on a standard 1.5 T clinical imager was used to investigate 10 schizophrenic patients receiving clozapine and 10 healthy volunteers. All subjects were right-handed. Color-coded statistical parametric maps (SPM) based on the Students t-test were calculated. A grid overlay was used for global and regional quantification. Activation strength was defined as the mean t-value of the respective region. All patients and volunteers showed a significant activation in the contralateral and ipsilateral sensorimotor cortex during motor task performance. The schizophrenic patients showed a significantly reduced global activation strength compared with healthy volunteers (p < .005). Selective evaluation of left-hand compared to right-hand movement demonstrated an increase in global activation strength in volunteers in contrast to a decrease in patients. Furthermore a reduced coactivation in the dominant left hemisphere was found in patients compared to volunteers during movement of the ipsilateral (left) hand. We conclude that alterations of the right and left hemispheric balance can be detected in schizophrenic patients using functional MRI at 1.5 T. These changes may indicate a disturbed interhemispheric interaction in schizophrenia. The reduction in cortical activation may result from several causes, however, taken together with previous studies and the underlying physiological effects, the most likely explanation is a combined effect of the disease and the neuroleptic medication.

Transient enlargement of contrast uptake on MRI after linear accelerator (linac) stereotactic radiosurgery for brain metastases

PURPOSE/OBJECTIVE With the increasing number of patients successfully treated with stereotactic radiosurgery for brain metastases, decision making after therapy based on follow-up imaging findings becomes more and more important. Magnetic resonance imaging (MRI) is the most sensitive means for follow-up studies. The objective of this study was to investigate the treatment outcome of our radiosurgery program and to describe the response of brain metastases to contrast-enhanced MRI after linear accelerator (linac) stereotactic radiosurgery and identify factors to distinguish among local control and local failure. METHODS AND MATERIALS Using serial MRI, we followed the course of 87 brain metastases in 48 consecutive patients treated between September 1996 and November 1997 with linac-based radiosurgery with 15-MV photons. Treatment planning was performed on an MR data cube. For spherical metastases, radiosurgery was delivered using a 9 noncoplanar arc technique with circular-shaped collimators. For irregularly shaped targets, radiosurgery was delivered using a manually driven multi-leaf collimator with a leaf width of 1.5 mm projected to the isocenter. Median radiosurgery dose was 20 Gy prescribed to the 80% isodose. Together with whole brain radiotherapy (20 x 2 Gy, 5/w), a median radiosurgical dose of 15 Gy was delivered. Median follow-up was 8 (range 2--36) months. Factors influencing local control and survival rates were analyzed with respect to MRI response, and Kaplan-Meier curves were calculated. RESULTS Actuarial local tumor control was 91% at one and two years. Patient survival at one and two years was 30% and 18%. Median survival was 9 months. During follow-up in 70 (81%) of the 87 treated metastases, the contrast-enhancing volumes on T1W images were stable or disappeared partly or completely. A transient enlargement of contrast-enhancing volumes was observed in 11 (12%) of the 87 lesions treated, while a progressive enlargement due to local treatment failure was observed in 6 (7%) of the 87 treated metastases. Younger age, early contrast onset after radiosurgery, and previous chemotherapy were associated with this transient enlargement of contrast-enhancing lesion volume. CONCLUSIONS Linac-based radiosurgery is an effective, noninvasive, and safe treatment option for patients with brain metastases. A marked enlargement of the contrast-enhancing volume on T(1)-weighted MR images after radiosurgery is a sensitive predictor for, but not equivalent with, local failure. In as many as two-thirds of the cases with contrast enlargement in MRI follow-up, the contrast enlargement is transient with no need for further treatment. While some MRI findings are more likely if transient enlargement is present, a clear decision cannot be made based on MRI, and ultimately the clinical status dictates further action.

Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging

The aim of our study was to investigate the quantitative microcirculation parameters amplitude A (hypothetical intravascular volume) and exchange rate constant k21 (hypothetical vascular permeability) by contrast‐enhanced dynamic magnetic resonance imaging (dMRI) as markers of angiogenesis in multiple myeloma (MM). Therefore lumbar spine and spina iliaca superior posterior of 16 normal controls and 41 patients with active MM were assessed using a dMRI protocol with a pump controlled bolus infusion of Gadolinium‐DTPA. Pharmacokinetic parameters, amplitude A and exchange rate constant k21 were calculated according to a 2‐compartment model. Color‐coded parameter images were generated from pharmacokinetic data analysis and superimposed onto the conventional MR images. Amplitude A and k21 parameters were significantly increased in patients with MM compared with controls (p = 0.001; median Actr, 0.2 [range, 0.09–0.4]; median AMM, 0.93 [range, 0.2–2.2]; median k21ctr, 0.09 min−1 [range, 0.03–0.9]; median k21MM, 4.58 [range, 0.22–23.8]). Within the group of MM patients the pattern of color‐coded parameter images were found to be either of “diffuse” (n = 13, 31%) or “focal” (n = 28, 69%) type of distribution of microcirculation. Comparison of amplitude A in patients with “focal” vs. “diffuse” pattern of the pharmacokinetic maps revealed a significant increase in the median of amplitude A in the “focal” group. Amplitude A values allowed a classification of patients according to severe osteolytic bone involvement (p = 0.023) with the best cutoff value of 0.7 for amplitude A. Downmodulation of amplitude A was observed in a MM patient treated with standard VAD chemotherapy. Our data demonstrate that dMRI is a novel imaging technique for the detection and monitoring of MM bone lesions. It provides independent evidence for angiogenesis in MM.