[Increased signal intensities and gadolinium levels in the brain after administration of gadolinium-based MR contrast agents : Clinical observations and results from preclinical research]. / Erhöhte Signalintensitäten und Gadolinium-Werte im Gehirn nach Gabe Gadolinium-haltiger MR-Kontrastmittel : Klinische Beobachtungen und Ergebnisse aus präklinischer Forschung.

BACKGROUND: Numerous clinical MRI studies have been published that describe an association between the repeated administration of (linear) gadolinium-based contrast agents and increased signal intensity in certain brain areas. In November 2017, the European Commission suspended the use of some of these contrast agents. OBJECTIVES: The background for this decision, both regulatory and scientific, are presented and discussed. MATERIALS AND METHODS: The regulatory decisions are evaluated and the clinical and preclinical literature is discussed. RESULTS: Differences in the structure and stability of gadolinium-based contrast agent molecules explain the observed increased signal intensities in individual brain regions (e. g. dentate nucleus) after administration of multiple doses of linear contrast agents. This phenomenon was not observed after administration of multiple doses of macrocyclic contrast agents. Preclinical studies have confirmed these results. CONCLUSION: To date, no clinical symptoms have been confirmed to be associated with the increased signal intensity or gadolinium presence in the brain.

Use, timing and factors associated with tracheal intubation in septic shock: a prospective multicentric observational study.

BACKGROUND: No recommendation exists about the timing and setting for tracheal intubation and mechanical ventilation in septic shock. PATIENTS AND METHODS: This prospective multicenter observational study was conducted in 30 ICUs in France and Spain. All consecutive patients presenting with septic shock were eligible. The use of tracheal intubation was described across the participating ICUs. A multivariate analysis was performed to identify parameters associated with early intubation (before H8 following vasopressor onset). RESULTS: Eight hundred and fifty-nine patients were enrolled. Two hundred and nine patients were intubated early (24%, range 4.5-47%), across the 18 centers with at least 20 patients included. The cumulative intubation rate during the ICU stay was 324/859 (38%, range 14-65%). In the multivariate analysis, seven parameters were significantly associated with early intubation and ranked as follows by decreasing weight: Glasgow score, center effect, use of accessory respiratory muscles, lactate level, vasopressor dose, pH and inability to clear tracheal secretions. Global R-square of the model was only 60% indicating that 40% of the variability of the intubation process was related to other parameters than those entered in this analysis. CONCLUSION: Neurological, respiratory and hemodynamic parameters only partially explained the use of tracheal intubation in septic shock patients. Center effect was important. Finally, a vast part of the variability of intubation remained unexplained by patient characteristics. Trial registration Clinical trials NCT02780466, registered on May 23, 2016. https://clinicaltrials.gov/ct2/show/NCT02780466?term=intubatic&draw=2&rank=1.

Magnetic resonance imaging of focal liver lesions. Comparison of the superparamagnetic iron oxide resovist versus gadolinium-DTPA in the same patient.

RATIONALE AND OBJECTIVES: The authors assess the efficacy of static and dynamic magnetic resonance (MR) imaging using the superparamagnetic iron oxide SHU-555A (Resovist) versus standard dose of gadolinium (Gd)-DTPA in patients with focal liver lesions. METHODS: Magnetic resonance imaging was performed in 30 patients suffering from histopathologically verified malignant (n = 22) and benign (n = 8) liver lesions. T2-weighted conventional and fat-suppressed as well as T1-weighted sequences were used before, during, and after fast intravenous administration of Resovist (1 mL/minute) at three doses of 4, 8, and 16 mumol/kg body weight. One week before the Resovist-enhanced MR imaging study 20 patients underwent Gd-DTPA-enhanced MR imaging. RESULTS: Detection rate was improved for metastatic lesions revealing 36 lesions unenhanced versus 53 focal lesions using Resovist-enhanced MR imaging. Gadolinium-DTPA-enhanced scans showed no additional lesion versus unenhanced and Resovist-enhanced MR imaging. Static and dynamic imaging demonstrated no measurable percentage signal intensity loss (PSIL) using Resovist-enhanced MR imaging versus a percentage enhancement of 79.7% in Gd-DTPA enhanced scans. In the dynamic T2-weighted sequences, hepatocellular carcinoma nodules (n = 4) showed a rapid decrease in signal intensity starting at 44 seconds. Postinfusion of Resovist followed by a low, constant increase in signal intensity. Gadolinium-DTPA enhanced scans showed a percentage enhancement of 73.4 focal nodular hyperplasia (FNH) and hemangioma revealed a strong and early dose-dependent PSIL 44 to 60 seconds postinfusion with a prolonged signal loss for the FNH in the late study. Statistical evaluation revealed a statistically significant superiority of Resovist-enhanced MR imaging concerning the detection and delineation of focal liver lesions compared with unenhanced and Gd-DTPA enhanced scans (P < 0.05). CONCLUSIONS: The fast infusion of the new superparamagnetic contrast agent Resovist shows advantages for dynamic and static MR imaging of focal liver lesions.

MR enhancement of brain lesions: increased contrast dose compared with magnetization transfer.

PURPOSE: To compare image contrast and lesion conspicuity of enhancing intracranial lesions obtained with T1-weighted and magnetization transfer T1-weighted spin-echo sequences after administration of standard (0.1 mmol/kg body weight) and triple doses of gadobutrol. METHODS: Twenty-four patients with a total of 34 enhancing intracranial lesions were studied with T1-weighted and magnetization transfer T1-weighted spin-echo MR imaging. An incremental dose technique was used with intravenous injections of 0.1 and 0.2 mmol/kg body weight gadobutrol. Lesion-to-white matter contrast and white matter-to-edema contrast were calculated. RESULTS: The lesion-to-white matter contrast of the magnetization transfer T1-weighted studies was significantly higher than that of the T1-weighted studies when identical doses of gadobutrol were compared. The lesion-to-white matter contrast was not significantly different on the triple-dose T1-weighted study and the standard-dose magnetization transfer T1-weighted study. Two lesions were visible only on the standard-dose magnetization transfer T1-weighted and the triple-dose studies. CONCLUSION: Standard-dose magnetization transfer T1-weighted and triple-dose T1-weighted spin-echo MR studies are equally well suited to increase the lesion-to-white matter contrast in patients with enhancing intracranial lesions. Triple-dose magnetization transfer T1-weighted studies further increase lesion-to-white matter contrast but do not show additional lesions.

[Safety and use of gadobutrol in patients with brain tumors (phase III trial)]. / Sicherheit und Nutzen von Gadobutrol bei Patienten mit zerebralen Tumoren (Phase-III-Studie).

PURPOSE: The purpose of the study was to investigate the use and safety of Gadobutrol, a new low-osmolar, non-ionic contrast agent for MRI using a total dose of 0.3 mmol/kg b.w. on the basis of a clinical phase 3 study. METHODS: 30 patients with primary brain tumours (n = 15) or cerebral metastases (n = 15) were examined via MRI before and after application of a total of 0.3 mmol/kg b.w. given in two fractions (0.1 and 0.2 mmol/kg b.w.). T2-weighted images were performed before, T1-weighted images before, between and after application of contrast material. RESULTS: In this study one-molar Gadobutrol showed a good tolerance. In half of the cases the contrast between lesion and brain was improved comparing single and triple dose, but this means only a slightly improvement of information for the primary brain tumours compared with single dose. The detected metastatic lesions increased in 40% of the patients after the single dose and in 53% of the patients after cumulative triple dose. There was a consecutive change in therapy in 20% of the patients. CONCLUSION: For the differentiation of primary brain tumours the single dose was sufficient, in metastatic lesions triple dose was essential for the detection or exclusion of multifocality.

[Does the administration of a high dose of a paramagnetic contrast medium (Gadovist) improve the diagnostic value of magnetic resonance tomography in glioblastomas?]. / Verbessert die Hochdosisgabe eines paramagnetischen Kontrastmittels (Gadovist) die diagnostische Aussage der Magnetresonanztomographie bei Glioblastomen?

PURPOSE: To assess the efficacy of high-dose contrast enhanced magnetic resonance imaging (MRI) in detection and delineation of infiltrating tumour in glioblastoma. MATERIAL AND METHODS: In a phase II clinical trial 14 patients with suspected supratentorial glioblastoma underwent MRI with Gd-DO3A-butriol (Gadovist, Schering AG, Berlin) with doses of 0.1 up to 0.3 mmol/kg. RESULTS: Increasing the dose of Gd-DO3A-butriol resulted in improved enhancement (14/14) and better delineation of infiltrating tumour (9/14) up to 2 cm beyond enhancement after standard dose. In two of the 9 patients additional enhancement in the peritumoural oedema was only seen after the third injection. CONCLUSIONS: Successful surgery requires precise preoperative delineation of tumour borders. After high-dose MRI it might be possible to select those patients who would benefit from more radical attempts at eradicating the macroscopic as well as most of the microscopic compartment of glioblastoma.

[Renal enhancement and excretion of the hepatobiliary contrast agent Gd-EOB-DTPA]. / Renales Anreicherungsverhalten und Elimination des hepatobiliären Kontrastmittels Gd-EOB-DTPA in der Magnetresonanztomographie.

PURPOSE: To evaluate the clinical value of the renal clearance using MR imaging with different doses of gadolinium ethoxybenzyl-DTPA (Gd-EOB-DTPA) in comparison to gadolinium DTPA (Gd-DTPA). MATERIAL AND METHODS: In a double-blind and randomized clinical phase II study. MR imaging at 1.5 T was performed in 61 patients with five different doses of Gd-EOB-DTPA (3, 6, 12.5, 25 and 50 micromol/kg b. w. as a bolus injection). The study protocol comprised T(1)- and T(2)-weighted spin-echo magnetic resonance and two-dimensional fast low-angle shot imaging before and at increasing intervals for up to 45 min after injection of Gd-EOB-DTPA. These images were compared with Gd-DTPA-enhanced imaging (0.1 mmol/kg b. w. as a bolus injection). RESULTS: After bolus injection of the hepatobiliary MR contrast agent Gd-EOB-DTPA a renal elimination was observed. Immediately after the injection of Gd-EOB-DTPA until the eighth minute a corticomedullary enhancement of the kidney was conspicuous. After the fourth minute a contrast enhancement could be seen in the renal pelvis. The best enhancement was noted after 20 minutes in the FLASH GRE and T(1)-weighted images with good pelvicaliceal contrast. After 45 minutes an outflow of Gd-EOB-DTPA into the ureter could be observed. CONCLUSION: In addition to the hepatobiliary secretion Gd-EOB-DTPA appears useful for the evaluation of renal structures and renal function on account of the renal excretion without diuretic preparation of the patients.

[T1-weighted dynamic MRI with new superparamagnetic iron oxide particles (Resovist): results of a phantom study as well as 25 patients]. / T1-gewichtete dynamische MRT mit neuen superparamagnetischen Eisenoxidpartikeln (Resovist): Ergebnisse einer Studie am Phantom sowie an 25 Patienten.

PURPOSE: Evaluation of the diagnostic usefulness of the T1-effect of Resovist (SPIO) for dynamic MRI of the liver. METHOD: In-vitro measurements of a dilution series with T1-weighted FLASH and SE sequences and investigation of 25 patients with known focal liver lesions with a T2-weighted TSE sequence and a dynamic T1-FLASH sequence. RESULTS: T1-weighted MRI with Resovist in vitro showed a positive enhancement at low concentrations and a negative enhancement at higher concentrations. In-vivo T1-weighted dynamic MRI liver parenchyma demonstrated a positive enhancement 30 s post contrast, followed by a continuous slope of signal intensity and a negative enhancement (> or = 60 s). Spleen, portal venous vessels and haemangiomas showed an early increase in signal intensity followed by a decreasing positive enhancement, but without negative enhancement. During the perfusion phase metastases showed a small but not significant increase in signal intensity. In 80% a positive ring enhancement could be observed around metastases. CONCLUSION: Resovist exhibits a diagnostically useful T1-effect. An evaluation of the perfusion of focal liver lesions during the distribution phase is possible with dynamic T1-weighted MRI. This approach may further improve characterisation of focal liver lesions.

[Dynamic and static MRI using superparamagnetic MRI contrast medium Resovist for visualizing primary and secondary liver tumors]. / Dynamische und statische MRT mit dem superparamagnetischen MRT-Kontrastmittel Resovist zur Darstellung von primären und sekundären Lebertumoren.

PURPOSE: To analyse characteristics of benign and malignant liver tumours in dynamic and static MR imaging with the superparamagnetic MR contrast medium Resovist. MATERIAL AND METHODS: All 30 patients were examined on a 1.5 Tesla MR unit (Magnetom 63 SP, Siemens AG, Erlangen, Germany) using proton density (PD) weighted (w), T2-weighted-spin-echo, a T1-weighted SE, and a T1-weighted FLASH-2 D gradient echo (GRE) sequence before, during and after the application of Resovist. Dynamic imaging was performed using a T2-weighted GRE-sequence (TurboFLASH; TR/TE = 11/30; flip angle = 10 degrees; Tl = 600 ms). Histopathology revealed benign liver lesions in 8 patients and malignant lesions in 22 patients. RESULTS: Dynamic T2-weighted sequence revealed an early loss of signal intensity in normal liver parenchyma (percentage signal intensity loss (PSIL) = 40.0 +/- 12.2% by 4 mumol Fe/kg, 47.2 +/- 18.8% by 8 mumol Fe/kg and 62.7 +/- 13.0% by 16 mumol Fe/kg), in the spleen, as well as in FNH (PSIL = 49.5 +/- 7.3% by 8 mumol Fe/kg), and regenerating nodules in the first minute after application of Resovist. In two of 4 cases with HCC a short drop in signal intensity was immediately observed after the application, whereas signal intensity remained unchanged in all other malignant liver tumours. Enhanced PDw and T2-weighted SE-sequences revealed an improved detection and delineation of malignant liver lesions versus plain MR imaging. 17 liver lesions of a size lower 10 mm were additionally detected in postcontrast T2-weighted SE-sequences in 4 patients. CONCLUSION: Dynamic and static versus plain MR imaging of primary and secondary liver lesions is markedly improved by the superparamagnetic contrast material Resovist, especially in case of intravenous bolus application of this liver-specific contrast medium.

Drug and chemical blood-level data 2001.

Current blood-level data are presented for drugs and chemicals of toxicologic interest. The data represent an update of previously published compilations of therapeutic, toxic and lethal blood-levels.

Imaging characteristics of hepatocellular carcinoma using the hepatobiliary contrast agent Gd-EOB-DTPA.

PURPOSE: To evaluate the ability of contrast-enhanced magnetic resonance imaging (MRI) with Gd-EOB-DTPA in comparison with non-enhanced imaging and spiral computed tomography (CT) to provide additional information for classification and characterization of hepatocellular carcinoma. MATERIAL AND METHODS: Forty patients with histopathology-proven hepatocellular carcinoma were selected for this subgroup analysis from a phase-III multicenter study in 235 patients with known or suspected liver lesions. The primary analysis was comparison of the proportion of hepatocellular carcinoma correctly classified and characterized by combined pre-/post-contrast MRI compared with pre-contrast MRI alone or with spiral CT. All images were evaluated on site, and in a blinded reading by three independent readers off site. RESULTS: In the on-site evaluation, the lesions were correctly classified as a malignant tumor with combined MRI in 90.3%, with pre-contrast imaging alone in 82.9% and with spiral CT in 87.8% (n.s.). The proportion of correct characterization (lesion type diagnosis) with combined MRI was 85.4%, 75.6% for pre-contrast imaging, and 77.5% for spiral CT (n.s.), respectively. In the blinded reading, one reader showed a significant increase in the proportion of correctly characterized lesions by 27% (P<0.05). The other two readers showed a reduction in the proportion of correct characterization by 12% and 15%, respectively (n.s.). CONCLUSION: With regard to lesion classification, no difference was found between combined pre-/post-contrast MRI and spiral CT. A non-significant trend in favor of Gd-EOB-DTPA-enhanced MRI with regard to characterization of hepatocellular carcinoma was found, although the CT scans were not optimized as the MRI scans.

[Physiologic and pathologic age related changes in the small intestine]. / Physiologische und pathologische Alternsveränderungen des Dünndarms.

Age-related morphological or functional changes are known to occur in numerous organ systems. In the case of the small bowel, only mild impairment of such functions as carbohydrate absorption and in particular vitamin D and calcium absorption have so far been reported. The latter is possibly of significance for the pathogenesis and treatment of osteoporosis. Other disturbances appear to have no clinical relevance, since the considerable functional reserve capacity of the small bowel can largely compensate them. To date, no morphological correlate has been established for the known functional disorders.

Changes in the lectin-binding pattern of PNA-agglutinin and UEA1 during the DMH-induced carcinogenesis in the normal appearing colonic mucosa of the rat.

The purpose of this study was the investigation of changes in the lectin-binding pattern prior to tumour formation in an experimental model. Female Wistar rats were treated with 1,2-dimethylhydrazine (DMH). After 4, 8, 16, 24, 32 and 40 weeks of treatment the lectin-binding-pattern of the colonic mucosa appearing morphologically normal was examined at the caecum, proximal colon, distal colon and rectum, using FITC-conjugated Peanut-agglutinin (PNA) and Ulex europaeus-agglutinin1 (UEA1). In contradistinction to what has been reported earlier by other authors, PNA did not indicate constant cancer-associated mucin changes. In addition, there was no difference in the UEA1-binding between the control animals and the DMH-treated rats. Thus, in the rat there is no specific PNA- and UEA1-binding pattern during tumour induction in the gut.

Contrast-enhanced 3D-MRA of the upper abdomen with a bolus-injectable SPIO (SH U 555 A).

The purpose of this study was to study temporal changes in signal intensity of liver, spleen, abdominal vessels, and focal liver lesions following iv bolus injection of a superparamagnetic iron oxide (SPIO) using a breath-held three-dimensional magnetic resonance angiography (3D-MRA) sequence. Dynamic SH U 555 A-enhanced 3D-MRA studies were performed in 20 patients with focal liver lesions. Sequential coronal 3D-MRA-FISP scans were acquired (TR 5.0 msec, TE 2.0 msec, flip angle 25 degrees, 140 x 256 matrix, and 80 mm slab) within 15 seconds. Scanning was started immediately after bolus injection of 10 micromol Fe/kg bodyweight and was repeated at multiple time points (baseline and 30, 60, 90, 120, 180, 240, 300, 360, and 420 seconds). Signal intensity values of liver, focal liver lesions, spleen, the portal venous system, the abdominal aorta, and the inferior vena cava were obtained to calculate relative enhancement (ENH = [SI post - SI pre]/SI pre x 100). Visibility of vessels was assessed by consensus of two readers. Signal enhancement within abdominal vessels peaked during the first pass; however, significant signal enhancement was still present 420 seconds following injection. The liver and the spleen also demonstrated a biphasic enhancement pattern with prolonged parenchymal enhancement. Dynamic MRA with bolus injectable SH U 555 A is clinically feasible, and significant vessel enhancement can be achieved even at the dose of 10 micromol Fe/kg bodyweight. However, further refinements are required to improve contrast effects.

Application of a superparamagnetic iron oxide (Resovist) for MR imaging of human cerebral blood volume.

The authors describe the feasibility of dynamic MRI using a novel superparamagnetic iron oxide contrast agent. Resovist was injected as a bolus at doses of 4, 8, and 16 mumol Fe/kg bodyweight in three consented patients participating in a Phase 2 clinical multicenter trial for hepatic MRI. Dynamic images of the brain were obtained with a conventional FLASH sequence. Results were analyzed by evaluation of dynamic images, cerebral blood volume maps, and normalized signal intensity time curves. Resovist enabled rapid injections and a dose-dependent strong reduction in gray and white matter signal intensity. The small injection volume and good tolerability may enable Resovist to serve as a perfusion agent. Dedicated clinical trials are warranted to assess the potentials of Resovist for perfusion MRI and fMRI.

Characterization of stereomicroscopically identified preneoplastic lesions during dimethylhydrazine-induced colonic carcinogenesis.

Preneoplastic mucosal changes were studied at six different time-points during dimethylhydrazine (DMH)-induced colorectal carcinogenesis in the rat. After 40 weeks of treatment, seven of 10 animals were bearing a total of 11 colorectal adenocarcinomas. The crypt cell production rate in the normal mucosa of DMH-treated animals was greatly increased in the left colon and rectum and further rose with the duration of the experiment. Focal disturbances of the mucosal architecture could be detected as early as 4 weeks after the initiation of DMH-treatment using a stereomicroscope. Their incidence was greatest in the left colon and rectum and increased strongly with the duration of carcinogen exposure. Characterization of these mucosal alterations, by means of conventional histology, morphometry after microdissection, cell kinetics, mucin histochemistry and quantitative enzyme histochemistry performed with serial sections, revealed mild epithelial dysplasia, a considerable elongation and dilatation of the crypts and a marked increase of the crypt cell production, including a shift of the main proliferative compartment from the basal to the medial crypt segment as well as the occurrence of mitotic figures in the luminal epithelium. In affected crypts, the goblet cells completely lacked sulphomucins and exclusively contained sialomucins. The activities of the enzymes diaminopeptidase IV (brush-border), succinate dehydrogenase (mitochondria) and acid beta-galactosidase (lysosomes) were markedly reduced. We conclude that these early mucosal alterations are indeed preneoplastic lesions and indicate the existence of the adenoma-carcinoma sequence in this animal model.(ABSTRACT TRUNCATED AT 250 WORDS)

Color doppler ultrasound of liver lesions: signal enhancement after intravenous injection of the ultrasound contrast agent Levovist.

Patients with focal liver lesions (hemangioma, focal nodular hyperplasia, adenoma, hepatocellular carcinoma, metastatic lesions, focal fatty lesion) received the ultrasound contrast agent Levovist (300 mg/mL and 400 mg/mL) intravenously. This ultrasound contrast agent (a suspension of micrometer-sized microparticles of galactose and microscopic gaseous bubbles) can pass through the lungs without impairment. After the administration of Levovist, increased color flow signals were detected in the liver. Five of 6 patients with metastatic liver lesions showed previously undetected blood flow in the rim of the tumor. In 4 patients with hepatocellular carcinoma, enhanced signal intensity was observed in the vessels of the rim and in 3 of those patients in the center of the tumor. One patient with adenoma and one patient with focal nodular hyperplasia showed signal enhancement in the central area of the tumor. No signal enhancement was observed in hemangiomas, a focal fatty lesion, or in a carcinoid metastatic lesion. Levovist increased the echointensity of normal and tumor vessels in liver lesions. This new ultrasound contrast agent led to the detection of tumor vessels previously not detectable by conventional color flow imaging.

Identification of patients at high risk for colorectal carcinoma from biopsy studies of the apparently normal colorectal mucosa. A multivariate analysis.

A number of phenotypic abnormalities of the colorectal mucosa which appears normal have been described to be biomarkers of cancer development. To improve their sensitivity and specificity, we simultaneously determined 10 morphological and histochemical parameters in biopsies from the colonoscopically normal mucosa of the descending colon, sigmoid, and rectum. The results were analysed by multivariate statistical methods. We tested the discriminating power of proliferative, morphometric, enzyme and mucin histochemical parameters from 80 patients either at average risk (controls), with an increased risk for colorectal carcinoma (high-risk), or with a manifest carcinoma. The following parameters were investigated: number of mitotic figures per crypt, crypt length, apical, medial and basal crypt diameter, crypt surface, activity of succinate dehydrogenase (EC 1.3.99.1), activity of acid beta-galactosidase (EC 3.2.1.23), sulpho- and sialomucin contents. Univariate statistical analyses revealed that crypt length, crypt diameter and crypt surface were significantly increased in the high-risk group, the carcinoma carriers having intermediate values between average-risk and high-risk patients. In a two-group discriminant analysis, high-risk or carcinoma patients could be separated from average-risk patients with a sensitivity of 92.9% and a specificity of 100%. When the analysis was repeated for three groups (carcinoma carriers separated from high-risk patients), sensitivity and specificity were 100% for each group. We conclude that identification of patients at risk for colorectal carcinoma is possible from the normal-appearing left colonic and rectal mucosa by morphometric and cytochemical analysis of biopsies.