Improved survival of Swedish glioblastoma patients treated according to Stupp.

OBJECTIVES: The median survival in glioblastoma (GBM) patients used to be less than 1 year. Surgical removal of the tumor with subsequent concomitant radiation/temozolomide (the Stupp regimen) has been shown to prolong survival. The Stupp protocol was implemented in the county of Jönköping in 2006. The purpose of this study was to examine if the Stupp treatment has prolonged overall survival, in an unselected patient cohort with histologically verified GBM. MATERIAL AND METHOD: This study includes all patients from the county of Jönköping, with a diagnosis of GBM from January 2001 to December 2012. Patients were divided into 2 cohorts, 2001-2005 and 2006-2012, that is before and after implementation of the Stupp regimen. By reviewing the medical case notes, the dates of the histological diagnosis and of death were identified. The median and mean overall survival and Kaplan-Meier survival analysis were calculated and compared between the 2 cohorts. RESULTS: The mean survival was 110 days longer in the cohort treated according to the Stupp regimen. Four patients in the 2006-2012 cohort and 1 patient in the 2001-2005 cohort are still alive. When comparing survival in patients with radical surgery vs biopsy, those that underwent radical surgery survived longer. The significance was slightly greater in the 2001-2005 cohort (mean 163 vs 344 days, P < .001) than in the 2006-2012 cohort (mean 220 vs 397 days, P = .02). CONCLUSION: Survival significantly improved after the implementation of the Stupp regimen in the study region of Sweden.

Effectiveness of open and arthroscopic rotator cuff repair (UKUFF): a randomised controlled trial.

AIMS: The appropriate management for patients with a degenerative tear of the rotator cuff remains controversial, but operative treatment, particularly arthroscopic surgery, is increasingly being used. Our aim in this paper was to compare the effectiveness of arthroscopic with open repair of the rotator cuff. PATIENTS AND METHODS: A total of 273 patients were recruited to a randomised comparison trial (136 to arthroscopic surgery and 137 to open surgery) from 19 teaching and general hospitals in the United Kingdom. The surgeons used their usual preferred method of repair. The Oxford Shoulder Score (OSS), two years post-operatively, was the primary outcome measure. Imaging of the shoulder was performed at one year after surgery. The trial is registered with Current Controlled Trials, ISRCTN97804283. RESULTS: The mean OSS improved from 26.3 (standard deviation (sd) 8.2) at baseline, to 41.7 (sd 7.9) two years post-operatively for arthroscopic surgery and from 25.0 (sd 8.0) to 41.5 (sd 7.9) for open surgery. Intention-to-treat (ITT) analysis showed no statistical difference between the groups at two years (difference in OSS score -0.76; 95% confidence interval (CI) -2.75 to 1.22; p = 0.452). The confidence interval excluded the pre-determined clinically important difference in the OSS of three points. The rate of re-tear was not significantly different between the two groups (46.4% for arthroscopic and 38.6% for open surgery; 95% CI -6.9 to 25.8; p = 0.256). Healed repairs had the most improved OSS. These findings were the same when analysed per-protocol. CONCLUSION: There is no evidence of difference in effectiveness between open and arthroscopic repair of rotator cuff tears. The rate of re-tear is high in both groups, for all sizes of tear and ages and this adversely affects the outcome. Cite this article: Bone Joint J 2017;99-B:107-15.

Protocol for the United Kingdom Rotator Cuff Study (UKUFF): a randomised controlled trial of open and arthroscopic rotator cuff repair.

This protocol describes a pragmatic multicentre randomised controlled trial (RCT) to assess the clinical and cost effectiveness of arthroscopic and open surgery in the management of rotator cuff tears. This trial began in 2007 and was modified in 2010, with the removal of a non-operative arm due to high rates of early crossover to surgery. Cite this article: Bone Joint Res 2014;3:155-60.

Anticipating agoraphobic situations: the neural correlates of panic disorder with agoraphobia.

BACKGROUND: Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia. METHOD: We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm). RESULTS: During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures. CONCLUSIONS: This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobia-specific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.

Theoretical description of spherically confined, strongly correlated Yukawa plasmas.

A theoretical description of the radial density profile for charged particles with Yukawa interaction in a harmonic trap is described. At strong Coulomb coupling shell structure is observed in both computer simulations and experiments. Correlations responsible for such shell structure are described here using a recently developed model based in density functional theory. A wide range of particle number, Coulomb coupling, and screening lengths is considered within the fluid phase. A hypernetted chain approximation shows the formation of shell structure, but fails to give quantitative agreement with Monte Carlo simulation results at strong coupling. Significantly better agreement is obtained within the hypernetted chain structure using a renormalized coupling constant, representing bridge function corrections.

A new paradigm (Westphal-Paradigm) to study the neural correlates of panic disorder with agoraphobia.

Agoraphobia (with and without panic disorder) is a highly prevalent and disabling anxiety disorder. Its neural complexity can be characterized by specific cues in fMRI studies. Therefore, we developed a fMRI paradigm with agoraphobia-specific stimuli. Pictures of potential agoraphobic situations were generated. Twenty-six patients, suffering from panic disorder and agoraphobia, and 22 healthy controls rated the pictures with respect to arousal, valence, and agoraphobia-related anxiety. The 96 pictures, which discriminated best between groups were chosen, split into two parallel sets and supplemented with matched neutral pictures from the International Affective Picture System. Reliability, criterion, and construct validity of the picture set were determined in a second sample (44 patients, 28 controls). The resulting event-related "Westphal-Paradigm" with cued and uncued pictures was tested in a fMRI pilot study with 16 patients. Internal consistency of the sets was very high; parallelism was given. Positive correlations of picture ratings with Mobility Inventory and Hamilton anxiety scores support construct validity. FMRI data revealed activations in areas associated with the fear circuit including amygdala, insula, and hippocampal areas. Psychometric properties of the Westphal-Paradigm meet necessary quality requirements for further scientific use. The paradigm reliably produces behavioral and fMRI patterns in response to agoraphobia-specific stimuli. To our knowledge, it is the first fMRI paradigm with these properties. This paradigm can be used to further characterize the functional neuroanatomy of panic disorder and agoraphobia and might be useful to contribute data to the differentiation of panic disorder and agoraphobia as related, but conceptually different clinical disorders.

[Haemostaseologic effects of fractionated snake venoms]. / Wirkungen von Schlangengiftfraktionen auf das Gerinnungssystem.

Comparative investigation concerning gelfiltration as well as haemostaseologic analysis of venoms and venom fractions of some snakes (elapidae and viperidae) have shown that in elapidae an inhibition of coagulation is dominant whilst in viperidae the stimulation of coagulation is of importance. Our investigations produce a basis to select substances for activation of coagulation and substances for inhibition of coagulation. Under pharmacological viewpoints the data may produce information to use snake fractions for anticoagulation or for procoagulant therapy in bleeding tendency.

Quantitative proton magnetic resonance spectroscopy of the normal liver and malignant hepatic lesions at 3.0 Tesla.

This comparative study of tumour patients and volunteers aimed at differentiating liver parenchyma from neoplastic lesions by using localised (1)H MRS at 3.0 T as an adjunct to MRI. In total 186 single-voxel proton spectra of the liver were acquired at 3.0 T using the body transmit receive coil. Consecutive stacks of breath-hold spectra were acquired in the PRESS technique at a short echo time of 35 ms and a repetition time of 2,000 ms. Processing of the spectra included spectral alignment with the software package SAGE and quantitative processing with LCModel. The resulting metabolite concentrations were presented in arbitrary units relative to the internal water. In general, the spectra showed four main groups of resonances originating from the methyl protons (0.8-1.1 ppm) and methylene protons of the lipids (1.1-1.5 ppm; 2.0-2.2 ppm) as well as the methyl protons of choline-containing compounds (CCC) at 3.2 ppm. Overall, the CCC and lipid values in malignant liver tumours showed no significant differences to liver parenchyma. On average, total lipid measurements in normal liver parenchyma increased with age, while those of the CCC did not show pertinent changes. Significant differences between the contents of CCC in malignant liver tumours and normal liver parenchyma were not observed, because in patients and volunteers normal liver tissue showed a large variability in the content of CCC.

Magnetic resonance imaging of the cranial nerves in the posterior fossa: a comparative study of t2-weighted spin-echo sequences at 1.5 and 3.0 tesla.

BACKGROUND: High-field magnetic resonance imaging (MRI) at 3.0 Tesla (T) is rapidly gaining clinical acceptance. Whether doubling of the field strength of 1.5T and the subsequent increase in signal-to-noise ratio (SNR) leads to a significant improvement of image quality is not automatically given. PURPOSE: To evaluate the depiction of fine anatomic detail in the posterior fossa, focusing on brain nerves, on T2-weighted imaging, and to define the potential advantage of imaging at 3.0T versus 1.5T. MATERIAL AND METHODS: In total, 10 brainstem nerve pairs of 12 volunteers were identified on T2-weighted MR images of 2- and 5-mm section thickness acquired at 1.5T and 3.0T. The MR images were compared for each subject at both field strengths by three independent readers who rated image quality according to depiction of anatomic detail and contrast by using a rating scale. RESULTS: In general, MR images at 3.0T were considered more conspicuous and less noisy than images at 1.5T. The SNR value measured was almost doubled. With respect to structural identification and contrast according to the rating scale, observer scores were significantly improved both for standard imaging with 5-mm sections and high-resolution imaging with 2-mm sections at 3.0T. Direct comparison revealed a significant increase for evaluated image quality criteria and the number of nerves detected. CONCLUSION: The comparison revealed a clear advantage in favor of T2-weighted MRI at 3.0T vs. 1.5T in depicting the roots and course of brain nerves in the posterior fossa.

Assessment of 3D-TOF-MRA at 3.0 Tesla in the characterization of the angioarchitecture of cerebral arteriovenous malformations: a preliminary study.

BACKGROUND: The characterization of brain arteriovenous malformation (AVM) angioarchitecture remains rewarding in planning and predicting therapy. The increased signal-to-noise ratio at higher field strength has been found advantageous in vascular brain pathologies. PURPOSE: To evaluate whether 3.0T time-of-flight (TOF) magnetic resonance angiography (MRA) is superior to 1.5T TOF-MRA for the characterization of cerebral AVMs. MATERIAL AND METHODS: Fifteen patients with AVM underwent TOF-MRA at 3.0T and 1.5T and catheter angiography (DSA), which was used as the gold standard. Blinded readers scored image quality on a four-point scale, nidus size, and number of feeding arteries and draining veins. RESULTS: Image quality of TOF-MRA at 3.0T was superior to 1.5T but still inferior to DSA. Evaluation of nidus size was equally good at 3.0T and 1.5T for all AVMs. In small AVMs, however, there was a tendency of size overestimation at 3.0T. MRA at 3.0T had increased detection rates for feeding arteries (+21%) and superficial (+13%) and deep draining veins (+33%) over 1.5T MRA. CONCLUSION: 3.0T TOF-MRA offers superior characterization of AVM angioarchitecture compared with 1.5T TOF-MRA. The image quality of MRA at both 3.0 and 1.5T is still far from equal to DSA, which remains the gold standard for characterization of AVM.

Magnetic resonance imaging in suspected rectal cancer: determining tumor localization, stage, and sphincter-saving resectability at 3-Tesla-sustained high resolution.

PURPOSE: To assess image quality and overall accuracy of 3-Tesla (3T)-sustained high-resolution magnetic resonance (MR) imaging for diagnostic preoperative workup in suspected rectal carcinoma. MATERIAL AND METHODS: Twenty-three patients with suspected rectal cancer underwent unenhanced and contrast-enhanced fat-suppressed pelvic high-resolution MR imaging using a four-channel phased-array pelvic coil at 3T. Image quality, tumor stage, distance from the anorectal margin, and sphincter-saving resectability were prospectively assessed by two blinded readers. The results were correlated with clinical, surgical, and histopathologic findings. RESULTS: In all 23 patients, MR images were of diagnostic quality, and malignancy was correctly identified in 21 patients. The accuracy for determining sphincter-saving resectability was 100% (19/19). T stage and N stage were correctly diagnosed in 95% and 91%, respectively. MRI allowed correct identification of tumor extension and its relation to surgically relevant pelvic structures including the anorectal margin and mesorectal fascia. Transverse T2-weighted fast spin-echo images compared superiorly to all other sequences for the diagnosis of mesorectal infiltration and lymph node involvement. Moreover, transverse fat-suppressed contrast-enhanced T1-weighted images were valuable for identifying tumor infiltration, while sagittal sections were useful for the detection of longitudinal tumor extension. CONCLUSION: MR imaging with phased-array receiver coils at 3T facilitated both visualization of different pathologic conditions of the rectum and accurate determination of tumor stage in rectal carcinomas. Thus, this noninvasive diagnostic approach appeared highly suitable for the assessment of patients with suspected rectal carcinoma.

Embolization of experimental wide-necked aneurysms with iodine-containing polyvinyl alcohol solubilized in a low-angiotoxicity solvent.

BACKGROUND AND PURPOSE: To evaluate the ready-to-use iodine-containing polyvinyl alcohol (I-PVA) dissolved in the low angiotoxic solvent N-methyl pyrrolidone (NMP) for embolization of porcine wide-necked aneurysms. METHODS: Fourteen broad-based carotid sidewall aneurysms were surgically constructed in 7 swine. I-PVA (40%) in NMP was injected under temporary balloon occlusion bridging the aneurysm neck. After 4 weeks, follow-up angiography, multisection CT angiography (MSCTA), and 3T MR imaging including MR angiography (MRA) sequences were performed. Afterward, harvested aneurysms were investigated histopathologically. RESULTS: The liquid embolic was well visible under fluoroscopy and displayed a favorable precipitation pattern, allowing for controlled polymer delivery. Ten aneurysms (71%) were initially completely occluded, whereas in 1 aneurysm, a minimal polymer leakage was observed. The other 4 aneurysms (29%) were almost completely occluded. One animal suffered a lethal rebleeding from the anastomosis after uneventful embolization. Aneurysms embolized with I-PVA could be discriminated well from the parent artery without beam-hardening artifacts on MSCTA, and no susceptibility artifacts were encountered on MR imaging. Histologic examination revealed all aneurysms covered with a membrane of fibroblasts and an endothelial cell layer while a moderate intraaneurysmal inflammatory response to the polymer was observed. CONCLUSION: I-PVA dissolved in NMP has proved its effectiveness for the embolization of experimental wide-necked aneurysms. This precipitating liquid embolic offers several interesting features in that it needs no preparation before use and no radiopaque admixtures, the latter allowing for artifact-free evaluation of treated aneurysms with MSCTA and MRA. Moreover, it uses NMP as a solvent, which has only a low angiotoxicity.

[Mutation in factor II and factor V gene in patients with peripheral arterial occlusive disease]. / Chronisch-arterielle Verschlusskrankheit der Beine im Stadium IIb-IV: Molekulargenetische Diagnostik von Mutationen im Faktor-II-und Faktor-V-Gen.

Mutations in factor-V- and factor-II-genes are correlated with an increased risk for venous thrombosis according to the literature. The significance of the mutations in factor- II- and factor-V-genes for the development of the peripheral arterial occlusive disease is not known. Therefore, we investigated the presence of these mutations in 152 patients with documented peripheral arterial occlusive disease and 318 controls without peripheral arterial occlusive disease with polymerase chain reaction (PCR). There was no association between factor-II-mutation and peripheral arterial occlusive disease. The factor-V-mutation, however, was increased in patients with peripheral arterial occlusive disease double fold (12 positive cases in 318 controls, 12 positive cases in 152 patients with peripheral arterial occlusive disease). The significance level was reached (p = 0.05) in statistical analysis but the result did not fall below the significance level as necessary to reach statistical significance (odds ratio 2.19). Nevertheless, from these data we have to discuss a biological relevance of factor-V-mutation in the pathogenesis of peripheral arterial occlusive disease.

Imaging of serotonin transporters and its blockade by citalopram in patients with major depression using a novel SPECT ligand [123I]-ADAM.

We studied the midbrain SERT availability in patients with major depression and assessed the relation of SERT occupancy by citalopram to the treatment response. 21 non-medicated patients with major depression and 13 healthy controls were examined by [(123)I]-ADAM SPECT. The midbrain SERT availability (SERT V(3)'') was calculated using individual MRI scans. In 13/21 patients SPECT was repeated 7 days after oral medication with citalopram (10 mg/day). We found no significant difference in the mean midbrain SERT availability between the studied patients with major depression and healthy controls (0.86 +/- 0.27 vs. 0.71 +/- 0.44, p = 0.069). The mean SERT occupancy accounted to 61%. The degree of SERT blockade by citalopram did not correlate with the reduction in HAMD total score. Treatment with low-dosed citalopram caused individually variable occupancy of the midbrain-SERT and a rapid clinical improvement in 54% of the investigated patients.

[The effect of the field strength on standardized MRI of the brain to demonstrate cranial nerves and vessels: a comparison of 1.5 and 3.0 Tesla]. / Auswirkung der Feldstärke bei der standardisierten Kernspintomographie des Gehirns am Beispiel der Darstellung von Hirnnerven und Gefässen in den basalen Zisternen: Vergleich zwischen 1.5 und 3.0 Tesla.

PURPOSE: Comparison of MR images acquired as routine examinations at a field strength of 3.0 T and 1.5 T to determine whether and to which degree the image quality improves at the higher field strength of 3.0 T. MATERIALS AND METHODS: Routine MR images of 200 patients were examined retrospectively, with 100 images obtained at 1.5 T and 100 obtained at 3.0 T. The examinations were performed with a quadrature head coil and focused on the basal cisterns because of the abundance of small distinct structures in this region. We selected the T2-weighted 2D-FSE sequence in transverse direction for comparison. At both field strengths, the same section thickness of 5 mm and a matrix of 512 x 388 (FOV: 220 mm) were used. The quality of the images was evaluated with regard to depicting the cranial nerves N. III, V - X, the AICA and PICA. For comparison, image quality was rated with a score from 1 (well defined) to 5 (not depicted). RESULTS: A score of 1 was obtained in 46 % of the anatomic structures examined at 3.0 T and in only 9.2 % at 1.5 T. A score of 2 was given in 27.6 % of the anatomic structures at 3.0 T vs. 23.5 % at 1.5 T, a score of 3 in 17.2 % vs. 28.1 %, a score of 4 in 8.6 % vs. 28.7 %, and a score of 5 in 0.4 % vs. 10.3 %, respectively. The Mann-Whitney U test showed significance at p < 0.001 for the comparison of images at 1.5 and 3.0 Tesla. CONCLUSION: Routine magnetic resonance imaging using the same quadrature coil technique and similar acquisition times at 3.0 T and 1.5 T shows an improvement for T2-weighted images at the higher field strength.

Magnetic resonance imaging of hyaline cartilage defects at 1.5T and 3.0T: comparison of medium T2-weighted fast spin echo, T1-weighted two-dimensional and three-dimensional gradient echo pulse sequences.

PURPOSE: To evaluate and compare the diagnostic accuracy of appropriate magnetic resonance (MR) sequences in the detection of cartilage lesions at 1.5T and 3.0T. MATERIAL AND METHODS: Twelve chondral defects of varying depths, widths, and locations were created in the retropatellar hyaline cartilage in six sheep cadaver limbs. Axial images employing three fat-suppressed imaging sequences--(1) a T2-weighted fast spin-echo (FSE) sequence, (2) a two-dimensional (2D) and (3) three-dimensional (3D) gradient-echo (GE) sequence at 1.5T and 3.0T using an extremity quadrature coil--were evaluated by three experienced radiologists. Statistical analysis of the results consisted of receiver operating characteristics (ROC) and significant testing using the bivariate chi-square test. In addition, signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) were evaluated with significance testing using the Wilcoxon test. RESULTS: The 3D GE sequence compared favorably with other sequences at 3.0T and 1.5T (Az=0.88 at 3.0T and Az=0.85 at 1.5T) missing only one small grade 2 lesion. 2D GE imaging was inferior to 3D imaging at both field strengths (P<0.05) in general. However, compared to 1.5T, lesion detectability was improved at the higher magnetic field of 3.0T (Az=0.81 and 0.73 at 3.0T and 1.5T, respectively). FSE images showed significantly inferior sensitivity and less anatomical detail compared to the GE sequences at both field strengths (Az=0.64 and 0.72 at 3.0T and 1.5T, respectively; P<0.05). However, compared to 1.5T, lesion detectability SNR and CNR values were superior in all sequences tested at 3.0T. CONCLUSION: MRI at 3.0T improves SNR and CNR significantly in the most common sequences for cartilage MRI, resulting in an improvement in chondral lesion detection. GE imaging therefore allows resolution to be increased in an acceptable time manner for patient comfort, and the 3D GE fat-suppressed sequence at 3.0T appears to be best suited for cartilage imaging in a clinical setting.

[Value of various MR sequences using 1.5 and 3.0 Tesla in analyzing cartilaginous defects of the patella in an animal model]. / Wertigkeit verschiedener MR-Sequenzen bei einer Feldstärke von 1.5- und 3.0 Tesla für die Analyse von Knorpeldefekten der Patella im Tiermodell.

PURPOSE: Comparison of MRI and macropathologic evaluation using various sequences and field strengths in the detection, localization and measurement of cartilage defects in an animal model. MATERIALS AND METHODS: After open creation of retropatellar cartilage defects of various widths, depths and locations in 8 cadaveric sheep knee joints, the knees were examined using a fat-suppressed (FS), proton density-weighted (PD) fast spin echo (FSE), and 2D and 3D gradient echo (GE) sequences on 1.5 T and 3.0 T MR scanners. The images were analyzed by two independent radiologists in a blinded manner, by dividing the patella into 15 virtual segments. The results were correlated with the macropathologic findings with regards to location, width, and depth of the defects. RESULTS: The highest sensitivity (67.1 %), diagnostic accuracy (85.4 %), positive (87.3 %), and negative (84.7 %) predictive values in detecting defects were obtained using the 3.0 T FS-3D-GE sequence. The highest specificity (95.6 %) yielded the 3.0 T FS-2D-GE sequence, with the other sequences inferior by no more than 2.6 %. In general, FS-3D-GE sequences were superior to FS-2D-GE (3.0 T: p < 0.05; 1.5 T: p < 0.05) and especially to FS-PD-FSE sequences (3.0 T: p < 0.01; 1.5 T: p < 0.05). In determining the defects' widths, the 3.0 T FS-3D-GE sequence was superior to all other sequences (correct measurements: 50.0 %), with only slight superiority to the 1.5 T FS-3D-GE sequence (46.9 %, p > 0.05) but clear superiority to the other sequences (28.1 - 40.6 %, vs. 1.5 T FS-PD-FSE: p < 0.05, vs. other sequences: p > 0.05). To determine the defects' depths, the 1.5 T FS-3D-GE sequence was most reliable (correct measurements: 53.1 %), followed by the 3.0 T FS-3D-GE sequence (50.0 %, significance of difference: p > 0.05). CONCLUSION: In detecting cartilage defects, the field strength of 3.0 Tesla was only superior to 1.5 T MRI using fat-saturated 3D- or 2D-GE-sequences but not in fat-saturated proton density-weighted SE-sequences. In determination of depth and length of the defects, the higher field strength was not advantageous.

Vascular compression in glossopharyngeal neuralgia: demonstration by high-resolution MRI at 3 tesla.

We report a case of glossopharyngeal neuralgia with vascular compression. High-resolution MRI at 3 tesla demonstrated the posterior inferior cerebellar artery to be closely related to the rootlets of the left glossopharyngeal nerve in a patient who suffered attacks of burning sensation in the left side of the throat. The MRI findings were confirmed at curative surgery.

[Chromogenic substrate as antidote against the thrombin inhibitor Melagatran?]. / Chromogenes Substrat als Antidot gegen den Thrombininhibitor Melagatran?

It could be shown in vitro that a chromogenic substrate (Chromozym TH, Roche Mannheim) acts at least partially as antidote against the new thrombin inhibitor Melagatran (AstraZeneca, Mölndal, Sweden). It is discussed that this antidote effect of a chromogenic substrate might be due to a substrate competition of fibrinogen, thrombin inhibitor, and chromogenic substrate for thrombin. Further animal experiments will clarify whether this in vitro observation is of practical relevance in vivo, too.

Thrombin as a survival factor for cancer cells: thrombin activation in malignant effusions in vivo and inhibition of idarubicin-induced cell death in vitro.

OBJECTIVES: The aim of the experiments shown here, is to demonstrate exemplarily that thrombin can be a survival factor for malignant cells. METHODS: Activation of the coagulation system has been examined in patients with acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) before and after chemotherapy as well as in malignant effusions of heavily pretreated patients with solid tumors. Thrombin receptor expression (PAR-I) has been examined on HL-60 cells; the effect ofthrombin on the proliferation of the cells and inhibition of apoptosis induction by idarubicin has been shown. RESULTS: Using fibrinopeptide A as an indirect parameter for thrombin activation, we found elevated levels in patients with AML and NHL before and a significant 2-fold increase after chemotherapy (p < 0.02 for the AML group; p < 0.0006 for the NHL group). Apparently, this does not only affect patients with hematological diseases, but also with solid tumors. In order to find out if the tumor cells directly activate thrombin, we examined malignant effusions of patients with different solid tumors. Comparing prothrombin fragment 1 + 2 in ascites and pleural effusions with the patients' serum levels, we found it significantly increased in all cases (mean of 1.96 +/- 0.5 nmol/l in the serum vs. 12.1 +/- 3.6 nmol/l in effusions; p < 0.001). The majority of patients presented elevated serum levels. Additionally, we incubated HL-60 cells (human promyelocytic leukemia) with thrombin prior to treatment with idarubicin. Expression of thrombin receptor (PAR-1) could be verified by FACS-analysis using a monoclonal antibody. HL-60 cells responded with increased proliferation to thrombin exposure with concentrations between 0.3 and 3 U/ml. This effect could be abolished by the addition of hirudin, demonstrating thrombin specificity. In these concentrations, thrombin was able to abrogate the induction of apoptosis by idarubicin completely (p < 0.005). CONCLUSIONS: Here we give evidence for the role of thrombin as a resistance factor for tumor cells towards chemotherapy. In the light of the fact that thrombin is regularly activated in cancer patients, these findings indicate that thrombin is a clinically relevant cellular resistance factor. A number of pre-clinical and clinical studies imply that inhibition of the coagulation system, e.g. by low-molecular weight heparins or warfarin, increases the effect of chemotherapy.