Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo

BACKGROUND: As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo. METHODS: In 10 male severe combined immunodeficient (SCID) mice, pieces of SW1353 chondrosarcomas were implanted into a cranial window preparation where the calvaria serves as the site for the orthotopic implantation of bone tumors. From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control). Angiogenesis, microcirculation, and growth of SW 1353 tumors were analyzed by means of intravital microscopy. RESULTS: SU6668 induced a growth arrest of chondrosarcomas within 7 days after the initiation of the treatment. Compared to Controls, SU6668 decreased functional vessel density and tumor size, respectively, by 37% and 53% on day 28 after tumor implantation. The time course of the experiments demonstrated that the impact on angiogenesis preceded the anti-tumor effect. Histological and immunohistochemical results confirmed the intravital microscopy findings. CONCLUSION: SU6668 is a potent inhibitor of chondrosarcoma tumor growth in vivo. This effect appears to be induced by the antiangiogenic effects of SU6668, which are mediated by the inhibition of the key angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1. The experimental data obtained provide rationale to further develop the strategy of the use of the angiogenesis inhibitor SU6668 in the treatment of chondrosarcomas in addition to established therapies such as surgery.

Differential distribution of vasa vasorum in different vascular beds in humans

OBJECTIVE: Vasa vasorum (VV) have been implicated to play a role in the pathogenesis of atherosclerosis. This study was designed to describe the distribution of VV density in different vascular beds in humans and to investigate the association between VV density and the known distribution of atherosclerosis in human arteries. METHODS: Forty-two human arteries, harvested at autopsy or after explantation, were analyzed by three-dimensional microscopic-computed tomography (micro-CT). VV density, endothelial-surface-fraction (Sigma VV endothelial-surface-area/vessel-wall-volume) and vascular-area-fraction (Sigma VV area/vessel-wall-area) were calculated for coronary, renal and femoral arteries. Representatively five coronary, renal and femoral arteries were stained for endothelial cells (von Willebrand-Factor), macrophages (CD68), vascular endothelial growth factor (VEGF) and collagen (Sirius Red). RESULTS: Coronary arteries showed a higher VV density compared to renal and femoral arteries (2.12+/-0.26 n/mm(2) versus 0.61+/-0.06 n/mm(2) and 0.66+/-0.11 n/mm(2); P<0.05 for both) as well as a higher endothelial-surface-fraction and vascular-area-fraction. Histology showed a positive correlation between histologically derived VV density and CD68-positive cells/area (r=0.54, P<0.01), VEGF-immunoreactivity/area (r=0.55, P<0.01) and a negative correlation between VV density and collagen I content (r=0.66, P<0.05). CONCLUSION: This micro-CT study highlights a higher VV density in coronary than in peripheral arteries, supporting the relation between VV density and the susceptibility to atherosclerosis in different vascular beds in humans.

Anteroposterior pelvic radiographs to assess acetabular retroversion: high validity of the "cross-over-sign"

Acetabular retroversion has been proposed to contribute to the development of osteoarthritis of the hip. For the diagnosis of this condition, conventional AP pelvic radiographs may represent a reliable, easily available diagnostic modality as they can be obtained with a reproducible technique allowing the anterior and posterior acetabular rims to be visible for assessment. This study was designed to: (i) determine cranial, central, and caudal anatomic acetabular version (AV) from cadaveric specimens; (ii) establish the validity and reliability of the radiographic measurements of central acetabular anteversion; and (iii) determine the validity and reliability of the radiographic "cross-over-sign" to detect acetabular retroversion. Using 43 desiccated pelvises (86 acetabuli) the anatomic AVs were measured at three different transverse planes (cranially, centrally, and caudally). From these pelvises, standardized AP pelvic radiographs were obtained. To directly measure central AV, a modified radiographic method is introduced for the use of AP pelvic radiographs. The validity and reliability of this radiographic method and of the radiographic cross-over-sign to detect cranial acetabular retroversion were determined. The mean central and caudal anatomic AVs were approximately 20 degrees , and the mean cranial AV was 8 degrees . Cranial retroversion (AV < 0 degrees ) was present in 19 of 86 hips (22%). A linear correlation was found between the central and cranial AV. Below 10 degrees of central AV, all acetabuli were cranially retroverted. Between 10 degrees and 20 degrees , 30% of the acetabuli were cranially retroverted, and above 20 degrees , only 1 of 45 acetabuli was cranially retroverted. The radiographic measurement of the central AV (20.3 +/- 6.5 degrees ) correlated strongly with the anatomic AV (20.1 +/- 6.4 degrees ). The sensitivity of the cross-over-sign to detect a cranial acetabular anteversion of less than 4 degrees was 96%, its specificity 95%, and the positive predictive and negative predictive values 90% and 98%, respectively. Both the modified radiographic anteversion measurements and the cross-over-sign demonstrated substantial inter- and intraobserver reliability. Retroversion is almost exclusively a problem of the cranial acetabulum. The cranial AV is on average 12 degrees lower than the central AV, with the latter directly measurable from AP pelvic radiographs. A central AV of less than 10 degrees was associated with cranial retroversion. The presence of a positive cross-over-sign is a highly reliable indicator of cranial AV of <4 degrees.

Fat implant is superior to muscle implant in vestibular schwannoma surgery for the prevention of cerebrospinal fluid fistulae

OBJECTIVE: Meticulous sealing of opened air cells in the petrous bone is necessary for the prevention of cerebrospinal fluid (CSF) fistulae after vestibular schwannoma surgery. We performed a retrospective analysis to determine whether muscle or fat tissue is superior for this purpose. METHODS: Between January 2001 and December 2006, 420 patients underwent retrosigmoidal microsurgical removal by a standardized procedure. The opened air cells at the inner auditory canal and the mastoid bone were sealed with muscle in 283 patients and with fat tissue in 137 patients. Analysis was performed regarding the incidence of postoperative CSF fistulae and correlation with the patient's sex and tumor grade. RESULTS: The rate of postoperative CSF leak after application of fat tissue was lower (2.2%) than after use of muscle (5.7%). Women had less postoperative CSF leakage (3.4%) than men (5.6%). There was an inverse correlation with tumor grade. Patients with smaller tumors seemed to have a higher rate of CSF leakage than those with large tumors without hydrocephalus. Only large tumors with severe dislocation of the brainstem causing hydrocephalus showed a higher incidence of CSF leaks. CONCLUSION: Fat implantation is superior to muscle implantation for the prevention of CSF leakage after vestibular schwannoma surgery and should, therefore, be used for the sealing of opened air cells in cranial base surgery.

Radiological factors related to pre-operative hearing levels in patients with vestibular schwannomas

The pathogenetic mechanism of hearing loss in patients with vestibular schwannomas (VS) remains unclear. Our aim was to determine the radiological and clinical parameters that might be related to hearing. The radiological images and charts of 99 patients were reviewed. Image processing software was used to analyse the maximal tumor diameter in three planes; its volume; its extension cranially, caudally, anteriorly and posteriorly; the width and length of the intrameatal tumor portion, its shape and consistency; and the tumor-fundus distance. These parameters were correlated with the patient's pre-operative hearing range. The degree of hearing correlated significantly with the tumor size, volume and coronal diameter, the degree of intrameatal tumor growth, and the distance between the lateral tumor end and the fundus (p < 0.05). No correlation was found regarding tumor extension, shape and consistency, the presence of hydrocephalus, or the extent of erosion of the internal auditory canal. Loss of hearing in the VS appears to be multifactorial. Determining the radiological parameters related to the hearing level can help to clarify the pathophysiological mechanisms involved.

Prognostic clinical and radiological parameters for immediate facial nerve function following vestibular schwannoma surgery

OBJECTIVE: The paper aims to define the parameters available before surgery which could predict immediate facial nerve function after excision of a vestibular schwannoma (VS). METHODS: Ninety-nine patients with VS operated consecutively by a single surgeon using an identical surgical technique have been evaluated retrospectively. Data were collected regarding patients' sex, age at onset of symptoms and at surgery, initial symptoms, neurological status at presentation, early post-operative neurological status and complications. The main radiological parameters included in the study were tumour extension pattern, diameters, shape, and volume, as well as extent of bony changes of the internal auditory canal. RESULTS: As the tumour stage and volume increase, facial nerve function is worse after surgery (p < 0.001 and p < 0.05, respectively). Concomitantly, larger extra-meatal tumour diameters in three dimensions (sagittal, coronal and axial) led to worse function (p < 0.01). Anterior and/or caudal tumour extension (p = 0.001 and p = 0.004, respectively) had more significant correlation than posterior and/or cranial extension (p = 0.022 and p = 0.353, respectively). Polycyclic VS had the worst prognosis, followed by the tumours with oval shape. The extent of intra-meatal tumour growth does not correlate with immediate facial nerve outcome. The different angles, lengths and diameters of the internal auditory channel showed no significant correlation with facial nerve outcome. Patients with headache as an initial symptom and those with gait instability and/or pre-operative poor facial nerve function had significantly worse immediate facial nerve outcome. CONCLUSION: Our data suggests that the analysis of the radiological and neurological patient data prior to surgery could give reliable clues regarding the immediate post-operative facial nerve function.

Reliability of intraoperative high-resolution 2D ultrasound as an alternative to high-field strength MR imaging for tumor resection control: a prospective comparative study

OBJECT: Ultrasound may be a reliable but simpler alternative to intraoperative MR imaging (iMR imaging) for tumor resection control. However, its reliability in the detection of tumor remnants has not been definitely proven. The aim of the study was to compare high-field iMR imaging (1.5 T) and high-resolution 2D ultrasound in terms of tumor resection control. METHODS: A prospective comparative study of 26 consecutive patients was performed. The following parameters were compared: the existence of tumor remnants after presumed radical removal and the quality of the images. Tumor remnants were categorized as: detectable with both imaging modalities or visible only with 1 modality. RESULTS: Tumor remnants were detected in 21 cases (80.8%) with iMR imaging. All large remnants were demonstrated with both modalities, and their image quality was good. Two-dimensional ultrasound was not as effective in detecting remnants<1 cm. Two remnants detected with iMR imaging were missed by ultrasound. In 2 cases suspicious signals visible only on ultrasound images were misinterpreted as remnants but turned out to be a blood clot and peritumoral parenchyma. The average time for acquisition of an ultrasound image was 2 minutes, whereas that for an iMR image was approximately 10 minutes. Neither modality resulted in any procedure-related complications or morbidity. CONCLUSIONS: Intraoperative MR imaging is more precise in detecting small tumor remnants than 2D ultrasound. Nevertheless, the latter may be used as a less expensive and less time-consuming alternative that provides almost real-time feedback information. Its accuracy is highest in case of more confined, deeply located remnants. In cases of more superficially located remnants, its role is more limited.

Factors affecting postoperative cerebrospinal fluid leaks after retrosigmoidal craniotomy for vestibular schwannomas

OBJECT: The aim of this study was to identify patients likely to develop CSF leaks after vestibular schwannoma surgery using a retrospective analysis for the identification of risk factors. METHODS: Between January 2001 and December 2006, 420 patients underwent retrosigmoidal microsurgical tumor removal in a standardized procedure. Of these 420 patients, 363 underwent treatment for the first time, and 27 suffered from recurrent tumors. Twenty-six patients had bilateral tumors due to neurofibromatosis Type 2, and 4 patients had previously undergone radiosurgical treatment. An analysis was performed to examine the incidence of postoperative CSF fistulas in all 4 groups. RESULTS: The incidence of CSF leakage was higher in the tumor recurrence group (11.1%) than in patients undergoing surgery for the first time (4.4%). There were no CSF fistulas in the neurofibromatosis Type 2 group or in patients with preoperative radiosurgical treatment. Tumor size was identified as a possible risk factor in a previous study. CONCLUSIONS: Surgery for recurrent tumors is a significant risk factor for the development of CSF leaks.

Microvascular decompression for trigeminal neuralgia in the elderly: long-term treatment outcome and comparison with younger patients

OBJECTIVE: Multiple studies have proved that microvascular decompression (MVD) is the treatment of choice in cases of medically refractory trigeminal neuralgia (TN). In the elderly, however, the surgical risks related to MVD are assumed to be unacceptably high and various alternative therapies have been proposed. We evaluated the outcomes of MVD in patients aged older than 65 years of age and compared them with the outcomes in a matched group of younger patients. The focus was on procedure-related morbidity rate and long-term outcome. METHODS: This was a retrospective study of 112 patients with TN operated on consecutively over 22 years. The main outcome measures were immediate and long-term postoperative pain relief and neurological status, especially function of trigeminal, facial, and cochlear nerves, as well as surgical complications. A questionnaire was used to assess long-term outcome: pain relief, duration of a pain-free period, need for pain medications, time to recurrence, pain severity, and need for additional treatment. RESULTS: The mean age was 70.35 years. The second and third branches of the trigeminal nerve were most frequently affected (37.3%). The mean follow-up period was 90 months (range, 48-295 months). Seventy-five percent of the patients were completely pain free, 11% were never pain free, and 14% experienced recurrences. No statistically significant differences existed in the outcome between the younger and older patient groups. Postoperative morbidity included trigeminal hypesthesia in 6.25%, hypacusis in 5.4%, and complete hearing loss, vertigo, and partial facial nerve palsy in 0.89% each. Cerebrospinal fluid leak and meningitis occurred in 1 patient each. There were no mortalities in both groups. CONCLUSION: MVD for TN is a safe procedure even in the elderly. The risk of serious morbidity or mortality is similar to that in younger patients. Furthermore, no significant differences in short- and long-term outcome were found. Thus, MVD is the treatment of choice in patients with medically refractory TN, unless their general condition prohibits it.

Simulationsgestütztes Design eines Spritzgieß-Werkzeugeinsatzes mit kontur-angepasster Kühlung

Moderne generische Fertigungsverfahren für innengekühlte Werkzeuge bieten nahezu beliebige Freiheitsgrade zur Gestaltung konturnaher Kühlkanäle. Daraus resultiert ein erhöhter Anspruch an das Werkzeugengineering und die Optimierung der Kühlleistung. Geeignete Simulationsverfahren (wie z.B. Computational Fluid Dynamics - CFD) unterstützen die optimierte Werkzeugauslegung in idealer Weise. Mit der Erstellung virtueller Teststände können Varianten effizient und kostengünstig verglichen und die Kosten für Prototypen und Nacharbeiten reduziert werden. Im Computermodell des Werkzeugs erlauben Soft-Sensoren an beliebiger Position die Überwachung temperatur-kritischer Stellen sowohl im Fluid- als auch im Solidbereich. Der hier durchgeführte Benchmark vergleicht die Performance eines optimierten Werkzeugeinsatzes mit einer konventionellen Kühlung. Die im virtuellen Prozess vorhergesagte Zykluszeitreduzierung steht in guter Übereinstimmung mit realen Experimenten an den ausgeführten Werkzeugen.

Endocardial Ablation to Eliminate Epicardial Arrhythmia Substrate in Scar-Related Ventricular Tachycardia

OBJECTIVES We evaluated the feasibility and safety of epicardial substrate elimination using endocardial radiofrequency (RF) delivery in patients with scar-related ventricular tachycardia (VT). BACKGROUND Epicardial RF delivery is limited by fat or associated with bleeding, extra-cardiac damages, coronary vessels and phrenic nerve injury. Alternative ablation approaches may be desirable. METHODS Forty-six patients (18 ischemic cardiomyopathy [ICM], 13 non-ischemic dilated cardiomyopathy [NICM], 15 arrhythmogenic right ventricular cardiomyopathy [ARVC]) with sustained VT underwent combined endo- and epicardial mapping. All patients received endocardial ablation targeting local abnormal ventricular activities in the endocardium (Endo-LAVA) and epicardium (Epi-LAVA), followed by epicardial ablation if needed. RESULTS From a total of 173 endocardial ablations targeting Epi-LAVA at the facing site, 48 (28%) applications (ICM: 20/71 [28%], NICM: 3/39 [8%], ARVC: 25/63 [40%]) successfully eliminated the Epi-LAVA. Presence of Endo-LAVA, most delayed and low bipolar amplitude of Epi-LAVA, low unipolar amplitude in the facing endocardium, and Epi-LAVA within a wall thinning area at CT scan were associated with successful ablation. Endocardial ablation could abolish all Epi-LAVA in 4 ICM and 2 ARVC patients, whereas all patients with NICM required epicardial ablation. Endocardial ablation was able to eliminate Epi-LAVA at least partially in 15 (83%) ICM, 2 (13%) NICM, and 11 (73%) ARVC patients, contributing to a potential reduction in epicardial RF applications. Pericardial bleeding occurred in 4 patients with epicardial ablation. CONCLUSIONS Elimination of Epi-LAVA using endocardial RF delivery is feasible and may be used first to reduce the risk of epicardial ablation.

Electrophysiologic characterization of local abnormal ventricular activities in postinfarction ventricular tachycardia with respect to their anatomic location.

BACKGROUND Local abnormal ventricular activities (LAVA) in patients with scar-related ventricular tachycardia (VT) may appear at any time during or after the far-field electrogram. Although they may be separated from the far-field signal by an isoelectric line and extend beyond the end of surface QRS, they may also appear fused or buried within the QRS. OBJECTIVE The purpose of this study was to characterize LAVA in postinfarction VT patients with respect to their anatomic locations. METHODS Thirty-one patients with postinfarction VT underwent mapping/ablation during sinus rhythm with a three-dimensional electroanatomic mapping system. From a total of 18,270 electrograms reviewed in all study subjects, 1104 LAVA (endocardium 839, epicardium 265) were identified and analyzed. RESULTS The interval from onset of QRS complex to ventricular electrogram (EGM onset) on the endocardium was significantly shorter than the epicardium (P < .001). EGM onset was shortest in the septal endocardium and longest in the inferior and lateral epicardium. There was a significant positive correlation between EGM onset and LAVA lateness as estimated by the interval from surface QRS onset to LAVA (r = 0.52, P < .001). LAVA were more frequently detected after the QRS complex in the epicardium (241/265 [91%]) than in the endocardium (551/839 [66%], P < .001). Only 43% of endocardial septal LAVA were detected after the QRS complex. CONCLUSION Lateness of LAVA is affected to a large extent by their locations. The chance of detecting late LAVA increases when electrogram onset is later. Substrate-based approach targeting delayed signals relative to the QRS complex may miss critical the arrhythmogenic substrate, particularly in the septum and other early-to-activate regions.

Validation of novel 3-dimensional electrocardiographic mapping of atrial tachycardias by invasive mapping and ablation: a multicenter study

OBJECTIVES This study prospectively evaluated the role of a novel 3-dimensional, noninvasive, beat-by-beat mapping system, Electrocardiographic Mapping (ECM), in facilitating the diagnosis of atrial tachycardias (AT). BACKGROUND Conventional 12-lead electrocardiogram, a widely used noninvasive tool in clinical arrhythmia practice, has diagnostic limitations. METHODS Various AT (de novo and post-atrial fibrillation ablation) were mapped using ECM followed by standard-of-care electrophysiological mapping and ablation in 52 patients. The ECM consisted of recording body surface electrograms from a 252-electrode-vest placed on the torso combined with computed tomography-scan-based biatrial anatomy (CardioInsight Inc., Cleveland, Ohio). We evaluated the feasibility of this system in defining the mechanism of AT-macro-re-entrant (perimitral, cavotricuspid isthmus-dependent, and roof-dependent circuits) versus centrifugal (focal-source) activation-and the location of arrhythmia in centrifugal AT. The accuracy of the noninvasive diagnosis and detection of ablation targets was evaluated vis-à-vis subsequent invasive mapping and successful ablation. RESULTS Comparison between ECM and electrophysiological diagnosis could be accomplished in 48 patients (48 AT) but was not possible in 4 patients where the AT mechanism changed to another AT (n = 1), atrial fibrillation (n = 1), or sinus rhythm (n = 2) during the electrophysiological procedure. ECM correctly diagnosed AT mechanisms in 44 of 48 (92%) AT: macro-re-entry in 23 of 27; and focal-onset with centrifugal activation in 21 of 21. The region of interest for focal AT perfectly matched in 21 of 21 (100%) AT. The 2:1 ventricular conduction and low-amplitude P waves challenged the diagnosis of 4 of 27 macro-re-entrant (perimitral) AT that can be overcome by injecting atrioventricular node blockers and signal averaging, respectively. CONCLUSIONS This prospective multicenter series shows a high success rate of ECM in accurately diagnosing the mechanism of AT and the location of focal arrhythmia. Intraprocedural use of the system and its application to atrial fibrillation mapping is under way.

Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation: combined magnetic resonance imaging and high-density mapping

OBJECTIVES This study sought to evaluate the relationship between fibrosis imaged by delayed-enhancement (DE) magnetic resonance imaging (MRI) and atrial electrograms (Egms) in persistent atrial fibrillation (AF). BACKGROUND Atrial fractionated Egms are strongly related to slow anisotropic conduction. Their relationship to atrial fibrosis has not yet been investigated. METHODS Atrial high-resolution MRI of 18 patients with persistent AF (11 long-lasting persistent AF) was registered with mapping geometry (NavX electro-anatomical system (version 8.0, St. Jude Medical, St. Paul, Minnesota)). DE areas were categorized as dense or patchy, depending on their DE content. Left atrial Egms during AF were acquired using a high-density, 20-pole catheter (514 ± 77 sites/map). Fractionation, organization/regularity, local mean cycle length (CL), and voltage were analyzed with regard to DE. RESULTS Patients with long-lasting persistent versus persistent AF had larger left atrial (LA) surface area (134 ± 38 cm(2) vs. 98 ± 9 cm(2), p = 0.02), a higher amount of atrial DE (70 ± 16 cm(2) vs. 49 ± 10 cm(2), p = 0.01), more complex fractionated atrial Egm (CFAE) extent (54 ± 16 cm(2) vs. 28 ± 15 cm(2), p = 0.02), and a shorter baseline AF CL (147 ± 10 ms vs. 182 ± 14 ms, p = 0.01). Continuous CFAE (CFEmean [NavX algorithm that quantifies Egm fractionation] <80 ms) occupied 38 ± 19% of total LA surface area. Dense DE was detected at the left posterior left atrium. In contrast, the right posterior left atrium contained predominantly patchy DE. Most CFAE (48 ± 14%) occurred at non-DE LA sites, followed by 41 ± 12% CFAE at patchy DE and 11 ± 6% at dense DE regions (p = 0.005 and p = 0.008, respectively); 19 ± 6% CFAE sites occurred at border zones of dense DE. Egms were less fractionated, with longer CL and lower voltage at dense DE versus non-DE regions: CFEmean: 97 ms versus 76 ms, p < 0.0001; local CL: 153 ms versus 143 ms, p < 0.0001; mean voltage: 0.63 mV versus 0.86 mV, p < 0.0001. CONCLUSIONS Atrial fibrosis as defined by DE MRI is associated with slower and more organized electrical activity but with lower voltage than healthy atrial areas. Ninety percent of continuous CFAE sites occur at non-DE and patchy DE LA sites. These findings are important when choosing the ablation strategy in persistent AF.