Showing papers by "Ulrich Bogdahn published in 2005"

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Abstract: methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

Doublecortin expression levels in adult brain reflect neurogenesis.

Abstract: Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain Doublecortin (DCX) has recently been used as a marker for neurogenesis However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions

Gray matter decrease in patients with chronic tension type headache

Abstract: Using MRI and voxel-based morphometry, the authors investigated 20 patients with chronic tension type headache (CTTH) and 20 patients with medication-overuse headache and compared them to 40 controls with no headache history. Only patients with CTTH demonstrated a significant gray matter decrease in regions known to be involved in pain processing. The finding implies that the alterations are specific to CTTH rather than a response to chronic head pain or chronification per se.

Neuronal precursor-specific activity of a human doublecortin regulatory sequence.

Abstract: The doublecortin (DCX) gene encodes a 40-kDa microtubule-associated protein specifically expressed in neuronal precursors of the developing and adult CNS. Due to its specific expression pattern, attention was drawn to DCX as a marker for neuronal precursors and neurogenesis, thereby underscoring the importance of its promoter identification and promoter analysis. Here, we analysed the human DCX regulatory sequence and confined it to a 3.5-kb fragment upstream of the ATG start codon. We demonstrate by transient transfection experiments that this fragment is sufficient and specific to drive expression of reporter genes in embryonic and adult neuronal precursors. The activity of this regulatory fragment overlapped with the expression of endogenous DCX and with the young neuronal markers class III β-tubulin isotype and microtubule-associated protein Map2ab but not with glial or oligodendroglial markers. Electrophysiological data further confirmed the immature neuronal nature of these cells. Deletions within the 3.5-kb region demonstrated the relevance of specific regions containing transcription factor-binding sites. Moreover, application of neurogenesis-related growth factors in the neuronal precursor cultures suggested the lack of direct signalling of these factors on the DCX promoter construct.

Predictors of survival after severe dysphagic stroke.

Abstract: Dysphagia is estimated to occur in up to 50% of the stroke neurorehabilitation population. Those patients with severe neurogenic oropharyngeal dysphagia (NOD) may receive feeding gastrostomy tubes (FGT) if noninvasive therapies prove ineffective in eliminating aspiration or sustaining adequate nutritional intake. Our aim was to quantify the recovery of swallowing function, and to identify variables predictive of survival after dysphagic stroke requiring FGT placement. We identified consecutive stroke patients with severe dysphagic stroke requiring FGT placement admitted to a rehabilitation hospital between May 1998 and October 2001. The medical records were reviewed, and demographic, clinical, videofluoroscopic (VSS) and neuroimaging information were abstracted. A follow–up telephone interview was performed to determine whether the FGT was still in use, had been removed,or if the patient had died. State death certificate records were reviewed to ascertain date of death for subjects who had expired by the time of follow–up. Univariate and multivariate analyses were performed. 11.6 % (77/664) of stroke patients admitted during the study period had severe dysphagic stroke with FGT insertion. Follow–up was available for 66 (85.7 %) of these individuals at a mean of two years after acute stroke. On follow–up 64% (42/66) of the patients were alive and 45 % had had the FGT removed and resumed oral diets. On univariate analysis patients who were alive at the time of follow–up had received FGT feeding for a shorter period of time (p < 0.0003), showed no signs of aspiration on the Clinical Assessment of Feeding & Swallowing (CAFS,p < 0.020) and on the Videofluoroscopic Swallowing Study (VSS, 0.001), had a better discharge FIM–Score (Functional Independence Measure) for eating (p < 0.0002) and cognitive function (p < 0.002) as well as better discharge FCM–Score (Functional Communication Measure) for swallowing (p < 0.0001). On multivariate analysis we developed a model consisting of FGT removal at discharge from the rehabilitation hospital (p < 0.011) and non–aspiration during VSS (p < 0.040) that was significantly associated with longer survival time during follow–up. Severe dysphagia requiring FGT is common in patients with stroke referred for neurorehabilitation. Patients who had a FGT in place at the time of discharge from the stroke rehabilitation unit or aspirated during VSS were substantially more likely to have died by the time of follow–up compared to those who had had the FGT removed and had no signs of aspiration on VSS. However functional outcome measurements (FIM, FCM) including the cognitive function (attention, concentration etc.) could play an important role for prediction of swallowing regeneration and survival in neurorehabilitation. These findings may have practical utility in guiding physicians and speech language pathologists when advising patients and families about prognosis in stroke survivors with severe dysphagia.

Adult medulloblastoma: prognostic factors and response to therapy at diagnosis and at relapse.

Abstract: Adult medulloblastoma is a rare tumor with few retrospective studies published so far. The role of adjuvant chemotherapy or chemotherapy at relapse is unclear. This study reports therapy and outcome in all adult (>or=16 years old) medulloblastoma (n=34) and supratentorial primitive neuroectodermal tumor (PNET) patients (n=2) treated in 2 neuro-oncological centers between 1976 and 2002. The median age was 24.5 years (range 16-76). After resection, 16 patients were treated with craniospinal radiotherapy alone, 20 patients also received adjuvant chemotherapy (8 vincristine, CCNU, cisplatin; 7 methotrexate alone or methotrexate/vincristine-based polychemotherapy; 5 other protocols). Median survival in the whole cohort was 126 months (2+ - 200+months). Five-year and 10-year survival rates were 79 % and 56%. Adjuvant chemotherapy was associated with a non-significant trend to prolonged survival (relative risk (RR) 1.89; p=0.068). The median progression-free survival (PFS) after primary therapy was 83 months. At relapse, 10 of 12 evaluable patients achieved a complete response upon second-line therapy. The median survival times from first (n=17) and second relapse (n=9) were 21 months (0-67+ months; 5/17 without second relapse) and 20 months (1-29 months). Cox regression analysis revealed the infiltration of the floor of the 4(th) ventricle at diagnosis as the only therapy-independent prognostic factor (RR 0.48; p=0.03). In conclusion, adjuvant chemotherapy may prolong survival in adult medulloblastoma patients. Moreover, second-line therapy may be beneficial for these patients. As in pediatric medulloblastoma patients, primary infiltration of the floor of the 4(th) ventricle indicates a poor prognosis.

Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety.

Abstract: Here, we provide first evidence that long-term continuous infusion of highly purified antisense phosphorothioate oligodeoxynucleotides (S-ODN) into brain parenchyma is well tolerated and thus highly suitable for in vivo application. AP 12009 is an S-ODN for the therapy of malignant glioma. It is directed against human transforming growth factor-beta (TGF-beta2) mRNA. In the clinical setting, AP 12009 is administered intratumorally by continuous infusion directly into the brain tumor. In view of this clinical application, the focus of our data is on local toxicology studies in rabbits and monkeys to evaluate the safety of AP 12009. AP 12009 was administered either by intrathecal bolus injection into the subarachnoidal space of the lumbar region of both cynomolgus monkeys and rabbits or by continuous intraparenchymatous infusion directly into the brain tissue of rabbits. Intrathecal bolus administration of 0.1 ml of 500 microM AP 12009 showed neither clinical signs of toxicity nor macroscopically visible or histomorphologic changes. After a 7-day intraparenchymatous continuous infusion of 500 microM AP 12009 at 1 microl/h in rabbits, there was no evidence of toxicity except for local mild to moderate lymphocytic leptomeningoencephalitis. Additionally, AP 12009 showed good tolerability in safety pharmacology as well as in acute toxicity studies and 4-week subchronic toxicity studies in mice, rats, and monkeys. This favorable safety profile proves the suitability of AP 12009 for local administration in brain tumor patients from the point of view of toxicology.

Can telemedicine contribute to fulfill WHO Helsingborg Declaration of specialized stroke care

Abstract: Background: Providing stroke unit treatment for all stroke patients is a cross-national goal as stated in the WHO Helsingborg Declaration. In order to achieve specialized stroke care for a large area, two stroke centers and 12 community hospitals established an integrative stroke network. This evaluation was performed to analyze achieved advances in stroke management. Methods: Core network elements are: (1) establishing stroke wards in all hospitals; (2) continuous training in stroke treatment; (3) telemedicine service staffed by a 24 h/day ‘strokologist’ with capability for high-speed videoconferencing and transfer of CT/MRI images. Data were prospectively documented in the databank of the telestroke service, in the Bavarian Stroke Registry and in the controlling departments. Results: In 2003, 4,179 stroke patients were admitted to the regional network hospitals. Between February 2003 and January 2004 a total of 2,182 teleconsultations were conducted. 250 teleconsultations yielded a nonvascular diagnosis. Indicators for stroke management quality improved compared with other hospitals without stroke unit: the frequency of CT/MRI within 3 h was 59% compared to 46%, frequency of speech therapy 36% (21%), and of occupational therapy 38% (12%). Eighty-six (2.1%) of the patients received systemic thrombolysis compared to 10 patients in the preceding year. Mean length of in-hospital stay decreased from 12.4 in 2002 to 9.7 days in 2003. Conclusions: This stroke network concept leads to a substantial improvement of stroke management. Telemedicine contributes to an early etiological assessment and fills the gap of specialized stroke expertise in neurologically underserved areas.

Greater occipital nerve block is ineffective in chronic tension type headache.

Abstract: Patients with primary headache syndromes often describe a pain distribution, that does not respect the trigeminal innervation of the head. In addition to pain in frontal areas, innervated by the fi...

The use of telemedicine in combination with a new stroke-code-box significantly increases t-PA use in rural communities.

Abstract: Background: The benefit of tissue plasminogen activator (t-PA) is strongly associated with the time to treatment. In Bavaria, Germany, only half of the population has the opportunity to be transferred to 1 of the 19 stroke units within the critical time window of less than 3 hours. The aim of this study was to investigate the benefit of a new stroke-code-box for t-PA thrombolysis combined with a telemedicine network system to increase the use of acute stroke thrombolysis. Methods: Two specialized stroke centers in Germany established a 24-hour telemedicine network (Telemedicine Pilot Project of an Integrated Stroke Care [TEMPiS]) to advise 12 community hospitals in eastern Bavaria. These clinics are linked via telemedicine in a 24-hour/7-day service network that allows patients to be examined by experts via a video-conference system Additionally, a special stroke-code-box for acute t-PA thrombolysis was designed to reduce time in the application and documentation process. Results: In the 12-month period before implementation of the TEMPiS network system, 10 patients had received systemic thrombolysis. In our 6-month study period (from July to December 2003) and after implementation of a stroke-code-box for t-PA thrombolysis within the telestroke network, 164 patients with acute stroke were presented with t-PA treatment indications. Of this patient population, 27.4% (45 of 164) received t-PA. Conclusions: Stroke care, including t-PA thrombolysis in non-urban areas, is feasible using a modern stroke unit concept within a telestroke network. With the expertise of specialized stroke centers accessed via telemedicine and the design of a stroke-code-box for t-PA thrombolysis, nearly one-third of patients presented with a possible indication for systemic thrombolysis can be treated with t-PA, thereby increasing the options for a successful stroke treatment.

Transcranial Ultrasound Brain Perfusion Assessment With a Contrast Agent-Specific Imaging Mode: Results of a Two-Center Trial

Abstract: Background and Purpose— The purpose of this study was to assess brain perfusion with an ultrasound contrast-specific imaging mode and to prove if the results are comparable between 2 centers using a standardized study protocol. Methods— A total of 32 individuals without known cerebrovascular disease were included in the study. Perfusion studies were performed ipsilaterally in an axial diencephalic plane after intravenous administration of 0.75 mL of Optison. Offline time intensity curves (TIC) were generated in different anatomic regions. Both centers used identical study protocols, ultrasound machines, and contrast agent. Results— In both centers, the comparison of the parameter time to peak intensity (TPI) revealed significantly shorter TPIs in the main vessel structures compared with any parenchymal region of interest (ROI), whereas no significant differences were seen between the parenchymal ROIs. The parameter peak intensity (PI) varied widely interindividually in both centers, whereas the inter-ROI ...

The relationship between plasma D-dimer concentrations and acute ischemic stroke subtypes.

Abstract: Elevated concentrations of D-dimers (DDs) in patients with acute ischemic stroke may cause differential diagnostic problems with regard to pulmonar or deep venous thrombosis The true relationship between plasma DDs and acute ischemic stroke remains uncertain We studied acute stroke patients admitted to a single acute neurology department with a specialized stroke unit As part of our clinical protocol, blood samples of each patient had been taken within the first 24 hours after the onset of stroke symptoms and before anticoagulant treatment had been started, to evaluate the coagulation profile Each patient’s medical record was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted Univariate and multivariate statistical analyses were performed A total of 59 patients admitted to our stroke unit between October 2003 and March 2004 with different stroke subtypes according to the TOAST criteria were evaluated to characterize the impact of stroke category on DD concentration Family members (n = 23) served as controls in this study Multivariate regression analysis revealed that patients who sustained cardioembolic stroke had significantly higher DD concentrations than controls and patients who sustained transient ischemic attacks We identified a correlation between plasma DD levels and different acute ischemic stroke subtypes before any stroke treatment was started Thus DD concentrations may be considered a direct consequence of marked cerebral infarction and may be useful for physicians when making decisions on treatment for acute ischemic stroke

Thrombolysis for stroke in the elderly.

Abstract: Introduction. Systemic thrombolysis with intravenous recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke had been licensed for patients up to 75 years in age in many European countries and was recently extended to 80 years. This age restriction results from the potential higher risk of cerebral bleeding in the elderly. The major rtPA trials included only 42 patients above 80 years showing a potential benefit from treatment. Further data is still rare.

Experimental autoimmune encephalomyelitis in the rat spinal cord: lesion detection with high-resolution MR microscopy at 17.6 T.

Abstract: BACKGROUND AND PURPOSE: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disorder of the CNS and an animal model of multiple sclerosis. We used high-field MR microscopy at 17.6 T to image spinal cord inflammatory lesions in the acute stage of chronic relapsing rat EAE. We sought to compare lesions detected on MR imaging with histopathologic findings and to quantify the inflammatory lesion load. METHODS: Imaging of fixed spinal cord specimens was performed by using a 3D gradient-echo sequence with a spatial resolution of 35 × 35 × 58 μm 3 and a total imaging time of 5.5 hours. Histopathologic analysis was performed by staining axial sections with hematoxylin-eosin or Luxol fast blue to identify cellular infiltration and demyelination. RESULTS: Clinical signs of EAE occurred on days 10–14 after immunization. On day 22, healthy white matter and gray matter were differentiated by high contrast on T2*-weighted images, with white matter lesions appearing as hyperintense areas in the normal-appearing white matter. Inflammatory lesions identified on histopathologic evaluation were readily detected with MR imaging and vice versa. MR imaging and histopathologic analysis had excellent correlation regarding the extent of white matter lesions. Inflammatory infiltrates of gray matter were not detectable with MR imaging. Using a semiautomatic segmentation of the acquired MR data, we could quantify white matter lesion load. CONCLUSION: Ex vivo high-resolution MR microscopy of the spinal cord at 17.6 T allows rapid and highly accurate determination of CNS inflammation by demonstrating virtually all histologically detectable white matter inflammatory lesions.

Inhibition of immunosuppressive effects of melanoma-inhibiting activity (MIA) by antisense techniques

Abstract: Melanoma inhibitory activity (MIA) is an 11 kD protein secreted by malignant melanomas. Recent studies revealed an interaction of MIA with epitopes of extracellular matrix proteins including fibronectin. Structural homology of MIA with the binding sites of alpha4beta1 integrin results in complex interactions of MIA with molecules binding to alpha4beta1 integrin. As cells of the immune system express alpha4beta1 integrins (VLA-4), we investigated whether MIA may modulate the function of human leukocytes. Here we describe the effects of MIA on the activation of human PBMCs and auto-/allogeneic lymphokine-activated killer cell (LAK) cytotoxicity in human MIA-negative glioma cell lines and MIA-positive melanoma cell lines in vitro. MIA inhibits PHA- or IL-2-induced human PBMC proliferation in a dose-dependent manner up to 63% ((3)H-Tdr incorporation) and 59% (cell count), respectively, when added to the cell culture prior to mitogen stimulation. In addition, both autologous (GL and HW) and allogeneic (HTZ-17, HTZ-243 and HTZ-374) antitumor LAK cytotoxicity was reduced by the addition of exogenous rhMIA (500 ng/ml, f.c.). Consequently, endogenous inhibition of MIA expression in human melanoma cells by MIA-specific phosphorothioate antisense oligonucleotides enhanced the autologous LAK-cell activity to the same level as observed in MIA-negative human HMB melanoma cells expressing an MIA-antisense construct. Our results indicate that MIA may contribute to immunosuppression frequently seen in malignant melanomas by inhibiting cellular antitumor immune reactions. Antagonization of MIA activity using antisense techniques may represent a novel therapeutic strategy for treatment of malignant melanomas.

[Spinal and cerebral leptomeningeal seeding from a melanocytoma of the cerebello-pontine angle].

Abstract: Meningeal melanocytoma refers to the uncommon clinical appearance of a generally benign tumour deriving from leptomeningeal melanocytes. Meningeal spread of this tumour is very rarely observed. We present the case of a 38-year-old man with meningeal melanocytoma of the cerebello-pontine angle, who showed a biphasic course of this disease, with a stable period followed by a steady progress within few months. After surgical resection of the melancytoma in the left skull base and of a first local recurrence five years later, a second local recurrence occurred 6 years after diagnosis, with intracerebral and spinal meningeal seeding. This tumor did not respond to a combined radiochemotherapy including oral temozolomide, and the patient died 5 months after starting treatment for this relapse. Secondary malignisation of the melancytoma is suggested.

Detection of cardiac right-to-left shunts by contrast-enhanced harmonic carotid duplex sonography

Abstract: OBJECTIVE: Paradoxical embolization by cardiac right-to-left shunts (RLS) is increasingly recognized as an important factor for embolic stroke. Contrast-enhanced transcranial Doppler sonography (ce-TCDS) is an established diagnostic tool for RLS detection but is frequently limited because of an inadequate temporal acoustic bone window. The purpose of this study was to determine whether extracranial sonography (ECS) using harmonic frequencies improves detection of RLS. METHODS: Extracranial color duplex sonography using harmonic frequencies enables visualization of even single ultrasound contrast agent microbubbles because of oscillation. Patients with stroke and positive RLS findings on transesophageal echocardiography underwent a simultaneous extracranial and transcranial sonographic examination of the proximal common carotid artery (CCA) and middle cerebral artery (MCA) on the same side. A Valsalva strain was performed for 10 seconds after intravenous bolus injection of a galactose-based nontranspulmonary contrast agent. The B-mode frame sequences of the transverse plane of the CCA obtained by harmonic ECS and the ce-TCDS recordings of high-intensity transient signals from the MCA were analyzed offline. RESULTS: In all patients with RLS, the shunts could be identified by harmonic ECS. A close correlation could be seen between the count of visualized microbubbles in the CCA and the number of high-intensity transient signals detected on ce-TCDS in the ipsilateral MCA. CONCLUSIONS: The results of this study indicate that contrast-enhanced ultrasound harmonic imaging of the CCA using a Valsalva strain might be an optional screening tool for detection of cardiac RLS in patients with insufficient acoustic bone windows.

Adverse Effects of the Intraluminal Filament Model of Middle Cerebral Artery Occlusion

Abstract: To the Editor: Animal models of ischemic stroke are of major importance for experimental stroke research Comprehensive knowledge of the methodological aspects of the different stroke models available is crucial for data interpretation and correlation to human stroke We therefore appreciate the recent work of Gerriets et al on complications in different models of focal ischemia in rats, taking advantage of high-resolution magnetic resonance imaging (MRI) and magnetic resonance angiography1 In addition to their findings of subarachnoid hemorrhage and hypothalamic infarction as a cause of hyperthermia, the appearance of ipsilateral masticatory hyperintensities in early MRI associated with temporal muscle necrosis (Figure) has also been identified recently as a complication of the intraluminal filament model of middle cerebral artery occlusion (MCAO) These lesions resulted in impaired body weight evolution and delayed restoration of neurological function in Wistar rats2 This is neither a laboratory-specific nor a rat strain-specific problem, as can be learned from …

Inhibitors of tgf-r signaling for treatment of cns disorders

Abstract: The present invention relates to the use of oligonucleotides for the preparation of a pharmaceutical composition for the prevention or treatment of a disease, wherein neurogenesis and/or neuroregeneration has a beneficial effect, in particular a disease like Morbus Alzheimer, Morbus Parkinson, Lewy Body Dementia,-Amyotrophic Lateral Sclerosis, Spinocerebellar Atrophies, Creutzfeldt Jakob Disease, Frontemporal Dementia, Morbus Pick, AIDS Dementia Complex, Vascular Dementia, Progressive Supranuclear Palsy, Corticobasal Degeneration, Multisystem-Atrophy, Hallervorden Spatz Disease, Huntington's disease, Stroke, Traumatic Brain and spinal cord Injury, Retinitis Pigmentosa, Macular Degeneration, Glaucoma, Cochlea Degeneration, Depression, Schizophrenia, Multiple Sclerosis, and developmental neurodegeneration.

Targeted downregulation of TGF-beta2 as immunotherapy for high-grade glioma: A phase IIb study

Abstract: 1537 Background: High-grade (malignant) glioma are highly aggressive tumors showing marked overexpression of transforming growth factor-beta2 (TGF-beta2). TGF-beta plays a key role in malignant pro...

Multiple Ischämien im vertebrobasilären Stromgebiet bei Arteriitis temporalis

Abstract: Berichtet wird uber einen 73-jahrigen Patienten mit vordiagnostizierter Arteriitis temporalis, der sich mit einer Parese des rechten Armes sowie einer Dysarthrie vorstellte. Eine entzundliche Mitbeteiligung der Vertebralarterien bei Riesenzellarteriitis (RZA) verursachte multiple zerebrale Ischamien im Bereich des vertebrobasilaren Stromgebietes, die trotz intensiver immunsuppressiver Therapie zu einem zentralen Kreislaufversagen fuhrten. Der Fall verdeutlicht, dass ein promptes Ansprechen der Symptome der RZA auf Steroide nicht mit einer Remission des systemischen vaskulitischen Gefasprozesses gleichzusetzen ist und die Reduktion der Steroiddosis nur sehr langsam erfolgen darf. Eine erhohte Wachsamkeit fur einen moglichen, initial okkulten Mitbefall hirnversorgender Gefase dieser primar systemischen Vaskulitis ist geboten.

Longterm treatment with temozolomide in high-grade gliomas is feasible and leads to longterm survival in a significant subset of patients

Abstract: Proc Amer Assoc Cancer Res, Volume 46, 2005 5765 Introduction: Although survival in patients with high-grade gliomas is relatively poor warranting intensified treatment approaches, postoperative radio-chemotherapy is frequently limited by bone marrow toxicity, usually terminating chemotherapy after 6 cycles of chemotherapy. Clinical studies using Temozolomide (Temodar™; TMZ) have produced promising results concerning survival and long-term feasibility, which is in part due to the lacking cumulative toxicity of TMZ. Nevertheless, no systematic data concerning longterm feasibility of TMZ have been acquired yet. Methods: Within a retrospective field analysis, german neuro-oncologists were approached to report on their treatment strategies with TMZ in high-grade gliomas using a standardized questionnaire. Longterm application of TMZ (more than 12 cycles or more than 12 months of any dose) were analyzed and evaluated for feasibility, efficacy and tolerability. Results: Altogether, 128 patients with WHO Grade III or IV gliomas who fulfilled the study criteria were identified by 49 neuro-oncologists. Most of the patients were treated with the standard scheme using 150 to 200 mg/m2, some were treated according to protocol EORTC 26981/22981 or by modified schemes. In first-line treatment (n=64), the median number of applied cycles was 13 (range, 12 to 40) with a mean progression free duration of 56 weeks (range 52 to 160 weeks). Recurrent patients (n=55) received a median number of 14 cycles (range 12 to 44 cycles), with a median duration of 62 weeks (range 52 to 176 weeks). Grade 3 or 4 (NCI-CTC) toxicity concerning the gastrointestinal system (n=7), leukopenia (n=13), thrombocytopenia (n=7) or infection (n=5) was observed only in a small amount of patients. Nevertheless, toxicity data may underestimate the true incidence of toxicity due to the retrospective character of the study. Conclusion: Although this was a retrospective analysis, we could identify a significant number of patients with longterm application of TMZ. Up to 44 cycles were given and times of up to 160 weeks in the first-line and 176 weeks in the recurrent setting without signs of tumor progression could be reached, indicating that patients with active high-grade gliomas may have well controlled disease over significant periods of time.

Combined regimen of temozolomide and liposomal pegylated doxorubicin in glioblastoma - toxicity and efficacy

Abstract: 11501 Background: Temozolomide (Temodar, TMZ) recently showed promising efficacy in an EORTC trial on first-line therapy of glioblastoma (Stupp R, 2005). Pegylated liposomal doxorubicin (Caelyx, PEG-DOX) was evaluated in patients with recurrent high-grade glioma and showed an overall response rate of 40% (Hau P, 2002). Therefore, a combination of both agents seems promising. METHODS TMZ was given orally 75 mg/m2 daily during standard radiotherapy (initiation) and 150-200 mg/m2 days 1-5 in 28 days starting 4 weeks after radiotherapy (maintainance). PEG-DOX was given as a short-time infusion in a dose-escalation regimen once prior to radiotherapy and on days 1 and 15 starting 4 weeks after radiotherapy. PEG-DOX was escalated for 5 mg/m2 in groups of three patients starting with 5 mg/m2 (group 1) and a highest dose of 20 mg/m2 (group 4). RESULTS In the dose escalation part of this study, the regime detailed above was feasible, tolerable, and able to induce objective responses and stabilizations in patients with glioblastoma. In the first treatment group (5 mg/m2 of PEG-Dox), one out of 7 evaluable patients had a dose limiting toxicity (DLT). In the second, third and fourth treatment groups, the regimen was tolerated without DLT. Concerning efficacy in the \"treated-patients\" analysis of 18 patients, 1 had a partial response in MRI, and 12 patients had tumor stabilization 4 weeks after conclusion of radiotherapy. Only 5 patients progressed early. Twelve patients responded with progression free survival times of 13 to 76 weeks. One patient is still progression free after 120 weeks of treatment. CONCLUSION As no DLT was observed in dose group 4, MTD was not reached and we proceed to the efficacy phase of the trial with PEG-DOX in a dose of 20 mg/m2. Seventeen patients are included so far. Results will be compared to the published study EORTC 26981/22981 (Stupp R et al., 2005) which did set a new standard in the first-line treatment of glioblastoma as survival times of more than 14 months and a 2-year overall survival of 26% were reached. Regarding the promising preliminary survival data of study RNOP-09, we expect even better results with the regimen used in this protocol. [Table: see text].