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Astrid Weyerbrock, Brunhilde Baumer and Anna Papazoglou

Object

Exogenous nitric oxide (NO) from NO donors has cytotoxic, chemosensitizing, and radiosensitizing effects, and increases vascular permeability and blood flow in tumors. Yet little is known about whether these cytotoxic and chemosensitizing effects can be observed in glioma cells at doses that alter tumor physiological characteristics in vivo and whether these effects are tumor selective.

Methods

The effect of NO released from proline NONOate, diethylamine NONOate, spermine NONOate, and sodium nitrite on cell proliferation, apoptosis, and chemosensitivity to carboplatin of cultured glioma cells was studied in C6, U87 glioma cells, human glioblastoma cells, and human astrocytes and fibroblasts.

Results

Although proline NONOate failed to induce cell death, the other NO donors induced growth arrest when present in high concentrations (10−2 M) in all cell lines. Chemosensitization was observed after concomitant incubation with spermine NONOate and carboplatin in C6 and human glioblastoma cells. There is strong evidence that cell death occurs primarily by necrosis and to a lesser degree by apoptosis. The NO doses, which altered tumor physiology in vivo, were not cytotoxic, indicating that NO alters vascular permeability and cell viability in vivo by different mechanisms.

Conclusions

The authors found that NO-generating agents at high concentrations are potent growth inhibitors and might also be useful as chemosensitizers in glioma cells. These data corroborate the theory that the use of NOgenerating agents may play a role in the multimodal treatment of malignant gliomas but that the NO release must be targeted more specifically to tumor cells to improve selectivity and efficacy.

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Ramazan Jabbarli, Matthias Reinhard, Roland Roelz, Klaus Kaier, Astrid Weyerbrock, Christian Taschner, Christian Scheiwe and Mukesch Shah

OBJECTIVE

An asymmetry of the A1 segments (A1SA) of the anterior cerebral arteries (ACAs) is an assumed risk factor for the development of anterior communicating artery aneurysms (ACoAAs). It is unknown whether A1SA is also clinically relevant after aneurysm rupture. The authors of this study investigated the impact of A1SA on the clinical course and outcome of patients with aneurysmal subarachnoid hemorrhage (SAH).

METHODS

The authors retrospectively analyzed data on consecutive SAH patients treated at their institution between January 2005 and December 2012. The occurrence and severity of cerebral infarctions in the ACA territories were evaluated on follow-up CT scans up to 6 weeks after SAH. Moreover, the risk for an unfavorable outcome (defined as > 3 points on the modified Rankin Scale) at 6 months after SAH was assessed.

RESULTS

A total of 594 patients were included in the final analysis. An A1SA was identified on digital subtraction angiography studies from 127 patients (21.4%) and was strongly associated with ACoAA (p < 0.0001, OR 13.7). An A1SA independently correlated with the occurrence of ACA infarction in patients with ACoAA (p = 0.047) and in those without an ACoAA (p = 0.015). Among patients undergoing ACoAA coiling, A1SA was independently associated with the severity of ACA infarction (p = 0.023) and unfavorable functional outcome (p = 0.045, OR = 2.4).

CONCLUSIONS

An A1SA is a common anatomical variation in SAH patients and is strongly associated with ACoAA. Moreover, the presence of A1SA independently increases the likelihood of ACA infarction. In SAH patients undergoing ACoAA coiling, A1SA carries the risk for severe ACA infarction and thus an unfavorable outcome.

Clinical trial registration no.: DRKS00005486 (http://www.drks.de/)

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Astrid Weyerbrock, Stuart Walbridge, Ryszard M. Pluta, Joseph E. Saavedra, Larry K. Keefer and Edward H. Oldfield

Object. The response of brain tumors to systemic chemotherapy is limited by the blood—tumor barrier (BTB). Nitric oxide (NO) has been implicated in the regulation of vascular permeability and blood flow. The authors evaluated the effects of exogenous NO, which was released from a short-acting NO donor (Proli/NO), and those of NO metabolites on the capillary permeability of tumors and normal brain tissue by using quantitative autoradiography in a C6 glioma model in rats.

Methods. The Proli/NO was infused at a wide dose range (10−2 to 10−12 M) either intravenously or into the internal carotid artery (ICA) and demonstrated substantial tumor-selective increases in blood-brain barrier (BBB) permeability in response to various-sized tracers ([14C]aminoisobutyric acid, [14C]sucrose, [14C]dextran). Internal carotid artery or intravenous administration of sodium nitrite had a comparable effect on BTB permeability. The NO effect on microvascular permeability could be obtained without causing hemodynamic side effects. The effect of NO on the efficacy of carboplatin chemotherapy was investigated in intracerebral C6 gliomas. Simultaneous intravenous infusions of Proli/NO (10−6 M) and carboplatin (20 mg/kg) led to long-term survival in 40% of rats harboring intracerebral C6 gliomas compared with control animals receiving ICA or intravenous infusions of carboplatin, Proli/NO, or vehicle alone. No residual tumor was demonstrated on histological or magnetic resonance imaging studies performed in rats treated with Proli/NO and carboplatin, and no toxicity was observed.

Conclusions. This new approach demonstrated the in vivo efficacy and safety of NO and nitrite in enhancing the delivery of systemically delivered radiolabeled tracers and carboplatin into rat gliomas. The NO-induced tumor-selective BBB disruption and intravenous carboplatin chemotherapy may be more efficacious than current chemotherapy strategies against brain tumors.

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Martin N. Stienen, Nicolai Maldaner, Holger Joswig, Marco V. Corniola, David Bellut, Peter Prömmel, Luca Regli, Astrid Weyerbrock, Karl Schaller and Oliver P. Gautschi

OBJECTIVE

Patient-reported outcome measures (PROMs) are standard of care for the assessment of functional impairment. Subjective outcome measures are increasingly complemented by objective ones, such as the “Timed Up and Go” (TUG) test. Currently, only a few studies report pre- and postoperative TUG test assessments in patients with lumbar spinal stenosis (LSS).

METHODS

A prospective two-center database was reviewed to identify patients with LSS who underwent lumbar decompression with or without fusion. The subjective functional status was estimated using PROMs for pain (visual analog scale [VAS]), disability (Roland-Morris Disability Index [RMDI] and Oswestry Disability Index [ODI]), and health-related quality of life (HRQoL; 12-Item Short-Form Physical Component Summary [SF-12 PCS] and the EQ-5D) preoperatively, as well as on postoperative day 3 (D3) and week 6 (W6). Objective functional impairment (OFI) was measured using age- and sex-standardized TUG test results.

RESULTS

Sixty-four patients (n = 32 [50%] male, mean age 66.8 ± 11.7 years) were included. Preoperatively, they reported a mean VAS back pain score of 4.1 ± 2.7, VAS leg pain score of 5.4 ± 2.7, RMDI of 10.4 ± 5.3, ODI of 41.9 ± 16.2, SF-12 PCS score of 32.7 ± 8.3, and an EQ-5D index of 0.517 ± 0.226. The preoperative rates of severe, moderate, and mild OFI were 4.7% (n = 3), 12.5% (n = 8), and 7.8% (n = 5), respectively, and the mean OFI T-score was 116.3 ± 23.7. At W6, 60 (93.8%) of 64 patients had a TUG test result within the normal population range (no OFI); 3 patients (4.7%) had mild and 1 patient (1.6%) severe OFI. The mean W6 OFI T-score was significantly decreased (103.1 ± 13.6; p < 0.001). Correspondingly, the PROMs showed a decrease in subjective VAS back pain (1.6 ± 1.7, p < 0.001) and leg pain (1.0 ± 1.8, p < 0.001) scores, disability (RMDI 5.3 ± 4.7, p < 0.001; ODI 21.3 ± 16.1, p < 0.001), and increase in HRQoL (SF-12 PCS 40.1 ± 8.3, p < 0.001; EQ-5D 0.737 ± 0.192, p < 0.001) at W6. The W6 responder status (clinically meaningful improvement) ranged between 81.3% (VAS leg pain) and 29.7% (EQ-5D index) of patients.

CONCLUSIONS

The TUG test is a quick and easily applicable tool that reliably measures OFI in patients with LSS. Objective tests incorporating longer walking time should be considered if OFI is suspected but fails to be proven by the TUG test, taking into account that neurogenic claudication may not clinically manifest during the brief TUG examination. Objective tests do not replace the subjective PROM-based assessment, but add valuable information to a comprehensive patient evaluation.

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Nicolai Maldaner, Marketa Sosnova, Anna M. Zeitlberger, Michal Ziga, Oliver P. Gautschi, Luca Regli, Astrid Weyerbrock, Martin N. Stienen and for the International 6WT Study Group

OBJECTIVE

Digital transformation enables new possibilities to assess objective functional impairment (OFI) in patients with lumbar degenerative disc disease (DDD). This study examines the psychometric properties of an app-based 6-minute walking test (6WT) and determines OFI in patients with lumbar DDD.

METHODS

The maximum 6-minute walking distance (6WD) was determined in patients with lumbar DDD. The results were expressed as raw 6WDs (in meters), as well as in standardized z-scores referenced to age- and sex-specific values of spine-healthy volunteers. The 6WT results were assessed for reliability and content validity using established disease-specific patient-reported outcome measures.

RESULTS

Seventy consecutive patients and 330 volunteers were enrolled. The mean 6WD was 370 m (SD 137 m) in patients with lumbar DDD. Significant correlations between 6WD and the Core Outcome Measures Index for the back (r = −0.31), Zurich Claudication Questionnaire (ZCQ) symptom severity (r = −0.32), ZCQ physical function (r = −0.33), visual analog scale (VAS) for back pain (r = −0.42), and VAS for leg pain (r = −0.32) were observed (all p < 0.05). The 6WT revealed good test-retest reliability (intraclass correlation coefficient 0.82), and the standard error of measurement was 58.3 m. A 4-tier severity stratification classified patients with z-scores > −1 (no OFI), −1 to −1.9 (mild OFI), −2 to −2.9 (moderate OFI), and ≤ −3 (severe OFI).

CONCLUSIONS

The smartphone app-based self-measurement of the 6WT is a convenient, reliable, and valid way to determine OFI in patients with lumbar DDD. The 6WT app facilitates the digital evaluation and monitoring of patients with lumbar DDD.

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Nicolai Maldaner, Valentin K. Steinsiepe, Johannes Goldberg, Christian Fung, David Bervini, Adrien May, Philippe Bijlenga, Karl Schaller, Michel Roethlisberger, Daniel W. Zumofen, Donato D’Alonzo, Serge Marbacher, Javier Fandino, Rodolfo Maduri, Roy Thomas Daniel, Jan-Karl Burkhardt, Alessio Chiappini, Thomas Robert, Bawarjan Schatlo, Martin A. Seule, Astrid Weyerbrock, Luca Regli, Martin Nikolaus Stienen and for the Swiss SOS Study Group

OBJECTIVE

The objective of this study was to determine patterns of care and outcomes in ruptured intracranial aneurysms (IAs) of the middle cerebral artery (MCA) in a contemporary national cohort.

METHODS

The authors conducted a retrospective analysis of prospective data from a nationwide multicenter registry of all aneurysmal subarachnoid hemorrhage (aSAH) cases admitted to a tertiary care neurosurgical department in Switzerland in the years 2009–2015 (Swiss Study on Aneurysmal Subarachnoid Hemorrhage [Swiss SOS]). Patterns of care and outcomes at discharge and the 1-year follow-up in MCA aneurysm (MCAA) patients were analyzed and compared with those in a control group of patients with IAs in locations other than the MCA (non-MCAA patients). Independent predictors of a favorable outcome (modified Rankin Scale score ≤ 3) were identified, and their effect size was determined.

RESULTS

Among 1866 consecutive aSAH patients, 413 (22.1%) harbored an MCAA. These MCAA patients presented with higher World Federation of Neurosurgical Societies grades (p = 0.007), showed a higher rate of concomitant intracerebral hemorrhage (ICH; 41.9% vs 16.7%, p < 0.001), and experienced delayed cerebral ischemia (DCI) more frequently (38.9% vs 29.4%, p = 0.001) than non-MCAA patients. After adjustment for confounders, patients with MCAA were as likely as non-MCAA patients to experience DCI (aOR 1.04, 95% CI 0.74–1.45, p = 0.830). Surgical treatment was the dominant treatment modality in MCAA patients and at a significantly higher rate than in non-MCAA patients (81.7% vs 36.7%, p < 0.001). An MCAA location was a strong independent predictor of surgical treatment (aOR 8.49, 95% CI 5.89–12.25, p < 0.001), despite statistical adjustment for variables traditionally associated with surgical treatment, such as (space-occupying) ICH (aOR 1.73, 95% CI 1.23–2.45, p = 0.002). Even though MCAA patients were less likely to die during the acute hospitalization (aOR 0.52, 0.30–0.91, p = 0.022), their rate of a favorable outcome was lower at discharge than that in non-MCAA patients (55.7% vs 63.7%, p = 0.003). At the 1-year follow-up, 68.5% and 69.6% of MCAA and non-MCAA patients, respectively, had a favorable outcome (p = 0.676).

CONCLUSIONS

Microsurgical occlusion remains the predominant treatment choice for about 80% of ruptured MCAAs in a European industrialized country. Although patients with MCAAs presented with worse admission grades and greater rates of concomitant ICH, in-hospital mortality was lower and long-term disability was comparable to those in patients with non-MCAA.