Niels Soerensen

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

Purpose: To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. Experimental Design: Fifty-six patients with relapsed GBM (WHO grade IV) were treated with at least three vaccinations. Children and adults were treated similarly in three consecutive cohorts, with progressively shorter vaccination intervals per cohort. Feasibility and toxicity were assessed as well as effect of age, extent of resection, Karnofsky Performance Score, and treatment cohort on the progression-free (PFS) and overall survival (OS) using univariable and multivariable analysis. Results: Since the prevaccine reoperation, the median PFS and OS of the total group was 3 and 9.6 months, respectively, with a 2-year OS of 14.8%. Total resection was a predictor for better PFS both in univariable analysis and after correction for the other covariates. For OS, younger age and total resection were predictors of a better outcome in univariable analysis but not in multivariable analysis. A trend to improved PFS was observed in favor of the faster DC vaccination schedule with tumor lysate boosting. Vaccine-related edema in one patient with gross residual disease before vaccination was the only serious adverse event. Conclusion: Adjuvant DC-based immunotherapy for patients with relapsed GBM is safe and can induce long-term survival. A trend to PFS improvement was shown in the faster vaccination schedule. The importance of age and a minimal residual disease status at the start of the vaccination is underscored.

Frequency, risk-factors and survival of children with atypical teratoid rhabdoid tumors (AT/RT) of the CNS diagnosed between 1988 and 2004, and registered to the German HIT database.

To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor.

Intra-operative colour-duplex-sonography in the surgical management of cerebral AV-malformations.

Summary In this prospective study the role of intra-operative Colour-Duplex-Sonography (=CDS) during surgery of arteriovenous malformations (=AVM) is evaluated. During the last three years 20 consecutive patients with supratentorial AVMs were examined by intra-operative CDS in order to evaluate the potential of CDS to 1) localize the AVM, 2) differentiate between embolized and perfused parts, 3) identify feeding and draining vessels and 4) control the complete excision of the AVM. All AVMs were localized supratentorially, 9 were grade I and II (according to Spetzler and Martin [31]), 8 grade III and 3 grade IV. 11 were partly embolized and 8 associated with an intracerebral bleeding. In all cases the nidus was correctly localized sonographically by its typical bidirectional flow pattern in Colour-mode. CDS guided the surgeon directly to all (11 cases) deep-seated AVMs (2 to 4cm subcortically). The smallest nidus measured 10 mm. 28 of 34 angiographically defined main feeding and 18 of 23 draining vessels were identified. 14 patients were controlled sonographically at the end of the resection regarding the completeness of excision. In 11 patients CDS was negative and was confirmed by either postoperative angiography or MRI in 10 patients. In one case residual AVM tissue was missed by CDS. Positve CDS findings in 3 cases were all confirmed by microscopic re-inspection, angiography and CCT. Our results suggest that CDS is able to localize AVMs intra-operatively with minimal instrumentation. It allows safe navigation to deep-seated malformations with high accuracy. Feeding and draining vessels can be identified and completeness of resection can be controlled.

Ultrasound-guided neuronavigation of deep-seated cavernous haemangiomas: clinical results and navigation techniques

The aim of this study was to evaluate guidance techniques and patient outcomes of ultrasound-guided neuronavigation of deep-seated intracerebral cavernous hemangiomas (CAs). Thirty-five patients with deep-seated intracerebral CAs with sizes ranging between 7 and 45 mm were operated upon only with ultrasound-guidance. Twenty-seven were located in or near eloquent regions. In 30 patients dissection to the lesion was performed through sulci and fissures. The best approach to a lesion based on surface anatomy and depth was determined using sonographic information. Navigation was done sonographically. In five patients the shortest approach via a corticotomy was determined sonographically. Twenty-six patients had no neurological deficit postoperatively. Preoperative deficits improved in seven of nine patients. Fifteen of 19 patients suffering epileptic seizures had no seizures postoperatively. Intraoperative sonography revealed residual CA tissue after microsurgical extirpation in two cases. This report shows that intraoperative sonographic navigation provides safe guidance to deep-seated CAs with good clinical outcome independent of size.

Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: Report from the HIT-LGG 1996 trial†‡

We describe demographic data of disseminated childhood low‐grade glioma (DLGG) prospectively recruited in the HIT‐LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series.

Localization and Characterization of Intracerebral Cavernous Angiomas by Intra-Operative High-Resolution Colour-Duplex-Sonography

Summary The aim of this prospective study was to evaluate the reliability of high-resolution Colour-Duplex-Sonography (= CDS) in intra-operative localization, guiding and characterization of intracerebral cavernous angiomas (= CA). During a time period from 5/93 to 12/96 a total of 26 patients with 21 supratentorial and 5 infratentorial CA (15 of them deep-seated) were examined intra-operatively by CDS. The study focussed on 1. sonographic characterization, 2. localization in relationship to anatomical landmarks, 3. navigation, 4. correlation of sonographic to magnetic resonance imaging (= MRI), intra-arterial angiography (= DSA) and histological results and 5. control of complete resection. All CA appeared sonographically as hyperechoic lesions without flow-signals in Colour-mode. Imaging of anatomical landmarks as cerebral sulci, brain stem, insular cistern, falx, ventricles and vessels could be used for precise localization and successful guiding to 15 deep-seated lesions. The correlation of the size between MRI and CDS was excellent (1.4 mm mean difference, range from 0 to 5 mm). All 4 associated venous anomalies, as verified by pre-operative DSA, could be visualized and identified by CDS. The completeness of exstirpation was controlled sonographically in 14 cases and confirmed by MRI (= 10) and CT (= 4). This study provides the first comprehensive intra-operative characterization of CAs by CDS and correlation to MRI and DSA. Furthermore it demonstrates the reliability of CDS for intra-operative localization and guiding as well as its potential to control the complete exstirpation.

New ultrasound techniques and their application in neurosurgical intra-operative sonography

Abstract We describe a variety of new ultrasound techniques by their physical background, potentials and applications regarding usefulness during intra-operative neurosurgical procedures. Transducers like highfrequency and small rotating probes fitting into neuroendoscopes, imaging techniques as extended field-ofview technique, harmonic imaging, echo-enhancers, 3-D imaging and the real-time integration of neurosonography with pre-operative CT- or MR-data are mentioned. The technical or physical principles are explained, followed by a discussion of these techniques from available literature dealing with their intra-operative neurosurgical applications and the experience of the authors with the techniques. With higher frequencies micromillimeter imaging is possible and small probe allows endoneurosonography. Echo-enhancers and harmonic imaging improve the signal-to-noise ratio and 3-D imaging and extended field-of-view techniques allows a better understanding of the pathoanatomy. With the real-time integration of intra-operative ultrasound images and pre-operative CT or MR images additional information, like hemodynamic pattern, are available for the neurosurgeon. Although until now only a limited number of reports about new sonographic techniques during intra-operative application in neurosurgery exist, the methods seem to be promising in creating images easier to understand, incorporating more information about pathoanatomy and supplying the neurosurgeon with information additional to that provided by CT and MRI. [Neurol Res 2001; 23: 697-705]

Three‐dimensional Intraoperative Ultrasound of Vascular Malformations and Supratentorial Tumors

The benefits and limits of a magnetic sensor‐based 3‐dimensional (3D) intraoperative ultrasound technique during surgery of vascular malformations and supratentorial tumors were evaluated. Twenty patients with 11 vascular malformations and 9 supra‐tentorial tumors undergoing microsurgical resection or clipping were investigated with an interactive magnetic sensor data acquisition system allowing freehand scanning. An ultrasound probe with a mounted sensor was used after craniotomies to localize lesions, outline tumors or malformation margins, and identify supplying vessels. A 3D data set was obtained allowing reformation of multiple slices in all 3 planes and comparison to 2‐dimensional (2D) intraoperative ultrasound images. Off‐line gray‐scale segmentation analysis allowed differentiation between tissue with different echogenicities. Color‐coded information about blood flow was extracted from the images with a reconstruction algorithm. This allowed photorealistic surface displays of perfused tissue, tumor, and surrounding vessels. Three‐dimensional intraoperative ultrasound data acquisition was obtained within 5 minutes. Off‐line analysis and reconstruction time depends on the type of imaging display and can take up to 30 minutes. The spatial relation between aneurysm sac and surrounding vessels or the skull base could be enhanced in 3 out of 6 aneurysms with 3D intraoperative ultrasound. Perforating arteries were visible in 3 cases only by using 3D imaging. 3D ultrasound provides a promising imaging technique, offering the neurosurgeon an intraoperative spatial orientation of the lesion and its vascular relationships. Thereby, it may improve safety of surgery and understanding of 2D ultrasound images.

Low level of microsatellite instability in paediatric malignant astrocytomas.

Aim: Microsatellite instability (MSI) has been proposed as a possible mechanism in the development of cancer. The aim of the current study was to determine whether MSI is involved in the pathogenesis of paediatric malignant astrocytomas. Methods: We screened a cohort of 126 high‐grade astrocytoma samples for MSI using a sensitive and precise method of DNA analysis including a panel of five mononucleotide repeats, in combination with immunohistochemistry for DNA mismatch repair (MMR) proteins. Results: We identified low level of MSI (MSI‐L) in four of 126 (3.2%) paediatric malignant astrocytic tumours. To analyse the molecular profile associated with MSI‐L positive tumours, we performed immunohistochemistry for protein expression of hMSH6 and p53 as well as mutational analysis of the K‐ras gene. In MSI‐L paediatric malignant astrocytic tumours we detected retained nuclear expression of hMSH6 protein and strong nuclear accumulation of p53 protein indicating possible mutations of TP53. There was no correlation between K‐ras mutational status and frequency of MSI in this patient population. Conclusion: Our results suggest that the MSI‐L phenotype is associated with p53 accumulation and/or mutations. However, this represents only a small subgroup of paediatric gliomas with possible distinct biological features, and the deficiencies of DNA MMR genes do not play a main role in the tumourigenesis of the majority of paediatric malignant astrocytomas.

Biological activity of paediatric cerebral cavernomas: an immunohistochemical study of 28 patients

ObjectiveAccording to the hypothesis that paediatric cerebral cavernomas may have different biological activity compared to adult cavernomas, immunohistochemical analysis was used to elucidate the biological nature of paediatric cavernomas.Patients and methodsWe examined the histological features and the proliferative and angiogenic capacity of the tissue specimens acquired from 28 paediatric patients. Normal paediatric brain tissues obtained from paediatric autopsy cases were used as a control group. The proliferative activity of the endothelium and the neoangiogenetic capacity were investigated by immunohistochemistry for proliferating cell nuclear antigen (PCNA), Ki-67 epitope (MIB-1), Flk-1 receptor, vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1 α, and endoglin antibody, respectively. Afterwards, the results of the paediatric lesions were analysed and compared with the correspondent values of previously reported immunohistochemical analysis in adult cavernomas.ResultsPositive immunostaining of VEGF was detected significantly less in paediatric cavernomas compared to adult cases (p<0.05). In contrast, endoglin, a protein that is upregulated during an increased vascular shear stress, was expressed more often in paediatric cavernomas (p<0.05). Neither the expression of the PCNA nor the expression of the HIF-1α was found significantly different between paediatric and adult cavernomas. However, the positive immunoreaction for MIB-1 occurred more often in the paediatric cases (p<0.05).ConclusionsThe immunohistochemical study indicates that paediatric cavernomas are dynamic lesions. The VEGF/Flk-1 associated neoangiogenesis may play a minor role for the biology of paediatric cavernomas, while endoglin seems to act more prominently than previously thought, particularly for the biology of paediatric cavernomas.