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Manfred Westphal

Publications and source records attributed to Manfred Westphal.

At least 19 recordsLinked to original sources
PubMed2006

A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo.

PURPOSE: Expression of the receptor tyrosine kinase c-Met and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly increased in glioblastomas, where they promote tumor proliferation, migration, invasion, and angiogenesis. We used a novel one-armed anti-c-Met antibody to inhibit glioblastoma growth in vivo. EXPERIMENTAL DESIGN: U87 glioblastoma cells (c-Met and SF/HGF positive) or G55 glioblastoma cells (c-Met positive and SF/HGF negative) were used to generate intracranial orthotopic xenografts in nude mice. The one-armed 5D5 (OA-5D5) anti-c-Met antibody was infused intratumorally using osmotic minipumps. Following treatment, tumor volumes were measured and tumors were analyzed histologically for extracellular matrix (ECM) components and proteases relevant to tumor invasion. Microarray analyses were done to determine the effect of the antibody on invasion-related genes. RESULTS: U87 tumor growth, strongly driven by SF/HGF, was inhibited > 95% with OA-5D5 treatment. In contrast, G55 tumors, which are not SF/HGF driven, did not respond to OA-5D5, suggesting that the antibody can have efficacy in SF/HGF-activated tumors. In OA-5D5-treated U87 tumors, cell proliferation was reduced > 75%, microvessel density was reduced > 90%, and apoptosis was increased > 60%. Furthermore, OA-5D5 treatment decreased tumor cell density > 2-fold, with a consequent increase in ECM deposition and increased immunoreactivity for laminin, fibronectin, and tenascin. Microarray studies showed no increase in these ECM factors, rather down-regulation of urokinase-type plasminogen activator and matrix metalloproteinase 16 in glioblastoma cells treated with OA-5D5. CONCLUSIONS: Local treatment with OA-5D5 can almost completely inhibit intracerebral glioblastoma growth when SF/HGF is driving tumor growth. The mechanisms of tumor inhibition include antiproliferative, antiangiogenic, and proapoptotic effects.

Animals↗
PubMed2006

Low-grade and anaplastic gliomas: differences in architecture evaluated with diffusion-tensor MR imaging.

PURPOSE: To prospectively evaluate whether diffusion-tensor magnetic resonance (MR) imaging depicts differences in World Health Organization (WHO) grade II and III glial brain tumors on the basis of tumor architecture and peritumoral tract invasion. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee, and written informed consent was obtained. Diffusion-tensor MR imaging was performed in 23 patients (15 men, eight women; mean age, 47 years) with histologically confirmed brain gliomas. Eleven of the 23 tumors were low-grade gliomas (WHO grade II) and 12 were anaplastic gliomas (WHO grade III). Regions of interest were placed in the tumor center, tumor border, normal-appearing white matter (NAWM) adjacent to the tumor, and NAWM of the contralateral hemisphere. fractional anisotropy (FA) ratios were calculated for regions of interest in relation to the NAWM of the contralateral hemisphere. Pairwise comparisons were performed by using the Mann-Whitney U test. RESULTS: Median FA ratios for grade II versus grade III gliomas were 0.406 versus 0.405, respectively, for tumor center, 0.733 versus 0.449, respectively, for tumor border, and 0.962 versus 0.943, respectively, for NAWM adjacent to the tumor. Differences in FA ratio between low-grade and high-grade tumors were significant in the tumor border only (P = .01). Differences in FA ratio were not significant between low-grade and high-grade gliomas in the tumor center or in the NAWM adjacent to the tumor. CONCLUSION: The periphery of low-grade gliomas contains a considerable amount of preserved fiber tracts. In high-grade gliomas, however, most of these tracts are disarranged. Low FA ratios in the tumor center are consistent with a high degree of disorganization of myelinated fiber tracts in the center of both low-grade and high-grade gliomas.

Adult↗
PubMed2006

Intraoperative measurement of pharynx/esophagus retraction during anterior cervical surgery. Part I: pressure.

Temporary dysphagia after anterior cervical discectomy (ACD) is common. However, its mechanism is poorly understood. Pressure induced by retractor blades onto pharynx/esophagus were measured intraoperatively in order to gain more information regarding traumatization of the pharynx/esophagus wall. Thirty-one patients underwent anterior cervical discectomy and fusion (ACDF) for degenerative disc disease. An online pressure transducer was applied to the rear side of the medial retractor blade (epi-esophageal-pressure, epi-P) and a cylindric, inflatable transducer was preoperatively inserted into the pharynx/esophagus under fluoroscopic guidance at the level to be operated on (endo-esophageal-pressure, endo-P). Pressure values were recorded continuously during the operation. Mean arterial pressure (MAP) and endotracheal cuff pressure (ETCP) were recorded additionally. An in vitro model was developed in order to analyze the impact of the retractor blade design onto the epi-esophageal-pressure. Mean epi-P before and following adequate retractor opening for exposure of the disc space was 58.3 and 92.7 mmHg. Thirty, 60 and 90 min later the epi-P decreased to 79, 70 and 66%, respectively. Mean basal endo-P was 9.8 mmHg and increased to 20.6 mmHg after retractor placement. Thirty, 60 and 90 min later the endo-P decreased to 80, 71 and 62%, respectively. The mean MAP was 76 mmHg and the ECTP was adjusted to 25 mmHg during the procedures. In the in vitro model retraction pressure correlated inversely with the contact area between visceral wall and retractor blade. During ACDF the retraction pressure onto the pharyngeal/esophageal wall exceeds MAP and even more the mucosal perfusion pressure of 25 mmHg. Over time the pharynx/esophageal wall adapts to the applied pressure induced by the retractor blade. The contact area between them influences the retraction pressure.

Adult↗
PubMed2006

Intraoperative measurement of pharynx/esophagus retraction during anterior cervical surgery. Part II: perfusion.

Early postoperative dysphagia after anterior cervical surgery is a well-known phenomenon with so far unknown etiology. We hypothesised that direct pressure induced by the medial retractor blade on pharynx/esophagus mucosal wall leads to local ischemia. Subsequently postoperative hyperemia and swelling of the pharynx/esophagus may result in swallowing disturbance. To prove the hypothesis local blood flow inside the pharynx/esophagus wall during anterior cervical surgery was measured using a laser Doppler (LD) perfusion monitor unit. Fifteen patients underwent standard anterior cervical discectomy and fusion (ACDF). The LD probe was placed underneath the medial retractor blade in order to gain information at the maximum point of pressure applied onto the pharynx/esophagus wall. Local perfusion was measured prior to retractor opening (5 min), during spreading of the retractor and after its closure (5 min). Perfusion was measured semiquantitatively in perfusion units (PU). Local perfusion ranged from 30 to 210 PU (mean 107) prior to retractor opening, from 7 to 60 PU (mean 30) with open retractor and from 15 to 280 PU (mean 117) after retractor closure. In all 15 patients the open retractor led to hypoperfusion ranging from 21 to 93% compared to the baseline level. In seven patients a reactive hyperemia at the end of the procedure was detected (32-89% compared to baseline level). In four patients after hypoperfusion during spreading of the retractor the baseline levels were reached again and in four patients perfusion remained diminished even after retractor closure. To best of our knowledge, this is the first report on intraoperative measurement of local perfusion of the pharynx/esophagus wall during anterior cervical surgery. Diminished local perfusion was observed in all patients during spreading of the retractor and post-procedure hyperemia was recorded in 46% of the patients. The local ischemia of the pharynx/esophagus wall may be a crucial step in the development of postoperative dysphagia.

Adult↗
PubMed2006

Contactin is expressed in human astrocytic gliomas and mediates repulsive effects.

Contactin is a cell surface adhesion molecule that is normally expressed by neurons and oligodendrocytes. Particularly high levels of contactin are present during brain development. Using subtractive cloning, we identified contactin transcripts as overexpressed in glioblastomas compared with normal brain. We confirmed contactin overexpression in glioblastomas at the protein level, and localized contactin to the surface of glial fibrillary acidic protein (GFAP)-expressing glioblastoma cells. In contrast, normal astrocytes did not express contactin. Analyzing different types of astrocytic tumors, we detected an association between increasing malignancy grade and contactin expression. Functionally, contactin had repellent effects on glioma cells in vitro, as demonstrated by adhesion and migration assays. Overexpression of contactin by transfection into glioblastoma cells did not alter the proliferation rate or adhesion to various extracellular matrix proteins as well as adhesion to cells expressing the specific contactin ligand the protein tyrosine phosphatase zeta (PTPzeta). Our findings suggest that contactin has repellent effects on glioma cells to which it is presented as a ligand, but it does not alter the proliferative or adhesive capacities of cells that overexpress the molecule. The repulsive properties of contactin may be a key factor in glioma disaggregation, and may contribute to the diffuse infiltration pattern characteristic of glioma cells in human brain.

Astrocytes↗
PubMed2006

Ultrasound in the diagnosis of craniosynostosis.

Diagnosis of craniosynostosis is based on clinical aspects but may be difficult in some cases where characteristic features are missing and radiographic imaging is necessary. In this context near-field high-frequency ultrasound has been used to evaluate the sonographic characteristics of synostotic sutures and its potential confirming the correct diagnosis. Sutures of 26 infants, aged 2-7 months, were investigated by ultrasound (Siemens Elegra, 7.5 MHz linear scanner). Sonographic features of synostotic sutures were correlated to CT imaging and compared to the sonographic and histopathological findings of normal cranial sutures. Hyperechogenic bridging of sutures with or without ridging were the characteristic aspects of synostotic sutures. All 26 patients could be reliable diagnosed showing partial (n = 21) or total fusion (n = 5) of one or more sutures consisting with craniosynostosis. Length of synostosis was identified exactly by sonography and imaging found to enable a classification of ultrastructural details of bony and soft tissue next to the synostotic suture. Ultrasound is a less expensive, nonradiating and easy-to-handle tool ensuring the diagnosis of craniosynostosis. Sonography offers the potential to be a standard investigation for infants with head deformities suspecting a suture pathology and has been therefore integrated in our craniofacial outpatient clinic as a daily routine method.

Cranial Sutures↗
PubMed2006

RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo.

The protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta (PTPzeta/RPTPbeta) and its ligand pleiotrophin (PTN) are overexpressed in human glioblastomas. Both molecules are involved in neuronal cell migration during CNS development. In addition, PTN can induce glioma cell migration which is at least in part mediated through binding to PTPzeta/RPTPbeta. To study the relevance of this ligand-receptor pair for glioma growth in vitro and in vivo, we transfected the human glioblastoma cell line U251-MG with small interfering RNA (siRNA) directed against PTPzeta/RPTPbeta. Stable siRNA transfection resulted in strong down-regulation of PTPzeta/RPTPbeta expression. When injected subcutaneously into nude mice, clones that expressed normal levels of PTPzeta/RPTPbeta (PTPzeta + clones) formed exponentially growing tumours, whereas tumour growth was almost completely abrogated for clones that expressed reduced PTPzeta/RPTPbeta levels (PTPzeta - clones). Similar results were obtained using an orthotopic intracerebral model. Proliferation of PTPzeta - cells in vitro was significantly reduced compared with that of control clones. Matrix-immobilized PTN stimulated the proliferation of PTPzeta + cells but not of PTPzeta - cells. Haptotactic migration induced by PTN was reduced for PTPzeta - clones compared with control clones. Our findings suggest that antagonization of PTPzeta/RPTPbeta expression can inhibit glioma growth in vivo and may thus represent a potentially promising treatment strategy.

Animals↗
PubMed2006

Consensus document on European brain research.

Brain disease psychiatric and neurologic disease combined represents a considerable social and economic burden in Europe. Data collected by the World Health Organization (WHO) suggest that brain diseases are responsible for 35% of Europe's total disease burden. An analysis of all health economic studies of brain diseases in Europe, published by the European Brain Council (EBC) in June 2005, estimated the total cost of brain disease in Europe in 2004 to be Euro 386 billion. That burden is set to grow, mainly due to the fact that the European population is ageing. Investment in brain sciences does not match that burden now, let alone in the future. Brain research received only 8% of the life science budget in the European Commission's Fifth Framework Programme, which represents less than 0.01% of the annual cost of brain disorders for that period. Over the last decade, Europe has been losing ground to the USA and Japan in terms of both basic and clinical research. Many of Europe's young researchers are taking up posts in the USA and staying there. Big pharmaceutical companies are fleeing Europe for the USA, taking their drug development programmes with them. Research in the brain sciences now holds the promise of therapies that halt and even reverse neurodegeneration, of better diagnostic tools, neural prostheses for the paralysed and drugs for depression and anxiety that are tailored to the individual, thereby eliminating or reducing side effects. Our growing understanding of the normal brain could lead to better prevention of brain disease and to more effective teaching methods. The need for innovative treatments has never been greater, and Europe boasts clusters of excellent researchers in biotechnology who could collaborate with brain scientists and the pharmaceutical industry to realise this promise. But if Europe is to seize these opportunities and meet the challenge of brain disease, it needs to go forward on the basis of greater collaboration between countries, greater collaboration between industry, academia and patient organisations, and increased investment in the brain sciences. The EBC was formed in 2002 to bring together scientists, clinicians, the pharmaceutical industry, charities and patient organisations from all over Europe to campaign for these goals. It takes a novel, bottom-up approach to research policy, and in developing this consensus document, it aims to promote a greater and more focused effort in this area, to improve public understanding of the brain sciences and above all, to support brain research as a priority under the European Commission's Seventh Framework Programme (FP7, 2007-2013). The research programme outlined here was first conceived by the EBC board. An outline was sent to all member organisations and a number of individual experts for comments. Following that, a table of contents was developed. The 45 research themes were written by groups of experts from across Europe who represent a wide range of disciplines. Each one contains a proposal for future research on a specific brain-related theme which the EBC believes could form the basis of one or more integrated projects or strategic targeted research projects (STREP) funded under FP7. The EBC has deliberately focused on the major diseases and then described the basic research needed to understand and treat or perhaps even cure those diseases. The programme is therefore constructed "from man to molecule" and not the other way round, with equal importance attached to basic and clinical research. The EBC suggests that each of the proposed integrated projects or STREP should be awarded a budget in the order of Euro 10 to 15 million. In addition, brain research should be treated as an important element of many other parts of FP7, such as the European Research Council and research programmes on information technology and the causes of violence. Any research programme that concerns human behaviour should, by definition, take account of brain research. The EBC envisages that the priority for brain research it proposes at the European level will translate into higher priority for brain research at the national level, and this document may also serve as a starting point for the development of national consensus programmes. It seems likely that consensus conferences on brain research in Europe may further develop the themes and ideas discussed here. An EBC task force may also be established to further the consensus process. In general, increasing funding in the brain sciences would bring enormous economic returns by lightening the burden on healthcare systems and increasing the productivity of affected individuals-and might easily pay for itself. The human and social returns of such an investment are inestimable. And the time to act is now.

Biomedical Research↗
PubMed2005

Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin.

PURPOSE: Inhibition of angiogenesis can influence tumor cell invasion and metastasis. We previously showed that blockade of vascular endothelial growth factor receptor-2 (VEGFR-2) with the monoclonal antibody DC101 inhibited intracerebral glioblastoma growth but caused increased tumor cell invasion along the preexistent vasculature. In the present study, we attempted to inhibit glioma cell invasion using a monoclonal antibody against the epidermal growth factor receptor (EGFR), which in the context of human glioblastomas, has been implicated in tumor cell invasion. In addition, we analyzed whether blockade of vascular endothelial (VE)-cadherin as a different antiangiogenic target could also inhibit glioblastoma angiogenesis and growth. EXPERIMENTAL DESIGNS: Nude mice who received intracerebral glioblastoma xenografts were treated using monoclonal antibodies against VEGFR-2 (DC101), EGFR (C225), and VE-cadherin (E4G10) either alone or in different combinations. RESULTS: Increased tumor cell invasion provoked by DC101 monotherapy was inhibited by 50% to 66% by combined treatment with C225 and DC101. C225 inhibited glioblastoma cell migration in vitro, but had no effect on the volume of the main tumor mass or on tumor cell proliferation or apoptosis in vivo, either alone or in combination with DC101. The anti-VE-cadherin monoclonal antibody E4G10 was a weaker inhibitor of tumor angiogenesis and growth than DC101, and also caused a weaker increase in tumor cell invasion. CONCLUSIONS: Inhibition of angiogenesis achieved by blocking either VEGFR-2 or VE-cadherin can cause increased glioma cell invasion in an orthotopic model. Increased tumor cell invasion induced by potent inhibition of angiogenesis with DC101 could be inhibited by simultaneous blockade of EGFR.

Animals↗
PubMed2005

Intraoperative sonography of intra- and extramedullary tumors.

Intraoperative ultrasound (IOUS) was used in planning the operative resection of intradural spinal tumors, to define its diagnostic potential and limitations. Since 1997, 78 patients diagnosed with an ependymoma (n = 24), astrocytoma (n = 7), hemangioblastoma (n = 7), neurinoma (n = 15), meningioma (n = 17) and filum terminale ependymoma (n = 8) were examined using intraoperative transdural sonography. Intramedullary tumors turned out to show a heterogeneous image with occasional cystic alterations and an indistinct demarcation to the myelon of comparable echogenicity. Intramedullary tumors are easily distinguishable from their extramedullary counterparts, which display a homogeneous signal intensity and sharp demarcation on IOUS. In conclusion, IOUS allows a reliable diagnosis of intraspinal tumors, allowing the distinction between intra- and extramedullary tumors through their respective signal characteristics. Using IOUS, the extension of the neurosurgical approach can be adopted to the true extent of the tumor; thus, avoiding further bone work while the dura is already opened and the frequently edematous spinal cord protrudes through the opening. Our experiences have shown that IOUS may reduce the procedure-related morbidity and should, therefore, be used as a standard intraoperative tool in these high-risk surgical entities. (E-mail: ).

Arm↗
PubMed2005

August 2004: 64-year-old man with intermittent paresthesia of the abdomen and of the legs.

A 64-year-old-man had a 2-year history beginning with a sense of abdominal "constriction." Additional slowly rising symptoms, such as tingling of the legs, mild gait ataxia and painful micturition, led to MRI investigation of the spinal cord. A fusiform enlargement of the cord extending from T5 to T8 was shown. The space occupying lesion infiltrated diffusely the spinal cord. A contrast medium enhancing exophytic tumor pellet was approached via a 2-level laminoplasty and resected. Biopsies were taken from different exophytic tumor areas whereas the intramedullary part was spared. The histologic examination confirmed the typical pattern of a pilocytic astrocytoma in all specimens. In our surgical experience with 226 intramedullary tumors and with 117 patients affected by intracranial pilocytic astrocytoma this case is unique because of its combination of tumor location, growth pattern and age of the patient.

Abdomen↗
PubMed2005

November 2004: intradural mass of the cauda equina in a woman in her early 60s.

November 2004. A 63-year-old woman presented with slowly aggravating lower back pain and recent urinary urge incontinence. MRI revealed a sharply-delineated, partly cystic intradural mass with inhomogenous contrast-enhancement and ectatic vessels at the upper pole. An ependymoma was suspected, and the tumor was resected in toto. Histologically, at first glance, the tumor strongly resembled an ependymoma, showing a monomorphic cellular pattern, perivascular pseudorosettes and ependymal canal-like structures. However, the finding of a delicate collagen capsule, compartmentation of tumor cells into zellballen and the presence of ganglionic cells were untypical. These features were indicative of a paraganglioma with a gangliocytic component. Immunoreactivity of the tumor cells for neuroendocrine antigens, the detection of GFAP-positive sustentacular cells and the ultrastructural confirmation of neurosecretory granules substantiated this diagnosis. The clinical, radiological and morphological similarity between ependymomas, which are far more common in the cauda equina region than paragangliomas, has led to substantial diagnostic confusion in the past.

Cauda Equina↗
PubMed2005

Well-differentiated neurocytoma: what is the best available treatment?

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features. This analysis focuses on well differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional relevant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses < or =54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.

Adolescent↗
PubMed2005

Neural stem cell migration toward gliomas in vitro.

Various in vivo studies demonstrated a migration tendency of neural stem cells (NSCs) toward gliomas, making these cells a potential carrier for delivery of therapeutic genes to disseminated glioma cells. We analyzed which factors determine NSC migration and invasion in vitro. Conditioned media prepared from 10 different human glioma cell lines, as well as 13 different tumor-associated growth factors, were analyzed for their chemotactic effects on murine C17.2 NSCs. The growth factor receptor status was analyzed by reverse transcriptase-polymerase chain reaction. Invasion of NSCs into multicellular tumor spheroids generated from 10 glioma cell lines was quantified. NSCs displayed a heterogeneous migration pattern toward glioma spheroids as well as toward glioma-cell-conditioned medium. Chemotactic migration was stimulated up to fivefold by conditioned medium as compared to controls. In coculture assays, NSC invasion varied from single cell invasion into glioma spheroids to complete dissemination of NSCs into glioma spheroids of different cell lines. Among 13 different growth factors, scatter factor/hepatocyte growth factor (SF/HGF) was the most powerful chemoattractant for NSCs, inducing a 2.5-fold migration stimulation. An antibody against SF/HGF inhibited migratory stimulation induced by conditioned media. NSC migration can be stimulated by various growth factors, similar to glioma cell migration. The extent to which NSCs infiltrate three-dimensional glioma cell aggregates appears to depend on additional factors, which are likely to include cell-to-cell contacts and interaction with extracellular matrix proteins.

Animals↗
PubMed2004

Angiogenesis-related growth factors in brain tumors.

Numerous growth factors have been implicated in glioma angiogenesis. This chapter focuses on the role of scatter factor/hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor and transforming growth factor beta. We review the expression pattern of these factors in gliomas, their functional contribution to tumor angiogenesis - also in relation to vascular endothelial growth factor, and the effects resulting from their inhibition or overexpression in gliomas in vivo.

Animals↗
PubMed2004

Perspectives of Cellular and Molecular Neurosurgery.

Therapeutic efforts for human glial tumors have over the past years been redirected towards a compartmental treatment concept. The diffusely infiltrative nature of the disease calls for therapeutic agents to reach single cells far beyond the focus of attention which present therapies like surgery and radiation are able to treat. Specific drug discovery approaches which seek to define targets which are specific for gliomas have generated therapeutic options which allow for a highly selective development of new reagents. Combined with new modalities for compartmental drug delivery, systemic complications might be reduced and advantage taken of a compartmental specificity of a target which otherwise in the context of systemic application would not be as specific or burdened with side effects. From the present status of therapeutic developments in neuro-oncology it can be expected that a sufficient number of drug targets emerge which can be exploited by means of interstitial or intracavitary delivery, which are not neurotoxic and which may even be imaged in their action with the new metabolic imaging modalities. Convection enhanced delivery, conditionally replicating oncolytic viruses and motile, genetically engineered neural stem cells all seem to fulfill the distribution requirements which an effective therapeutic for gliomas will need to overcome the very limited efficacy which surgery, conventional chemotherapy and radiation have to offer. Whereas the genomics based discovery approaches are not specific for neuro-oncology, the development of delivery strategies is highly specific for the central nervous system, thus creating a unique set of organ and disease specific therapies.

Journal Article↗
PubMed2004

Pattern of recurrence following local chemotherapy with biodegradable carmustine (BCNU) implants in patients with glioblastoma.

OBJECTIVE: Recently a randomized placebo-controlled phase III trial of biodegradable polymers containing carmustine has demonstrated a significant survival benefit for patients treated with local chemotherapy. A local chemotherapy applied directly to the resection cavity may act directly on residual tumor cells in adjacent brain possibly leading to a local control of the tumor and increased survival. METHODS: We have analyzed the pattern of recurrence using serial MRI studies of 24 patients treated with GLIADEL Wafers or placebo wafers following resection of glioblastomas. RESULTS: Of 24 patients 11 received carmustine wafers and 13 placebo. The age distribution and Karnowsky performance scores of the two populations were not different. However, the median survival (14.7 versus 9.5 months; P = 0.007) and the time to neurological deterioration (12.9 +/- 4.85 vs. 9.4 +/- 2.73 months; P = 0.035) was significantly longer in the treatment group versus the placebo treated control. Preoperative and follow up MRI studies were evaluated in a blinded fashion. Out of 24 patients that entered the analysis 11 showed clearance of all contrast enhancement following resection of glioblastomas. Seventeen tumors progressed locally and 7 showed different patterns of distant failure. Within the carmustine treated group 8 patients showed a local treatment failure with recurrent tumors immediately adjacent to the resection cavity or progression form a residual tumor. Three patients showed a multifocal distant and local pattern of failure after complete or subtotal removal. In no case the local chemotherapy resulted in a distant recurrence only. However, the time to radiographic progression was 165.1 +/- 80.75 days for the GLIADEL Wafer group and 101.9 +/- 43.06 days for the placebo group (P = 0.023). CONCLUSION: In this subgroup analysis of a phase III trial population both the clinical progression and radiological progression were significantly delayed in patients treated with local chemotherapy, resulting in an increased survival time. Local chemotherapy with carmustine containing wafer implants did not result in an altered pattern of recurrence and did not promote multifocal patterns of recurrence.

Absorbable Implants↗