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M Westphal

Publications and source records attributed to M Westphal.

At least 37 records · Page 2Linked to original sources
PubMed2004

New approach to an ovine model of hypodynamic endotoxaemia.

BACKGROUND AND OBJECTIVE: Since the moribund hypodynamic phase of septic shock has primarily been studied in small animal models, the objective of this study was to investigate the usefulness of infusing Salmonella typhosa endotoxin at incrementing doses to establish an ovine model of hypodynamic endotoxaemia. METHODS: In a prospective laboratory experiment, eight adult ewes were instrumented for a chronic study. Following a baseline measurement in the healthy state, a continuous endotoxin infusion was started with 10 ng kg(-1) min(-1) and was doubled every hour seven times. Haemodynamics, key variables of oxygen transport, and arterial lactate concentrations were determined every hour. RESULTS: In a dose-dependent manner, endotoxin infusion caused pulmonary hypertension, decreased cardiac output and mean arterial pressure, increased heart rate, and to a certain extent, systemic vascular resistance index. Following 4h of endotoxaemia, the maximum decrease in cardiac output occurred (4.8+/-0.2 vs. 7.6+/-0.3 Lmin(-1); P < 0.001). This was accompanied by tissue dysoxia, represented by decreases in oxygen delivery (797+/-20 vs. 1041+/-28 mLmin(-1)), oxygen consumption (277+/-14 vs. 396+/-15 mLmin(-1)) and oxygen extraction rate (0.35+/-0.01 vs. 0.38+/-0.01%; each P < 0.01), as well as an increase in arterial lactate concentration (1.7+/-0.1 vs. 0.7+/-0.1 mmolL(-1); P < 0.05). CONCLUSIONS: This large animal model may be helpful to study the pathophysiology responsible for cardiovascular failure, and also new therapeutic approaches relevant to management of hypodynamic circulation in the common setting of progressed systemic inflammation.

Animals↗
PubMed2004

Pressure or flow?

Explore the source record for details and available documents.

Hemodynamics↗
PubMed2003

Percutaneous fetoscopic tracheal balloon occlusion in sheep.

BACKGROUND: In order to minimize maternal trauma from current techniques for temporary fetoscopic tracheal occlusion, we tried to develop a percutaneous fetoscopic technique in sheep. METHODS: In nine ewes between 77 and 128 days of gestation, the amniotic cavity was entered percutaneously. Each fetus was positioned and the feasibility of fetal laryngoscopy and percutaneous fetoscopic tracheal balloon occlusion was assessed. RESULTS: Percutaneous intraamniotic access, fetal positioning, oropharyngeal sheath insertion, and fetoscopic laryngoscopy were achieved in all nine fetal sheep. Following some technical modifications to the working channel of the fetoscope, percutaneous fetoscopic tracheal balloon occlusion was successfully achieved in the last seven sheep. CONCLUSION: Percutaneous fetoscopic balloon occlusion of the fetal trachea can effectively and safely be achieved in sheep. Because intraamniotic spatial relationships, fetal position, and umbilical cord length are technically less favorable in sheep, our operative techniques might be feasible in humans even if difficult intraamniotic conditions are encountered.

Animals↗
PubMed2003

Percutaneous fetoscopic patch coverage of experimental lumbosacral full-thickness skin lesions in sheep.

BACKGROUND: In order to minimize maternal trauma from open fetal surgery for prenatal coverage of fetal myelomeningoceles in humans, we assessed the feasibility of a percutaneous fetoscopic approach in sheep. METHODS: In seven ewes between 90 and 100 days of gestation, the amniotic cavity was entered percutaneously. Each fetus was postured and a full-thickness skin lesion was created in the lumbosacral region. Then, the feasibility of covering this lesion with a patch and fetal skin by standard endoscopic suturing techniques (n = 3) or robot assistance (n = 4) was assessed. RESULTS: Percutaneous fetoscopic patch and skin coverage of the full-thickness skin lesion was achieved in six of the seven fetal sheep. Five fetuses survived gestation and were delivered healthy. CONCLUSIONS: Percutaneous fetoscopic posturing and patch coverage of lumbosacral full-thickness skin lesions can effectively and safely be achieved in sheep. This approach promises to provide a substantial reduction of maternal trauma from fetal surgery for myelomeningoceles.

Animals↗
PubMed2003

Cost of migration: invasion of malignant gliomas and implications for treatment.

Tumors of glial origin consist of a core mass and a penumbra of invasive, single cells, decreasing in numbers towards the periphery and still detectable several centimeters away from the core lesion. Several decades ago, the diffuse nature of malignant gliomas was recognized by neurosurgeons when super-radical resections using hemispherectomies failed to eradicate these tumors. Local invasiveness eventually leads to regrowth of a recurrent tumor predominantly adjacent to the resection cavity, which is not significantly altered by radiation or chemotherapy. This raises the question of whether invasive glioma cells activate cellular programs that render these cells resistant to conventional treatments. Clinical and experimental data demonstrate that glioma invasion is determined by several independent mechanisms that facilitate the spread of these tumors along different anatomic and molecular structures. A common denominator of this cellular behavior may be cell motility. Gene-expression profiling showed upregulation of genes related to motility, and functional studies demonstrated that cell motility contributes to the invasive phenotype of malignant gliomas. There is accumulating evidence that invasive glioma cells show a decreased proliferation rate and a relative resistance to apoptosis, which may contribute to chemotherapy and radiation resistance. Interestingly, interference with cell motility by different strategies results in increased susceptibility to apoptosis, indicating that this dynamic relationship can potentially be exploited as an anti-invasive treatment paradigm. In this review, we discuss mechanisms of glioma invasion, characteristics of the invasive cell, and consequences of this cellular phenotype for surgical resection, oncologic treatments, and future perspectives for anti-invasive strategies.

Brain Neoplasms↗
PubMed2003

Intracavitary chemotherapy for glioblastoma: present status and future directions.

Considerable efforts have been invested to improve local control of the glioma disease although its infiltrative nature leading to whole brain involvement is a fundamental characteristic and antagonistic to this endeavour. The typically local recurrence of glioblastoma in about 80% of the cases has prompted intracavitary treatments of which presently only a biodegradable wafer containing carmustine has shown statistically significant benefit regarding survival in three phase III trials. Based on that proof of principle, many new developments are attempting to improve on this concept, introducing different agents with otherwise high systemic toxicity and poor penetration. New pharmacological formulations offer longer sustained release, better adaptation to the geometry of the resection cavity, and allow repeated administration. Should local recurrence become effectively controlled, significant progress can be made to increase survival with very limited local and virtually no systemic side effects. Since all agents so far show only limited activity against solid tumor, complete resection seems to be the prerequisite for effective local therapies.

Antineoplastic Agents↗
PubMed2003

Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma.

PURPOSE: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas Exotoxin (NBI-3001) in patients with recurrent malignant glioma. PATIENTS AND METHODS: A total of 31 patients with histologically verified supratentorial grade 3 and 4 astrocytoma were studied. Of these, twenty-five patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma (AA). Patients were over 18 years of age and had Karnofsky performance scores > or = 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 microg/ml x 40 ml, 9 microg/ml x 40 ml, 15 microg/ml x 40 ml, or 9 microg/ml x 100 ml of NBI-3001 administered intratumorally via stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. RESULTS: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related Grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 microg/ml x 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. CONCLUSIONS: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Adult↗
PubMed2003

Gene therapy of gliomas.

Malignant glioma formation is associated with characteristic genetic alterations, although epigenetic mechanisms may contribute in tumorigenesis. Until recently, our knowledge has mainly been based on chromosomal and molecular studies performed in the last two decades. This has increased tremendously with the advent of new technologies, in particular expression arrays for simultaneous analysis of thousands of genes. Consequently, gene therapy of gliomas may aim at molecular interference with 'gain of function' genes (oncogenes) or replacement of 'loss of function' genes (tumor suppressor genes). Such approaches require transgene expression in whole tumor cell populations (if not other mechanisms come into play) which cannot be achieved with current vector systems. Hence other strategies have been pursued which may be independent of genes actually involved in tumorigenesis. Microbial genes (e.g. herpes simplex virus thymidine kinase) may be transferred into the tumors allowing for prodrug activation (e.g. ganciclovir). Furthermore, cytokines or other immunomodulatory genes may be used for vaccination purposes which frequently involves ex vivo transfection of autologous tumor cells with such genes. These approaches proved promising in preclinical studies performed in cell culture and different inbred rodent models. A considerable number of clinical trials have been initiated based on these approaches. Although most therapeutic strategies proved safe, clinical responses fell short of expectations raised by preclinical results. This, to a large extent, has to be attributed to a lag in the development of efficient vector systems. Although much effort has been put into this area of research, neuro-oncologists are still in await of a vector system allowing for selective and efficient tumor cell transduction. This has led to increased interest in distinct but related strategies, e.g. oncolytic viruses or direct intra-tumoral delivery of anti-sense oligonucleotides.

Animals↗
PubMed2003

Invasion as limitation to anti-angiogenic glioma therapy.

The inhibition of tumor angiogenesis could be an efficient therapeutic strategy for the treatment of malignant gliomas. Prominent neovascularization is induced by these tumors, and microvascular proliferation is a malignancy grading criterion. However, glioma cells can also invade the brain diffusely over long distances without necessarily requiring angiogenesis. Experimentally, it was shown that especially during early stages of growth in rodent brain, glioma cells can coopt the preexistent host vasculature to recruit their blood supply in the absence of neovascularization. This phenomenon was only observed in orthotopic models in which the tumor cells were implanted into the brain which is a densely vascularized environment, but not in subcutaneous models in which tumor cells are implanted into a virtual space. Using an orthotopic mouse model, we analyzed whether systemic anti-angiogenic therapy with an antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2) could inhibit intracerebral growth of xenografted human glioblastoma cells and what effect this treatment had on tumor morphology and invasiveness. We found that anti-angiogenic therapy inhibited tumor growth by 80% compared to buffer-treated controls. The intratumoral microvessel density was reduced by at least 40% in treated animals compared to controls. However, in mice treated with the anti-VEGFR-2 antibody, we noticed a striking increase in the number and total area of small satellite tumors clustered around the primary mass. These satellites usually contained central vessel cores, and tumor cells often had migrated along blood vessels over long distances to eventually reach the surface and spread in the subarachnoid space. Systemic anti-angiogenic therapy can thus apparently increase the invasiveness of gliomas in the orthotopic model. Tumor cell invasion was tightly associated with preexistent blood vessels, suggesting that increased cooption of the host vasculature could represent a compensatory mechanism that is selected for by inhibiting adequate tumor vascularization.

Angiogenesis Inhibitors↗
PubMed2003

Improved method for the intracerebral engraftment of tumour cells and intratumoural treatment using a guide screw system in mice.

BACKGROUND: Orthotopic in vivo models for the experimental treatment of malignant gliomas have become indispensable to evaluate the efficacy of novel therapeutic regimens. Recently, a guide screw system was introduced which is implanted into the cranium of small rodents where it facilitates fast, repeated and exactly reproducible intracerebral injections, avoiding time consuming stereotactic procedures. Here we report our experience with this system, and describe several modifications which we introduced to improve its reliability and to simplify its application. FINDINGS: The most important modification made was the optimization of the guide screw implantation site, which needs to be adapted to the age of the mice. Other improvements were the fixation of the guide screw to the cranium of the mice using a two component adhesive. This avoids the tendency, when daily intratumoural injections are performed over several weeks, for the screw to loosen, making precise injections impossible. The injection procedure, initially described as a free-hand approach, was improved by mounting the syringe to a Greenberg retractor. This provided additional stability and speeded up the process. Applying this modified technique, we were able to achieve reproducible results with regard to engraftment rate, tumour growth, and intratumoural treatment in immunocompromized mice. INTERPRETATION: We introduced several major and some minor improvements to make working with the guide screw system more reliable, faster and more comfortable. Daily injections over a period of three weeks using this system are feasible and well tolerated by mice.

Animals↗
PubMed2003

Adsorption of sufentanil to epidural filters and catheters.

BACKGROUND AND OBJECTIVE: Stable drug concentrations must be administered to provide adequate patient-controlled epidural analgesia. This study investigated the stability of sufentanil after the epidural delivery system had been flushed with solutions containing the drug. METHODS: Sufentanil citrate, 5 microg mL(-1) was injected through an epidural catheter system into a glass container. The concentrations of the drug leaving the system, in 1 mL aliquots (1-5 mL) were measured using high-performance liquid chromatography. In the same manner, sufentanil samples were analysed after flushing the filter, as well as after priming the filter and catheter. RESULTS: ANOVA for repeated measurements demonstrated that sufentanil concentrations remained constant as long as the catheter had been adequately flushed. However, the concentration of sufentanil in the solution exiting the filter was reduced significantly. Hardly any sufentanil could be detected (0.09 +/- 0.01 microg mL(-1), P < 0.001) in the first 1 mL aliquot (probe) leaving the filter. Altogether, 3 mL sufentanil solution was needed to pass through the filter before the baseline values were restored (P > 0.05). The greatest decrease occurred when the whole epidural delivery apparatus (catheter and filter) was primed; to regain baseline values, as much as 4 mL solution was needed to flush the system. CONCLUSIONS: Sufentanil citrate is adsorbed by the materials used to manufacture systems (catheters, filters) used in epidural anaesthesia. Hence, the epidural catheter system should be primed with sufentanil before connecting it to the patient so as to deliver reliable concentrations.

Adsorption↗
PubMed2003

[Intraoperative ultrasound of intra- and extramedullary tumours].

AIM: Spinal tumours can be diagnosed precisely by magnetic resonance imaging (MRI). Planning the surgical procedure of intradural tumours, intraoperative ultrasound (IOUS) has been used to evaluate its diagnostic potential. METHOD: From 1997 to 9/2002 32 patients with the diagnosis of an ependymoma (n = 9), astrocytoma (n = 5), haemangioblastoma (n = 5), neurinoma (n = 4), meningeoma (n = 4) and filum terminale ependymoma (n = 5) were investigated by intraoperative transdural sonography. The sonographic results were correlated to the preoperative MRI-findings and histopathological work-up. RESULTS: Intramedullary tumours characteristically present with a heterogenous morphology, sometimes carrying intralesional or perilesional cysts. The tumour margins are frequently poorly defined, and there is a perifocal oedema. Extramedullary tumours frequently display a homogenous signal intensity, well defined tumour margins and the abscence of perifocal oedema. Haemangioblastomas turned out to be a specific sonographic entity among intramedullary tumours, as they most often contain only a cystic part with a small tumour nodule. IOUS influenced the surgical approach as laminotomy has to be extended in 7/32 cases to reach the tips of the tumour. CONCLUSION: The precision of surgical exposure of intradural spinal lesions can be optimised by IOUS which shows a high correlation with MRI characterizing extra- and intramedullary tumours. Using IOUS, the exact position of the laminectomy/laminotomy can be adapted to the true extent of the tumour, thus avoiding the necessity of further bone work in the case of the frequently oedematous spinal cord protruding through the opening in the dura. Overall, IOUS guidance can help to reduce postoperative morbidity in surgery for all spinal intradural lesions.

Astrocytoma↗
PubMed2002

Diffuse arachnoidal enhancement of a well differentiated choroid plexus papilloma.

INTRODUCTION: The case of a 38-year old man with a histologically benign choroid plexus papilloma arising within the fourth ventricle with en plaque growth around the brain stem and medulla is described in detail. Up to this point this particular growth pattern has not been published and is a rare presentation for this tumour. CLINICAL PRESENTATION: The patient presented with a 1.5 year history of headache, nausea, and vomiting in the morning. Additional symptoms like blurred vision and gait ataxia lead to hospital admission. MRI demonstrated a homogeneously contrast-enhancing tumour completely filling the fourth ventricle and subsequent obstructive hydrocephalus. In addition Gd enhancement encasing the brain stem, the lower aspect of the medulla and the conus medullaris was seen suggesting a disseminated ependymoma or medulloblastoma. INTERVENTION: An extensive resection of the tumour in the fourth ventricle and CP angle was performed. Infiltrative growth into the structures of the left CP angle and into the rhomboid fossa hampered complete removal. Surprisingly histological examination revealed a well-differentiated papillary choroid plexus papilloma without signs of anaplasia. On follow up imaging the Gd enhancement encasing the pons vanished completely. A growing cyst adjacent to a small tumour residuum left behind on the floor of the fourth ventricle led to re-operation after 8 months with complete removal. DISCUSSION: This case presents several biological, neuroradiological and surgical aspects which make it noteworthy and we hope that the informations provided add to the understanding of these tumours, expand the differential diagnostic thinking of lesions which present with diffuse arachnoid Gd enhancement upon first presentation.

Adult↗
PubMed2002

Cyclo-oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells.

We have previously identified thromboxane synthase as an important regulator of glioma cell migration. Inhibitors of this enzyme abrogate cell motility and induce apoptosis. However, the formation rate of thromboxanes is indirectly dependent on the activity of cyclo-oxygenase, which represents the rate-limiting step in the synthesis of prostaglandins and thromboxanes. In this study we have analyzed the expression of COX-1 and COX-2 in glioma cell lines and biopsies of glial tumors. In normal glia no expression of both COX isoforms was present, however, reactive astrocytes and glial tumors of all grades demonstrated expression of both COX-1 and COX-2. In contrast to inhibitors of thromboxane synthase, selective and non-selective cyclo-oxygenase inhibitors did not block cell motility. Specific COX-2 inhibitors resulted in growth inhibition and induction of intracellular DNA fragmentation indicative of apoptotic cell death. Treatment of glioma cells with thromboxane synthase inhibitors had a synergistic effect on induction of apoptosis by camptothecin, whereas COX inhibitors had not. Furthermore, combined treatment using COX-2 inhibitors and specific thromboxane synthase inhibitors did not show a synergistic increase of apoptosis. These data indicate that COX inhibitors and thromboxane synthase inhibitors influence apoptosis in glioma cells through different pathways. We hypothesize that, in contrast to the COX-2 inhibitors, thromboxane synthase inhibitors block the invasive phenotype of glioma cells and therefore increase the pro-apoptotic disposition of the cells and increase the susceptibility to induced apoptosis. This effect may be independent of prostaglandin synthesis controlled by cyclo-oxygenases.

Apoptosis↗