Post-mortem studies in glioblastoma patients treated with thermotherapy using magnetic nanoparticles.

Patients with glioblastoma multiforme (GBM), the most common primary brain tumor in adults, have still a poor prognosis though new strategies of radio- and chemotherapy have been developed. Recently, our group demonstrated the feasibility, tolerability and anti-tumoral effects of a newly developed therapeutic approach, termed thermotherapy using magnetic nanoparticles or magnetic fluid hyperthermia (MFH), in a murine model of malignant glioma. Currently, the efficacy of MFH is being evaluated in a phase II study. Here, we report on post-mortem neuropathological findings of patients with GBM receiving MFH. In brain autopsies the installed magnetic nanoparticles were dispersed or distributed as aggregates within geographic tumor necroses, restricted in distribution to the sites of instillation. Therefore, our results underscore the need for multiple trajectories of instillation. The typical GBM necrosis with pseudopalisading was free of particles. Dispersed particles and particle aggregates were phagocytosed mainly by macrophages whereas glioblastoma cells showed an uptake to a minor extent. MFH therapy further promotes uptake of nanoparticles in macrophages, likely as a consequence of tumor inherent and therapy induced formation of necrosis with subsequent infiltration and activation of phagocytes. We did not observe bystander effects of MFH such as sarcomatous tumour formation, formation of a sterile abscess or foreign body giant cell reaction. Furthermore, all patients did not present any clinical symptoms related to possible adverse effects of MFH.

The effects of frequency in pallidal deep brain stimulation for primary dystonia.

The effect of stimulation frequency for pallidal deep brain stimulation in five patients with either generalized or segmental dystonia was evaluated three to twelve months postoperatively via a randomized, double-blind paradigm. The quality of life and the severity of dystonic symptoms improved by approximately 60% and 43% respectively using a frequency of 130 Hz. Compared with 130 Hz a significant further clinical improvement was observed at frequencies of 180 and 250 Hz, which contrasted with a significant deterioration at lower frequencies (5, 50 Hz) compared to 130 Hz.

[Percutaneous vertebroplasty]. / Perkutane Vertebroplastie.

PURPOSE: To describe the procedure of percutaneous vertebroplasty and to present our first clinical results of patients treated for benign or malignant painful vertebral body disease. MATERIAL AND METHODS: We performed percutaneous vertebroplasty in 31 painful lesions of the spine. Liquid bone cement was injected into the affected vertebral body using fluoroscopic guidance through a bilateral transpedicular approach. Etiology of the bone disease was assessed by biopsy. Pain intensity was assessed before and 1 week after the procedure by standardized catalogue. RESULTS: Percutaneous vertebroplasty was performed in 17 thoracic and in 14 lumbar spine bodies of benign (n = 23) or malignant (n = 8) disease; no clinically relevant complications occurred. All patients reported significant pain relief 1 week after the intervention. One week after treatment, patients were pain-free in 15/31 vertebral bodies, and reported mild residual pain not necessitating narcotic medication in 16/31 cases. CONCLUSION: In accordance with the literature, percutaneous vertebroplasty proved to be a highly effective, minimal invasive interventional procedure to treat severely painful bone lesions of benign and malignant origin.

Pallidal and thalamic neurostimulation in severe tardive dystonia.

A 70 year old woman presented with a 6 year history of medically refractory severe tardive dystonia. After informed consent, a bilateral stereotactic electrode placement targeting the ventral intermediate thalamic nucleus (VIM) and the globus pallidus internus (GPi) was performed. After bilateral stimulation of the GPi, the patient showed a clear and stable improvement of the painful dystonic syndrome within hours. Stimulation of the VIM did not improve the hyperkinetic movements and simultaneous stimulation of both the GPi and the VIM did not result in any additional benefit. The possible pathophysiological mechanisms are discussed.

Determination of C1-C5 alkyl nitrates in rain, snow, white frost, lake, and tap water by a combined codistillation head-space gas chromatography technique. Determination of Henry's law constants by head-space GC.

Alkyl nitrates with a chain length up to five carbon atoms have been determined in snow, white frost, and surface water. The samples were taken in the vicinity of Ulm, Germany, a region in central Europe. The determination of C1-C5-alkyl nitrates in water samples was achieved with a new water codistillation enrichment technique directly coupled with on-column head-space gas chromatography. The concentrations of the short chain alkyl nitrates in the different forms of wet deposition range from 89 ng L-1 for 1-propyl nitrate down to 35 ng L-1 for 1-pentyl nitrate. C1-C5-alkyl nitrates in wet depositions were also directly determined by static head-space gas chromatography. Gas-water partition coefficients KGW (Henry's law constant H) were determined by head-space gas chromatography and secondly by calculating the Henry's law constant by the ratio of vapor pressure to water solubility. The gas-water partition constants (dimensionless) or Henry's law constants range from KGW = 0.038 (H = 93 Pa m3 mol-1) for 1-propyl nitrate up to KGW = 0.122 (H = 302 Pa m3 mol-1) for 2-pentyl nitrate.

[The use of an early postoperative interstitial-hyperthermia combination therapy in malignant gliomas]. / Einsatz einer früh postoperativen interstitiellen Hyperthermiekombinationstherapie bei malignen Gliomen.

BACKGROUND: The survival of people suffering from malignant gliomas (WHO level III and IV) is predominantly limited by local progress in the primary tumor region. Interstitial hyperthermia combined with radiotherapy or chemotherapy is one approach for the intensification of local therapy. It is possible to combine (partial) tumor resection with hyperthermia as well as with brachytherapy by implanting catheters intraoperatively. PATIENTS AND METHODS: A pilot study was performed to examine practicality, tolerability, effectiveness and scope for improvement in early postoperative hyperthermia treatment following catheter implantation as part of (partial) tumor resection. Each CT data set was transferred into a VAX 3100 workstation for retrospective analysis of the hyperthermia treatment. The implanted catheters were segmented and the distributions of power density and temperature were simulated. We sought to achieve the best possible temperature distributions by optimising the catheter arrangement in the planning calculations. The corresponding Ir-192-source brachytherapy treatments were simulated in a similar way using the implanted, as well as optimised catheter arrays. RESULTS: Intraoperative catheter implantation in 4 patients was problem-free. Postoperative complications were not observed, neither were infections. Interstitial microwave hyperthermia in combination with percutaneous irradiation or chemotherapy a few days after the operation was also tolerated well by all patients. Effective temperatures (of at least 42 degrees C) were regularly achieved at measurement points, but the temperature distributions were unsatisfactory, with T90 values (the temperature reached in at least 90% of the target volume) of under 38 degrees C. Measured temperature/position curves showed qualitative correlation with the simulated calculations. The catheter positions determined by optimisation varied significantly from the positions clinically used. CONCLUSIONS: Early postoperative combination therapy using hyperthermia for the treatment of malignant gliomas is a very practical approach. The optimisation strategies described should be used preoperatively to plan catheter arrays for interstitial hyperthermia and brachytherapy, and these arrays should be implanted using stereotaxic surgery.

DNA-damage caused by antibiotic drugs - quinolones.

In the present investigation, the genotoxic potencies (SOSIP) of 10 antibiotic quinolones (topoisomerase LT inhibitors) were tested in the sfiA::lacZ fusion containing strain Escherichia coli PQ37 using a modified procedure of the SOS chromotest. A number of quinolones exhibited extremely high DNA damaging effects in the absence of an exogenous metabolizing system. The highest SOS inducing potencies (SOSIP) exhibited sparfloxacin with 2,400 Delta IF/nmole, ciprofloxacin (SOSIP = 184 Delta IF/nmole) and norfloxacin (SOSIP=120 Delta IF/nmole), whereas pipemic acid (SOSIP=4.6 Delta IF/nmole), cinoxacin (SOSIP=0.5 Delta IF/nmole) and nalidixic acid (SOSIP=0.5 Delta IF/nmole) showed only weak genotoxicity. The possibility of mutagenic effects caused by quinolones in eukaryotic cells is discussed.

[Pediatric craniocerebral trauma. Special characteristics, therapy and prognosis]. / Das kindliche Schädel-Hirn-Trauma. Besonderheiten, Therapie und Prognose.

The mortality rate after traumatic brain injury in children ranges between 2.5% and 21%. Standardized diagnostic procedures and therapeutic strategies for the management of traumatic brain damage are presented in this article. Children with traumatic cerebral lesions have a better clinical outcome than head-injured adults. Optimized medical management and intensive rehabilitation may help to reduce the frequency of mental retardation and physical disability following such injuries in children.

Primary leptomeningeal gliomatosis with predominant involvement of the spinal cord.

The authors report on a 43-year-old male with apparent myelomeningeal encephalitis. The most important clinical symptoms included severe lymphocytosis of the CSF, cranial nerve palsies, obstructive hydrocephalus, progressive coma, and presence of an intramedullary mass causing paraplegia. Neither CSF analysis, nor the intraoperative findings gave evidence of a neoplastic process. Regarding the paraclinical data we supposed a CNS inflammatory process, but autopsy revealed the diagnosis of an intraspinal, leptomeningeal gliomatosis.

Release of glutamate and of free fatty acids in vasogenic brain edema.

The pathophysiological potential of mediator substances in manifestations of secondary brain damage is attracting increased attention. This is particularly true of the excitatory transmitters glutamate and arachidonic acid. Noxious properties of these compounds in central nervous tissue have been demonstrated. The current study was performed to determine whether glutamate and arachidonate are released in brain tissue secondary to focal trauma. For this purpose, a cold injury of exposed cerebral cortex was induced in cats. Marked accumulation of glutamate was observed in interstitially drained edema fluid, reaching 10 to 15 times the level that was assessed in normal cerebrospinal fluid (CSF) prior to trauma. The extracellular release of glutamate was further dramatically enhanced by a critical decrease of the cerebral perfusion pressure due to a malignant increase of intracranial pressure. Under these conditions, glutamate concentrations 1000 to 1500 times normal levels accumulated in vasogenic edema fluid, demonstrating a relationship between the extent of the release of glutamate in damaged brain and the severity of the insult. Although under normal conditions glutamate concentrations in plasma were considerably higher than in the interstitial fluid, the pronounced increase of glutamate in this compartment due to trauma cannot be explained by transport of the compound together with the plasma-like edema from the intravascular space. Corresponding findings were obtained for free fatty acid concentrations in edema fluid. Almost all fatty acids that were studied had a significantly higher concentration in edema fluid than in normal CSF obtained as a control prior to trauma. However, contrary to the findings for glutamate, fatty acid concentrations in edema fluid were lower than in plasma. Accumulation of fatty acids in vasogenic edema fluid might, therefore, have resulted from uptake of the material together with edema fluid through the breached blood-brain barrier. Arachidonic acid was an exception. Its concentrations were significantly higher in edema fluid than in plasma, suggesting that it was released from cerebral parenchyma as the underlying mechanism of its extracellular accumulation. The current observations provide further support for a mediator function of glutamate and arachidonic acid in acute traumatic lesions of the brain. Quantitative assessment of the release of highly active mediator substances in brain tissue may facilitate analysis of the therapeutic efficiency of specific treatment aimed at interfering with the release or pathological function of mediators of secondary brain damage.

Mediators of brain edema and secondary brain damage.

Progress is our understanding of the roles of vasogenic and cytotoxic brain edema in secondary brain damage can be expected from studies of the ability of biochemical factors to open the blood-brain barrier, derange the microcirculation, and cause cell swelling and necrosis. Mediator compounds are considered to form or to become released in an area of primarily damaged brain (necrosis) and to enter the cerebral parenchyma through the broken blood-brain barrier from the intravascular space. Many biochemical factors must be considered. We suggested three criteria for determining the roles of mediators: a) they must inflict brain tissue damage, b) they must occur in pathologic concentrations or in compartments not normally present, and c) specific inhibition should attenuate secondary brain damage. These requirements are met by the kallikrein-kinin system and by glutamate. In the case of arachidonic acid and its many metabolites, the concept is difficult to test because fatty acids may be active only if not bound to proteins, and therapeutic inhibition might be difficult. A variety of mediators may enhance each other in a cascade manner by various initiating reactions that might be amenable for pharmacologic inhibition.

The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue.

Vasogenic edema was induced in mongrel cats by cold injury to study uptake and activation of the plasma-kallikrein-kinin system in central nervous system (CNS) tissue. A method was developed for quantitative assessment of kinin formation in affected brain tissue areas. Gross disruption of the blood-brain barrier by focal trauma causes marked penetration of plasma kininogens into necrotic and edematous brain tissue. Moreover, the kallikrein-kinin (KK) system was activated in both necrotic and perifocal edematous areas, and was markedly enhanced by additional cerebral ischemia. Formation of kinins in necrotic brain tissue led to consumption of approximately 60% to 80% of the amount of kininogens being taken up. In perifocal edematous tissue, formation of kinins was less pronounced, or even absent. However, if cerebral ischemia evolved after severe intracranial hypertension, kinins were also formed in the perifocal edematous brain. The intravascular origin of kininogens found in pathological tissue areas secondary to injury was deduced from the observation that cerebral tissue of the contralateral hemisphere with an intact blood-brain barrier had no measurable quantities of kininogens. Consumption of plasma kininogens or formation of kinins were assessed as the difference of the total amount of plasma kininogens taken up into the tissue minus the amount of kininogens found in the brain at postmortem examination. The data indicate that uptake and activation of the plasma-KK system might occur under all pathological conditions in which blood-brain barrier damage permits cerebral penetration of plasma proteins, such as with cerebral contusion, focal ischemia, and tumors. The potent pathophysiological mechanisms induced by kinins in CNS tissue, such as formation of brain edema, microcirculatory dysfunction, and enhancement of blood-brain barrier permeability, together with their formation in focal and perifocal pathological brain tissue, provide further support for a mediator function of the KK system. Methods that specifically interfere with the formation of kinins in damaged brain should therefore be expected to attenuate vasogenic edema.

Therapeutic considerations in blood-brain barrier disturbances.

Current methods of treatment of brain damage, as e.g. edema by steroids and barbiturates, have components which benefit the blood-brain barrier. Protection of the blood-brain barrier may result from: (a) prevention of endothelial lesions, perhaps pinocytosis (b) reduction of secondary necrosis formation, (c) interference with release, or activation of mediator compounds causing endothelial lesions such as: biogenic amines, free fatty acids, prostaglandins, free radicals, or kinins, (d) stabilization of lysosomal membranes, and (e) prevention of microcirculatory disturbances. Other methods, or compounds aiming at mechanisms of barrier damage have a therapeutic potential as shown with regard to indomethacin, free radical scavengers, or phenothiazines. However, further studies appear necessary to demonstrate the benefit of these compounds under clinical circumstances. Reversible opening of the blood-brain barrier may be considered as a therapeutic approach to provide access of drugs to brain tissue which are normally excluded by the barrier.