Mast cell proliferation in the cerebrospinal fluid after intraventricular administration of anti-B7H3 immunotherapy.

Omburtamab is a B7H3-specific murine monoclonal antibody. B7H3 (CD 276) is a member of the B7 family of immune checkpoint co-inhibitory receptors overexpressed on many human malignancies. Radioimmunotherapy with 124I- or 131I-omburtamab administered in the cerebrospinal fluid (CSF), intraperitoneal or intratumoral cavity is currently under investigation for the treatment of CNS malignancies. The immunologic effects of anti-B7H3 therapy are not fully elucidated. A 6-year-old male was diagnosed with metastates of neuroblastoma to the received intraventricular 131I-omburtamab on an IRB-approved protocol. A treatment cycle consisted of a 2 mCi dosimetry dose and a 50 mCi treatment dose. Dosimetry by serial imaging, pharmacokinetics and safety were investigated. Clinical status, magnetic resonance imaging, CSF cell count and cytology were evaluated pre- and post-131I-omburtamab at 5 and 26 weeks. The patient did well with cycle 1. Three hours after the dosimetry dose of cycle 2, he developed a fever (39 °C), chills and headache. Blood and CSF samples were sent for culture. CSF was notable for nucleated cell pleocytosis with profound mast cell proliferation consistent with chemical meningitis. He was treated with supportive care; symptoms resolved over 48 h. Further therapy with 131I-omburtamab was electively discontinued. CSF cell count 5 weeks later demonstrated resolution of CSF pleocytosis. Local-regional administration of intraventricular 131I-omburtamab targeting B7H3 can result in a profound nucleated CSF pleocytosis with mastocytosis consistent with an acute allergic reaction.

Localización del punto de fuga de líquido cefalorraquídeo en un caso de hipotensión de líquido cefalorraquídeo / Locating the site of cerebrospinal fluid leak in a patient with low cerebrospinal fluid pressure

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Computational exploration of wave propagation and heating from transcranial focused ultrasound for neuromodulation.

OBJECTIVE: While ultrasound is largely established for use in diagnostic imaging, its application for neuromodulation is relatively new and crudely understood. The objective of the present study was to investigate the effects of tissue properties and geometry on the wave propagation and heating in the context of transcranial neuromodulation. APPROACH: A computational model of transcranial-focused ultrasound was constructed and validated against empirical data. The models were then incrementally extended to investigate a number of issues related to the use of ultrasound for neuromodulation, including the effect on wave propagation of variations in geometry of skull and gyral anatomy as well as the effect of multiple tissue and media layers, including scalp, skull, CSF, and gray/white matter. In addition, a sensitivity analysis was run to characterize the influence of acoustic properties of intracranial tissues. Finally, the heating associated with ultrasonic stimulation waveforms designed for neuromodulation was modeled. MAIN RESULTS: The wave propagation of a transcranially focused ultrasound beam is significantly influenced by the cranial domain. The half maximum acoustic beam intensity profiles are insensitive overall to small changes in material properties, though the inclusion of sulci in models results in greater peak intensity values compared to a model without sulci (1%-30% greater). Finally, heating using currently employed stimulation parameters in humans is highest in bone (0.16 °C) and is negligible in brain (4.27 × 10(-3) °C) for a 0.5 s exposure. SIGNIFICANCE: Ultrasound for noninvasive neuromodulation holds great promise and appeal for its non-invasiveness, high spatial resolution and deep focal lengths. Here we show gross brain anatomy and biological material properties to have limited effect on ultrasound wave propagation and to result in safe heating levels in the skull and brain.

Extending the viability of acute brain slices.

The lifespan of an acute brain slice is approximately 6-12 hours, limiting potential experimentation time. We have designed a new recovery incubation system capable of extending their lifespan to more than 36 hours. This system controls the temperature of the incubated artificial cerebral spinal fluid (aCSF) while continuously passing the fluid through a UVC filtration system and simultaneously monitoring temperature and pH. The combination of controlled temperature and UVC filtering maintains bacteria levels in the lag phase and leads to the dramatic extension of the brain slice lifespan. Brain slice viability was validated through electrophysiological recordings as well as live/dead cell assays. This system benefits researchers by monitoring incubation conditions and standardizing this artificial environment. It further provides viable tissue for two experimental days, reducing the time spent preparing brain slices and the number of animals required for research.

Early expansion of the intracranial CSF volume after palliative whole-brain radiotherapy: results of a longitudinal CT segmentation analysis.

PURPOSE: To assess cerebral atrophy after radiotherapy, we measured intracranial cerebrospinal fluid volume (ICSFV) over time after whole-brain radiotherapy (WBRT) and compared it with published normal-population data. METHODS AND MATERIALS: We identified 9 patients receiving a single course of WBRT (30 Gy in 10 fractions over 2 weeks) for ipsilateral brain metastases with at least 3 years of computed tomography follow-up. Segmentation analysis was confined to the tumor-free hemi-cranium. The technique was semiautomated by use of thresholds based on scanned image intensity. The ICSFV percentage (ratio of ICSFV to brain volume) was used for modeling purposes. Published normal-population ICSFV percentages as a function of age were used as a control. A repeated-measures model with cross-sectional (between individuals) and longitudinal (within individuals) quadratic components was fitted to the collected data. The influence of clinical factors including the use of subependymal plate shielding was studied. RESULTS: The median imaging follow-up was 6.25 years. There was an immediate increase (p < 0.0001) in ICSFV percentage, which decelerated over time. The clinical factors studied had no significant effect on the model. CONCLUSIONS: WBRT immediately accelerates the rate of brain atrophy. This longitudinal study in patients with brain metastases provides a baseline against which the potential benefits of more localized radiotherapeutic techniques such as radiosurgery may be compared.

A comparison between transport and diffusion calculations using a finite element-spherical harmonics radiation transport method.

Most researchers choose the diffusion approximation to the transport equation as the model to describe photon migration in biological tissues. However, the applicability of this approximation is limited and, in certain cases, invalid. In this paper we introduce a two-dimensional, finite element-spherical harmonics (FE-P(N)) radiation transport method for the simulation of light propagation in tissue. The propagation of light is investigated first in a layered cylinder, which can be seen as a very simplistic approximation of a human head. Effects of the anisotropy factor g on the photon migration is then examined in homogeneous and heterogeneous media for different values of g and mu(s). The influence of void-like heterogeneities and channels in which absorption and scattering are very small compared with the surrounding medium on the transport of photons is also investigated. Significant differences between transport and diffusion calculations are shown to occur in all cases.

Magnetic field exposures for UK live-line workers.

Dosimetry is evaluated for live-line workers exposed to 50 Hz non-uniform magnetic fields from typical high-voltage transmission lines in the United Kingdom. The configurations involve twin-, triple- and quadruple-conductor transmission line bundles. Scenarios include three worker postures for the twin and triple bundles, and four postures for the quadruple bundle. The postures are selected to simulate worst case scenarios representative of work practices and result in highest values of dosimetric measures in critical organs. Only single-phase bundles are considered, as adjacent bundles of differing phase result only in a small reduction of the dosimetric measures. Reported data include various measures of the electric field and current density induced in tissues, as well as of the current density averaged over 1 cm2 areas normal to the current flow. A value of this latter quantity of 10 mA m(-2) is suggested as a threshold for neural tissue in the UK and international regulations. Critical tissues considered in this study include the retina, spinal cord, brain and cerebrospinal fluid. Some discussion is devoted to problems associated with the concept of current-density averaging, and two algorithms are considered. For a nominal load of 1 kA per subconductor, averaged current densities exceed the guideline bounds, only for a small number of postures and bundle configurations, in the brain, retina and cerebrospinal fluid. Non-averaged current densities in the cerebrospinal fluid exceed the suggested bound for all scenarios modelled, as well as in the retina for three postures involving a quadruple bundle.

Absence of cerebrospinal fluid abnormalities and spinal cord lesions after iotrolan cervical myelography in normal cats: an open placebo-controlled study.

Iotrolan (Isovist 300, Schering AG) at a volume of 0.5 ml/kg B.W. was injected into the cerebellomedullary cistern of 12 cats (Isovist group); the same volume of normal saline was injected in four other cats (control group). Two ml of CSF was collected from each anaesthetized cat by cisternal tap immediately before, and 7 and 15 days after, injection. The physical characteristics, specific gravity, total cell count and total protein concentration of each CSF sample were recorded. The cats were euthanized on day 15 immediately after CSF samples and spinal cord specimens had been obtained. Spinal cord histopathology was examined with the aid of light and transmission electron microscopy. The physical characteristics of all the CSF samples were within the reference range. No significant differences were found for CSF specific gravity, total cell count and total protein concentration between the pre-injection samples and those collected 7 and 15 days post-injection in both groups; no spinal cord lesions were detected in histopathology.

Effect of brain irradiation on blood-CSF barrier permeability of chemotherapeutic agents.

Effect of irradiation on blood-cerebrospinal fluid (CSF) barrier (BCB) was studied quantitatively by observing the effect of methotrexate (MTX) permeation into the CSF before, during, and after brain irradiation after i.v. injection of MTX. Observation of 15 brain tumor patients indicated that in large brain tumors, the BCB was seriously damaged; in small tumors, the BCB would gradually open. Compared with the findings before irradiation, the increase of permeability of MTX was zero to threefold. It is thus advisable to give chemotherapy only after 20 Gy of irradiation.

Impact of radiation technique upon the outcome of treatment for medulloblastoma.

Craniospinal irradiation (CSI) is an essential component of the therapy of medulloblastoma. Because medulloblastoma disseminates via the cerebrospinal fluid (CSF), CSI technique involves the irradiation of all CSF-bearing areas which are at risk for tumor seeding. Underdosing with radiation because of inadequacies in CSI technique will produce dose "cold spots" which have the potential of serving as a nidus for tumor recurrence. A simple mathematic model of subclinical disease in medulloblastoma based on the available data concerning the radiosensitivity of medulloblastoma cell lines as well as the known clinical dose-response relationships support the hypothesis that for most cases of medulloblastoma, the radiotherapist is working in a range of doses arrayed on the steep portion of the tumor control probability curve. Underdosing of CSF-bearing areas because of technical problems at the junction of the cranial and spinal fields of irradiation, placement of shielding blocks in the cribiform plate-subfrontal region, and/or anatomic errors in the design of the caudal end of the CSI fields may lead to significant risks of tumor relapse. One may debate the necessity of a posterior fossa boost encompassing the entire anatomic posterior fossa rather than the primary tumor volume with a margin. This review critically evaluates the potential impact of CSI technique upon the outcome of treatment for medulloblastoma, and suggests future areas of inquiry.

[UV irradiation of the cerebrospinal fluid in the treatment of patients with disseminated sclerosis]. / UF-obluchenie tserebrospinal'noi zhidkosti v lechenii bol'nykh rasseiannym sklerozom.

Cerebrospinal fluid (SF) in the quantity 5-7 ml from 26 multiple sclerosis patients was exposed to UV radiation with subsequent reinfusion. The assessment of clinical symptoms and immunological indices 7 days later showed that positive results (6 scores by Sipe scale) were achieved in 14 patients with cell abundance in the SF. The improvement was indicated by positive trends in pelvic functions, sensory and coordination disorders, normalization of the blood immunological picture. The responders exhibited elevated SF levels of B-lymphocytes, phagocytosing cells and IgM concentrations. High levels of IgG registered in 58% of the patients did not change. The only side effect was represented by short-term postpuncture syndrome in 4 patients with arterial hypotension. In 12 patients with progressive sclerosis the treatment was ineffective.

Immunoreactivity, pharmacokinetics and bone marrow dosimetry of intrathecal radioimmunoconjugates.

Ten patients with neoplastic meningitis were treated with a variety of 131I-monoclonal antibody (MAb) conjugates, chosen to bind to their particular malignancy. Pharmacokinetic studies revealed that MAbs leave the ventricular compartment, enter the sub-arachnoid space and then pass into the blood. Once the MAbs enter the blood compartment, their clearance is determined by factors such as circulating anti-mouse Ig and circulating antigens. These lead to complex formations and the clearance of the conjugate by the reticuloendothelial system. In one individual, the anti-mouse Ig response observed systemically was not mirrored within the CSF, which has implications for planning future therapy of this type. In other patients, formation of immune complexes was due to binding to circulating antigen within the blood. The major toxicity associated with the intrathecal administration of 131I-MAbs was bone-marrow suppression. The doses to the bone marrow, resulting from the form of therapy, were calculated but showed no direct correlation with WHO grade 3/4 toxicity. Doses to the ventricular lining were also calculated, but due to the complex geometry of the compartment, calculation of potential tumour doses was not practicable.

Electrolytes, amino acids and proteins in lumbar CSF during the treatment of acute leukemia in childhood.

We performed analyses of electrolytes, amino acids, albumin, alpha 2-macroglobulin, gamma-globulin and LDH in the lumbar cerebrospinal fluid of children undergoing treatment for acute lymphoblastic leukemia, non-Hodgkin-lymphoma or acute myeloid leukemia. At the time of diagnosis signs of a disturbance of the blood-brain barrier were found in some patients. During induction treatment with L-asparaginase a rise of glutamic acid and a decrease of glutamine occurred. This finding correlated with slowing of the EEG. Treatment with vincristine was associated with a slight drop of sodium and chloride concentration in serum, but not in the cerebrospinal fluid. Central nervous system prophylaxis with cranial irradiation, and to a lesser degree with intravenous medium-dose methotrexate, gave rise to a further deterioration of the blood-brain barrier function as indicated by an increase in albumin, alpha 2-macroglobulin and LDH levels. During radiotherapy the concentration of several amino acids rose, probably due to a disturbance of active carrier mechanisms. Patients with elevated albumin at the end of radiotherapy more often suffered an early leukemia relapse while still on treatment. No other clinical or electroencephalographic correlations of altered barrier function could be found.

[Chemoluminescence of the cerebrospinal fluid in spinal cord tumors]. / Khemoliuminestsentsiia tserebrospinal'noi zhidkosti pri opukholiakh spinnogo mozga.

The article discusses a new method for recognising tumors of the spinal cord--spontaneous and photoinduced chemoluminescence of the cerebrospinal fluid. Twenty-seven patients with tumors of the spinal cord of various localization and histological structure and 15 individuals of the control group were examined. Statistically significant differences in chemoluminescence in extra- and intramedullary tumors and in the control group were revealed. The effect of intensified luminescence of the cerebrospinal fluid in exposure to ultraviolet radiation was demonstrated, especially in cases with extramedullary tumors. The described method is an auxiliary criterion in c.s.f. diagnosis of spinal tumors.

Biological effects of ultrasound.

In summary, there are many deficiencies and gaps in the current data base for ultrasound-induced bioeffects. More information is needed on the effects of low intensity ultrasound, the effects of pulsed ultrasound, the relationship between peak intensities and average intensities of pulsed ultrasound, the possibility of cumulative effects, and the possibility of long-term effects. Also, very little of the data, either positive or negative, has been verified by other laboratories. Although there is presently no evidence to indicate that diagnostic ultrasound involves a significant risk, the evidence is insufficient to justify an unqualified acceptance of safety. The potential for acute adverse effects has not been systematically explored, and the potential for delayed effects has been virtually ignored. Because of the difficulties involved in searching for and defining potential risks from exposure to low levels of chemicals, radiation, or other forms of energy, it is unreasonable to expect that in the near future, the degree of risk, if any, will be clearly defined for diagnostic ultrasound. As in other areas (e.g., the effects of ionizing radiation) no single study, epidemiological or experimental, can accomplish this goal. In the meantime, a prudent public health policy calls for judicious use of diagnostic ultrasound, using it only when diagnostic benefits to patients are indicated, and keeping any exposure to diagnostic ultrasound as low as practicable, consistent with its intended purpose.

Pathology of radiation damage to the normal brain of the monkey.

Model I: A portion of the monkey brain, the right occipital lobe, was exposed to 3,500 rads of orthovoltage radiation in a single dose. This demonstrated a) the delayed, 4 to 5 months, massive break in blood-brain barrier with extravasation of plasmatic fluid throughout the right hemisphere causing gross brain distortion, and b) after a protracted course, a remaining impairment in function extending beyond the irradiation lesion. Model II: The whole brain was exposed to supervoltage radiation in single doses of 1,000, 1,500, and 2,000 rads, respectively. This demonstrated a) the lack of effect from 1,000 rads; b) the wide scatter of necrotic lesions in the forebrain white matter from 1,500 rads at 6 months, followed by confluent necrosis in the cerebral hemispheres at 12 months; and c) the numerous focal lesions throughout the brain from 2,000 rads, with the lesions in the brain stem precluding survival beyond 6 months. Model III: The whole brain was exposed to fractionated doses of 4,000, 6,000 and 8,000 rads in 4, 6, and 8 weeks, respectively. This demonstrated a) the lack of effect from 4,000 rads; b) the wide scatter of small focal lesions at different stages of breakdown and repair accompanied by focal edema from 6,000 rads at 6 months, followed by more of the reparative processes including mineralization of focal lesions, and widespread telangiectasia, at 12 months; and c) with 8,000 rads, at 6 months, focal lesions similar to those from 6,000 rads, but at 12 months, gross brain loss from coalescing necrosis.