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PubMed1988

Preoperative evaluation with radionuclide brain scanning and computerized axial tomography of the brain in patients with breast cancer.

To determine the roles of radionuclide brain scanning and computerized tomography of brain in the pretreatment evaluation of patients with primary and locoregional recurrence of breast cancer, we reviewed the clinical and radiologic findings in 226 patients with breast cancer who underwent one of these scans either preoperatively or within 6 weeks of operation and in 34 patients presenting with locoregional recurrence. Four of 131 radionuclide brain scans in primary breast cancer suggested calvarial metastasis, and the findings were confirmed with bone scans and skull radiographs. One of 95 computerized tomographic scans of the brain showed brain metastasis, and this patient had profound neurologic deficits. With respect to locoregional recurrence, the results of 2 of 23 radionuclide scans and 1 of 11 computerized tomographic scans were positive. All three patients had clinical evidence for brain metastasis. We conclude that in the absence of signs and symptoms, routine evaluation for brain metastasis is not justified in primary and locoregional recurrence of breast cancer.

Brain Neoplasms↗
PubMed1998

Brain-specific gene expression by immortalized microglial cell-mediated gene transfer in the mammalian brain.

The intra-arterial injection of immortalized microglia transfected with the lacZ gene, resulted in the expression of beta-galactosidase in the rat brain at 48 h and the activity of -galactosidase was detected for up to 3 weeks post-injection. More than 30-fold higher activity of beta-galactosidase was detected in the brain than in the liver, lung or spleen at 48 h post-injection. This method allows us to easily deliver the gene of interest to the brain without influencing other organs. Our brain-targeting gene delivery system can facilitate gene therapy of several brain disorders, including brain tumor, metabolic disorders, and degenerative disorders, as well as investigation into the roles of particular genes in brain function and development.

Animals↗
PubMed1989

Abnormal brain-stem function (brain-stem auditory evoked response) correlates with acoustic cry features in term infants with hyperbilirubinemia.

We hypothesized that changes in brain-stem auditory evoked responses related to bilirubin would be associated with changes in cry because of the anatomic proximity in the brain stem of cranial nerves 8 (auditory) and 9 to 12 (vagal complex, which controls cry). Brain-stem auditory evoked responses and computerized cry analysis were used to study the concurrent effects of moderate hyperbilirubinemia on auditory function and cry. Fifty term infants were divided equally into two groups on the basis of serum bilirubin concentrations: low (less than 8 mg/dl; 136) mumol/L and moderate (10 to 20 mg/dl, 170 to 342 mumol/L). Forty-three infants had successful tracings of brain-stem auditory evoked responses recorded with a Cadwell model 5200A evoked response unit during two successive trials, and a cry recording of each infant was analyzed by computer. The moderate serum bilirubin group had an increase in percent cry phonation (p less than 0.02) and an increase in the variability of the first formant (p less than 0.04) in comparison with the low serum bilirubin group. Serum bilirubin values correlated positively with brain-stem conduction time (r = 0.36, p less than 0.01), percent phonation (r = 0.42, p less than 0.004), and variability of the first formant (r = 0.39, p less than 0.02). Percent phonation, the voiced component produced by increased neural control, correlated with the interpeak of waves latencies I to III (r = 0.32, p less than 0.03) and brain-stem conduction time (wave I to V) (r = 0.35, p less than 0.01). We conclude that hyperbilirubinemia affects adjoining areas of the brain stem that control hearing and cry production.

Brain Stem↗
PubMed2004

Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial.

BACKGROUND: Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG). METHODS: Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements. FINDINGS: From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121). INTERPRETATION: WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.

Adult↗
PubMed1998

A new slicing method for the lower vertebrate brain: brain mould and adjustable stage.

This paper describes a new method for slicing the lower vertebrate brain which is too small and soft to be sliced using conventional methods. The brain is sliced in a pre-prepared agar mould glued to a special stage placed in a conventional vibratome. The mould is constructed from a plaster model prepared by embedding a paraformaldehyde fixed brain in a paraffin and vaseline mixture. The brain to be sliced is placed within two prepared agar half cylinders which are in turn placed in a pre-prepared larger agar collar glued to a special stage. The study describes in detail the preparation of the interlocking collar and inner cylinders of agar. The plexiglass stage allows the agar block containing the brain, to be rotated and inclined to improve the angle of cut. By using this method, small and soft brain even with thin walls and large ventricles could be sliced coronally, sagittally, horizontally or obliquely. Brain slices obtained by this method have good viability showing spontaneous and evoked activity.

Animals↗
PubMed2001

Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier.

Dextrans and albumin exit brain from blood following intra-cerebral injection by a slow process of convection with a halftime of 10-12 h in the rat. The present studies show that immunoglobulin G (IgG) molecules rapidly efflux from brain to blood across the blood-brain barrier (BBB) following intracerebral injection. The IgG efflux is rapid with a halftime of 48 min in the rat. The efflux of [3H]mouse IgG(2a) from brain to blood is competitively inhibited by intracerebral injection of unlabeled mouse IgG molecules, but is not inhibited by intracerebral injection of comparable doses of unlabeled rat albumin. The IgG efflux system has characteristics of an Fc receptor, as the efflux from brain is competitively inhibited by Fc fragments but is not blocked by F(ab')(2) fragments. Precipitation of brain homogenate by trichloroacetic acid indicates there is no significant metabolism of the IgG molecules during the experimental time period. In conclusion, these studies provide evidence for a BBB Fc receptor that mediates the reverse transcytosis of IgG molecules in the direction of brain to blood.

Animals↗
PubMed2002

Distribution of rabies antigen in infected brain material: determining the reliability of different regions of the brain for the rabies fluorescent antibody test.

To assist in making recommendations for sampling of brains for the fluorescent antibody test (FAT), a study was conducted to determine the regions of the brain where rabies antigen is found most reliably. Each identifiable part of 252 rabies-positive brains of various species was re-tested using routine FA tests. It was found that there was frequent variation in the quantity of antigen between regions of the brain. The thalamus, pons and medulla were the most reliable parts of the brain as they were positive in all specimens tested. The cerebellum, hippocampus and different parts of the cerebrum were negative in, respectively, 4.5, 4.9 and 3.9-11.1% of positive brains. It is recommended that specimens for rabies diagnosis must include the brain stem. The structure of choice would be the thalamus as it was positive in all specimens and had the most frequent prevalence (97.8%) of abundant antigen. These findings contradict many old studies that state that the hippocampus should be the structure of choice for rabies diagnosis. The current data demonstrate that the reason for the old recommendations is that the hippocampus has the highest frequency of large inclusion bodies, as the reliability of the histological tests used previously depended on inclusion body size.

Animals↗
PubMed1997

How should brain nuclei be delineated? Consequences for developmental mechanisms and for correlations of area size, neuron numbers and functions of brain nuclei.

The measurement of the size of brain areas and their neuron numbers depends on the delineation of the boundaries of a brain area. The comparison of cytoarchitectural, cytochemical and connectional delineation of a brain area, such as the vocal control nucleus HVC (nucleus hyperstriatalis ventralis, pars caudalis) of songbirds, shows that the estimated size of a nucleus depends on the delineation criterion. In correlation, the cytoarchitectural, cytochemical and projection properties of the same brain area change independently both during development and in adulthood. This needs to be considered in cross-species, intersexual, developmental and temporal comparisons of brain areas. The combination of cytoarchitectural criteria with area-specific cytochemical and connectional markers to delineate the boundaries of a brain nucleus gives new insights into neural plasticity and parcelation of brain areas.

Animals↗
PubMed1999

Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain.

In this manuscript, our recent studies on the transporters on the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier responsible for the excretion of ligands from the central nervous system (CNS) to the blood are summarized. By comparing the brain entry of quinidine in normal and mdr 1a knock out mice, the predominant role of P-glycoprotein in the brain distribution of this compound was demonstrated. In addition to P-glycoprotein, the presence of transporters responsible for the efflux of organic anions from the brain has been suggested by a pharmacokinetic analysis of the CNS distribution of cefodizime, a third generation cephalosporin antibiotic. This suggestion was confirmed by demonstrating the presence of a specific mechanism for the elimination of p-aminohippuric acid from the brain after microinjection into the cerebral hemisphere. In vitro, the energy-dependent luminal preferential efflux of glutathione-bimane was demonstrated in a monolayer of MBEC4 cells which were derived from mouse brain endothelial cells. Studies with isolated membrane vesicles from MBEC4 cells suggested the presence of a primary active transporter(s) for organic anions, and Western blot analysis indicated the presence of multidrug resistance associated protein (MRP1) and/or its related transporters on MBEC4 cells and freshly isolated rat cerebral endothelial cells. The transcellular transport of 17beta estradiol 17beta-D-glucuronide (E(2)17betaG) across the choroid plexus was also demonstrated by examining the efflux of this compound from CSF after intracerebroventricular administration. The functional significance of organic anion transporting polypeptide (oatp-1) on the brush border membrane of the choroid plexus was demonstrated by comparing the uptake of E(2)17betaG into the isolated choroid plexus and oatp-1 transfected COS-7 cells; in addition, reverse transcription-polymerase chain reaction and Western blot analysis indicated the presence of MRP in the choroid plexus. Together with the direction of transcellular transport, the basolateral localization of MRP on the choroid plexus was suggested. By regulating the activity of these efflux transporters, it is possible to improve the brain entry of certain substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull.

PURPOSE: To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) using noninvasive fixation of the skull on solitary or oligo brain metastatic patients as an alternative to stereotactic radiosurgery (SRS) using invasive fixation. PATIENTS AND METHODS: The subjects were 87 patients who had 4 or fewer brain metastases (50 solitary, 37 oligometastases). Treatment was conducted on 159 metastases by using a linac-based stereotactic system. The median isocentric dose was 35 Gy in 4 fractions. Whole-brain irradiation was not applied as an initial treatment. For the salvage treatment of metachronous brain metastases, repeat HSRT or whole-brain irradiation was applied. RESULTS: The actuarial 1-year local tumor control rate was 81%. Treatment-related complications were observed in 4 patients in the early period (<3 months) and in 2 patients in the late period. The median survival period was 8.7 months. Metachronous brain metastases occurred in 30 patients, and none of the 18 patients who were eligible for salvage HSRT refused to receive it again. CONCLUSIONS: Hypofractionated stereotactic radiotherapy achieved tumor control and survival equivalent to those of SRS reported in the literature. The results suggested that HSRT could be an alternative for solitary or oligo brain metastatic patients with less toxicity and less invasiveness compared to SRS.

Actuarial Analysis↗
PubMed1998

Prognostic factors derived from recursive partition analysis (RPA) of Radiation Therapy Oncology Group (RTOG) brain metastases trials applied to surgically resected and irradiated brain metastatic cases.

PURPOSE: (a) To identify the prognostic factors that determine survival after surgical resection and irradiation of tumors metastatic to brain. (b) To determine if the prognostic factors used in the recursive partition analysis (RPA) of brain metastases cases from Radiation Therapy Oncology Group (RTOG) studies into three distinct survival classes is applicable to surgically resected and irradiated patients. METHOD: The medical records of 125 patients who had surgical resection and radiotherapy for brain metastases from 1985 to 1997 were reviewed. The patients' disease and treatment related factors were analyzed to identify factors that independently determine survival after diagnosis of brain metastasis. The patients were also grouped into three classes using the RPA-derived prognostic parameters which are: age, performance status, state of the primary disease, and presence or absence of extracranial metastases. Class 1: patients < or = 65 years of age, Karnofsky performance status (KPS) of > or =70, with controlled primary disease and no extracranial metastases; Class 3: patients with KPS < 70. Patients who do not qualify for Class 1 or 3 are grouped as Class 2. The survival of these patients was determined from the time of diagnosis of brain metastases to the time of death. RESULTS: The median survival of the entire group was 9.5 months. The three classes of patients as grouped had median survivals of 14.8, 9.9, and 6.0 months respectively (p=0.0002). Age of < 65 years, KPS of > or = 70, controlled primary disease, absence of extracranial metastases, complete surgical resection of the brain lesion(s) were found to be independent prognostic factors for survival; the total dose of radiation was not. CONCLUSION: Based on the results of this study, the patients and disease characteristics have significant impact on the survival of patients with brain metastases treated with a combination of surgical resection and radiotherapy. These parameters could be used in selecting patients who would benefit most from such treatment.

Adult↗
PubMed2000

Comparison of mRNA and protein levels of four members of the protein 4.1 family: the type II brain 4.1/4.1B/KIAA0987 is the most predominant member of the protein 4.1 family in rat brain.

The human gene for the fourth member of the protein 4.1 family, KIAA0987, was recently identified by comprehensive cDNA analysis. To further characterize the corresponding gene and its product in rats, we cloned and sequenced rat KIAA0987 cDNA. RNA blot analyses revealed that the rat KIAA0987 gene was abundantly expressed only in the brain, kidney, and testis. Although we have previously reported that the third member of the protein 4.1 family, the KIAA0338 gene product, is predominantly expressed in rat brain, and thus was named brain 4.1, quantitative RNA blot analyses indicated that KIAA0987 should be called something other than brain 4.1 because the level of KIAA0987 mRNA was found to be of the same order as that of KIAA0338 mRNA. Our quantitative immunoblot analysis showed that the most predominant member of the protein 4.1 family at the protein level was the product of the KIAA0987 gene, not that of the KIAA0338 gene. Taking these results together, we consider it reasonable to name the KIAA0338 and KIAA0987 gene products 'type I brain 4.1' and 'type II brain 4.1,' respectively, because these two products were found to be more prominently produced in rat brain than the other two members of the protein 4.1 family, erythroid 4.1 and 4.1G.

Amino Acid Sequence↗
PubMed1998

A hybrid neural network analysis of subtle brain volume differences in children surviving brain tumors.

In the treatment of children with brain tumors, balancing the efficacy of treatment against commonly observed side effects is difficult because of a lack of quantitative measures of brain damage that can be correlated with the intensity of treatment. We quantitatively assessed volumes of brain parenchyma on magnetic resonance (MR) images using a hybrid combination of the Kohonen self-organizing map for segmentation and a multilayer backpropagation neural network for tissue classification. Initially, we analyzed the relationship between volumetric differences and radiologists' grading of atrophy in 80 subjects. This investigation revealed that brain parenchyma and white matter volumes significantly decreased as atrophy increased, whereas gray matter volumes had no relationship with atrophy. Next, we compared 37 medulloblastoma patients treated with surgery, irradiation, and chemotherapy to 19 patients treated with surgery and irradiation alone. This study demonstrated that, in these patients, chemotherapy had no significant effect on brain parenchyma, white matter, or gray matter volumes. We then investigated volumetric differences due to cranial irradiation in 15 medulloblastoma patients treated with surgery and radiation therapy, and compared these with a group of 15 age-matched patients with low-grade astrocytoma treated with surgery alone. With a minimum follow-up of one year after irradiation, all radiation-treated patients demonstrated significantly reduced white matter volumes, whereas gray matter volumes were relatively unchanged compared with those of age-matched patients treated with surgery alone. These results indicate that reductions in cerebral white matter: 1) are correlated significantly with atrophy; 2) are not related to chemotherapy; and 3) are correlated significantly with irradiation. This hybrid neural network analysis of subtle brain volume differences with magnetic resonance may constitute a direct measure of treatment-induced brain damage.

Adolescent↗
PubMed2000

Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and[3H]rolipram binding autoradiography. Comparison with monkey and rat brain.

We have examined the distribution of four different cyclic AMP-specific phosphodiesterase isozyme (PDE4A, PDE4B, PDE4C and PDE4D) mRNAs in the brain of different species by in situ hybridization histochemistry and by autoradiography with [3H]rolipram. We have compared the localization of each isozyme in human brain with that in rat and monkey brain. We have found that the four PDE4 isoforms display a differential expression pattern at both regional and cellular level in the three species. PDE4A, PDE4B and PDE4D are widely distributed in human brain, with the two latter appearing more abundant. In contrast, PDE4C in human brain, presents a more restricted distribution, limited to cortex, some thalamic nuclei and cerebellum. This is at variance with the distribution of PDE4C in rat brain, where it is found exclusively in olfactory bulb. In monkey brain, the highest expression for this isoform is found in the claustrum, and at lower levels in cortical areas and cerebellum. PDE4B presented a broad distribution, being expressed in both neuronal and non neuronal cell populations. In general, the distribution of binding sites visualized with [3H]rolipram correlated well with the expression of each PDE4 isozyme.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Radiotherapy of brain tumours: reduced irradiation of normal brain.

We analysed the dose-volume distribution in normal brain in eight patients undergoing localized external beam radiotherapy for brain tumours. The results have been represented as integral dose-volume histograms and show that large volumes of normal brain receive clinically significant doses of radiation. A mean of 43% (range 24%-57%) of normal brain volume received more than 50% and a mean of 22% (range 9%-38%) received more than 85% of the maximum tumour dose. The amount of normal brain irradiated increased with enlarging target volume. With the use of customized shielding blocks the mean volume reduction of normal brain receiving more than 50% and 85% maximum tumour dose was 178 ml (median 183 ml; range 89-244 ml) and 110 ml (median 110 ml; 40-179 ml) respectively. This represents an average reduction of 13% and 8% of normal brain volume. Although clinically important this may not be sufficient for a significant improvement in therapeutic ratio.

Brain Neoplasms↗
PubMed2003

Homocysteine-induced changes in brain membrane composition correlate with increased brain caspase-3 activities and reduced chick embryo viability.

In adult systems, high homocysteine (HoCys) levels inhibit methylation reactions and can induce apoptosis in the central nervous system. In embryos, exogenous HoCys is teratogenic and is associated with neural tube defects. Because, methylation inhibitors and inducers of apoptosis can influence membrane composition, we have studied whether or not embryonic exposure to HoCys influenced membrane phospholipid levels, membrane fatty acid composition, and Caspase-3 activities in embryonic chick brains. Embryonic exposure to HoCys caused reduced brain phosphatidylcholine levels and increased levels of brain phosphatidylethanolamine. Exogenous HoCys also promoted decreased levels of long-chain, unsaturated membrane fatty acids and increased levels of saturated short-chain membrane fatty acids. These HoCys-induced brain membrane changes correlated with HoCys-induced increases in brain Caspase-3 activities, HoCys-induced reductions in brain mass, HoCys-induced reductions in embryo mass, and HoCys-induced reductions in the percentage of embryos that survived to 11 days of development (theoretical stage 37). Thus, HoCys-induced changes in brain membrane composition correlated with HoCys-induced apoptosis and reduced embryo viability.

Animals↗
PubMed2001

Accumulation of the 1-methyl-4-phenylpyridinium ion in suncus (Suncus murinus) brain: implication for flavin-containing monooxygenase activity in brain microvessels.

The metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was examined in an effort to evaluate the role of flavin-containing monooxygenase (FMO) expressed in the brain of suncus (Suncus murinus) and rats. MPTP was metabolized to generate both 1-methyl-4-phenylpyridinium ion (MPP(+)) and MPTP N-oxide by brain homogenates from rats. Although the level of MPP(+)-producing activity was similar in suncus and rats, a remarkable difference was found between the animal species in MPTP N-oxygenase activity, which was not detectable in brain homogenates from suncus. The concentrations of MPP(+) in suncus brain after a single ip administration of MPTP were markedly higher than that in rats, probably because of the lack of FMO activity in the suncus brain. The MPTP N-oxygenase activity of microvessel homogenates of rat brain was 21-fold greater than that of whole brain homogenates. These results suggest that FMO(s) plays a significant role in the detoxification of MPTP in cerebral endothelial cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Resection and permanent I-125 brachytherapy without whole brain irradiation for solitary brain metastasis from non-small cell lung carcinoma.

We assessed a treatment plan of local therapy (resection and placement of permanent low dose-rate I-125 seeds) without whole brain irradiation in 15 patients with solitary brain metastasis (SBM) from primary non-small cell lung cancer between January, 1991 and May, 1996. Thirteen lesions were confirmed as solitary by MRI scan, and 2 patients had CT scan only. With median follow up of 14 months, 3 patients remain alive at 6, 33, and 62 months post-resection. Median survival is 14 months for all patients and 26 months for patients with SBM as the only site of disease. Five tumors failed in the brain: 2 solitary recurrences adjacent to the site of SBM, 2 multiple metastases outside the primary site, and 1 multiple recurrence including the primary site. No failures were seen with SBM <2.5 cm. Only 2 of 13 patients with SBM confirmed with MRI experienced relapses elsewhere in the brain. Recurrence rates both adjacent and outside the area of the initial brain lesion are similar to studies employing resection plus whole brain irradiation (WBI), and the patient is spared the acute and potential late toxicity of WBI. This approach may be considered for selected patients with solitary brain metastases (SBMs), although further experience with larger patient numbers is needed.

Brachytherapy↗